From the University of Arizona College of Medicine, Tucson, AZ (Dr. Beatty), and the Baylor College of Medicine, Houston, TX (Dr. Mohajer).

Abstract

• Objective: To review management issues regarding health care–associated urinary tract infections (UTIs) commonly encountered by practicing clinicians.
• Methods: Review of the literature.
• Results: Because urinary catheter (UC) placement plays a major role in the development of catheter-associated UTIs (CA-UTI), clinicians should be aware of the appropriate and inappropriate uses of UCs and their association with CA-UTI development. Removal of a UC when no longer necessary is key to preventing CA-UTI. Treatment of asymptomatic bacteriuria is generally not indicated. Percutaneous nephrostomy and ureteral stenting need close monitoring, and early removal should be performed if infection is suspected. Candiduria rarely leads to symptoms unless it is related to an ascending process. Proper urine collection is crucial in determining whether contamination, colonization, or infection is present. Fluconazole is recommended in most cases of Candida UTI, while intravenous amphotericin B is recommended for fluconazole-resistant Candida species.
• Conclusion: Continued use of evidence-based strategies for preventing and managing health care–associated UTI should lead to further improvements in patient outcomes and overall decreased rates of infection.

Keywords: bacteriuria; catheter-associated UTI; catheterization; percutaneous nephrostomy; candiduria.

Health care–associated urinary tract infections (UTIs) are estimated to be the most common adverse infectious event in U.S. hospitals, occurring in 1 of 10 admitted patients.^1-3 Approximately 32% of all health care–associated infections are UTIs.¹ Furthermore, urinary catheters (UCs) are associated with 8% to 21% of health care–associated infections that occur in the intensive care unit.⁴ The most important predisposing factor for nosocomial UTI is urinary catheterization.⁵ Genitourinary manipulation and/or implementation also play a major role in the development of nosocomial UTIs.

In 2008, the U.S. Centers for Medicare & Medicaid Services instituted a new policy that reduced reimbursement rates for hospitalizations linked to health care–associated infections.⁶ Indwelling UCs are among the most overused health care devices in the hospital setting. They are placed in an estimated 15% to 25% of all hospitalized patients,^7,8 and are often inserted in the emergency department (ED) without a physician order or appropriate indication.⁹ Intermittent straight catheterization, male or female condom catheterization, and/or placement of an indwelling UC are the most common causes of catheter-associated asymptomatic bacteriuria (CA-ASB) and catheter-associated UTIs (CA-UTI).⁵ Prevention and management of CA-ASB and CA-UTI can be challenging and require an evidence-based approach. Furthermore, guidelines for the management of UTIs in the setting of active percutaneous nephrostomy (PCN) drainage and/or ureteral stenting are not established.⁵ This may leave clinicians with little mainstream data to aid in management decisions.

In 2009 the Centers for Disease Control and Prevention provided a guideline for the appropriate and inappropriate use of indwelling UCs to help promote their proper use.¹⁰ In the time since the guideline’s initiatives were instituted around the United States, published data have shown some improvement in the use of UCs,^11,12 but other recent reports indicate that rates of UC use have remained unchanged.¹³ This review discusses management issues regarding health care–associated UTIs that are commonly encountered by practicing clinicians, with a focus on current guidelines and evidence.

Catheter-Associated UTI

CA-UTI is defined as the presence of signs or symptoms of UTI with no other explainable infectious source along with ≥ 1000 colony-forming units (cfu) of ≥ 1 bacterial species per milliliter in a urine specimen from a catheter that has been changed within 48 hours of collection of the urine specimen.⁵ Signs and symptoms of CA-UTI include, but are not limited to: new-onset or worsening fever, chills, altered sensorium from baseline, lethargy, malaise, flank pain, pelvic pain, costovertebral angle tenderness, and acute hematuria.⁵ New-onset “foul-smelling” (odorous)urine and “cloudy” urine are neither sensitive nor specific when assessing for CA-UTI, and do not have significant clinical relevance when found alone.^14,15 Patients who have removed or exchanged the UC during this event and then experience dysuria, increased frequency, urgency, or suprapubic pain are likely having symptoms of CA-UTI.⁵

What is the recommended method for collecting urine samples when CA-UTI is suspected?

In a patient with an indwelling catheter that has been in place for more than 2 weeks at the onset of a suspected CA-UTI, the catheter should be replaced (if still indicated) or removed to accelerate resolution of symptoms and to reduce the risk of subsequent catheter-associated bacteriuria and CA-UTI. The urine culture should be acquired from the freshly placed UC.⁵

When should a patient be empirically treated?

A patient presenting with evidence of sepsis should be empirically treated with antimicrobials. Empiric coverage should be based on risk factors for multidrug-resistant organisms and data pertaining to local antimicrobial resistance patterns. A urine specimen for urinalysis and possible culture should be sent prior to administering empiric antibiotics (if possible) in a symptomatic patient.⁵

What bacteria are commonly associated with CA-UTI?

The bacteria most commonly associated with CA-UTI are found in or around the gastrointestinal and genitourinary tracts and also are part of the normal skin flora. The introduction and/or facilitated ascension of these microorganisms is believed to occur during UC insertion.^16,17 Two-thirds of all isolated uropathogens in those with indwelling UCs are extraluminally acquired (via ascension along the catheter-urethral mucosa interface), and one-third are believed to be intraluminally acquired.¹⁸

The most commonly isolated bacteria in CA-UTI are Enterobacteriaceae, which include Escherichia coli (most common), Klebsiella species (K. oxytoca, K. pneumoniae), Serratia species (S. marcescens), Citrobacter species (C. koseri), Enterobacter species (E. cloacae), and Proteus species; non-Enterobacteriaceae such as Pseudomonas species; and gram-positive cocci, which include coagulase-negative staphylococci (S. saprophyticus), Staphylococcus aureus, group B streptococci, and Enterococcus species (E. faecalis, E. faecium).^19-21 Coagulase-negative staphylococci and Enterococcus species can lead to CA-UTI but are usually avirulent and more commonly isolated from asymptomatic individuals.¹⁹ Also, coagulase-negative staphylococci such as S. epidermidis and S. lugdunensis are usually the manifestation of contamination during the collection process and their presence should prompt a repeat sample collection under sterile techniques. Monomicrobial infection is usually seen in those with short-term catheter use and CA-UTI. In contrast, polymicrobial infection is more common in those with long-term indwelling UCs and CA-UTI.¹⁹ Providencia stuartii, Proteus mirabilis, S. aureus, and Morganella morganii have all been associated with CA-UTI in those with long-term indwelling UCs.

Growth of S. aureus in the urine should prompt further investigation with blood cultures to explore the possibility of hematogenous dissemination to the urinary tract. Organisms leading to bacteremia due to CA-UTI are most commonly gram-negative bacilli (E. coli, Klebsiella species, Pseudomonas aeruginosa) and E. faecalis.²¹

What is the difference between CA-ASB and CA-UTI?

CA-ASB is defined as the presence of ≥ 1 bacteria species growing on urine culture at ≥ 100,000 cfu/mL in a patient with a history of urinary catheterization and/or indwelling UC who lacks signs or symptoms of UTI. In a man with a condom catheter, CA-ASB is defined using the same criteria, but the urine sample is collected after a fresh condom catheter is applied.⁵ The difference between CA-ASB and CA-UTI is simply the presence or absence of signs and symptoms related to UTI. Currently, there is no standard definition for significant bacteriuria in a catheterized patient.⁵ Pyuria found on urinalysis is indicative of genitourinary inflammation and can be present in both CA-ASB and CA-UTI. The absence, presence, and/or degree of pyuria in catheterized patients does not accurately differentiate between CA-ASB and CA-UTI.^5,22,23 On the other hand, the absence of pyuria in a symptomatic catheterized patient suggests an etiology other than CA-UTI.⁵

How can CA-UTI be prevented in patients with a short-term indwelling urinary catheter?

If a short-term UC is essential, the most important approach to preventing CA-UTI is limiting the duration of time it will be used. Strategies such as computer-based order entry and care maps with automated discontinuation of UCs have been shown to decrease catheter usage.¹⁹ Using closed-systems for UC collection with ports in the distal catheter for needle aspiration of urine has also been shown to decrease the incidence of CA-UTI.⁵ Securing the UC to avoid urethral trauma, aseptic techniques for insertion and repositioning, and placement of the tubing and collection bag below the level of the bladder to prevent reflux will likely also prevent CA-UTI, but these strategies have not been evaluated thoroughly.¹⁹

When should you screen for and treat CA-ASB?

The 2009 Infectious Diseases Society of America (IDSA) guidelines recommend that the only patients who should be screened and treated for CA-ASB are pregnant women and those who will undergo a potentially traumatic urologic procedure for which mucosal breaching may occur, causing bleeding. Routinely screening or treating patients for CA-ASB in not recommended in any other group of patients and will lead to unnecessary antibiotic use and antibiotic resistance.⁵

UTI Associated with Percutaneous Nephrostomy and Ureteral Stenting

Similar systemic symptoms of infection (fever, rigors, malaise, shock) are present in patients with and without percutaneous nephrostomy (PCN) and/or ureteral stent placement. Dysuria is not commonly present in those with PCN. The first signs of CA-UTI may be decreased urine output and pericatheter leakage due to an obstructive process resulting from the encrustation.^24-27 The most common complaint among patients with either acute or chronic ureteral stenting is discomfort, which has been described as “urinary symptoms” and “body pain.”²⁸ This discomfort can be related to ureteral hyperperistalsis after placement of the stent and is usually self-limiting. Ureteral stent migration, usually at the distal end, can also lead to discomfort, but is easily rectified with cystoscopy.²⁵ Body pain and/or urinary symptoms in the setting of ureteral stenting are not indicative of infection alone.

What is urinary catheter and/or ureteral stent encrustation?

Encrustation is the formation of a conditioning film that develops on the surface of the UC or ureteral stent. The exact mechanism is not well understood, but it is believed to involve electrostatic interactions of urinary proteins that stimulate binding onto the stent or UC surface.²⁵ Encrustation increases exponentially with the dwell time. Among patients with ureteral stents placed due to urolithiasis, encrustation occurred in 9.2% of stents removed prior to 6 weeks, 47.5% of stents removed at 6 weeks, and 76.3% of stents removed at 12 weeks.²⁶ Encrustation is most common at the proximal and distal ends (pigtails) of the ureteral stent and usually spares or presents last within the lumen.²⁹ Attempts have been made to prevent ureteral stent encrustation through the development of biodegradable, drug-eluting, and tissue-engineered substrates. These developments are promising, but currently there is limited observational data from large randomized trials to suggest that these new modalities decrease rates of encrustation.²⁵ Encrustation is highly associated with certain microorganisms, especially those that create biofilms.³⁰ Urease-producing bacteria, most commonly P. mirabilis, play a role in encrustation formation.³¹ Bacteria most commonly associated with encrustation include Proteus species (P. mirabilis is most common), P. aeruginosa, K. pneumoniae, Providencia species (P. stuartii is most common), and M. morganii.

Does ureteral stent bacterial colonization correlate with UTI?

Ureteral stent colonization with bacteria increases with dwell time and is found in 40% to 98.5% of stents placed.^32-35 If UTI is suspected in a patient with an active indwelling ureteral stent, a sample of urine should be cultured while the stent is in place.²⁵ Typically, genitourinary and normal skin flora pathogens are found when the ureteral stent is cultured. The top 3 organisms cultured from ureteral stents are S. aureus, P. aeruginosa, and E. faecalis.³⁴ Urine culture usually does not correlate with stent culture results, which has brought up the debate of how bacterial colonization occurs. It has been postulated that colonization is actually a manifestation of contamination during the insertion procedure, but this has yet to be validated.²⁵ In patients with symptoms of UTI in the setting of an indwelling ureteral stent, a positive culture has low sensitivity, with estimates between 21% and 40%.³⁵ Therefore, a negative urine culture does not rule out UTI alone in a symptomatic patient. Multiple studies have suggested that colonization of the ureteral stent does not correlate strongly with developing a UTI.^25,32-34

How can UTI be prevented in those receiving PCN or ureteral stent placement?

Antibiotic prophylaxis has been recommended to prevent UTI in patients who will undergo PCN or ureteral stent placement. The American Urological Association recommends empiric treatment even in the absence of signs and symptoms of UTI,³⁶ but substantial evidence is lacking that this approach prevents infection.³⁷ Ciprofloxacin or trimethoprim/sulfamethoxazole has been recommended by some for empiric coverage for enteric gram-negative bacilli and enterococcus in those undergoing genitourinary manipulation or instrumentation.^32,38 Most patients who develop CA-UTI and pyelonephritis do so within the first 2 to 6 weeks after placement.^37,39 Bacteriuria, candiduria, and/or pyuria are present in all patients approximately within 9 weeks even when sterile urine is confirmed prior to PCN placement.³⁹ Data on the effectiveness of antibiotic prophylaxis to prevent CA-UTI in those with PCN or ureteral stenting is limited. Currently, there are no recommendations from the IDSA on how to prevent infection in these situations.⁵ Early or frequent stent removal or exchanges has been proven to reduce UTI in those with ureteral stenting.³³ Patients with diabetes mellitus and chronic renal failure are at high-risk for UTI when ureteral stents are in place. This population should undergo close monitoring for UTI development and may warrant more frequent stent exchanges.^27,40

What is the treatment of CA-UTI associated with PCN and/or ureteral stenting?

The IDSA guidelines do not apply to patients with PCN and/or ureteral stenting.⁵ There is no treatment protocol for UTI related to these processes. Generally speaking, they are considered “complicated UTI” by most experts. Broad-spectrum, empiric antibiotic administration along with prompt removal of the PCN and/or ureteral stent is the gold standard of therapy.²⁷ The recommended duration of targeted antibiotic therapy is generally between 5 and 14 days.¹⁹ Most clinicians will treat this complicated UTI for at least 10 to 14 days. Antibiotic administration should be continued even after removal of the catheter and/or stent to complete the full course. Repeat urinalysis and culture is not indicated at the end of therapy if the patient is clinically improving or has remission of symptoms.

What is the exchange rate for those who require chronic PCN and/or ureteral stent use?

On average a PCN or ureteral stent should be exchanged every 2 to 3 months in patients who require chronic usage.^24,27 Some patients with persistent complications may require more frequent exchanges (< 10 weeks).²⁷ Encrustation and bacterial colonization become more prevalent the longer the devices are in place. This process is estimated to begin within the first 2 weeks after placement.^27,33,34 A “forgotten stent” is one that has been left in place after the patient is lost to follow-up. This unfortunate event can lead to massive encrustation, UTI, stent fracturing, and complete ureteral obstruction.²⁴ As noted, patients with diabetes mellitus, chronic renal failure, and frequent UTI may warrant more frequent exchanges, but this should be determined on a case-by-case basis.

 

 

Catheter-Associated UTI in Patients with Spinal Cord Injury

Spinal cord injury (SCI) at any level can cause neurogenic bladder. This process ultimately leads to urinary stasis and colonization of the bladder with bacteria. According to the IDSA, the acceptable indications for UC insertion are: clinically significant urinary retention (if medical therapy is not effective), urinary incontinence, accurate urine output monitoring required, and patient is unable and/or unwilling to collect urine (Table 1).⁵ Recently, further guidelines were published regarding appropriate and inappropriate indwelling UC placement in hospitalized medical patients (Table 2 and Table 3), expanding upon the earlier acceptable criteria provided by the IDSA.⁴¹ According to the IDSA and Ann Arbor Criteria for Appropriate Urinary Catheter Use, patients with SCI and subsequent neurogenic bladder without obstruction where intermittent bladder straight catheterization for the drainage of urine is not feasible will likely need an indwelling UC.⁴¹ SCI patients often experience decubitus ulcers, and an indwelling UC can be used if needed to help with wound healing if other urinary management alternatives have been attempted. Other such situations in which an indwelling UC can used before attempting alternative approaches would be in a patient who is actively dying and is pursuing comfort care and/or hospice.⁴¹

Which indwelling UCs should be used in patients with SCI?

Efforts to reduce the likelihood of infection in patients with SCI have led to several advances in the design and manufacturing of UCs. UCs are made of either latex, plastic, silicone, or polytetrafluoroethylene (Teflon). None of these substrates is free of complications, but of them latex UCs have been studied the most in regards to their associated complications. Aside from being allergenic in nature, latex UCs have an increased propensity to allow bacteria to adhere to their surface due to microscopic planes of unevenness.⁴² Silicone UCs are less frequently associated with infection but are more rigid, leading to increased discomfort.^43,44 Hydrophilic and silver-hydrogel coatings are innovative methods that have been developed to increase comfort and reduce the likelihood of infection. Hydrophilic-coated UCs are associated with reduced microbial adherence, decreased encrustation, and better patient satisfaction.^45,46 In SCI patients, these UCs have demonstrated lower complication rates, including UTI; fewer episodes of post-, intra-, and inter-catheterization bleeding; and decreased rates of antibiotic-resistant bacteria.^45,46 Silver-hydrogel-coated UCs are less well studied but have also demonstrated reduced UTI rates in SCI patients; however, their efficacy over the long term has yet to be determined. Antibiotic-impregnated UCs are not currently recommended for either short- or long-term indwelling UC use.⁵

How can CA-UTI be prevented in a patient who will require a long-term indwelling catheter?

At this time, the data is insufficient to make a recommendation on routine UC exchange (eg, every 2 to 4 weeks) in patients who require long-term indwelling urethral or suprapubic catheters in an attempt to reduce the risk of CA-ASB or CA-UTI. This is also true for those who experience even repeated early catheter blockage from encrustation.⁵ Thus, the rate at which these exchanges occur can be controversial, but typically around every 4 weeks is a common approach. Some would argue that if the patient has repeated CA-UTI, an exchange rate of every 2 weeks might be needed, but data is currently lacking to support this practice.⁵ If intermittent urinary catheterization is feasible, it should be done at least every 6 hours and before bedtime. In general, when the volume of urine in the bladder reaches approximately 400 mL, the patient should undergo bladder catheterization to prevent stasis and infection.⁴⁷ A closed drainage system is recommended in all patients who require long-term indwelling UC use.^48,49 Placement of the collection bag above the catheter or above the level of the bladder and a breach in the closed drainage system have been shown to result in higher rates of catheter-associated bacteriuria.^48,50 Proper hand hygiene and sterile and/or clean techniques should be used when placing or exchanging a UC. However, in one study there was no difference in bacteremia or UTIs when using sterile versus clean techniques.⁵¹

Asymptomatic bacteriuria should not be treated in patients with long-term indwelling UCs, and prophylactic antibiotics have led to the emergence of resistance.⁵² At this time it is not clear whether prophylactic weekly oral cyclic antibiotic administration can effectively reduce the frequency of CA-UTI in patients with SCI and chronic indwelling UC use.

What are the signs and symptoms of CA-UTI in a patient with SCI?

Subjective and objective findings may be limited when a patient with SCI presents with CA-UTI. These patients often lack the usual symptoms of UTI (dysuria, suprapubic discomfort, urgency, increased frequency) and pyelonephritis (flank pain, costovertebral angle tenderness). Caregivers and health care providers should be aware that nonspecific symptoms such as foul-smelling urine, pyuria, increased residual volume of urine in the bladder, change in voiding habits, worsening detrusor spasticity, and aggravation of autonomic dysreflexia can be the only initial presenting symptoms.⁵³

 

 

What is the duration of therapy for CA-UTI in SCI, and how can antibiotic stewardship principles be applied in this patient population?

Antibiotic therapy is indicated for a duration of 7 days if there is prompt resolution of symptoms, or for a total of 10 to 14 days if the response is delayed, regardless of whether the patient remains with a UC.⁵ Antibiotic stewardship is very important to reduce the risk for developing drug resistance in this high-risk population. Methods such as prescriber education practices, institution protocols, guideline implementation, auditing and feedback, restriction and reauthorization practices, computer-assisted programs, de-escalation or streamlining, and antibiotic cycling or dosage optimization have all been shown to assist in antibiotic stewardship in UTIs.⁵⁴

Candida UTI

What is the initial evaluation for a patient with candiduria?

The workup for candiduria hinges on determining whether the candiduria likely represents contamination, colonization, or infection; certain predisposing risk factors are associated with Candida UTI (Table 4).^55-57 The most important aspect to candiduria is the patient’s clinical status and comorbid conditions.⁵⁸ Among funguria, Candida species are the most common and represent 95% of organisms isolated on urine cultures (Table 5).⁵⁹ Candiduria is usually present in those with significant comorbidities and rarely is associated with healthy individuals.^59,60 Candiduria is increasing in prevalence among hospitalized patients, representing 22% to 40% of all nosocomial UTIs.^59,60 Markers in the urine (leukocyte esterase, colony count of culture growth, presence or absence of Candida casts and pseudohyphae) cannot alone differentiate colonization from infection.⁵⁵ When candiduria is discovered in a patient with symptoms related to UTI in the setting of predisposing risk factors, it should be considered a real infection until proven otherwise.

In a situation where an asymptomatic patient without an indwelling UC has Candida species isolated from a urine culture, a repeat culture (clean-catch midstream sample) should be performed to assess for a likely contaminated collection.⁵⁵ If the patient has an indwelling UC then it should be exchanged and urine collected from the fresh catheter.⁶¹ When candiduria is found in healthy asymptomatic adults, it is most commonly associated with poor collection techniques or postcollection contamination.⁵⁹ If candiduria persists in an asymptomatic patient, the patient should be assessed for predisposing factors. This includes checking hemoglobin A1C for developing diabetes and renal ultrasound looking for urolithiasis, renal abscess, hydronephrosis, and fungus ball. Postvoid residual urinary retention should also be ruled out with bladder ultrasound. Treatment of predisposing factors can lead to resolution of candiduria without antifungal treatment, and a urine culture should be repeated (1 to 2 weeks later).⁶¹ Asymptomatic patients lacking any predisposing factors can be observed with repeat urine cultures in 1 to 3 months.⁶¹

Candiduria may actually represent candidemia in those patients who have a predisposing risk factor for disseminated candidiasis. These risk factors include central venous catheters, administration of total parental nutrition, antibiotic use (especially broad spectrum), critical illness, recent surgical intervention (especially intra-abdominal), acute renal failure, nasogastric tube use, and active gastric acid suppression (ie, proton pump inhibitors).^62,63 The hematogenous spread of Candida can lead to the detection of candiduria in 46% to 80% of persons who are experiencing candidemia.⁵⁹ If the patient is at risk for candidemia, then blood fungal cultures should be drawn. It is not unreasonable to also order a serum-D-glucan assay if suspicions are high. A thorough skin assessment should be completed and ophthalmology consulted for a detailed eye exam in the event that the patient has candidemia. Candiduria is highly prevalent among those who are candidemic, but overall candidemia is encountered in less than 5% of patients in most intensive care units.⁵⁹ Thus, most patients with candiduria do not have disseminated candidiasis.

Candiduria rarely leads to symptoms of UTI,⁵⁸ unless the pathogenesis is related to an ascending process.⁵⁶ Symptoms of Candida UTI are no different from those experienced from a bacterial etiology. Some patients may complain of pneumaturia and/or endorse seeing particulate matter in their urine.⁵⁵ Patients showing signs of sepsis (fever, chills, flank pain) should be investigated for possible Candida pyelonephritis in the setting of candiduria.⁶⁴

When should asymptomatic candiduria be treated?

In adult patients with asymptomatic candiduria, there are 2 situations in which antifungal therapy is recommended. A patient undergoing a traumatic urologic procedure would be treated to avoid the risk for candidemia caused by the procedure. Also, in neutropenic patients empiric antifungal therapy should be administered because there is a high likelihood that this candiduria may actually represent hematogenous spread from candidemia.^61,65

What is the treatment for symptomatic Candida cystitis?

Empiric treatment with oral fluconazole 200 to 400 mg daily for a total of 2 weeks is recommended in patients with persisting candiduria and symptoms of cystitis.⁶⁵ Identifying the species is a crucial step in the treatment of Candida UTI. Several species (C. glabrata, C. krusei) are known to be resistant to fluconazole. Species identification and antifungal sensitivities should be done and therapy directed after obtaining these results.⁵⁵

What is the recommended treatment for Candida pyelonephritis?

Treatment for pyelonephritis caused by fluconazole-susceptible Candida species is oral fluconazole 200 to 400 mg (3-6 mg/kg) for a total of 2 weeks.⁶⁵ A fluconazole-resistant organism should be suspected when a non-albicans Candida species is isolated, such as C. krusei or C. glabrata. In this circumstance, in vitro antifungal susceptibility testing should be done. Echinocandins are not a good option in this situation because they do not reach adequate urine concentration and treatment failure is well documented.^66-68 Amphotericin B deoxycholate (AmB) 0.3 to 0.6 mg/kg daily for 1 to 7 days, with or without oral flucytosine (25 mg/kg) 4 times daily, is recommended by the IDSA for the treatment of fluconazole-resistant isolates of C. glabrata and C. krusei.⁶⁵ Further imaging with ultrasound, CT, or magnetic resonance should be done to rule out urinary tract obstruction and/or “fungus ball” formation. Emphysematous pyelonephritis and necrosis can occur and usually require nephrectomy. Perinephric abscess will need drainage, which can be accomplished through interventional radiological techniques.⁵⁵

If a “fungus ball” is suspected in the kidney, how does the management change in a patient with Candida pyelonephritis?

A fungus ball must be treated with both antifungals and surgical intervention. Antifungal therapy should be continued during the surgical removal process to avoid fungemia. Interventional radiology should be consulted and is usually the best option for removal. Fungus ball(s) can and often do cause urinary obstruction. Temporary nephrostomy tube placement may be warranted in these situations to relieve the obstruction.^55,65 AmB can be infused through the nephrostomy tube to increase local concentrations. This route of administration is not known to be nephrotoxic.⁵⁵ Fluconazole infusion through a nephrostomy tube has also been used in the successful treatment of a fungus ball.⁶⁹

Summary

Health care–associated UTIs are the most common nosocomial infection in the United States. UC placement and genitourinary manipulation or instrumentation play a major role in the development of CA-UTI. Clinicians should be aware of the appropriate and inappropriate use of UCs and their association with CA-UTI development. Removal of a UC when no longer necessary is key in prevention of CA-UTI. Treatment of asymptomatic bacteriuria is generally not indicated. A multidisciplinary approach is essential when managing chronic indwelling UCs in SCI. PCN and ureteral stenting need close monitoring, and early removal should be performed if infection is suspected.

Candiduria is an emerging nosocomial source of UTI but rarely leads to symptoms unless related to an ascending process. Proper urine collection is crucial in determining whether you are dealing with contamination, colonization, or infection. If candiduria persists in an asymptomatic individual, then further investigations should be done in regards to possible predisposing risks factors. Fluconazole is recommended for treatment of most patients with Candida UTI, while intravenous AmB is the treatment of choice for fluconazole-resistant Candida species. As we continue to take an evidence-based approach to the prevention and management of health care-associated UTI, we will likely see continued improvement in patient outcomes and overall decreased rates of infection.

Corresponding author: Norman Beatty, MD, 1501 N. Campbell Ave., Tucson, AZ 85724; [email protected].

Financial disclosures: None.

From the University of Arizona College of Medicine, Tucson, AZ (Dr. Beatty), and the Baylor College of Medicine, Houston, TX (Dr. Mohajer).

Abstract

• Objective: To review management issues regarding health care–associated urinary tract infections (UTIs) commonly encountered by practicing clinicians.
• Methods: Review of the literature.
• Results: Because urinary catheter (UC) placement plays a major role in the development of catheter-associated UTIs (CA-UTI), clinicians should be aware of the appropriate and inappropriate uses of UCs and their association with CA-UTI development. Removal of a UC when no longer necessary is key to preventing CA-UTI. Treatment of asymptomatic bacteriuria is generally not indicated. Percutaneous nephrostomy and ureteral stenting need close monitoring, and early removal should be performed if infection is suspected. Candiduria rarely leads to symptoms unless it is related to an ascending process. Proper urine collection is crucial in determining whether contamination, colonization, or infection is present. Fluconazole is recommended in most cases of Candida UTI, while intravenous amphotericin B is recommended for fluconazole-resistant Candida species.
• Conclusion: Continued use of evidence-based strategies for preventing and managing health care–associated UTI should lead to further improvements in patient outcomes and overall decreased rates of infection.

Keywords: bacteriuria; catheter-associated UTI; catheterization; percutaneous nephrostomy; candiduria.

Health care–associated urinary tract infections (UTIs) are estimated to be the most common adverse infectious event in U.S. hospitals, occurring in 1 of 10 admitted patients.^1-3 Approximately 32% of all health care–associated infections are UTIs.¹ Furthermore, urinary catheters (UCs) are associated with 8% to 21% of health care–associated infections that occur in the intensive care unit.⁴ The most important predisposing factor for nosocomial UTI is urinary catheterization.⁵ Genitourinary manipulation and/or implementation also play a major role in the development of nosocomial UTIs.

In 2008, the U.S. Centers for Medicare & Medicaid Services instituted a new policy that reduced reimbursement rates for hospitalizations linked to health care–associated infections.⁶ Indwelling UCs are among the most overused health care devices in the hospital setting. They are placed in an estimated 15% to 25% of all hospitalized patients,^7,8 and are often inserted in the emergency department (ED) without a physician order or appropriate indication.⁹ Intermittent straight catheterization, male or female condom catheterization, and/or placement of an indwelling UC are the most common causes of catheter-associated asymptomatic bacteriuria (CA-ASB) and catheter-associated UTIs (CA-UTI).⁵ Prevention and management of CA-ASB and CA-UTI can be challenging and require an evidence-based approach. Furthermore, guidelines for the management of UTIs in the setting of active percutaneous nephrostomy (PCN) drainage and/or ureteral stenting are not established.⁵ This may leave clinicians with little mainstream data to aid in management decisions.

In 2009 the Centers for Disease Control and Prevention provided a guideline for the appropriate and inappropriate use of indwelling UCs to help promote their proper use.¹⁰ In the time since the guideline’s initiatives were instituted around the United States, published data have shown some improvement in the use of UCs,^11,12 but other recent reports indicate that rates of UC use have remained unchanged.¹³ This review discusses management issues regarding health care–associated UTIs that are commonly encountered by practicing clinicians, with a focus on current guidelines and evidence.

Catheter-Associated UTI

CA-UTI is defined as the presence of signs or symptoms of UTI with no other explainable infectious source along with ≥ 1000 colony-forming units (cfu) of ≥ 1 bacterial species per milliliter in a urine specimen from a catheter that has been changed within 48 hours of collection of the urine specimen.⁵ Signs and symptoms of CA-UTI include, but are not limited to: new-onset or worsening fever, chills, altered sensorium from baseline, lethargy, malaise, flank pain, pelvic pain, costovertebral angle tenderness, and acute hematuria.⁵ New-onset “foul-smelling” (odorous)urine and “cloudy” urine are neither sensitive nor specific when assessing for CA-UTI, and do not have significant clinical relevance when found alone.^14,15 Patients who have removed or exchanged the UC during this event and then experience dysuria, increased frequency, urgency, or suprapubic pain are likely having symptoms of CA-UTI.⁵

What is the recommended method for collecting urine samples when CA-UTI is suspected?

In a patient with an indwelling catheter that has been in place for more than 2 weeks at the onset of a suspected CA-UTI, the catheter should be replaced (if still indicated) or removed to accelerate resolution of symptoms and to reduce the risk of subsequent catheter-associated bacteriuria and CA-UTI. The urine culture should be acquired from the freshly placed UC.⁵

When should a patient be empirically treated?

A patient presenting with evidence of sepsis should be empirically treated with antimicrobials. Empiric coverage should be based on risk factors for multidrug-resistant organisms and data pertaining to local antimicrobial resistance patterns. A urine specimen for urinalysis and possible culture should be sent prior to administering empiric antibiotics (if possible) in a symptomatic patient.⁵

What bacteria are commonly associated with CA-UTI?

The bacteria most commonly associated with CA-UTI are found in or around the gastrointestinal and genitourinary tracts and also are part of the normal skin flora. The introduction and/or facilitated ascension of these microorganisms is believed to occur during UC insertion.^16,17 Two-thirds of all isolated uropathogens in those with indwelling UCs are extraluminally acquired (via ascension along the catheter-urethral mucosa interface), and one-third are believed to be intraluminally acquired.¹⁸

The most commonly isolated bacteria in CA-UTI are Enterobacteriaceae, which include Escherichia coli (most common), Klebsiella species (K. oxytoca, K. pneumoniae), Serratia species (S. marcescens), Citrobacter species (C. koseri), Enterobacter species (E. cloacae), and Proteus species; non-Enterobacteriaceae such as Pseudomonas species; and gram-positive cocci, which include coagulase-negative staphylococci (S. saprophyticus), Staphylococcus aureus, group B streptococci, and Enterococcus species (E. faecalis, E. faecium).^19-21 Coagulase-negative staphylococci and Enterococcus species can lead to CA-UTI but are usually avirulent and more commonly isolated from asymptomatic individuals.¹⁹ Also, coagulase-negative staphylococci such as S. epidermidis and S. lugdunensis are usually the manifestation of contamination during the collection process and their presence should prompt a repeat sample collection under sterile techniques. Monomicrobial infection is usually seen in those with short-term catheter use and CA-UTI. In contrast, polymicrobial infection is more common in those with long-term indwelling UCs and CA-UTI.¹⁹ Providencia stuartii, Proteus mirabilis, S. aureus, and Morganella morganii have all been associated with CA-UTI in those with long-term indwelling UCs.

Growth of S. aureus in the urine should prompt further investigation with blood cultures to explore the possibility of hematogenous dissemination to the urinary tract. Organisms leading to bacteremia due to CA-UTI are most commonly gram-negative bacilli (E. coli, Klebsiella species, Pseudomonas aeruginosa) and E. faecalis.²¹

What is the difference between CA-ASB and CA-UTI?

CA-ASB is defined as the presence of ≥ 1 bacteria species growing on urine culture at ≥ 100,000 cfu/mL in a patient with a history of urinary catheterization and/or indwelling UC who lacks signs or symptoms of UTI. In a man with a condom catheter, CA-ASB is defined using the same criteria, but the urine sample is collected after a fresh condom catheter is applied.⁵ The difference between CA-ASB and CA-UTI is simply the presence or absence of signs and symptoms related to UTI. Currently, there is no standard definition for significant bacteriuria in a catheterized patient.⁵ Pyuria found on urinalysis is indicative of genitourinary inflammation and can be present in both CA-ASB and CA-UTI. The absence, presence, and/or degree of pyuria in catheterized patients does not accurately differentiate between CA-ASB and CA-UTI.^5,22,23 On the other hand, the absence of pyuria in a symptomatic catheterized patient suggests an etiology other than CA-UTI.⁵

How can CA-UTI be prevented in patients with a short-term indwelling urinary catheter?

If a short-term UC is essential, the most important approach to preventing CA-UTI is limiting the duration of time it will be used. Strategies such as computer-based order entry and care maps with automated discontinuation of UCs have been shown to decrease catheter usage.¹⁹ Using closed-systems for UC collection with ports in the distal catheter for needle aspiration of urine has also been shown to decrease the incidence of CA-UTI.⁵ Securing the UC to avoid urethral trauma, aseptic techniques for insertion and repositioning, and placement of the tubing and collection bag below the level of the bladder to prevent reflux will likely also prevent CA-UTI, but these strategies have not been evaluated thoroughly.¹⁹

When should you screen for and treat CA-ASB?

The 2009 Infectious Diseases Society of America (IDSA) guidelines recommend that the only patients who should be screened and treated for CA-ASB are pregnant women and those who will undergo a potentially traumatic urologic procedure for which mucosal breaching may occur, causing bleeding. Routinely screening or treating patients for CA-ASB in not recommended in any other group of patients and will lead to unnecessary antibiotic use and antibiotic resistance.⁵

UTI Associated with Percutaneous Nephrostomy and Ureteral Stenting

Similar systemic symptoms of infection (fever, rigors, malaise, shock) are present in patients with and without percutaneous nephrostomy (PCN) and/or ureteral stent placement. Dysuria is not commonly present in those with PCN. The first signs of CA-UTI may be decreased urine output and pericatheter leakage due to an obstructive process resulting from the encrustation.^24-27 The most common complaint among patients with either acute or chronic ureteral stenting is discomfort, which has been described as “urinary symptoms” and “body pain.”²⁸ This discomfort can be related to ureteral hyperperistalsis after placement of the stent and is usually self-limiting. Ureteral stent migration, usually at the distal end, can also lead to discomfort, but is easily rectified with cystoscopy.²⁵ Body pain and/or urinary symptoms in the setting of ureteral stenting are not indicative of infection alone.

What is urinary catheter and/or ureteral stent encrustation?

Encrustation is the formation of a conditioning film that develops on the surface of the UC or ureteral stent. The exact mechanism is not well understood, but it is believed to involve electrostatic interactions of urinary proteins that stimulate binding onto the stent or UC surface.²⁵ Encrustation increases exponentially with the dwell time. Among patients with ureteral stents placed due to urolithiasis, encrustation occurred in 9.2% of stents removed prior to 6 weeks, 47.5% of stents removed at 6 weeks, and 76.3% of stents removed at 12 weeks.²⁶ Encrustation is most common at the proximal and distal ends (pigtails) of the ureteral stent and usually spares or presents last within the lumen.²⁹ Attempts have been made to prevent ureteral stent encrustation through the development of biodegradable, drug-eluting, and tissue-engineered substrates. These developments are promising, but currently there is limited observational data from large randomized trials to suggest that these new modalities decrease rates of encrustation.²⁵ Encrustation is highly associated with certain microorganisms, especially those that create biofilms.³⁰ Urease-producing bacteria, most commonly P. mirabilis, play a role in encrustation formation.³¹ Bacteria most commonly associated with encrustation include Proteus species (P. mirabilis is most common), P. aeruginosa, K. pneumoniae, Providencia species (P. stuartii is most common), and M. morganii.

Does ureteral stent bacterial colonization correlate with UTI?

Ureteral stent colonization with bacteria increases with dwell time and is found in 40% to 98.5% of stents placed.^32-35 If UTI is suspected in a patient with an active indwelling ureteral stent, a sample of urine should be cultured while the stent is in place.²⁵ Typically, genitourinary and normal skin flora pathogens are found when the ureteral stent is cultured. The top 3 organisms cultured from ureteral stents are S. aureus, P. aeruginosa, and E. faecalis.³⁴ Urine culture usually does not correlate with stent culture results, which has brought up the debate of how bacterial colonization occurs. It has been postulated that colonization is actually a manifestation of contamination during the insertion procedure, but this has yet to be validated.²⁵ In patients with symptoms of UTI in the setting of an indwelling ureteral stent, a positive culture has low sensitivity, with estimates between 21% and 40%.³⁵ Therefore, a negative urine culture does not rule out UTI alone in a symptomatic patient. Multiple studies have suggested that colonization of the ureteral stent does not correlate strongly with developing a UTI.^25,32-34

How can UTI be prevented in those receiving PCN or ureteral stent placement?

Antibiotic prophylaxis has been recommended to prevent UTI in patients who will undergo PCN or ureteral stent placement. The American Urological Association recommends empiric treatment even in the absence of signs and symptoms of UTI,³⁶ but substantial evidence is lacking that this approach prevents infection.³⁷ Ciprofloxacin or trimethoprim/sulfamethoxazole has been recommended by some for empiric coverage for enteric gram-negative bacilli and enterococcus in those undergoing genitourinary manipulation or instrumentation.^32,38 Most patients who develop CA-UTI and pyelonephritis do so within the first 2 to 6 weeks after placement.^37,39 Bacteriuria, candiduria, and/or pyuria are present in all patients approximately within 9 weeks even when sterile urine is confirmed prior to PCN placement.³⁹ Data on the effectiveness of antibiotic prophylaxis to prevent CA-UTI in those with PCN or ureteral stenting is limited. Currently, there are no recommendations from the IDSA on how to prevent infection in these situations.⁵ Early or frequent stent removal or exchanges has been proven to reduce UTI in those with ureteral stenting.³³ Patients with diabetes mellitus and chronic renal failure are at high-risk for UTI when ureteral stents are in place. This population should undergo close monitoring for UTI development and may warrant more frequent stent exchanges.^27,40

What is the treatment of CA-UTI associated with PCN and/or ureteral stenting?

The IDSA guidelines do not apply to patients with PCN and/or ureteral stenting.⁵ There is no treatment protocol for UTI related to these processes. Generally speaking, they are considered “complicated UTI” by most experts. Broad-spectrum, empiric antibiotic administration along with prompt removal of the PCN and/or ureteral stent is the gold standard of therapy.²⁷ The recommended duration of targeted antibiotic therapy is generally between 5 and 14 days.¹⁹ Most clinicians will treat this complicated UTI for at least 10 to 14 days. Antibiotic administration should be continued even after removal of the catheter and/or stent to complete the full course. Repeat urinalysis and culture is not indicated at the end of therapy if the patient is clinically improving or has remission of symptoms.

What is the exchange rate for those who require chronic PCN and/or ureteral stent use?

On average a PCN or ureteral stent should be exchanged every 2 to 3 months in patients who require chronic usage.^24,27 Some patients with persistent complications may require more frequent exchanges (< 10 weeks).²⁷ Encrustation and bacterial colonization become more prevalent the longer the devices are in place. This process is estimated to begin within the first 2 weeks after placement.^27,33,34 A “forgotten stent” is one that has been left in place after the patient is lost to follow-up. This unfortunate event can lead to massive encrustation, UTI, stent fracturing, and complete ureteral obstruction.²⁴ As noted, patients with diabetes mellitus, chronic renal failure, and frequent UTI may warrant more frequent exchanges, but this should be determined on a case-by-case basis.

 

 

Catheter-Associated UTI in Patients with Spinal Cord Injury

Spinal cord injury (SCI) at any level can cause neurogenic bladder. This process ultimately leads to urinary stasis and colonization of the bladder with bacteria. According to the IDSA, the acceptable indications for UC insertion are: clinically significant urinary retention (if medical therapy is not effective), urinary incontinence, accurate urine output monitoring required, and patient is unable and/or unwilling to collect urine (Table 1).⁵ Recently, further guidelines were published regarding appropriate and inappropriate indwelling UC placement in hospitalized medical patients (Table 2 and Table 3), expanding upon the earlier acceptable criteria provided by the IDSA.⁴¹ According to the IDSA and Ann Arbor Criteria for Appropriate Urinary Catheter Use, patients with SCI and subsequent neurogenic bladder without obstruction where intermittent bladder straight catheterization for the drainage of urine is not feasible will likely need an indwelling UC.⁴¹ SCI patients often experience decubitus ulcers, and an indwelling UC can be used if needed to help with wound healing if other urinary management alternatives have been attempted. Other such situations in which an indwelling UC can used before attempting alternative approaches would be in a patient who is actively dying and is pursuing comfort care and/or hospice.⁴¹

Which indwelling UCs should be used in patients with SCI?

Efforts to reduce the likelihood of infection in patients with SCI have led to several advances in the design and manufacturing of UCs. UCs are made of either latex, plastic, silicone, or polytetrafluoroethylene (Teflon). None of these substrates is free of complications, but of them latex UCs have been studied the most in regards to their associated complications. Aside from being allergenic in nature, latex UCs have an increased propensity to allow bacteria to adhere to their surface due to microscopic planes of unevenness.⁴² Silicone UCs are less frequently associated with infection but are more rigid, leading to increased discomfort.^43,44 Hydrophilic and silver-hydrogel coatings are innovative methods that have been developed to increase comfort and reduce the likelihood of infection. Hydrophilic-coated UCs are associated with reduced microbial adherence, decreased encrustation, and better patient satisfaction.^45,46 In SCI patients, these UCs have demonstrated lower complication rates, including UTI; fewer episodes of post-, intra-, and inter-catheterization bleeding; and decreased rates of antibiotic-resistant bacteria.^45,46 Silver-hydrogel-coated UCs are less well studied but have also demonstrated reduced UTI rates in SCI patients; however, their efficacy over the long term has yet to be determined. Antibiotic-impregnated UCs are not currently recommended for either short- or long-term indwelling UC use.⁵

How can CA-UTI be prevented in a patient who will require a long-term indwelling catheter?

At this time, the data is insufficient to make a recommendation on routine UC exchange (eg, every 2 to 4 weeks) in patients who require long-term indwelling urethral or suprapubic catheters in an attempt to reduce the risk of CA-ASB or CA-UTI. This is also true for those who experience even repeated early catheter blockage from encrustation.⁵ Thus, the rate at which these exchanges occur can be controversial, but typically around every 4 weeks is a common approach. Some would argue that if the patient has repeated CA-UTI, an exchange rate of every 2 weeks might be needed, but data is currently lacking to support this practice.⁵ If intermittent urinary catheterization is feasible, it should be done at least every 6 hours and before bedtime. In general, when the volume of urine in the bladder reaches approximately 400 mL, the patient should undergo bladder catheterization to prevent stasis and infection.⁴⁷ A closed drainage system is recommended in all patients who require long-term indwelling UC use.^48,49 Placement of the collection bag above the catheter or above the level of the bladder and a breach in the closed drainage system have been shown to result in higher rates of catheter-associated bacteriuria.^48,50 Proper hand hygiene and sterile and/or clean techniques should be used when placing or exchanging a UC. However, in one study there was no difference in bacteremia or UTIs when using sterile versus clean techniques.⁵¹

Asymptomatic bacteriuria should not be treated in patients with long-term indwelling UCs, and prophylactic antibiotics have led to the emergence of resistance.⁵² At this time it is not clear whether prophylactic weekly oral cyclic antibiotic administration can effectively reduce the frequency of CA-UTI in patients with SCI and chronic indwelling UC use.

What are the signs and symptoms of CA-UTI in a patient with SCI?

Subjective and objective findings may be limited when a patient with SCI presents with CA-UTI. These patients often lack the usual symptoms of UTI (dysuria, suprapubic discomfort, urgency, increased frequency) and pyelonephritis (flank pain, costovertebral angle tenderness). Caregivers and health care providers should be aware that nonspecific symptoms such as foul-smelling urine, pyuria, increased residual volume of urine in the bladder, change in voiding habits, worsening detrusor spasticity, and aggravation of autonomic dysreflexia can be the only initial presenting symptoms.⁵³

 

 

What is the duration of therapy for CA-UTI in SCI, and how can antibiotic stewardship principles be applied in this patient population?

Antibiotic therapy is indicated for a duration of 7 days if there is prompt resolution of symptoms, or for a total of 10 to 14 days if the response is delayed, regardless of whether the patient remains with a UC.⁵ Antibiotic stewardship is very important to reduce the risk for developing drug resistance in this high-risk population. Methods such as prescriber education practices, institution protocols, guideline implementation, auditing and feedback, restriction and reauthorization practices, computer-assisted programs, de-escalation or streamlining, and antibiotic cycling or dosage optimization have all been shown to assist in antibiotic stewardship in UTIs.⁵⁴

Candida UTI

What is the initial evaluation for a patient with candiduria?

The workup for candiduria hinges on determining whether the candiduria likely represents contamination, colonization, or infection; certain predisposing risk factors are associated with Candida UTI (Table 4).^55-57 The most important aspect to candiduria is the patient’s clinical status and comorbid conditions.⁵⁸ Among funguria, Candida species are the most common and represent 95% of organisms isolated on urine cultures (Table 5).⁵⁹ Candiduria is usually present in those with significant comorbidities and rarely is associated with healthy individuals.^59,60 Candiduria is increasing in prevalence among hospitalized patients, representing 22% to 40% of all nosocomial UTIs.^59,60 Markers in the urine (leukocyte esterase, colony count of culture growth, presence or absence of Candida casts and pseudohyphae) cannot alone differentiate colonization from infection.⁵⁵ When candiduria is discovered in a patient with symptoms related to UTI in the setting of predisposing risk factors, it should be considered a real infection until proven otherwise.

In a situation where an asymptomatic patient without an indwelling UC has Candida species isolated from a urine culture, a repeat culture (clean-catch midstream sample) should be performed to assess for a likely contaminated collection.⁵⁵ If the patient has an indwelling UC then it should be exchanged and urine collected from the fresh catheter.⁶¹ When candiduria is found in healthy asymptomatic adults, it is most commonly associated with poor collection techniques or postcollection contamination.⁵⁹ If candiduria persists in an asymptomatic patient, the patient should be assessed for predisposing factors. This includes checking hemoglobin A1C for developing diabetes and renal ultrasound looking for urolithiasis, renal abscess, hydronephrosis, and fungus ball. Postvoid residual urinary retention should also be ruled out with bladder ultrasound. Treatment of predisposing factors can lead to resolution of candiduria without antifungal treatment, and a urine culture should be repeated (1 to 2 weeks later).⁶¹ Asymptomatic patients lacking any predisposing factors can be observed with repeat urine cultures in 1 to 3 months.⁶¹

Candiduria may actually represent candidemia in those patients who have a predisposing risk factor for disseminated candidiasis. These risk factors include central venous catheters, administration of total parental nutrition, antibiotic use (especially broad spectrum), critical illness, recent surgical intervention (especially intra-abdominal), acute renal failure, nasogastric tube use, and active gastric acid suppression (ie, proton pump inhibitors).^62,63 The hematogenous spread of Candida can lead to the detection of candiduria in 46% to 80% of persons who are experiencing candidemia.⁵⁹ If the patient is at risk for candidemia, then blood fungal cultures should be drawn. It is not unreasonable to also order a serum-D-glucan assay if suspicions are high. A thorough skin assessment should be completed and ophthalmology consulted for a detailed eye exam in the event that the patient has candidemia. Candiduria is highly prevalent among those who are candidemic, but overall candidemia is encountered in less than 5% of patients in most intensive care units.⁵⁹ Thus, most patients with candiduria do not have disseminated candidiasis.

Candiduria rarely leads to symptoms of UTI,⁵⁸ unless the pathogenesis is related to an ascending process.⁵⁶ Symptoms of Candida UTI are no different from those experienced from a bacterial etiology. Some patients may complain of pneumaturia and/or endorse seeing particulate matter in their urine.⁵⁵ Patients showing signs of sepsis (fever, chills, flank pain) should be investigated for possible Candida pyelonephritis in the setting of candiduria.⁶⁴

When should asymptomatic candiduria be treated?

In adult patients with asymptomatic candiduria, there are 2 situations in which antifungal therapy is recommended. A patient undergoing a traumatic urologic procedure would be treated to avoid the risk for candidemia caused by the procedure. Also, in neutropenic patients empiric antifungal therapy should be administered because there is a high likelihood that this candiduria may actually represent hematogenous spread from candidemia.^61,65

What is the treatment for symptomatic Candida cystitis?

Empiric treatment with oral fluconazole 200 to 400 mg daily for a total of 2 weeks is recommended in patients with persisting candiduria and symptoms of cystitis.⁶⁵ Identifying the species is a crucial step in the treatment of Candida UTI. Several species (C. glabrata, C. krusei) are known to be resistant to fluconazole. Species identification and antifungal sensitivities should be done and therapy directed after obtaining these results.⁵⁵

What is the recommended treatment for Candida pyelonephritis?

Treatment for pyelonephritis caused by fluconazole-susceptible Candida species is oral fluconazole 200 to 400 mg (3-6 mg/kg) for a total of 2 weeks.⁶⁵ A fluconazole-resistant organism should be suspected when a non-albicans Candida species is isolated, such as C. krusei or C. glabrata. In this circumstance, in vitro antifungal susceptibility testing should be done. Echinocandins are not a good option in this situation because they do not reach adequate urine concentration and treatment failure is well documented.^66-68 Amphotericin B deoxycholate (AmB) 0.3 to 0.6 mg/kg daily for 1 to 7 days, with or without oral flucytosine (25 mg/kg) 4 times daily, is recommended by the IDSA for the treatment of fluconazole-resistant isolates of C. glabrata and C. krusei.⁶⁵ Further imaging with ultrasound, CT, or magnetic resonance should be done to rule out urinary tract obstruction and/or “fungus ball” formation. Emphysematous pyelonephritis and necrosis can occur and usually require nephrectomy. Perinephric abscess will need drainage, which can be accomplished through interventional radiological techniques.⁵⁵

If a “fungus ball” is suspected in the kidney, how does the management change in a patient with Candida pyelonephritis?

A fungus ball must be treated with both antifungals and surgical intervention. Antifungal therapy should be continued during the surgical removal process to avoid fungemia. Interventional radiology should be consulted and is usually the best option for removal. Fungus ball(s) can and often do cause urinary obstruction. Temporary nephrostomy tube placement may be warranted in these situations to relieve the obstruction.^55,65 AmB can be infused through the nephrostomy tube to increase local concentrations. This route of administration is not known to be nephrotoxic.⁵⁵ Fluconazole infusion through a nephrostomy tube has also been used in the successful treatment of a fungus ball.⁶⁹

Summary

Health care–associated UTIs are the most common nosocomial infection in the United States. UC placement and genitourinary manipulation or instrumentation play a major role in the development of CA-UTI. Clinicians should be aware of the appropriate and inappropriate use of UCs and their association with CA-UTI development. Removal of a UC when no longer necessary is key in prevention of CA-UTI. Treatment of asymptomatic bacteriuria is generally not indicated. A multidisciplinary approach is essential when managing chronic indwelling UCs in SCI. PCN and ureteral stenting need close monitoring, and early removal should be performed if infection is suspected.

Candiduria is an emerging nosocomial source of UTI but rarely leads to symptoms unless related to an ascending process. Proper urine collection is crucial in determining whether you are dealing with contamination, colonization, or infection. If candiduria persists in an asymptomatic individual, then further investigations should be done in regards to possible predisposing risks factors. Fluconazole is recommended for treatment of most patients with Candida UTI, while intravenous AmB is the treatment of choice for fluconazole-resistant Candida species. As we continue to take an evidence-based approach to the prevention and management of health care-associated UTI, we will likely see continued improvement in patient outcomes and overall decreased rates of infection.

Corresponding author: Norman Beatty, MD, 1501 N. Campbell Ave., Tucson, AZ 85724; [email protected].

Financial disclosures: None.

From the University of Arizona College of Medicine, Tucson, AZ (Dr. Beatty), and the Baylor College of Medicine, Houston, TX (Dr. Mohajer).

Abstract

• Objective: To review management issues regarding health care–associated urinary tract infections (UTIs) commonly encountered by practicing clinicians.
• Methods: Review of the literature.
• Results: Because urinary catheter (UC) placement plays a major role in the development of catheter-associated UTIs (CA-UTI), clinicians should be aware of the appropriate and inappropriate uses of UCs and their association with CA-UTI development. Removal of a UC when no longer necessary is key to preventing CA-UTI. Treatment of asymptomatic bacteriuria is generally not indicated. Percutaneous nephrostomy and ureteral stenting need close monitoring, and early removal should be performed if infection is suspected. Candiduria rarely leads to symptoms unless it is related to an ascending process. Proper urine collection is crucial in determining whether contamination, colonization, or infection is present. Fluconazole is recommended in most cases of Candida UTI, while intravenous amphotericin B is recommended for fluconazole-resistant Candida species.
• Conclusion: Continued use of evidence-based strategies for preventing and managing health care–associated UTI should lead to further improvements in patient outcomes and overall decreased rates of infection.

Keywords: bacteriuria; catheter-associated UTI; catheterization; percutaneous nephrostomy; candiduria.

Health care–associated urinary tract infections (UTIs) are estimated to be the most common adverse infectious event in U.S. hospitals, occurring in 1 of 10 admitted patients.^1-3 Approximately 32% of all health care–associated infections are UTIs.¹ Furthermore, urinary catheters (UCs) are associated with 8% to 21% of health care–associated infections that occur in the intensive care unit.⁴ The most important predisposing factor for nosocomial UTI is urinary catheterization.⁵ Genitourinary manipulation and/or implementation also play a major role in the development of nosocomial UTIs.

In 2008, the U.S. Centers for Medicare & Medicaid Services instituted a new policy that reduced reimbursement rates for hospitalizations linked to health care–associated infections.⁶ Indwelling UCs are among the most overused health care devices in the hospital setting. They are placed in an estimated 15% to 25% of all hospitalized patients,^7,8 and are often inserted in the emergency department (ED) without a physician order or appropriate indication.⁹ Intermittent straight catheterization, male or female condom catheterization, and/or placement of an indwelling UC are the most common causes of catheter-associated asymptomatic bacteriuria (CA-ASB) and catheter-associated UTIs (CA-UTI).⁵ Prevention and management of CA-ASB and CA-UTI can be challenging and require an evidence-based approach. Furthermore, guidelines for the management of UTIs in the setting of active percutaneous nephrostomy (PCN) drainage and/or ureteral stenting are not established.⁵ This may leave clinicians with little mainstream data to aid in management decisions.

In 2009 the Centers for Disease Control and Prevention provided a guideline for the appropriate and inappropriate use of indwelling UCs to help promote their proper use.¹⁰ In the time since the guideline’s initiatives were instituted around the United States, published data have shown some improvement in the use of UCs,^11,12 but other recent reports indicate that rates of UC use have remained unchanged.¹³ This review discusses management issues regarding health care–associated UTIs that are commonly encountered by practicing clinicians, with a focus on current guidelines and evidence.

Catheter-Associated UTI

CA-UTI is defined as the presence of signs or symptoms of UTI with no other explainable infectious source along with ≥ 1000 colony-forming units (cfu) of ≥ 1 bacterial species per milliliter in a urine specimen from a catheter that has been changed within 48 hours of collection of the urine specimen.⁵ Signs and symptoms of CA-UTI include, but are not limited to: new-onset or worsening fever, chills, altered sensorium from baseline, lethargy, malaise, flank pain, pelvic pain, costovertebral angle tenderness, and acute hematuria.⁵ New-onset “foul-smelling” (odorous)urine and “cloudy” urine are neither sensitive nor specific when assessing for CA-UTI, and do not have significant clinical relevance when found alone.^14,15 Patients who have removed or exchanged the UC during this event and then experience dysuria, increased frequency, urgency, or suprapubic pain are likely having symptoms of CA-UTI.⁵

What is the recommended method for collecting urine samples when CA-UTI is suspected?

In a patient with an indwelling catheter that has been in place for more than 2 weeks at the onset of a suspected CA-UTI, the catheter should be replaced (if still indicated) or removed to accelerate resolution of symptoms and to reduce the risk of subsequent catheter-associated bacteriuria and CA-UTI. The urine culture should be acquired from the freshly placed UC.⁵

When should a patient be empirically treated?

A patient presenting with evidence of sepsis should be empirically treated with antimicrobials. Empiric coverage should be based on risk factors for multidrug-resistant organisms and data pertaining to local antimicrobial resistance patterns. A urine specimen for urinalysis and possible culture should be sent prior to administering empiric antibiotics (if possible) in a symptomatic patient.⁵

What bacteria are commonly associated with CA-UTI?

The bacteria most commonly associated with CA-UTI are found in or around the gastrointestinal and genitourinary tracts and also are part of the normal skin flora. The introduction and/or facilitated ascension of these microorganisms is believed to occur during UC insertion.^16,17 Two-thirds of all isolated uropathogens in those with indwelling UCs are extraluminally acquired (via ascension along the catheter-urethral mucosa interface), and one-third are believed to be intraluminally acquired.¹⁸

The most commonly isolated bacteria in CA-UTI are Enterobacteriaceae, which include Escherichia coli (most common), Klebsiella species (K. oxytoca, K. pneumoniae), Serratia species (S. marcescens), Citrobacter species (C. koseri), Enterobacter species (E. cloacae), and Proteus species; non-Enterobacteriaceae such as Pseudomonas species; and gram-positive cocci, which include coagulase-negative staphylococci (S. saprophyticus), Staphylococcus aureus, group B streptococci, and Enterococcus species (E. faecalis, E. faecium).^19-21 Coagulase-negative staphylococci and Enterococcus species can lead to CA-UTI but are usually avirulent and more commonly isolated from asymptomatic individuals.¹⁹ Also, coagulase-negative staphylococci such as S. epidermidis and S. lugdunensis are usually the manifestation of contamination during the collection process and their presence should prompt a repeat sample collection under sterile techniques. Monomicrobial infection is usually seen in those with short-term catheter use and CA-UTI. In contrast, polymicrobial infection is more common in those with long-term indwelling UCs and CA-UTI.¹⁹ Providencia stuartii, Proteus mirabilis, S. aureus, and Morganella morganii have all been associated with CA-UTI in those with long-term indwelling UCs.

Growth of S. aureus in the urine should prompt further investigation with blood cultures to explore the possibility of hematogenous dissemination to the urinary tract. Organisms leading to bacteremia due to CA-UTI are most commonly gram-negative bacilli (E. coli, Klebsiella species, Pseudomonas aeruginosa) and E. faecalis.²¹

What is the difference between CA-ASB and CA-UTI?

CA-ASB is defined as the presence of ≥ 1 bacteria species growing on urine culture at ≥ 100,000 cfu/mL in a patient with a history of urinary catheterization and/or indwelling UC who lacks signs or symptoms of UTI. In a man with a condom catheter, CA-ASB is defined using the same criteria, but the urine sample is collected after a fresh condom catheter is applied.⁵ The difference between CA-ASB and CA-UTI is simply the presence or absence of signs and symptoms related to UTI. Currently, there is no standard definition for significant bacteriuria in a catheterized patient.⁵ Pyuria found on urinalysis is indicative of genitourinary inflammation and can be present in both CA-ASB and CA-UTI. The absence, presence, and/or degree of pyuria in catheterized patients does not accurately differentiate between CA-ASB and CA-UTI.^5,22,23 On the other hand, the absence of pyuria in a symptomatic catheterized patient suggests an etiology other than CA-UTI.⁵

How can CA-UTI be prevented in patients with a short-term indwelling urinary catheter?

If a short-term UC is essential, the most important approach to preventing CA-UTI is limiting the duration of time it will be used. Strategies such as computer-based order entry and care maps with automated discontinuation of UCs have been shown to decrease catheter usage.¹⁹ Using closed-systems for UC collection with ports in the distal catheter for needle aspiration of urine has also been shown to decrease the incidence of CA-UTI.⁵ Securing the UC to avoid urethral trauma, aseptic techniques for insertion and repositioning, and placement of the tubing and collection bag below the level of the bladder to prevent reflux will likely also prevent CA-UTI, but these strategies have not been evaluated thoroughly.¹⁹

When should you screen for and treat CA-ASB?

The 2009 Infectious Diseases Society of America (IDSA) guidelines recommend that the only patients who should be screened and treated for CA-ASB are pregnant women and those who will undergo a potentially traumatic urologic procedure for which mucosal breaching may occur, causing bleeding. Routinely screening or treating patients for CA-ASB in not recommended in any other group of patients and will lead to unnecessary antibiotic use and antibiotic resistance.⁵

UTI Associated with Percutaneous Nephrostomy and Ureteral Stenting

Similar systemic symptoms of infection (fever, rigors, malaise, shock) are present in patients with and without percutaneous nephrostomy (PCN) and/or ureteral stent placement. Dysuria is not commonly present in those with PCN. The first signs of CA-UTI may be decreased urine output and pericatheter leakage due to an obstructive process resulting from the encrustation.^24-27 The most common complaint among patients with either acute or chronic ureteral stenting is discomfort, which has been described as “urinary symptoms” and “body pain.”²⁸ This discomfort can be related to ureteral hyperperistalsis after placement of the stent and is usually self-limiting. Ureteral stent migration, usually at the distal end, can also lead to discomfort, but is easily rectified with cystoscopy.²⁵ Body pain and/or urinary symptoms in the setting of ureteral stenting are not indicative of infection alone.

What is urinary catheter and/or ureteral stent encrustation?

Encrustation is the formation of a conditioning film that develops on the surface of the UC or ureteral stent. The exact mechanism is not well understood, but it is believed to involve electrostatic interactions of urinary proteins that stimulate binding onto the stent or UC surface.²⁵ Encrustation increases exponentially with the dwell time. Among patients with ureteral stents placed due to urolithiasis, encrustation occurred in 9.2% of stents removed prior to 6 weeks, 47.5% of stents removed at 6 weeks, and 76.3% of stents removed at 12 weeks.²⁶ Encrustation is most common at the proximal and distal ends (pigtails) of the ureteral stent and usually spares or presents last within the lumen.²⁹ Attempts have been made to prevent ureteral stent encrustation through the development of biodegradable, drug-eluting, and tissue-engineered substrates. These developments are promising, but currently there is limited observational data from large randomized trials to suggest that these new modalities decrease rates of encrustation.²⁵ Encrustation is highly associated with certain microorganisms, especially those that create biofilms.³⁰ Urease-producing bacteria, most commonly P. mirabilis, play a role in encrustation formation.³¹ Bacteria most commonly associated with encrustation include Proteus species (P. mirabilis is most common), P. aeruginosa, K. pneumoniae, Providencia species (P. stuartii is most common), and M. morganii.

Does ureteral stent bacterial colonization correlate with UTI?

Ureteral stent colonization with bacteria increases with dwell time and is found in 40% to 98.5% of stents placed.^32-35 If UTI is suspected in a patient with an active indwelling ureteral stent, a sample of urine should be cultured while the stent is in place.²⁵ Typically, genitourinary and normal skin flora pathogens are found when the ureteral stent is cultured. The top 3 organisms cultured from ureteral stents are S. aureus, P. aeruginosa, and E. faecalis.³⁴ Urine culture usually does not correlate with stent culture results, which has brought up the debate of how bacterial colonization occurs. It has been postulated that colonization is actually a manifestation of contamination during the insertion procedure, but this has yet to be validated.²⁵ In patients with symptoms of UTI in the setting of an indwelling ureteral stent, a positive culture has low sensitivity, with estimates between 21% and 40%.³⁵ Therefore, a negative urine culture does not rule out UTI alone in a symptomatic patient. Multiple studies have suggested that colonization of the ureteral stent does not correlate strongly with developing a UTI.^25,32-34

How can UTI be prevented in those receiving PCN or ureteral stent placement?

Antibiotic prophylaxis has been recommended to prevent UTI in patients who will undergo PCN or ureteral stent placement. The American Urological Association recommends empiric treatment even in the absence of signs and symptoms of UTI,³⁶ but substantial evidence is lacking that this approach prevents infection.³⁷ Ciprofloxacin or trimethoprim/sulfamethoxazole has been recommended by some for empiric coverage for enteric gram-negative bacilli and enterococcus in those undergoing genitourinary manipulation or instrumentation.^32,38 Most patients who develop CA-UTI and pyelonephritis do so within the first 2 to 6 weeks after placement.^37,39 Bacteriuria, candiduria, and/or pyuria are present in all patients approximately within 9 weeks even when sterile urine is confirmed prior to PCN placement.³⁹ Data on the effectiveness of antibiotic prophylaxis to prevent CA-UTI in those with PCN or ureteral stenting is limited. Currently, there are no recommendations from the IDSA on how to prevent infection in these situations.⁵ Early or frequent stent removal or exchanges has been proven to reduce UTI in those with ureteral stenting.³³ Patients with diabetes mellitus and chronic renal failure are at high-risk for UTI when ureteral stents are in place. This population should undergo close monitoring for UTI development and may warrant more frequent stent exchanges.^27,40

What is the treatment of CA-UTI associated with PCN and/or ureteral stenting?

The IDSA guidelines do not apply to patients with PCN and/or ureteral stenting.⁵ There is no treatment protocol for UTI related to these processes. Generally speaking, they are considered “complicated UTI” by most experts. Broad-spectrum, empiric antibiotic administration along with prompt removal of the PCN and/or ureteral stent is the gold standard of therapy.²⁷ The recommended duration of targeted antibiotic therapy is generally between 5 and 14 days.¹⁹ Most clinicians will treat this complicated UTI for at least 10 to 14 days. Antibiotic administration should be continued even after removal of the catheter and/or stent to complete the full course. Repeat urinalysis and culture is not indicated at the end of therapy if the patient is clinically improving or has remission of symptoms.

What is the exchange rate for those who require chronic PCN and/or ureteral stent use?

On average a PCN or ureteral stent should be exchanged every 2 to 3 months in patients who require chronic usage.^24,27 Some patients with persistent complications may require more frequent exchanges (< 10 weeks).²⁷ Encrustation and bacterial colonization become more prevalent the longer the devices are in place. This process is estimated to begin within the first 2 weeks after placement.^27,33,34 A “forgotten stent” is one that has been left in place after the patient is lost to follow-up. This unfortunate event can lead to massive encrustation, UTI, stent fracturing, and complete ureteral obstruction.²⁴ As noted, patients with diabetes mellitus, chronic renal failure, and frequent UTI may warrant more frequent exchanges, but this should be determined on a case-by-case basis.

 

 

Catheter-Associated UTI in Patients with Spinal Cord Injury

Spinal cord injury (SCI) at any level can cause neurogenic bladder. This process ultimately leads to urinary stasis and colonization of the bladder with bacteria. According to the IDSA, the acceptable indications for UC insertion are: clinically significant urinary retention (if medical therapy is not effective), urinary incontinence, accurate urine output monitoring required, and patient is unable and/or unwilling to collect urine (Table 1).⁵ Recently, further guidelines were published regarding appropriate and inappropriate indwelling UC placement in hospitalized medical patients (Table 2 and Table 3), expanding upon the earlier acceptable criteria provided by the IDSA.⁴¹ According to the IDSA and Ann Arbor Criteria for Appropriate Urinary Catheter Use, patients with SCI and subsequent neurogenic bladder without obstruction where intermittent bladder straight catheterization for the drainage of urine is not feasible will likely need an indwelling UC.⁴¹ SCI patients often experience decubitus ulcers, and an indwelling UC can be used if needed to help with wound healing if other urinary management alternatives have been attempted. Other such situations in which an indwelling UC can used before attempting alternative approaches would be in a patient who is actively dying and is pursuing comfort care and/or hospice.⁴¹

Which indwelling UCs should be used in patients with SCI?

Efforts to reduce the likelihood of infection in patients with SCI have led to several advances in the design and manufacturing of UCs. UCs are made of either latex, plastic, silicone, or polytetrafluoroethylene (Teflon). None of these substrates is free of complications, but of them latex UCs have been studied the most in regards to their associated complications. Aside from being allergenic in nature, latex UCs have an increased propensity to allow bacteria to adhere to their surface due to microscopic planes of unevenness.⁴² Silicone UCs are less frequently associated with infection but are more rigid, leading to increased discomfort.^43,44 Hydrophilic and silver-hydrogel coatings are innovative methods that have been developed to increase comfort and reduce the likelihood of infection. Hydrophilic-coated UCs are associated with reduced microbial adherence, decreased encrustation, and better patient satisfaction.^45,46 In SCI patients, these UCs have demonstrated lower complication rates, including UTI; fewer episodes of post-, intra-, and inter-catheterization bleeding; and decreased rates of antibiotic-resistant bacteria.^45,46 Silver-hydrogel-coated UCs are less well studied but have also demonstrated reduced UTI rates in SCI patients; however, their efficacy over the long term has yet to be determined. Antibiotic-impregnated UCs are not currently recommended for either short- or long-term indwelling UC use.⁵

How can CA-UTI be prevented in a patient who will require a long-term indwelling catheter?

At this time, the data is insufficient to make a recommendation on routine UC exchange (eg, every 2 to 4 weeks) in patients who require long-term indwelling urethral or suprapubic catheters in an attempt to reduce the risk of CA-ASB or CA-UTI. This is also true for those who experience even repeated early catheter blockage from encrustation.⁵ Thus, the rate at which these exchanges occur can be controversial, but typically around every 4 weeks is a common approach. Some would argue that if the patient has repeated CA-UTI, an exchange rate of every 2 weeks might be needed, but data is currently lacking to support this practice.⁵ If intermittent urinary catheterization is feasible, it should be done at least every 6 hours and before bedtime. In general, when the volume of urine in the bladder reaches approximately 400 mL, the patient should undergo bladder catheterization to prevent stasis and infection.⁴⁷ A closed drainage system is recommended in all patients who require long-term indwelling UC use.^48,49 Placement of the collection bag above the catheter or above the level of the bladder and a breach in the closed drainage system have been shown to result in higher rates of catheter-associated bacteriuria.^48,50 Proper hand hygiene and sterile and/or clean techniques should be used when placing or exchanging a UC. However, in one study there was no difference in bacteremia or UTIs when using sterile versus clean techniques.⁵¹

Asymptomatic bacteriuria should not be treated in patients with long-term indwelling UCs, and prophylactic antibiotics have led to the emergence of resistance.⁵² At this time it is not clear whether prophylactic weekly oral cyclic antibiotic administration can effectively reduce the frequency of CA-UTI in patients with SCI and chronic indwelling UC use.

What are the signs and symptoms of CA-UTI in a patient with SCI?

Subjective and objective findings may be limited when a patient with SCI presents with CA-UTI. These patients often lack the usual symptoms of UTI (dysuria, suprapubic discomfort, urgency, increased frequency) and pyelonephritis (flank pain, costovertebral angle tenderness). Caregivers and health care providers should be aware that nonspecific symptoms such as foul-smelling urine, pyuria, increased residual volume of urine in the bladder, change in voiding habits, worsening detrusor spasticity, and aggravation of autonomic dysreflexia can be the only initial presenting symptoms.⁵³

 

 

What is the duration of therapy for CA-UTI in SCI, and how can antibiotic stewardship principles be applied in this patient population?

Antibiotic therapy is indicated for a duration of 7 days if there is prompt resolution of symptoms, or for a total of 10 to 14 days if the response is delayed, regardless of whether the patient remains with a UC.⁵ Antibiotic stewardship is very important to reduce the risk for developing drug resistance in this high-risk population. Methods such as prescriber education practices, institution protocols, guideline implementation, auditing and feedback, restriction and reauthorization practices, computer-assisted programs, de-escalation or streamlining, and antibiotic cycling or dosage optimization have all been shown to assist in antibiotic stewardship in UTIs.⁵⁴

Candida UTI

What is the initial evaluation for a patient with candiduria?

The workup for candiduria hinges on determining whether the candiduria likely represents contamination, colonization, or infection; certain predisposing risk factors are associated with Candida UTI (Table 4).^55-57 The most important aspect to candiduria is the patient’s clinical status and comorbid conditions.⁵⁸ Among funguria, Candida species are the most common and represent 95% of organisms isolated on urine cultures (Table 5).⁵⁹ Candiduria is usually present in those with significant comorbidities and rarely is associated with healthy individuals.^59,60 Candiduria is increasing in prevalence among hospitalized patients, representing 22% to 40% of all nosocomial UTIs.^59,60 Markers in the urine (leukocyte esterase, colony count of culture growth, presence or absence of Candida casts and pseudohyphae) cannot alone differentiate colonization from infection.⁵⁵ When candiduria is discovered in a patient with symptoms related to UTI in the setting of predisposing risk factors, it should be considered a real infection until proven otherwise.

In a situation where an asymptomatic patient without an indwelling UC has Candida species isolated from a urine culture, a repeat culture (clean-catch midstream sample) should be performed to assess for a likely contaminated collection.⁵⁵ If the patient has an indwelling UC then it should be exchanged and urine collected from the fresh catheter.⁶¹ When candiduria is found in healthy asymptomatic adults, it is most commonly associated with poor collection techniques or postcollection contamination.⁵⁹ If candiduria persists in an asymptomatic patient, the patient should be assessed for predisposing factors. This includes checking hemoglobin A1C for developing diabetes and renal ultrasound looking for urolithiasis, renal abscess, hydronephrosis, and fungus ball. Postvoid residual urinary retention should also be ruled out with bladder ultrasound. Treatment of predisposing factors can lead to resolution of candiduria without antifungal treatment, and a urine culture should be repeated (1 to 2 weeks later).⁶¹ Asymptomatic patients lacking any predisposing factors can be observed with repeat urine cultures in 1 to 3 months.⁶¹

Candiduria may actually represent candidemia in those patients who have a predisposing risk factor for disseminated candidiasis. These risk factors include central venous catheters, administration of total parental nutrition, antibiotic use (especially broad spectrum), critical illness, recent surgical intervention (especially intra-abdominal), acute renal failure, nasogastric tube use, and active gastric acid suppression (ie, proton pump inhibitors).^62,63 The hematogenous spread of Candida can lead to the detection of candiduria in 46% to 80% of persons who are experiencing candidemia.⁵⁹ If the patient is at risk for candidemia, then blood fungal cultures should be drawn. It is not unreasonable to also order a serum-D-glucan assay if suspicions are high. A thorough skin assessment should be completed and ophthalmology consulted for a detailed eye exam in the event that the patient has candidemia. Candiduria is highly prevalent among those who are candidemic, but overall candidemia is encountered in less than 5% of patients in most intensive care units.⁵⁹ Thus, most patients with candiduria do not have disseminated candidiasis.

Candiduria rarely leads to symptoms of UTI,⁵⁸ unless the pathogenesis is related to an ascending process.⁵⁶ Symptoms of Candida UTI are no different from those experienced from a bacterial etiology. Some patients may complain of pneumaturia and/or endorse seeing particulate matter in their urine.⁵⁵ Patients showing signs of sepsis (fever, chills, flank pain) should be investigated for possible Candida pyelonephritis in the setting of candiduria.⁶⁴

When should asymptomatic candiduria be treated?

In adult patients with asymptomatic candiduria, there are 2 situations in which antifungal therapy is recommended. A patient undergoing a traumatic urologic procedure would be treated to avoid the risk for candidemia caused by the procedure. Also, in neutropenic patients empiric antifungal therapy should be administered because there is a high likelihood that this candiduria may actually represent hematogenous spread from candidemia.^61,65

What is the treatment for symptomatic Candida cystitis?

Empiric treatment with oral fluconazole 200 to 400 mg daily for a total of 2 weeks is recommended in patients with persisting candiduria and symptoms of cystitis.⁶⁵ Identifying the species is a crucial step in the treatment of Candida UTI. Several species (C. glabrata, C. krusei) are known to be resistant to fluconazole. Species identification and antifungal sensitivities should be done and therapy directed after obtaining these results.⁵⁵

What is the recommended treatment for Candida pyelonephritis?

Treatment for pyelonephritis caused by fluconazole-susceptible Candida species is oral fluconazole 200 to 400 mg (3-6 mg/kg) for a total of 2 weeks.⁶⁵ A fluconazole-resistant organism should be suspected when a non-albicans Candida species is isolated, such as C. krusei or C. glabrata. In this circumstance, in vitro antifungal susceptibility testing should be done. Echinocandins are not a good option in this situation because they do not reach adequate urine concentration and treatment failure is well documented.^66-68 Amphotericin B deoxycholate (AmB) 0.3 to 0.6 mg/kg daily for 1 to 7 days, with or without oral flucytosine (25 mg/kg) 4 times daily, is recommended by the IDSA for the treatment of fluconazole-resistant isolates of C. glabrata and C. krusei.⁶⁵ Further imaging with ultrasound, CT, or magnetic resonance should be done to rule out urinary tract obstruction and/or “fungus ball” formation. Emphysematous pyelonephritis and necrosis can occur and usually require nephrectomy. Perinephric abscess will need drainage, which can be accomplished through interventional radiological techniques.⁵⁵

If a “fungus ball” is suspected in the kidney, how does the management change in a patient with Candida pyelonephritis?

A fungus ball must be treated with both antifungals and surgical intervention. Antifungal therapy should be continued during the surgical removal process to avoid fungemia. Interventional radiology should be consulted and is usually the best option for removal. Fungus ball(s) can and often do cause urinary obstruction. Temporary nephrostomy tube placement may be warranted in these situations to relieve the obstruction.^55,65 AmB can be infused through the nephrostomy tube to increase local concentrations. This route of administration is not known to be nephrotoxic.⁵⁵ Fluconazole infusion through a nephrostomy tube has also been used in the successful treatment of a fungus ball.⁶⁹

Summary

Health care–associated UTIs are the most common nosocomial infection in the United States. UC placement and genitourinary manipulation or instrumentation play a major role in the development of CA-UTI. Clinicians should be aware of the appropriate and inappropriate use of UCs and their association with CA-UTI development. Removal of a UC when no longer necessary is key in prevention of CA-UTI. Treatment of asymptomatic bacteriuria is generally not indicated. A multidisciplinary approach is essential when managing chronic indwelling UCs in SCI. PCN and ureteral stenting need close monitoring, and early removal should be performed if infection is suspected.

Candiduria is an emerging nosocomial source of UTI but rarely leads to symptoms unless related to an ascending process. Proper urine collection is crucial in determining whether you are dealing with contamination, colonization, or infection. If candiduria persists in an asymptomatic individual, then further investigations should be done in regards to possible predisposing risks factors. Fluconazole is recommended for treatment of most patients with Candida UTI, while intravenous AmB is the treatment of choice for fluconazole-resistant Candida species. As we continue to take an evidence-based approach to the prevention and management of health care-associated UTI, we will likely see continued improvement in patient outcomes and overall decreased rates of infection.

Corresponding author: Norman Beatty, MD, 1501 N. Campbell Ave., Tucson, AZ 85724; [email protected].

Financial disclosures: None.

From the Division of General Internal Medicine (Dr. Venkataramani), and the Department of Pediatrics (Dr. Venkataramani and Dr. Solomon), Johns Hopkins University School of Medicine, Baltimore, MD.

In 2003, the American Academy of Pediatrics (AAP) published the recommendations of its Task Force on the Family, an initiative borne of the recognition that pediatricians have an important role in promoting well-functioning families as a means of ultimately promoting pediatric health.¹ Among the various facets of “family pediatrics” discussed in these recommendations was the practice of addressing caregiver health or health behaviors which directly impact children’s health. “Pediatricians have both opportunity and reason to take note of the health of their young patients’ parents,” declared the Task Force.¹ Now, 15 years later, despite growing evidence to support the promotion of caregiver health as a means to improve child health, pediatric providers continue to face challenges in successfully fulfilling this aspect of family pediatrics, challenges that we believe deserve the attention of adult providers and health systems.

Benefits Beyond Pediatric Preventive Care

Drawing upon evidence showing that caregiver health or health behaviors impact children’s health (the “reason” to intervene), current guidelines identify several caregiver-related issues on which pediatric providers are encouraged to focus their caregiver health promotion efforts. Specifically, Bright Futures, the AAP’s comprehensive evidence-driven resource for guidance regarding pediatric preventive care in the United States, highlights several caregiver health-related issues to be addressed during pediatric primary care visits.² For example, in recognition of the multiple detrimental effects secondhand tobacco smoke exposure has on child health,^3-5 the AAP recommends pediatrician-led parental tobacco use screening, counseling, and support of cessation efforts (including prescription of nicotine replacement therapies), practices that are also supported by the American Medical Association.^2,3,5 Similarly, in order to promote the protection of children against pertussis and influenza, Bright Futures recommends screening and encouraging caregiver immunization against these diseases.² Pediatricians are encouraged to routinely screen for maternal depression, given the far-reaching implications of caregiver mental health on children’s health,^2,6,7 and more recently the AAP has recommended screening fathers for depression in the perinatal period as well.⁸ Screening and appropriate referral for caregivers (and thereby children) exposed to intimate partner violence is another practice highlighted by the guidelines.²

Efforts have been made to expand the framework to other issues with similar potential to impact current and future generations of children, such as caregiver family planning.^2,9,10 And there exist still other issues which may be particularly well-suited to being addressed through the caregiver health promotion framework, such as follow-up care for mothers with gestational diabetes. These mothers are at high-risk for the development of type 2 diabetes and having subsequent pregnancies affected by poor glycemic control, but traditionally have had poor follow-up rates in the postpartum period and beyond.¹¹ Their regular interactions with pediatric providers resulting from the frequent visits required for their infants presents an important, and as yet untapped, opportunity to re-engage them in recommended medical care and prevent adverse outcomes for their future children as well as themselves.

The maternal gestational diabetes example highlights an important point: caregiver health promotion in pediatric settings can have direct health benefits for caregivers. As such, there are arguably additional reasons for health systems and adult providers to support the practice of caregiver health promotion in pediatric settings. First, it may represent one of the only exposures to the health care setting and health promotion activities for certain caregivers. Caregivers are often younger adults, an age-group that is less likely to have a usual source of care or access preventive services, and low-income caregivers of any age are more likely to have limited health care access. Given the frequency of routine care (12 health maintenance visits in the child’s first 3 years of life),² caregivers are likely to have more consistent access with the pediatric health care system than with the adult health care system. Therefore, pediatric visits represent an important touchpoint for these adults that could be leveraged to deliver services and further engage them with the adult health care system. Improving the reach of these services is particularly important in the era of population health where health systems, and particularly accountable care organizations, assume responsibility for the health-related outcomes of communities at large.

Second, studies exploring caregiver perspectives on pediatricians addressing their depression or tobacco use suggest that caregivers appreciate and welcome pediatrician engagement in their care.^12,13 Thus, supporting these efforts enables patient-centered care delivery. And third, caregivers may be more motivated to address their own health issues or behaviors (such as substance use) when counseled on the implications of their actions on their children’s health. To the extent such counseling is more routinely (and effectively) delivered in the pediatric setting, supporting pediatrics-based counseling efforts is also in the best interest of adult health care providers.

Challenges to Caregiver Health Promotion in Pediatric Settings

Studies suggest that a fairly broad scope of caregiver health promotion activities do occur in pediatric practice. In our survey of a nationally representative sample of children’s primary care physicians (including pediatricians, family medicine physicians, and medicine-pediatrics physicians), over three-quarters of respondents reported addressing at least 3 caregiver health issues (including maternal depression, tobacco use, family planning, influenza immunization status, intimate partner violence exposure, and caregiver health insurance status) during well-infant or well-child visits.¹⁴ At the same time, we found limited depth in practice in terms of the regularity with which caregiver issues are addressed at visits or, when applicable, services beyond screening are offered to caregivers. For example, we found that only 36% of physicians addressed caregiver exposure to intimate partner violence in at least half of the well-infant or well-child visits they conducted.¹⁴ And while the vast majority of our respondents addressed parental tobacco use with some regularity, less than 15% reported assisting parents with cessation efforts by prescribing cessation therapies. Other studies exploring practices surrounding maternal depression, intimate partner violence screening, or tobacco cessation counseling have revealed similar patterns with regards to the reach of caregiver health promotion in practices across the country.^15-18

Such variability in practice seems to stem primarily from structural and/or organizational barriers to caregiver health promotion in pediatric primary care settings, such as limited time, inability to bill for services provided to caregivers, and lack of efficient systems to refer caregivers to adult providers or services. These structural barriers could lead to attitudinal barriers (ie, pediatric physicians’ reluctance to address caregiver health). Attitudinal or physician-associated barriers may arise in instances when the caregiver health issue’s relevance to child health is less clear or expected actions are perceived as being beyond the scope of pediatric practice, raising concerns about personal effectiveness and liability. But it appears that when caregiver health issues clearly impact child health, and the role of the pediatrician is to screen and counsel in the context of pediatric implications of caregiver health or health behaviors, the majority of pediatric providers do endorse a sense of personal responsibility to address these issues. In our survey, for example, the vast majority of pediatric primary care physicians endorsed maternal depression and caregiver tobacco use as relevant to child well-being, and also endorsed a sense of personal responsibility to address these issues.¹⁹

Structural or organizational barriers thus appear to play a larger role overall in influencing caregiver health promotion practices. Various studies have characterized these barriers as they relate to caregiver health promotion, and lack of time is a paramount concern.^14,20 This is not surprising, given the multiple competing interests for a pediatrician’s time during already time-constrained well-child visits (which include growth and development assessment, anticipatory guidance provision, delivery of children’s preventive care services, and addressing any acute concerns). The time constraints may be even more acutely felt if the results of screening necessitate additional action, such as referral to relevant services. We found that a lack of referral resources or complex referral mechanisms were cited by over half of children’s primary care physicians as general barriers to caregiver health promotion, and in particular by pediatricians (versus medicine-pediatrics or family medicine physicians).¹⁴

This highlights the key difference between family medicine and caregiver health promotion in pediatrics: the latter involves addressing adult health issues in a setting where care for adults is often not provided. While some practices that see children may provide care to adults (such as family medicine or medicine-pediatrics clinics) or are co-located with adult health care providers, most pediatric practices are not integrated with adult health care settings. As a result, the “next steps” in caregiver health promotion can prove challenging to pursue, thereby limiting the beneficial impact of these activities on both child and adult health. For example, in the absence of such integration, pediatricians may find it challenging to connect mothers with positive depression screens to appropriate mental health care or parents who smoke to tobacco cessation services. In addition to leading to missed opportunities to comprehensively address caregiver health issues, such obstacles may also discourage pediatric providers from pursuing caregiver health promotion activities to begin with.

The Way Forward

How can health systems and adult health care providers support the caregiver promotion activities of pediatric primary care providers? There are several ways to enhance integration with adult practices and adult health care services. The co-location and integration of relevant caregiver-related auxiliary services at pediatric clinics is one way. In fact, when asked to identify facilitators to caregiver health promotion, pediatricians who responded to our survey most frequently endorsed the co-location of relevant providers, such as mental health professionals or social workers, as facilitators for addressing caregiver depression or intimate partner violence.¹⁴ For example, at the Harriet Lane Clinic at Johns Hopkins, the integration of a comprehensive maternal mental health team (including a part-time licensed therapist, part-time psychiatrist from an affiliated psychiatric practice, and full-time maternal case manager) has proven to be an effective, patient-oriented approach to providing services for mothers with depression.²¹ The role of health systems and adult health care providers/practices in advancing such models of care delivery is two-fold: to provide necessary staff and financial support. The latter is particularly important as many of the relevant caregiver-related services (eg, social work or case manager visits) may not generate the revenue required to support their sustained presence at pediatric sites.

Pediatric practices would also benefit from enhanced mechanisms for referral to appropriate services that are not co-located, such as tobacco cessation “quitlines.” Adopting protocolized interventions that focus on connecting parents with existing resources for their own health, such as the CEASE intervention developed for parental tobacco control in pediatrics,^22,23 is one way to streamline the referral process for pediatric practices. Another is by advancing a truly integrated electronic medical record (EMR), which enables caregiver health screenings and referral to additional services to be completed during pediatric encounters.

Finally, while only a relative minority of physicians we surveyed suggested that a lack of reimbursement for their activities served as a general barrier to caregiver health promotion, ensuring that pediatric providers are adequately compensated for their efforts on behalf of parents and guardians would undoubtedly help support their activities. Integrated EMRs could be one way to support this, particularly for services that are traditionally billed for (eg, depression screening or tobacco cessation counseling). Novel ways to reimburse pediatric providers for their contribution to adult health indicators could also be considered; for example, to the extent caregiver health promotion activities contribute to adult quality indicators (eg, postpartum depression screening rates and completion of postpartum visits) that are associated with financial rewards, health systems could consider sharing these “bonuses” among pediatric providers.

From Family Pediatrics to Family-Oriented Care

While caregiver health promotion has long been considered part of the practice of “family pediatrics,” it should more accurately be seen as an integral component of the delivery of family-oriented primary care, as it represents a novel opportunity to advance the health of not only children, but also their caregivers. Following existing preventive care guidelines, pediatricians currently engage in a variety of activities to promote child and caregiver health, but require support to more consistently and effectively address issues such as caregiver tobacco use or maternal depression. The barriers faced by pediatricians could be most effectively addressed with the engagement of adult health care providers and health systems; this includes the development of an integrated EMR that would support screening activities and referral to connect caregivers with necessary follow-up resources. Further characterizing the barriers faced in pediatric settings, and exploring how health systems could provide the necessary support to address these barriers, is crucial to realizing the potential of caregiver health promotion to have multi-generational impacts on well-being.

Corresponding author: Maya Venkataramani, MD, MPH, 2024 E. Monument St., Suite 2-502, Baltimore, MD 21287; [email protected].

Financial disclosures: None.

From the Division of General Internal Medicine (Dr. Venkataramani), and the Department of Pediatrics (Dr. Venkataramani and Dr. Solomon), Johns Hopkins University School of Medicine, Baltimore, MD.

In 2003, the American Academy of Pediatrics (AAP) published the recommendations of its Task Force on the Family, an initiative borne of the recognition that pediatricians have an important role in promoting well-functioning families as a means of ultimately promoting pediatric health.¹ Among the various facets of “family pediatrics” discussed in these recommendations was the practice of addressing caregiver health or health behaviors which directly impact children’s health. “Pediatricians have both opportunity and reason to take note of the health of their young patients’ parents,” declared the Task Force.¹ Now, 15 years later, despite growing evidence to support the promotion of caregiver health as a means to improve child health, pediatric providers continue to face challenges in successfully fulfilling this aspect of family pediatrics, challenges that we believe deserve the attention of adult providers and health systems.

Benefits Beyond Pediatric Preventive Care

Drawing upon evidence showing that caregiver health or health behaviors impact children’s health (the “reason” to intervene), current guidelines identify several caregiver-related issues on which pediatric providers are encouraged to focus their caregiver health promotion efforts. Specifically, Bright Futures, the AAP’s comprehensive evidence-driven resource for guidance regarding pediatric preventive care in the United States, highlights several caregiver health-related issues to be addressed during pediatric primary care visits.² For example, in recognition of the multiple detrimental effects secondhand tobacco smoke exposure has on child health,^3-5 the AAP recommends pediatrician-led parental tobacco use screening, counseling, and support of cessation efforts (including prescription of nicotine replacement therapies), practices that are also supported by the American Medical Association.^2,3,5 Similarly, in order to promote the protection of children against pertussis and influenza, Bright Futures recommends screening and encouraging caregiver immunization against these diseases.² Pediatricians are encouraged to routinely screen for maternal depression, given the far-reaching implications of caregiver mental health on children’s health,^2,6,7 and more recently the AAP has recommended screening fathers for depression in the perinatal period as well.⁸ Screening and appropriate referral for caregivers (and thereby children) exposed to intimate partner violence is another practice highlighted by the guidelines.²

Efforts have been made to expand the framework to other issues with similar potential to impact current and future generations of children, such as caregiver family planning.^2,9,10 And there exist still other issues which may be particularly well-suited to being addressed through the caregiver health promotion framework, such as follow-up care for mothers with gestational diabetes. These mothers are at high-risk for the development of type 2 diabetes and having subsequent pregnancies affected by poor glycemic control, but traditionally have had poor follow-up rates in the postpartum period and beyond.¹¹ Their regular interactions with pediatric providers resulting from the frequent visits required for their infants presents an important, and as yet untapped, opportunity to re-engage them in recommended medical care and prevent adverse outcomes for their future children as well as themselves.

The maternal gestational diabetes example highlights an important point: caregiver health promotion in pediatric settings can have direct health benefits for caregivers. As such, there are arguably additional reasons for health systems and adult providers to support the practice of caregiver health promotion in pediatric settings. First, it may represent one of the only exposures to the health care setting and health promotion activities for certain caregivers. Caregivers are often younger adults, an age-group that is less likely to have a usual source of care or access preventive services, and low-income caregivers of any age are more likely to have limited health care access. Given the frequency of routine care (12 health maintenance visits in the child’s first 3 years of life),² caregivers are likely to have more consistent access with the pediatric health care system than with the adult health care system. Therefore, pediatric visits represent an important touchpoint for these adults that could be leveraged to deliver services and further engage them with the adult health care system. Improving the reach of these services is particularly important in the era of population health where health systems, and particularly accountable care organizations, assume responsibility for the health-related outcomes of communities at large.

Second, studies exploring caregiver perspectives on pediatricians addressing their depression or tobacco use suggest that caregivers appreciate and welcome pediatrician engagement in their care.^12,13 Thus, supporting these efforts enables patient-centered care delivery. And third, caregivers may be more motivated to address their own health issues or behaviors (such as substance use) when counseled on the implications of their actions on their children’s health. To the extent such counseling is more routinely (and effectively) delivered in the pediatric setting, supporting pediatrics-based counseling efforts is also in the best interest of adult health care providers.

Challenges to Caregiver Health Promotion in Pediatric Settings

Studies suggest that a fairly broad scope of caregiver health promotion activities do occur in pediatric practice. In our survey of a nationally representative sample of children’s primary care physicians (including pediatricians, family medicine physicians, and medicine-pediatrics physicians), over three-quarters of respondents reported addressing at least 3 caregiver health issues (including maternal depression, tobacco use, family planning, influenza immunization status, intimate partner violence exposure, and caregiver health insurance status) during well-infant or well-child visits.¹⁴ At the same time, we found limited depth in practice in terms of the regularity with which caregiver issues are addressed at visits or, when applicable, services beyond screening are offered to caregivers. For example, we found that only 36% of physicians addressed caregiver exposure to intimate partner violence in at least half of the well-infant or well-child visits they conducted.¹⁴ And while the vast majority of our respondents addressed parental tobacco use with some regularity, less than 15% reported assisting parents with cessation efforts by prescribing cessation therapies. Other studies exploring practices surrounding maternal depression, intimate partner violence screening, or tobacco cessation counseling have revealed similar patterns with regards to the reach of caregiver health promotion in practices across the country.^15-18

Such variability in practice seems to stem primarily from structural and/or organizational barriers to caregiver health promotion in pediatric primary care settings, such as limited time, inability to bill for services provided to caregivers, and lack of efficient systems to refer caregivers to adult providers or services. These structural barriers could lead to attitudinal barriers (ie, pediatric physicians’ reluctance to address caregiver health). Attitudinal or physician-associated barriers may arise in instances when the caregiver health issue’s relevance to child health is less clear or expected actions are perceived as being beyond the scope of pediatric practice, raising concerns about personal effectiveness and liability. But it appears that when caregiver health issues clearly impact child health, and the role of the pediatrician is to screen and counsel in the context of pediatric implications of caregiver health or health behaviors, the majority of pediatric providers do endorse a sense of personal responsibility to address these issues. In our survey, for example, the vast majority of pediatric primary care physicians endorsed maternal depression and caregiver tobacco use as relevant to child well-being, and also endorsed a sense of personal responsibility to address these issues.¹⁹

Structural or organizational barriers thus appear to play a larger role overall in influencing caregiver health promotion practices. Various studies have characterized these barriers as they relate to caregiver health promotion, and lack of time is a paramount concern.^14,20 This is not surprising, given the multiple competing interests for a pediatrician’s time during already time-constrained well-child visits (which include growth and development assessment, anticipatory guidance provision, delivery of children’s preventive care services, and addressing any acute concerns). The time constraints may be even more acutely felt if the results of screening necessitate additional action, such as referral to relevant services. We found that a lack of referral resources or complex referral mechanisms were cited by over half of children’s primary care physicians as general barriers to caregiver health promotion, and in particular by pediatricians (versus medicine-pediatrics or family medicine physicians).¹⁴

This highlights the key difference between family medicine and caregiver health promotion in pediatrics: the latter involves addressing adult health issues in a setting where care for adults is often not provided. While some practices that see children may provide care to adults (such as family medicine or medicine-pediatrics clinics) or are co-located with adult health care providers, most pediatric practices are not integrated with adult health care settings. As a result, the “next steps” in caregiver health promotion can prove challenging to pursue, thereby limiting the beneficial impact of these activities on both child and adult health. For example, in the absence of such integration, pediatricians may find it challenging to connect mothers with positive depression screens to appropriate mental health care or parents who smoke to tobacco cessation services. In addition to leading to missed opportunities to comprehensively address caregiver health issues, such obstacles may also discourage pediatric providers from pursuing caregiver health promotion activities to begin with.

The Way Forward

How can health systems and adult health care providers support the caregiver promotion activities of pediatric primary care providers? There are several ways to enhance integration with adult practices and adult health care services. The co-location and integration of relevant caregiver-related auxiliary services at pediatric clinics is one way. In fact, when asked to identify facilitators to caregiver health promotion, pediatricians who responded to our survey most frequently endorsed the co-location of relevant providers, such as mental health professionals or social workers, as facilitators for addressing caregiver depression or intimate partner violence.¹⁴ For example, at the Harriet Lane Clinic at Johns Hopkins, the integration of a comprehensive maternal mental health team (including a part-time licensed therapist, part-time psychiatrist from an affiliated psychiatric practice, and full-time maternal case manager) has proven to be an effective, patient-oriented approach to providing services for mothers with depression.²¹ The role of health systems and adult health care providers/practices in advancing such models of care delivery is two-fold: to provide necessary staff and financial support. The latter is particularly important as many of the relevant caregiver-related services (eg, social work or case manager visits) may not generate the revenue required to support their sustained presence at pediatric sites.

Pediatric practices would also benefit from enhanced mechanisms for referral to appropriate services that are not co-located, such as tobacco cessation “quitlines.” Adopting protocolized interventions that focus on connecting parents with existing resources for their own health, such as the CEASE intervention developed for parental tobacco control in pediatrics,^22,23 is one way to streamline the referral process for pediatric practices. Another is by advancing a truly integrated electronic medical record (EMR), which enables caregiver health screenings and referral to additional services to be completed during pediatric encounters.

Finally, while only a relative minority of physicians we surveyed suggested that a lack of reimbursement for their activities served as a general barrier to caregiver health promotion, ensuring that pediatric providers are adequately compensated for their efforts on behalf of parents and guardians would undoubtedly help support their activities. Integrated EMRs could be one way to support this, particularly for services that are traditionally billed for (eg, depression screening or tobacco cessation counseling). Novel ways to reimburse pediatric providers for their contribution to adult health indicators could also be considered; for example, to the extent caregiver health promotion activities contribute to adult quality indicators (eg, postpartum depression screening rates and completion of postpartum visits) that are associated with financial rewards, health systems could consider sharing these “bonuses” among pediatric providers.

From Family Pediatrics to Family-Oriented Care

While caregiver health promotion has long been considered part of the practice of “family pediatrics,” it should more accurately be seen as an integral component of the delivery of family-oriented primary care, as it represents a novel opportunity to advance the health of not only children, but also their caregivers. Following existing preventive care guidelines, pediatricians currently engage in a variety of activities to promote child and caregiver health, but require support to more consistently and effectively address issues such as caregiver tobacco use or maternal depression. The barriers faced by pediatricians could be most effectively addressed with the engagement of adult health care providers and health systems; this includes the development of an integrated EMR that would support screening activities and referral to connect caregivers with necessary follow-up resources. Further characterizing the barriers faced in pediatric settings, and exploring how health systems could provide the necessary support to address these barriers, is crucial to realizing the potential of caregiver health promotion to have multi-generational impacts on well-being.

Corresponding author: Maya Venkataramani, MD, MPH, 2024 E. Monument St., Suite 2-502, Baltimore, MD 21287; [email protected].

Financial disclosures: None.

From the Division of General Internal Medicine (Dr. Venkataramani), and the Department of Pediatrics (Dr. Venkataramani and Dr. Solomon), Johns Hopkins University School of Medicine, Baltimore, MD.

In 2003, the American Academy of Pediatrics (AAP) published the recommendations of its Task Force on the Family, an initiative borne of the recognition that pediatricians have an important role in promoting well-functioning families as a means of ultimately promoting pediatric health.¹ Among the various facets of “family pediatrics” discussed in these recommendations was the practice of addressing caregiver health or health behaviors which directly impact children’s health. “Pediatricians have both opportunity and reason to take note of the health of their young patients’ parents,” declared the Task Force.¹ Now, 15 years later, despite growing evidence to support the promotion of caregiver health as a means to improve child health, pediatric providers continue to face challenges in successfully fulfilling this aspect of family pediatrics, challenges that we believe deserve the attention of adult providers and health systems.

Benefits Beyond Pediatric Preventive Care

Drawing upon evidence showing that caregiver health or health behaviors impact children’s health (the “reason” to intervene), current guidelines identify several caregiver-related issues on which pediatric providers are encouraged to focus their caregiver health promotion efforts. Specifically, Bright Futures, the AAP’s comprehensive evidence-driven resource for guidance regarding pediatric preventive care in the United States, highlights several caregiver health-related issues to be addressed during pediatric primary care visits.² For example, in recognition of the multiple detrimental effects secondhand tobacco smoke exposure has on child health,^3-5 the AAP recommends pediatrician-led parental tobacco use screening, counseling, and support of cessation efforts (including prescription of nicotine replacement therapies), practices that are also supported by the American Medical Association.^2,3,5 Similarly, in order to promote the protection of children against pertussis and influenza, Bright Futures recommends screening and encouraging caregiver immunization against these diseases.² Pediatricians are encouraged to routinely screen for maternal depression, given the far-reaching implications of caregiver mental health on children’s health,^2,6,7 and more recently the AAP has recommended screening fathers for depression in the perinatal period as well.⁸ Screening and appropriate referral for caregivers (and thereby children) exposed to intimate partner violence is another practice highlighted by the guidelines.²

Efforts have been made to expand the framework to other issues with similar potential to impact current and future generations of children, such as caregiver family planning.^2,9,10 And there exist still other issues which may be particularly well-suited to being addressed through the caregiver health promotion framework, such as follow-up care for mothers with gestational diabetes. These mothers are at high-risk for the development of type 2 diabetes and having subsequent pregnancies affected by poor glycemic control, but traditionally have had poor follow-up rates in the postpartum period and beyond.¹¹ Their regular interactions with pediatric providers resulting from the frequent visits required for their infants presents an important, and as yet untapped, opportunity to re-engage them in recommended medical care and prevent adverse outcomes for their future children as well as themselves.

The maternal gestational diabetes example highlights an important point: caregiver health promotion in pediatric settings can have direct health benefits for caregivers. As such, there are arguably additional reasons for health systems and adult providers to support the practice of caregiver health promotion in pediatric settings. First, it may represent one of the only exposures to the health care setting and health promotion activities for certain caregivers. Caregivers are often younger adults, an age-group that is less likely to have a usual source of care or access preventive services, and low-income caregivers of any age are more likely to have limited health care access. Given the frequency of routine care (12 health maintenance visits in the child’s first 3 years of life),² caregivers are likely to have more consistent access with the pediatric health care system than with the adult health care system. Therefore, pediatric visits represent an important touchpoint for these adults that could be leveraged to deliver services and further engage them with the adult health care system. Improving the reach of these services is particularly important in the era of population health where health systems, and particularly accountable care organizations, assume responsibility for the health-related outcomes of communities at large.

Second, studies exploring caregiver perspectives on pediatricians addressing their depression or tobacco use suggest that caregivers appreciate and welcome pediatrician engagement in their care.^12,13 Thus, supporting these efforts enables patient-centered care delivery. And third, caregivers may be more motivated to address their own health issues or behaviors (such as substance use) when counseled on the implications of their actions on their children’s health. To the extent such counseling is more routinely (and effectively) delivered in the pediatric setting, supporting pediatrics-based counseling efforts is also in the best interest of adult health care providers.

Challenges to Caregiver Health Promotion in Pediatric Settings

Studies suggest that a fairly broad scope of caregiver health promotion activities do occur in pediatric practice. In our survey of a nationally representative sample of children’s primary care physicians (including pediatricians, family medicine physicians, and medicine-pediatrics physicians), over three-quarters of respondents reported addressing at least 3 caregiver health issues (including maternal depression, tobacco use, family planning, influenza immunization status, intimate partner violence exposure, and caregiver health insurance status) during well-infant or well-child visits.¹⁴ At the same time, we found limited depth in practice in terms of the regularity with which caregiver issues are addressed at visits or, when applicable, services beyond screening are offered to caregivers. For example, we found that only 36% of physicians addressed caregiver exposure to intimate partner violence in at least half of the well-infant or well-child visits they conducted.¹⁴ And while the vast majority of our respondents addressed parental tobacco use with some regularity, less than 15% reported assisting parents with cessation efforts by prescribing cessation therapies. Other studies exploring practices surrounding maternal depression, intimate partner violence screening, or tobacco cessation counseling have revealed similar patterns with regards to the reach of caregiver health promotion in practices across the country.^15-18

Such variability in practice seems to stem primarily from structural and/or organizational barriers to caregiver health promotion in pediatric primary care settings, such as limited time, inability to bill for services provided to caregivers, and lack of efficient systems to refer caregivers to adult providers or services. These structural barriers could lead to attitudinal barriers (ie, pediatric physicians’ reluctance to address caregiver health). Attitudinal or physician-associated barriers may arise in instances when the caregiver health issue’s relevance to child health is less clear or expected actions are perceived as being beyond the scope of pediatric practice, raising concerns about personal effectiveness and liability. But it appears that when caregiver health issues clearly impact child health, and the role of the pediatrician is to screen and counsel in the context of pediatric implications of caregiver health or health behaviors, the majority of pediatric providers do endorse a sense of personal responsibility to address these issues. In our survey, for example, the vast majority of pediatric primary care physicians endorsed maternal depression and caregiver tobacco use as relevant to child well-being, and also endorsed a sense of personal responsibility to address these issues.¹⁹

Structural or organizational barriers thus appear to play a larger role overall in influencing caregiver health promotion practices. Various studies have characterized these barriers as they relate to caregiver health promotion, and lack of time is a paramount concern.^14,20 This is not surprising, given the multiple competing interests for a pediatrician’s time during already time-constrained well-child visits (which include growth and development assessment, anticipatory guidance provision, delivery of children’s preventive care services, and addressing any acute concerns). The time constraints may be even more acutely felt if the results of screening necessitate additional action, such as referral to relevant services. We found that a lack of referral resources or complex referral mechanisms were cited by over half of children’s primary care physicians as general barriers to caregiver health promotion, and in particular by pediatricians (versus medicine-pediatrics or family medicine physicians).¹⁴

This highlights the key difference between family medicine and caregiver health promotion in pediatrics: the latter involves addressing adult health issues in a setting where care for adults is often not provided. While some practices that see children may provide care to adults (such as family medicine or medicine-pediatrics clinics) or are co-located with adult health care providers, most pediatric practices are not integrated with adult health care settings. As a result, the “next steps” in caregiver health promotion can prove challenging to pursue, thereby limiting the beneficial impact of these activities on both child and adult health. For example, in the absence of such integration, pediatricians may find it challenging to connect mothers with positive depression screens to appropriate mental health care or parents who smoke to tobacco cessation services. In addition to leading to missed opportunities to comprehensively address caregiver health issues, such obstacles may also discourage pediatric providers from pursuing caregiver health promotion activities to begin with.

The Way Forward

How can health systems and adult health care providers support the caregiver promotion activities of pediatric primary care providers? There are several ways to enhance integration with adult practices and adult health care services. The co-location and integration of relevant caregiver-related auxiliary services at pediatric clinics is one way. In fact, when asked to identify facilitators to caregiver health promotion, pediatricians who responded to our survey most frequently endorsed the co-location of relevant providers, such as mental health professionals or social workers, as facilitators for addressing caregiver depression or intimate partner violence.¹⁴ For example, at the Harriet Lane Clinic at Johns Hopkins, the integration of a comprehensive maternal mental health team (including a part-time licensed therapist, part-time psychiatrist from an affiliated psychiatric practice, and full-time maternal case manager) has proven to be an effective, patient-oriented approach to providing services for mothers with depression.²¹ The role of health systems and adult health care providers/practices in advancing such models of care delivery is two-fold: to provide necessary staff and financial support. The latter is particularly important as many of the relevant caregiver-related services (eg, social work or case manager visits) may not generate the revenue required to support their sustained presence at pediatric sites.

Pediatric practices would also benefit from enhanced mechanisms for referral to appropriate services that are not co-located, such as tobacco cessation “quitlines.” Adopting protocolized interventions that focus on connecting parents with existing resources for their own health, such as the CEASE intervention developed for parental tobacco control in pediatrics,^22,23 is one way to streamline the referral process for pediatric practices. Another is by advancing a truly integrated electronic medical record (EMR), which enables caregiver health screenings and referral to additional services to be completed during pediatric encounters.

Finally, while only a relative minority of physicians we surveyed suggested that a lack of reimbursement for their activities served as a general barrier to caregiver health promotion, ensuring that pediatric providers are adequately compensated for their efforts on behalf of parents and guardians would undoubtedly help support their activities. Integrated EMRs could be one way to support this, particularly for services that are traditionally billed for (eg, depression screening or tobacco cessation counseling). Novel ways to reimburse pediatric providers for their contribution to adult health indicators could also be considered; for example, to the extent caregiver health promotion activities contribute to adult quality indicators (eg, postpartum depression screening rates and completion of postpartum visits) that are associated with financial rewards, health systems could consider sharing these “bonuses” among pediatric providers.

From Family Pediatrics to Family-Oriented Care

While caregiver health promotion has long been considered part of the practice of “family pediatrics,” it should more accurately be seen as an integral component of the delivery of family-oriented primary care, as it represents a novel opportunity to advance the health of not only children, but also their caregivers. Following existing preventive care guidelines, pediatricians currently engage in a variety of activities to promote child and caregiver health, but require support to more consistently and effectively address issues such as caregiver tobacco use or maternal depression. The barriers faced by pediatricians could be most effectively addressed with the engagement of adult health care providers and health systems; this includes the development of an integrated EMR that would support screening activities and referral to connect caregivers with necessary follow-up resources. Further characterizing the barriers faced in pediatric settings, and exploring how health systems could provide the necessary support to address these barriers, is crucial to realizing the potential of caregiver health promotion to have multi-generational impacts on well-being.

Corresponding author: Maya Venkataramani, MD, MPH, 2024 E. Monument St., Suite 2-502, Baltimore, MD 21287; [email protected].

Financial disclosures: None.

Study Overview

Objective. To investigate the relationship between prescription drug coverage, receipt of active myeloma therapy, and overall survival (OS) among Medicare beneficiaries with multiple myeloma.

Design. Case-control and retrospective cohort archival data research.

Setting and participants. Authors examined SEER-Medicare registry and extracted patients with histologically confirmed multiple myeloma diagnosed in the period 2006 to 2011. Availability of complete Medicare part A/B claims from 1 year before diagnosis until December 2013 was required for analysis. Patients with Medicare advantage or managed care plans did not have claims data available and hence were excluded. Beneficiaries with a diagnosis of diffuse large B-cell lymphoma (DLBCL), who typically receive parenteral drugs for lymphoma therapy, were used as a control cohort.

Main outcome measures. Association between prescription drug coverage status and OS was the primary outcome measure of interest. Authors reported 3-year restricted survival time (RMST) ratios to compare OS among the beneficiaries with different prescription drug coverages. Receipt of active myeloma therapy among beneficiaries was also studied. Relative risk, adjusting for patient and disease-related characteristics, was reported to examine receipt of active myeloma therapy.

Results. Records of 9755 Medicare beneficiaries were evaluated. Of these, 1460 (15%) had no prescription coverage at diagnosis, 3283 (34%) had part D plan prescription benefits, 3607 (37%) had sponsored prescription coverage through an employer, federal employer, or veterans plan, and 1405 (14%) had a Medicaid prescription plan. Beneficiaries without coverage had fewer comorbidities, including anemia, neuropathy, or renal disease, than those with part D prescription coverage or Medicaid. Of those without any prescription drug coverage, 41% obtained prescription plan coverage after diagnosis of myeloma by the following January. Conversely, only 19% of patients with DLBCL and no coverage obtained a prescription plan.

Patients with myeloma were followed for 4.9 years and median survival was 2.3 years, with a 3-year OS rate of 43.1% (95% confidence interval [CI], 42.1%-44.1%). Relative to the group without coverage, survival was 16% longer in the Medicare part D group and sponsored plan group (RMST 1.16; 95% CI, 1.12-1.21). Medicaid/Medicare dual beneficiaries had worse OS in both myeloma and DLBCL consistent with poor performance status and unfavorable baseline comorbidities. However, among patients with myeloma, Medicaid/Medicare dual beneficiaries had better survival (RMST 1.08; 95% CI, 1.03-1.13) compared to the group without coverage. There was no difference in OS for those with or without prescription drug coverage in the DLBCL cohort.

There were significant differences in treatment of myeloma based on types of prescription drug coverage. Due to increasing use of bortezomib following its approval by the U.S. Food and Drug Administration (FDA), parenteral chemotherapy use doubled from 24% to 48% from 2006 to 2011, and utility of active myeloma care increased from 88% to 91%. Medicare part D plan enrollees were 6% more likely to receive active myeloma care, and both Medicaid group and sponsored plan group beneficiaries were equally likely to receive active myeloma care compared to beneficiaries without prescription coverage. Medicaid enrollees were less likely to receive parenteral therapy.

Conclusion. Medicare beneficiaries with prescription drug coverage and multiple myeloma are more likely to receive myeloma therapy and have longer OS compared to those without prescription drug coverage.

Commentary

First-line therapy of multiple myeloma has evolved over the past 2 decades. Parenteral agents such as vincristine, adriamycin, dexamethasone, and cyclophosphamide and oral therapy with melphalan and prednisone were the mainstay of treatment in the past. In the past decade, the arrival of oral therapy using thalidomide or lenalidomide and parenteral therapy using bortezomib has increased OS in patients with myeloma. Most recently, a combination of lenalidomide, bortezomib, and dexamethasone has emerged as one of the frontline therapies of choice.¹ Incorporation of bortezomib or an oral immunomodulatory drug is almost universal in first-line therapy.

Oral antineoplastic therapy is increasingly being approved by the FDA and being utilized in the community. During the period 2016-2018, more than half the new FDA-approved oncology drugs were in oral formulation.² As such, access to these agents is crucial in cancer therapy. The cost of oral therapy in patients without prescription drug coverage is sometimes more than $10,000 per month, which represents a significant impediment to its adoption. Forty-three states and Washington, DC, have enacted drug parity laws that require patients to pay no more for an oral cancer treatment than they would for an infusion. However, currently there is no such federal law, and Medicare beneficiaries must participate either through part D, state Medicaid, or a sponsored program to obtain prescription drug coverage. Despite being enrolled in part D, many beneficiaries fall into the “doughnut hole” (the requirement of Part D beneficiaries with high prescription drug expenses to pay more once the total cost of their medicines reaches a certain threshold) for prescription drugs at the time of need. From 2019 onward, enrollees will see significant, yet sometimes still insufficient, coverage benefits due to ending of the doughnut hole.³ Only a very limited number of oral chemotherapy agents are covered through Medicare part B, and of those covered, only oral melphalan is used for myeloma.

The authors have acknowledged multiple limitations of their investigation, including possible unobserved clinical differences between beneficiaries. SEER-Medicare registry has limitations in obtaining individual level data and may not contain specific results of cytogenetics, laboratory risk markers, and response to therapy, which are important to determine overall outcome. A prospective evaluation may be more suitable to assess these variables independently or through a multivariate analysis in determining receipt of therapy on OS, although such a study is currently not feasible.

The indicator of active myeloma care was defined as 2 or more outpatient physician visits or receipt of parenteral chemotherapy. This definition is somewhat suboptimal, as often patients with myeloma are under surveillance and may not necessarily be receiving active treatment. Moreover, the exact prescription pattern of lenalidomide, the most active first-line oral therapy, could not be captured from this retrospective registry review. Therefore, definitive conclusions regarding use of lenalidomide and thalidomide and receipt of therapy in this population cannot be made.

A significant improvement in OS has been established using maintenance lenalidomide following high-dose chemotherapy and stem cell transplantation.⁴ Only 5% of this study population received stem cell transplantation. This may be due to a median age of 77 years at diagnosis in the group studied, higher than the 66 to 70 years previously published.⁵ Stem cell transplantation is now commonly being used even in the older population. The 3-year survival of 83% following stem cell transplantation in myeloma patients aged 75 to 84 years was nearly identical to that of the younger population.⁶ Since stem cell transplantation is feasible in older Medicare beneficiaries and maintenance lenalidomide for 2 years following transplant improves survival, the option of providing maintenance therapy with oral lenalidomide must be made available to Medicare beneficiaries. Due to a very limited use of transplantation in this study, the impact of oral lenalidomide maintenance in OS cannot be judged.

Of the patients reviewed in this study, 6% had a listed diagnosis of plasmacytoma. These individuals typically are treated with radiation therapy only. It is unclear if these patients also received any systemic myeloma therapy or if they ever progressed to myeloma. Availability of prescription drug coverage may not be relevant to this group. Also, the authors reported that part D participants were less likely to receive classic cytotoxic chemotherapy. This may be somewhat irrelevant in Medicare beneficiaries with a median age of 77 years for current practice, as frontline induction with old classic cytotoxic chemotherapy is less commonly used in this population.

Investigators have appropriately recognized a lack of ability to discern whether inferior survival in the group without prescription drug coverage was the result of not receiving therapy at all or inability to receive oral immunomodulatory drugs. There would have been little reason for not proceeding to parenteral therapy. As noted, 41% of beneficiaries without coverage at diagnosis subsequently obtained coverage but continued to have significantly worse survival. Cause of death, including whether related to myeloma, was not reported. The authors suggest that early separation of survival curves could therefore be reflective of suboptimal first-line therapy that lacked oral immunomodulatory drugs. During the study period 2006-2011, first-line use of lenalidomide was common.

Median survival of patients with myeloma in this study was only 27 months. According to the American Cancer Society, in 2018 median survival for stage I myeloma has not been reached, stage II myeloma is 83 months, and stage III myeloma is 43 months. A robust and dynamic landscape in myeloma therapy prevents a clear attribution to individual agents, whether oral or parenteral, in improving OS. Thus, 3-year RMST, while appropriate for 2006-2011, may not be relevant today.

Applications for Clinical Practice

The oncology community routinely encounters difficulty in initiating therapy using oral agents rapidly after diagnosis of myeloma. The retrospective data analyzed in the current study suggests that delay in initiating or unavailability of oral agents may adversely impact OS. The common approach of initiating parenteral therapy while awaiting approvals from payers or charity programs and subsequently adding oral therapy when available has not been studied in assessing OS. The oncology community should initiate plans to obtain prescription drug coverage through either Medicare part D, Medicaid, a sponsored plan, or financial assistance charity programs as soon as possible after diagnosis of myeloma. Moreover, continuation of these prescription drug plans should be strongly considered throughout the course of myeloma, as subsequent lines of treatment will quite likely involve other active and approved oral agents, such as pomalidomide, ixazomib, and panobinostat, besides other supportive therapy.

One of the mechanisms to obtain prescription drug coverage includes enrollment in state Medicaid programs for those who are eligible. Currently, 17 states have not yet adopted Medicaid expansion under the Affordable Care Act. Expansion of Medicaid in these states could increase availability of prescription drug benefits. In this study, 15.8% of Medicare and Medicaid dual enrollees with access to oral agents at low or no cost did not receive myeloma care, slightly higher than the 13.1% with no prescription drug coverage. Lower utilization in this population may be explained based on differences in comorbidities or socioeconomic conditions rather than availability of a prescription plan.

The incidence of myeloma is expected to be higher in Medicare beneficiaries, and according to one estimate, in 2030 and beyond nearly 75% of diagnosed myeloma patients will be aged 64 to 84 years, an increase from nearly 66% today.⁷ Changing demographics, increasing oral therapy options, and patient convenience demand attention to providing prescription drug coverage to all Medicare beneficiaries. This study lends support to that demand.

—Rakesh Gaur, MD, MPH, FACP, Cancer and Blood Center at Kansas Institute of Medicine, Lenexa, KS

Study Overview

Objective. To investigate the relationship between prescription drug coverage, receipt of active myeloma therapy, and overall survival (OS) among Medicare beneficiaries with multiple myeloma.

Design. Case-control and retrospective cohort archival data research.

Setting and participants. Authors examined SEER-Medicare registry and extracted patients with histologically confirmed multiple myeloma diagnosed in the period 2006 to 2011. Availability of complete Medicare part A/B claims from 1 year before diagnosis until December 2013 was required for analysis. Patients with Medicare advantage or managed care plans did not have claims data available and hence were excluded. Beneficiaries with a diagnosis of diffuse large B-cell lymphoma (DLBCL), who typically receive parenteral drugs for lymphoma therapy, were used as a control cohort.

Main outcome measures. Association between prescription drug coverage status and OS was the primary outcome measure of interest. Authors reported 3-year restricted survival time (RMST) ratios to compare OS among the beneficiaries with different prescription drug coverages. Receipt of active myeloma therapy among beneficiaries was also studied. Relative risk, adjusting for patient and disease-related characteristics, was reported to examine receipt of active myeloma therapy.

Results. Records of 9755 Medicare beneficiaries were evaluated. Of these, 1460 (15%) had no prescription coverage at diagnosis, 3283 (34%) had part D plan prescription benefits, 3607 (37%) had sponsored prescription coverage through an employer, federal employer, or veterans plan, and 1405 (14%) had a Medicaid prescription plan. Beneficiaries without coverage had fewer comorbidities, including anemia, neuropathy, or renal disease, than those with part D prescription coverage or Medicaid. Of those without any prescription drug coverage, 41% obtained prescription plan coverage after diagnosis of myeloma by the following January. Conversely, only 19% of patients with DLBCL and no coverage obtained a prescription plan.

Patients with myeloma were followed for 4.9 years and median survival was 2.3 years, with a 3-year OS rate of 43.1% (95% confidence interval [CI], 42.1%-44.1%). Relative to the group without coverage, survival was 16% longer in the Medicare part D group and sponsored plan group (RMST 1.16; 95% CI, 1.12-1.21). Medicaid/Medicare dual beneficiaries had worse OS in both myeloma and DLBCL consistent with poor performance status and unfavorable baseline comorbidities. However, among patients with myeloma, Medicaid/Medicare dual beneficiaries had better survival (RMST 1.08; 95% CI, 1.03-1.13) compared to the group without coverage. There was no difference in OS for those with or without prescription drug coverage in the DLBCL cohort.

There were significant differences in treatment of myeloma based on types of prescription drug coverage. Due to increasing use of bortezomib following its approval by the U.S. Food and Drug Administration (FDA), parenteral chemotherapy use doubled from 24% to 48% from 2006 to 2011, and utility of active myeloma care increased from 88% to 91%. Medicare part D plan enrollees were 6% more likely to receive active myeloma care, and both Medicaid group and sponsored plan group beneficiaries were equally likely to receive active myeloma care compared to beneficiaries without prescription coverage. Medicaid enrollees were less likely to receive parenteral therapy.

Conclusion. Medicare beneficiaries with prescription drug coverage and multiple myeloma are more likely to receive myeloma therapy and have longer OS compared to those without prescription drug coverage.

Commentary

First-line therapy of multiple myeloma has evolved over the past 2 decades. Parenteral agents such as vincristine, adriamycin, dexamethasone, and cyclophosphamide and oral therapy with melphalan and prednisone were the mainstay of treatment in the past. In the past decade, the arrival of oral therapy using thalidomide or lenalidomide and parenteral therapy using bortezomib has increased OS in patients with myeloma. Most recently, a combination of lenalidomide, bortezomib, and dexamethasone has emerged as one of the frontline therapies of choice.¹ Incorporation of bortezomib or an oral immunomodulatory drug is almost universal in first-line therapy.

Oral antineoplastic therapy is increasingly being approved by the FDA and being utilized in the community. During the period 2016-2018, more than half the new FDA-approved oncology drugs were in oral formulation.² As such, access to these agents is crucial in cancer therapy. The cost of oral therapy in patients without prescription drug coverage is sometimes more than $10,000 per month, which represents a significant impediment to its adoption. Forty-three states and Washington, DC, have enacted drug parity laws that require patients to pay no more for an oral cancer treatment than they would for an infusion. However, currently there is no such federal law, and Medicare beneficiaries must participate either through part D, state Medicaid, or a sponsored program to obtain prescription drug coverage. Despite being enrolled in part D, many beneficiaries fall into the “doughnut hole” (the requirement of Part D beneficiaries with high prescription drug expenses to pay more once the total cost of their medicines reaches a certain threshold) for prescription drugs at the time of need. From 2019 onward, enrollees will see significant, yet sometimes still insufficient, coverage benefits due to ending of the doughnut hole.³ Only a very limited number of oral chemotherapy agents are covered through Medicare part B, and of those covered, only oral melphalan is used for myeloma.

The authors have acknowledged multiple limitations of their investigation, including possible unobserved clinical differences between beneficiaries. SEER-Medicare registry has limitations in obtaining individual level data and may not contain specific results of cytogenetics, laboratory risk markers, and response to therapy, which are important to determine overall outcome. A prospective evaluation may be more suitable to assess these variables independently or through a multivariate analysis in determining receipt of therapy on OS, although such a study is currently not feasible.

The indicator of active myeloma care was defined as 2 or more outpatient physician visits or receipt of parenteral chemotherapy. This definition is somewhat suboptimal, as often patients with myeloma are under surveillance and may not necessarily be receiving active treatment. Moreover, the exact prescription pattern of lenalidomide, the most active first-line oral therapy, could not be captured from this retrospective registry review. Therefore, definitive conclusions regarding use of lenalidomide and thalidomide and receipt of therapy in this population cannot be made.

A significant improvement in OS has been established using maintenance lenalidomide following high-dose chemotherapy and stem cell transplantation.⁴ Only 5% of this study population received stem cell transplantation. This may be due to a median age of 77 years at diagnosis in the group studied, higher than the 66 to 70 years previously published.⁵ Stem cell transplantation is now commonly being used even in the older population. The 3-year survival of 83% following stem cell transplantation in myeloma patients aged 75 to 84 years was nearly identical to that of the younger population.⁶ Since stem cell transplantation is feasible in older Medicare beneficiaries and maintenance lenalidomide for 2 years following transplant improves survival, the option of providing maintenance therapy with oral lenalidomide must be made available to Medicare beneficiaries. Due to a very limited use of transplantation in this study, the impact of oral lenalidomide maintenance in OS cannot be judged.

Of the patients reviewed in this study, 6% had a listed diagnosis of plasmacytoma. These individuals typically are treated with radiation therapy only. It is unclear if these patients also received any systemic myeloma therapy or if they ever progressed to myeloma. Availability of prescription drug coverage may not be relevant to this group. Also, the authors reported that part D participants were less likely to receive classic cytotoxic chemotherapy. This may be somewhat irrelevant in Medicare beneficiaries with a median age of 77 years for current practice, as frontline induction with old classic cytotoxic chemotherapy is less commonly used in this population.

Investigators have appropriately recognized a lack of ability to discern whether inferior survival in the group without prescription drug coverage was the result of not receiving therapy at all or inability to receive oral immunomodulatory drugs. There would have been little reason for not proceeding to parenteral therapy. As noted, 41% of beneficiaries without coverage at diagnosis subsequently obtained coverage but continued to have significantly worse survival. Cause of death, including whether related to myeloma, was not reported. The authors suggest that early separation of survival curves could therefore be reflective of suboptimal first-line therapy that lacked oral immunomodulatory drugs. During the study period 2006-2011, first-line use of lenalidomide was common.

Median survival of patients with myeloma in this study was only 27 months. According to the American Cancer Society, in 2018 median survival for stage I myeloma has not been reached, stage II myeloma is 83 months, and stage III myeloma is 43 months. A robust and dynamic landscape in myeloma therapy prevents a clear attribution to individual agents, whether oral or parenteral, in improving OS. Thus, 3-year RMST, while appropriate for 2006-2011, may not be relevant today.

Applications for Clinical Practice

The oncology community routinely encounters difficulty in initiating therapy using oral agents rapidly after diagnosis of myeloma. The retrospective data analyzed in the current study suggests that delay in initiating or unavailability of oral agents may adversely impact OS. The common approach of initiating parenteral therapy while awaiting approvals from payers or charity programs and subsequently adding oral therapy when available has not been studied in assessing OS. The oncology community should initiate plans to obtain prescription drug coverage through either Medicare part D, Medicaid, a sponsored plan, or financial assistance charity programs as soon as possible after diagnosis of myeloma. Moreover, continuation of these prescription drug plans should be strongly considered throughout the course of myeloma, as subsequent lines of treatment will quite likely involve other active and approved oral agents, such as pomalidomide, ixazomib, and panobinostat, besides other supportive therapy.

One of the mechanisms to obtain prescription drug coverage includes enrollment in state Medicaid programs for those who are eligible. Currently, 17 states have not yet adopted Medicaid expansion under the Affordable Care Act. Expansion of Medicaid in these states could increase availability of prescription drug benefits. In this study, 15.8% of Medicare and Medicaid dual enrollees with access to oral agents at low or no cost did not receive myeloma care, slightly higher than the 13.1% with no prescription drug coverage. Lower utilization in this population may be explained based on differences in comorbidities or socioeconomic conditions rather than availability of a prescription plan.

The incidence of myeloma is expected to be higher in Medicare beneficiaries, and according to one estimate, in 2030 and beyond nearly 75% of diagnosed myeloma patients will be aged 64 to 84 years, an increase from nearly 66% today.⁷ Changing demographics, increasing oral therapy options, and patient convenience demand attention to providing prescription drug coverage to all Medicare beneficiaries. This study lends support to that demand.

—Rakesh Gaur, MD, MPH, FACP, Cancer and Blood Center at Kansas Institute of Medicine, Lenexa, KS

Study Overview

Objective. To investigate the relationship between prescription drug coverage, receipt of active myeloma therapy, and overall survival (OS) among Medicare beneficiaries with multiple myeloma.

Design. Case-control and retrospective cohort archival data research.

Setting and participants. Authors examined SEER-Medicare registry and extracted patients with histologically confirmed multiple myeloma diagnosed in the period 2006 to 2011. Availability of complete Medicare part A/B claims from 1 year before diagnosis until December 2013 was required for analysis. Patients with Medicare advantage or managed care plans did not have claims data available and hence were excluded. Beneficiaries with a diagnosis of diffuse large B-cell lymphoma (DLBCL), who typically receive parenteral drugs for lymphoma therapy, were used as a control cohort.

Main outcome measures. Association between prescription drug coverage status and OS was the primary outcome measure of interest. Authors reported 3-year restricted survival time (RMST) ratios to compare OS among the beneficiaries with different prescription drug coverages. Receipt of active myeloma therapy among beneficiaries was also studied. Relative risk, adjusting for patient and disease-related characteristics, was reported to examine receipt of active myeloma therapy.

Results. Records of 9755 Medicare beneficiaries were evaluated. Of these, 1460 (15%) had no prescription coverage at diagnosis, 3283 (34%) had part D plan prescription benefits, 3607 (37%) had sponsored prescription coverage through an employer, federal employer, or veterans plan, and 1405 (14%) had a Medicaid prescription plan. Beneficiaries without coverage had fewer comorbidities, including anemia, neuropathy, or renal disease, than those with part D prescription coverage or Medicaid. Of those without any prescription drug coverage, 41% obtained prescription plan coverage after diagnosis of myeloma by the following January. Conversely, only 19% of patients with DLBCL and no coverage obtained a prescription plan.

Patients with myeloma were followed for 4.9 years and median survival was 2.3 years, with a 3-year OS rate of 43.1% (95% confidence interval [CI], 42.1%-44.1%). Relative to the group without coverage, survival was 16% longer in the Medicare part D group and sponsored plan group (RMST 1.16; 95% CI, 1.12-1.21). Medicaid/Medicare dual beneficiaries had worse OS in both myeloma and DLBCL consistent with poor performance status and unfavorable baseline comorbidities. However, among patients with myeloma, Medicaid/Medicare dual beneficiaries had better survival (RMST 1.08; 95% CI, 1.03-1.13) compared to the group without coverage. There was no difference in OS for those with or without prescription drug coverage in the DLBCL cohort.

There were significant differences in treatment of myeloma based on types of prescription drug coverage. Due to increasing use of bortezomib following its approval by the U.S. Food and Drug Administration (FDA), parenteral chemotherapy use doubled from 24% to 48% from 2006 to 2011, and utility of active myeloma care increased from 88% to 91%. Medicare part D plan enrollees were 6% more likely to receive active myeloma care, and both Medicaid group and sponsored plan group beneficiaries were equally likely to receive active myeloma care compared to beneficiaries without prescription coverage. Medicaid enrollees were less likely to receive parenteral therapy.

Conclusion. Medicare beneficiaries with prescription drug coverage and multiple myeloma are more likely to receive myeloma therapy and have longer OS compared to those without prescription drug coverage.

Commentary

First-line therapy of multiple myeloma has evolved over the past 2 decades. Parenteral agents such as vincristine, adriamycin, dexamethasone, and cyclophosphamide and oral therapy with melphalan and prednisone were the mainstay of treatment in the past. In the past decade, the arrival of oral therapy using thalidomide or lenalidomide and parenteral therapy using bortezomib has increased OS in patients with myeloma. Most recently, a combination of lenalidomide, bortezomib, and dexamethasone has emerged as one of the frontline therapies of choice.¹ Incorporation of bortezomib or an oral immunomodulatory drug is almost universal in first-line therapy.

Oral antineoplastic therapy is increasingly being approved by the FDA and being utilized in the community. During the period 2016-2018, more than half the new FDA-approved oncology drugs were in oral formulation.² As such, access to these agents is crucial in cancer therapy. The cost of oral therapy in patients without prescription drug coverage is sometimes more than $10,000 per month, which represents a significant impediment to its adoption. Forty-three states and Washington, DC, have enacted drug parity laws that require patients to pay no more for an oral cancer treatment than they would for an infusion. However, currently there is no such federal law, and Medicare beneficiaries must participate either through part D, state Medicaid, or a sponsored program to obtain prescription drug coverage. Despite being enrolled in part D, many beneficiaries fall into the “doughnut hole” (the requirement of Part D beneficiaries with high prescription drug expenses to pay more once the total cost of their medicines reaches a certain threshold) for prescription drugs at the time of need. From 2019 onward, enrollees will see significant, yet sometimes still insufficient, coverage benefits due to ending of the doughnut hole.³ Only a very limited number of oral chemotherapy agents are covered through Medicare part B, and of those covered, only oral melphalan is used for myeloma.

The authors have acknowledged multiple limitations of their investigation, including possible unobserved clinical differences between beneficiaries. SEER-Medicare registry has limitations in obtaining individual level data and may not contain specific results of cytogenetics, laboratory risk markers, and response to therapy, which are important to determine overall outcome. A prospective evaluation may be more suitable to assess these variables independently or through a multivariate analysis in determining receipt of therapy on OS, although such a study is currently not feasible.

The indicator of active myeloma care was defined as 2 or more outpatient physician visits or receipt of parenteral chemotherapy. This definition is somewhat suboptimal, as often patients with myeloma are under surveillance and may not necessarily be receiving active treatment. Moreover, the exact prescription pattern of lenalidomide, the most active first-line oral therapy, could not be captured from this retrospective registry review. Therefore, definitive conclusions regarding use of lenalidomide and thalidomide and receipt of therapy in this population cannot be made.

A significant improvement in OS has been established using maintenance lenalidomide following high-dose chemotherapy and stem cell transplantation.⁴ Only 5% of this study population received stem cell transplantation. This may be due to a median age of 77 years at diagnosis in the group studied, higher than the 66 to 70 years previously published.⁵ Stem cell transplantation is now commonly being used even in the older population. The 3-year survival of 83% following stem cell transplantation in myeloma patients aged 75 to 84 years was nearly identical to that of the younger population.⁶ Since stem cell transplantation is feasible in older Medicare beneficiaries and maintenance lenalidomide for 2 years following transplant improves survival, the option of providing maintenance therapy with oral lenalidomide must be made available to Medicare beneficiaries. Due to a very limited use of transplantation in this study, the impact of oral lenalidomide maintenance in OS cannot be judged.

Of the patients reviewed in this study, 6% had a listed diagnosis of plasmacytoma. These individuals typically are treated with radiation therapy only. It is unclear if these patients also received any systemic myeloma therapy or if they ever progressed to myeloma. Availability of prescription drug coverage may not be relevant to this group. Also, the authors reported that part D participants were less likely to receive classic cytotoxic chemotherapy. This may be somewhat irrelevant in Medicare beneficiaries with a median age of 77 years for current practice, as frontline induction with old classic cytotoxic chemotherapy is less commonly used in this population.

Investigators have appropriately recognized a lack of ability to discern whether inferior survival in the group without prescription drug coverage was the result of not receiving therapy at all or inability to receive oral immunomodulatory drugs. There would have been little reason for not proceeding to parenteral therapy. As noted, 41% of beneficiaries without coverage at diagnosis subsequently obtained coverage but continued to have significantly worse survival. Cause of death, including whether related to myeloma, was not reported. The authors suggest that early separation of survival curves could therefore be reflective of suboptimal first-line therapy that lacked oral immunomodulatory drugs. During the study period 2006-2011, first-line use of lenalidomide was common.

Median survival of patients with myeloma in this study was only 27 months. According to the American Cancer Society, in 2018 median survival for stage I myeloma has not been reached, stage II myeloma is 83 months, and stage III myeloma is 43 months. A robust and dynamic landscape in myeloma therapy prevents a clear attribution to individual agents, whether oral or parenteral, in improving OS. Thus, 3-year RMST, while appropriate for 2006-2011, may not be relevant today.

Applications for Clinical Practice

The oncology community routinely encounters difficulty in initiating therapy using oral agents rapidly after diagnosis of myeloma. The retrospective data analyzed in the current study suggests that delay in initiating or unavailability of oral agents may adversely impact OS. The common approach of initiating parenteral therapy while awaiting approvals from payers or charity programs and subsequently adding oral therapy when available has not been studied in assessing OS. The oncology community should initiate plans to obtain prescription drug coverage through either Medicare part D, Medicaid, a sponsored plan, or financial assistance charity programs as soon as possible after diagnosis of myeloma. Moreover, continuation of these prescription drug plans should be strongly considered throughout the course of myeloma, as subsequent lines of treatment will quite likely involve other active and approved oral agents, such as pomalidomide, ixazomib, and panobinostat, besides other supportive therapy.

One of the mechanisms to obtain prescription drug coverage includes enrollment in state Medicaid programs for those who are eligible. Currently, 17 states have not yet adopted Medicaid expansion under the Affordable Care Act. Expansion of Medicaid in these states could increase availability of prescription drug benefits. In this study, 15.8% of Medicare and Medicaid dual enrollees with access to oral agents at low or no cost did not receive myeloma care, slightly higher than the 13.1% with no prescription drug coverage. Lower utilization in this population may be explained based on differences in comorbidities or socioeconomic conditions rather than availability of a prescription plan.

The incidence of myeloma is expected to be higher in Medicare beneficiaries, and according to one estimate, in 2030 and beyond nearly 75% of diagnosed myeloma patients will be aged 64 to 84 years, an increase from nearly 66% today.⁷ Changing demographics, increasing oral therapy options, and patient convenience demand attention to providing prescription drug coverage to all Medicare beneficiaries. This study lends support to that demand.

—Rakesh Gaur, MD, MPH, FACP, Cancer and Blood Center at Kansas Institute of Medicine, Lenexa, KS

Study Overview

Objective. To evaluate the efficacy of the combination of ibrutinib plus rituximab in patients with previously untreated or recurrent and rituximab-sensitive Waldenström macroglobulinemia.

Design. International, randomized phase 3 trial.

Setting and participants. Patients from 45 sites in 9 countries were enrolled after receiving a centrally confirmed diagnosis of Waldenström macroglobulinemia that required treatment according to current guidelines.¹ Patients who were treatment-naive or had relapsed disease were eligible. Those with relapsed disease must have demonstrated response to rituximab in the past with a duration of response of at least 12 months. Patients who were rituximab resistant or those who received rituximab within the prior 12 months were excluded.

Intervention. Patients were randomized in a 1:1 fashion to receive oral ibrutinib 420 mg once daily or placebo. All patients received rituximab 375 mg/m² at weeks 1 to 4 and 17 to 20. Treatment was continued until disease progression or intolerable adverse effects developed. Patients were stratified according to International Prognostic Scoring System for Waldenström Macroglobulinemia (IPSS) score, number of prior therapies, and performance status. Those who received placebo were permitted to crossover to receive ibrutinib at the time of progression.

Main outcome measures. The primary outcome of this study was progression-free survival (PFS). Secondary endpoints included time to next treatment, overall survival (OS), response rate, sustained hematologic improvement, quality of life, and safety. MYD88 and CXCR4 mutational status were assessed on pre-treatment bone marrow specimens.

Results. 150 patients were randomized to receive ibrutinib-rituximab (75 patients) or placebo-rituximab (75 patients). The median age was 69 years, and approximately one-third of patients were over the age of 75 years; 45% were treatment-naive. Those with relapsed disease had received a median of 2 prior treatments, and 85% of these received prior rituximab. Baseline characteristics were well balanced between the 2 groups. Mutation data was available for 136 patients enrolled, and MYD88 L265P and CXCR4 WHIM mutations were found in 85% and 36%, respectively. Rituximab therapy was completed in 93% of patients in the ibrutinib group and 71% in the placebo group.

After a median follow up of 26.5 months, the 30-month PFS was 82% in the ibrutinib group and 28% in the placebo group (median not reached vs. 20.3 months; hazard ratio 0.20, 95% confidence interval [CI] 0.11-0.38). This translated into an 80% reduction in the risk of progression or death. Overall, there was a low rate of histologic transformation to diffuse large B-cell lymphoma in the study group (2 patients in ibrutinib arm and none in placebo arm). In the treatment-naive subgroup, at 24 months the PFS rate was 84% in the ibrutinib arm compared with 59% in the placebo arm. In those with recurrent disease, the 30-month PFS was 80% in the ibrutinib arm compared with 22% in the placebo arm. Analysis across different MYD88 and CXCR4 genotypes showed consistent rates of higher PFS with ibrutinib-rituximab (Table). In addition, 30-month PFS was higher with ibrutinib regardless of IPSS score.

The 30-month OS was 94% with ibrutinib and 92% with placebo. There were 30 patients in the placebo arm that crossed over to receive ibrutinib. As assessed by the independent review committee, response rates were significantly higher with ibrutinib-rituximab (overall response rate, 92% vs. 47%). The major response rate (complete response, very good partial response, or partial response) was higher in the ibrutinib arm (72% vs. 32%). Mutation status did not affect the response rate or quality of response. Among those with at least a partial response, the median duration of response was not reached in the ibrutinib group, as compared with a median duration of response of 21.2 months in the placebo group. Serum IgM response was greater and more rapid with ibrutinib compared to placebo. Furthermore, transient increases in serum IgM levels, or “IgM flare,” was seen less frequently with the addition of ibrutinib (8% vs. 47%). No patient receiving ibrutinib required plasmapheresis. Hemoglobin response was seen more frequently with ibrutinib (73% vs. 41%).

Grade 3 or higher adverse events (AE) were seen in 60% of patients in each group. Hypertension (13% vs. 4%) and atrial fibrillation (12% vs. 1%) occurred more commonly in the ibrutinib group compared with placebo. Serious AEs were seen more frequently with ibrutinib compared to placebo (43% vs. 33%). Atrial fibrillation of any grade occurred in 15% of patients receiving ibrutinib; however, 27% of these patients had a history of atrial fibrillation prior to enrollment. Bleeding occurred more frequently with ibrutinib; however, the vast majority of these were grade 1 or grade 2. Major bleeding occurred in 3 patients in each arm. No fatal adverse events were noted in the ibrutinib group, while 3 patients in the placebo group experienced a fatal event. Discontinuation rates were similar in both arms (5% vs. 4%). Dose reduction of ibrutinib occurred in 13 patients.

Conclusion. The combination of ibrutinib and rituximab reduced the risk of disease progression by 80% compared with rituximab alone. This combination should be considered as a standard treatment option for patients with symptomatic Waldenström macroglobulinemia.

Commentary

Waldenström macroglobulinemia is a B-cell lymphoma characterized by infiltrating IgM producing clonal lymphoplasmacytic cells. Observation remains the preferred approach to asymptomatic patients; however, the presence of clinical symptoms including anemia, hyperviscosity, fatigue, or other constitutional symptoms should prompt initiation of therapy. Given the relative lack of large studies to define standard treatment strategies, rituximab monotherapy has frequently been used, with response rates of approximately 40% to 50%.^2,3 Complete responses to single-agent rituximab have not been reported. Ibrutinib is an oral Bruton tyrosine kinase (BTK) inhibitor that has shown high response rates in the relapsed setting in previous studies. A study of single-agent ibrutinib in patients with relapsed disease showed overall and major response rates of 90% and 73%, respectively.⁴ The 2-year PFS was 69%. Additionally, such studies have suggested higher response rates in patients with mutated MYD88 genotype. This data led to the approval of ibrutinib for rituximab-refractory disease. In the treatment-naive setting, at least a minor response was seen in all patients (n = 30) in a small cohort treated with ibrutinib.⁵

In the reported trial, the combination of ibrutinib plus rituximab resulted in a more robust and durable response than single-agent rituximab, with significantly prolonged PFS. Of note, the response was similar for both treatment-naive and relapsed, rituximab-sensitive patients. Interestingly, a transient increase in serum IgM level was not seen in those treated with combination ibrutinib-rituximab. Improvements in PFS and response rates were independent of IPSS score. Previous studies have suggested that response to ibrutinib is related to MYD88 and CXCR4 mutational status. For example, in a phase 2 trial of ibrutinib in previously treated patients with symptomatic disease, major response rates for MYD88 L265P/CXCR WT, MYD88 L265P/CXCR4 WHIM, and MYD88 WT/CXCR4 WT groups were 91%, 62%, and 29%, respectively.⁴ In the current study, however, responses with ibrutinib-rituximab were seen across all genotypes at similar rates. Furthermore, PFS did not differ based on mutational status.

Similar rates of grade 3 or higher AEs were observed in each arm. Atrial fibrillation did occur in 15% of patients in the ibrutinib arm, but discontinuation rates were low. In addition, bleeding complications with ibrutinib have been increasingly recognized; however, in this cohort there did not seem to be an increased risk of major bleeding, with a vast majority of the bleeding events being grade 1 or grade 2.

Applications for Clinical Practice

The combination of ibrutinib plus rituximab represents a reasonable first-line treatment for patients with Waldenstrom macroglobulinemia. Importantly, mutational status does not appear to impact response rates and thus this combination can be considered irrespective of MYD88 status.

—Daniel Isaac, DO, MS

Study Overview

Objective. To evaluate the efficacy of the combination of ibrutinib plus rituximab in patients with previously untreated or recurrent and rituximab-sensitive Waldenström macroglobulinemia.

Design. International, randomized phase 3 trial.

Setting and participants. Patients from 45 sites in 9 countries were enrolled after receiving a centrally confirmed diagnosis of Waldenström macroglobulinemia that required treatment according to current guidelines.¹ Patients who were treatment-naive or had relapsed disease were eligible. Those with relapsed disease must have demonstrated response to rituximab in the past with a duration of response of at least 12 months. Patients who were rituximab resistant or those who received rituximab within the prior 12 months were excluded.

Intervention. Patients were randomized in a 1:1 fashion to receive oral ibrutinib 420 mg once daily or placebo. All patients received rituximab 375 mg/m² at weeks 1 to 4 and 17 to 20. Treatment was continued until disease progression or intolerable adverse effects developed. Patients were stratified according to International Prognostic Scoring System for Waldenström Macroglobulinemia (IPSS) score, number of prior therapies, and performance status. Those who received placebo were permitted to crossover to receive ibrutinib at the time of progression.

Main outcome measures. The primary outcome of this study was progression-free survival (PFS). Secondary endpoints included time to next treatment, overall survival (OS), response rate, sustained hematologic improvement, quality of life, and safety. MYD88 and CXCR4 mutational status were assessed on pre-treatment bone marrow specimens.

Results. 150 patients were randomized to receive ibrutinib-rituximab (75 patients) or placebo-rituximab (75 patients). The median age was 69 years, and approximately one-third of patients were over the age of 75 years; 45% were treatment-naive. Those with relapsed disease had received a median of 2 prior treatments, and 85% of these received prior rituximab. Baseline characteristics were well balanced between the 2 groups. Mutation data was available for 136 patients enrolled, and MYD88 L265P and CXCR4 WHIM mutations were found in 85% and 36%, respectively. Rituximab therapy was completed in 93% of patients in the ibrutinib group and 71% in the placebo group.

After a median follow up of 26.5 months, the 30-month PFS was 82% in the ibrutinib group and 28% in the placebo group (median not reached vs. 20.3 months; hazard ratio 0.20, 95% confidence interval [CI] 0.11-0.38). This translated into an 80% reduction in the risk of progression or death. Overall, there was a low rate of histologic transformation to diffuse large B-cell lymphoma in the study group (2 patients in ibrutinib arm and none in placebo arm). In the treatment-naive subgroup, at 24 months the PFS rate was 84% in the ibrutinib arm compared with 59% in the placebo arm. In those with recurrent disease, the 30-month PFS was 80% in the ibrutinib arm compared with 22% in the placebo arm. Analysis across different MYD88 and CXCR4 genotypes showed consistent rates of higher PFS with ibrutinib-rituximab (Table). In addition, 30-month PFS was higher with ibrutinib regardless of IPSS score.

The 30-month OS was 94% with ibrutinib and 92% with placebo. There were 30 patients in the placebo arm that crossed over to receive ibrutinib. As assessed by the independent review committee, response rates were significantly higher with ibrutinib-rituximab (overall response rate, 92% vs. 47%). The major response rate (complete response, very good partial response, or partial response) was higher in the ibrutinib arm (72% vs. 32%). Mutation status did not affect the response rate or quality of response. Among those with at least a partial response, the median duration of response was not reached in the ibrutinib group, as compared with a median duration of response of 21.2 months in the placebo group. Serum IgM response was greater and more rapid with ibrutinib compared to placebo. Furthermore, transient increases in serum IgM levels, or “IgM flare,” was seen less frequently with the addition of ibrutinib (8% vs. 47%). No patient receiving ibrutinib required plasmapheresis. Hemoglobin response was seen more frequently with ibrutinib (73% vs. 41%).

Grade 3 or higher adverse events (AE) were seen in 60% of patients in each group. Hypertension (13% vs. 4%) and atrial fibrillation (12% vs. 1%) occurred more commonly in the ibrutinib group compared with placebo. Serious AEs were seen more frequently with ibrutinib compared to placebo (43% vs. 33%). Atrial fibrillation of any grade occurred in 15% of patients receiving ibrutinib; however, 27% of these patients had a history of atrial fibrillation prior to enrollment. Bleeding occurred more frequently with ibrutinib; however, the vast majority of these were grade 1 or grade 2. Major bleeding occurred in 3 patients in each arm. No fatal adverse events were noted in the ibrutinib group, while 3 patients in the placebo group experienced a fatal event. Discontinuation rates were similar in both arms (5% vs. 4%). Dose reduction of ibrutinib occurred in 13 patients.

Conclusion. The combination of ibrutinib and rituximab reduced the risk of disease progression by 80% compared with rituximab alone. This combination should be considered as a standard treatment option for patients with symptomatic Waldenström macroglobulinemia.

Commentary

Waldenström macroglobulinemia is a B-cell lymphoma characterized by infiltrating IgM producing clonal lymphoplasmacytic cells. Observation remains the preferred approach to asymptomatic patients; however, the presence of clinical symptoms including anemia, hyperviscosity, fatigue, or other constitutional symptoms should prompt initiation of therapy. Given the relative lack of large studies to define standard treatment strategies, rituximab monotherapy has frequently been used, with response rates of approximately 40% to 50%.^2,3 Complete responses to single-agent rituximab have not been reported. Ibrutinib is an oral Bruton tyrosine kinase (BTK) inhibitor that has shown high response rates in the relapsed setting in previous studies. A study of single-agent ibrutinib in patients with relapsed disease showed overall and major response rates of 90% and 73%, respectively.⁴ The 2-year PFS was 69%. Additionally, such studies have suggested higher response rates in patients with mutated MYD88 genotype. This data led to the approval of ibrutinib for rituximab-refractory disease. In the treatment-naive setting, at least a minor response was seen in all patients (n = 30) in a small cohort treated with ibrutinib.⁵

In the reported trial, the combination of ibrutinib plus rituximab resulted in a more robust and durable response than single-agent rituximab, with significantly prolonged PFS. Of note, the response was similar for both treatment-naive and relapsed, rituximab-sensitive patients. Interestingly, a transient increase in serum IgM level was not seen in those treated with combination ibrutinib-rituximab. Improvements in PFS and response rates were independent of IPSS score. Previous studies have suggested that response to ibrutinib is related to MYD88 and CXCR4 mutational status. For example, in a phase 2 trial of ibrutinib in previously treated patients with symptomatic disease, major response rates for MYD88 L265P/CXCR WT, MYD88 L265P/CXCR4 WHIM, and MYD88 WT/CXCR4 WT groups were 91%, 62%, and 29%, respectively.⁴ In the current study, however, responses with ibrutinib-rituximab were seen across all genotypes at similar rates. Furthermore, PFS did not differ based on mutational status.

Similar rates of grade 3 or higher AEs were observed in each arm. Atrial fibrillation did occur in 15% of patients in the ibrutinib arm, but discontinuation rates were low. In addition, bleeding complications with ibrutinib have been increasingly recognized; however, in this cohort there did not seem to be an increased risk of major bleeding, with a vast majority of the bleeding events being grade 1 or grade 2.

Applications for Clinical Practice

The combination of ibrutinib plus rituximab represents a reasonable first-line treatment for patients with Waldenstrom macroglobulinemia. Importantly, mutational status does not appear to impact response rates and thus this combination can be considered irrespective of MYD88 status.

—Daniel Isaac, DO, MS

Study Overview

Objective. To evaluate the efficacy of the combination of ibrutinib plus rituximab in patients with previously untreated or recurrent and rituximab-sensitive Waldenström macroglobulinemia.

Design. International, randomized phase 3 trial.

Setting and participants. Patients from 45 sites in 9 countries were enrolled after receiving a centrally confirmed diagnosis of Waldenström macroglobulinemia that required treatment according to current guidelines.¹ Patients who were treatment-naive or had relapsed disease were eligible. Those with relapsed disease must have demonstrated response to rituximab in the past with a duration of response of at least 12 months. Patients who were rituximab resistant or those who received rituximab within the prior 12 months were excluded.

Intervention. Patients were randomized in a 1:1 fashion to receive oral ibrutinib 420 mg once daily or placebo. All patients received rituximab 375 mg/m² at weeks 1 to 4 and 17 to 20. Treatment was continued until disease progression or intolerable adverse effects developed. Patients were stratified according to International Prognostic Scoring System for Waldenström Macroglobulinemia (IPSS) score, number of prior therapies, and performance status. Those who received placebo were permitted to crossover to receive ibrutinib at the time of progression.

Main outcome measures. The primary outcome of this study was progression-free survival (PFS). Secondary endpoints included time to next treatment, overall survival (OS), response rate, sustained hematologic improvement, quality of life, and safety. MYD88 and CXCR4 mutational status were assessed on pre-treatment bone marrow specimens.

Results. 150 patients were randomized to receive ibrutinib-rituximab (75 patients) or placebo-rituximab (75 patients). The median age was 69 years, and approximately one-third of patients were over the age of 75 years; 45% were treatment-naive. Those with relapsed disease had received a median of 2 prior treatments, and 85% of these received prior rituximab. Baseline characteristics were well balanced between the 2 groups. Mutation data was available for 136 patients enrolled, and MYD88 L265P and CXCR4 WHIM mutations were found in 85% and 36%, respectively. Rituximab therapy was completed in 93% of patients in the ibrutinib group and 71% in the placebo group.

After a median follow up of 26.5 months, the 30-month PFS was 82% in the ibrutinib group and 28% in the placebo group (median not reached vs. 20.3 months; hazard ratio 0.20, 95% confidence interval [CI] 0.11-0.38). This translated into an 80% reduction in the risk of progression or death. Overall, there was a low rate of histologic transformation to diffuse large B-cell lymphoma in the study group (2 patients in ibrutinib arm and none in placebo arm). In the treatment-naive subgroup, at 24 months the PFS rate was 84% in the ibrutinib arm compared with 59% in the placebo arm. In those with recurrent disease, the 30-month PFS was 80% in the ibrutinib arm compared with 22% in the placebo arm. Analysis across different MYD88 and CXCR4 genotypes showed consistent rates of higher PFS with ibrutinib-rituximab (Table). In addition, 30-month PFS was higher with ibrutinib regardless of IPSS score.

The 30-month OS was 94% with ibrutinib and 92% with placebo. There were 30 patients in the placebo arm that crossed over to receive ibrutinib. As assessed by the independent review committee, response rates were significantly higher with ibrutinib-rituximab (overall response rate, 92% vs. 47%). The major response rate (complete response, very good partial response, or partial response) was higher in the ibrutinib arm (72% vs. 32%). Mutation status did not affect the response rate or quality of response. Among those with at least a partial response, the median duration of response was not reached in the ibrutinib group, as compared with a median duration of response of 21.2 months in the placebo group. Serum IgM response was greater and more rapid with ibrutinib compared to placebo. Furthermore, transient increases in serum IgM levels, or “IgM flare,” was seen less frequently with the addition of ibrutinib (8% vs. 47%). No patient receiving ibrutinib required plasmapheresis. Hemoglobin response was seen more frequently with ibrutinib (73% vs. 41%).

Grade 3 or higher adverse events (AE) were seen in 60% of patients in each group. Hypertension (13% vs. 4%) and atrial fibrillation (12% vs. 1%) occurred more commonly in the ibrutinib group compared with placebo. Serious AEs were seen more frequently with ibrutinib compared to placebo (43% vs. 33%). Atrial fibrillation of any grade occurred in 15% of patients receiving ibrutinib; however, 27% of these patients had a history of atrial fibrillation prior to enrollment. Bleeding occurred more frequently with ibrutinib; however, the vast majority of these were grade 1 or grade 2. Major bleeding occurred in 3 patients in each arm. No fatal adverse events were noted in the ibrutinib group, while 3 patients in the placebo group experienced a fatal event. Discontinuation rates were similar in both arms (5% vs. 4%). Dose reduction of ibrutinib occurred in 13 patients.

Conclusion. The combination of ibrutinib and rituximab reduced the risk of disease progression by 80% compared with rituximab alone. This combination should be considered as a standard treatment option for patients with symptomatic Waldenström macroglobulinemia.

Commentary

Waldenström macroglobulinemia is a B-cell lymphoma characterized by infiltrating IgM producing clonal lymphoplasmacytic cells. Observation remains the preferred approach to asymptomatic patients; however, the presence of clinical symptoms including anemia, hyperviscosity, fatigue, or other constitutional symptoms should prompt initiation of therapy. Given the relative lack of large studies to define standard treatment strategies, rituximab monotherapy has frequently been used, with response rates of approximately 40% to 50%.^2,3 Complete responses to single-agent rituximab have not been reported. Ibrutinib is an oral Bruton tyrosine kinase (BTK) inhibitor that has shown high response rates in the relapsed setting in previous studies. A study of single-agent ibrutinib in patients with relapsed disease showed overall and major response rates of 90% and 73%, respectively.⁴ The 2-year PFS was 69%. Additionally, such studies have suggested higher response rates in patients with mutated MYD88 genotype. This data led to the approval of ibrutinib for rituximab-refractory disease. In the treatment-naive setting, at least a minor response was seen in all patients (n = 30) in a small cohort treated with ibrutinib.⁵

In the reported trial, the combination of ibrutinib plus rituximab resulted in a more robust and durable response than single-agent rituximab, with significantly prolonged PFS. Of note, the response was similar for both treatment-naive and relapsed, rituximab-sensitive patients. Interestingly, a transient increase in serum IgM level was not seen in those treated with combination ibrutinib-rituximab. Improvements in PFS and response rates were independent of IPSS score. Previous studies have suggested that response to ibrutinib is related to MYD88 and CXCR4 mutational status. For example, in a phase 2 trial of ibrutinib in previously treated patients with symptomatic disease, major response rates for MYD88 L265P/CXCR WT, MYD88 L265P/CXCR4 WHIM, and MYD88 WT/CXCR4 WT groups were 91%, 62%, and 29%, respectively.⁴ In the current study, however, responses with ibrutinib-rituximab were seen across all genotypes at similar rates. Furthermore, PFS did not differ based on mutational status.

Similar rates of grade 3 or higher AEs were observed in each arm. Atrial fibrillation did occur in 15% of patients in the ibrutinib arm, but discontinuation rates were low. In addition, bleeding complications with ibrutinib have been increasingly recognized; however, in this cohort there did not seem to be an increased risk of major bleeding, with a vast majority of the bleeding events being grade 1 or grade 2.

Applications for Clinical Practice

The combination of ibrutinib plus rituximab represents a reasonable first-line treatment for patients with Waldenstrom macroglobulinemia. Importantly, mutational status does not appear to impact response rates and thus this combination can be considered irrespective of MYD88 status.

—Daniel Isaac, DO, MS

Editor's Note

Gastroenterologists are becoming increasingly involved in the management of obesity. While prior therapy for obesity was mainly based on lifestyle changes, medication, or surgery, the new and exciting field of endoscopic bariatric and metabolic therapies has recently garnered incredible attention and momentum.

In this quarter’s In Focus article, brought to you by The New Gastroenterologist, Pichamol Jirapinyo and Christopher Thompson (Brigham and Women’s Hospital) provide an outstanding overview of the gastric and small bowel endoscopic interventions that are either already approved for use in obesity or currently being studied. This field is moving incredibly fast, and knowledge and understanding of these endoscopic therapies for obesity will undoubtedly be important for our field.

Bryson W. Katona, MD, PhD
Editor in Chief, The New Gastroenterologist

Introduction

Obesity is a rising pandemic. As of 2016, 93.3 million U.S. adults had obesity, representing 39.8% of our adult population.¹ It is estimated that approximately $147 billion is spent annually on caring for patients with obesity. Traditionally, the management of obesity includes lifestyle therapy (diet and exercise), pharmacotherapy (six Food and Drug Administration–approved medications for obesity), and bariatric surgery (sleeve gastrectomy [SG] and Roux-en-Y gastric bypass [RYGB]). Nevertheless, intensive lifestyle intervention and pharmacotherapy are associated with approximately 3.1%-6.6% total weight loss (TWL),^2-7 and bariatric surgery is associated with 20%-33.3% TWL.⁸ However, less than 2% of patients who are eligible for bariatric surgery elect to undergo surgery, leaving a large proportion of patients with obesity untreated or undertreated.⁹

Copyright Elsevier and AGA Institute (2017)

Endoscopic bariatric and metabolic therapies (EBMTs) encompass an emerging field for the treatment of obesity. In general, EBMTs are associated with greater weight loss than are lifestyle intervention and pharmacotherapy, but with a less- invasive risk profile than bariatric surgery. EBMTs may be divided into two general categories – gastric and small bowel interventions (Figure 1 and Table 1). Gastric EBMTs are effective at treating obesity, while small bowel EBMTs are effective at treating metabolic diseases with a variable weight loss profile depending on the device.^10,11

Of note, a variety of study designs (including retrospective series, prospective series, and randomized trials with and without shams) have been employed, which can affect outcomes. Therefore, weight loss comparisons among studies are challenging and should be considered in this context.
 

Gastric interventions

Currently, there are three types of EBMTs that are FDA approved and used for the treatment of obesity. These include intragastric balloons (IGBs), plications and suturing, and aspiration therapy (AT). Other technologies that are under investigation also will be briefly covered.

Intragastric balloons

An intragastric balloon is a space-occupying device that is placed in the stomach. The mechanism of action of IGBs involves delaying gastric emptying, which leads to increased satiety.¹² There are several types of IGBs available worldwide differing in techniques of placement and removal (endoscopic versus fluoroscopic versus swallowable), materials used to fill the balloon (fluid-filled versus air-filled), and the number of balloons placed (single versus duo versus three-balloon). At the time of this writing, three IGBs are approved by the FDA (Orbera, ReShape, and Obalon), all for patients with body mass indexes of 30-40 kg/m², and two others are in the process of obtaining FDA approval (Spatz and Elipse).

Orbera gastric balloon (Apollo Endosurgery, Austin, Tex.) is a single fluid-filled IGB that is endoscopically placed and removed at 6 months. The balloon is filled with 400-700 cc of saline with or without methylene blue (to identify leakage or rupture). Recently, Orbera365, which allows the balloon to stay for 12 months instead of 6 months, has become available in Europe; however, it is yet to be approved in the United States. The U.S. pivotal trial (Orbera trial) including 255 subjects (125 Orbera arm versus 130 non-sham control arm) demonstrated 10.2% TWL in the Orbera group compared with 3.3% TWL in the control group at 6 months based on intention-to-treat (ITT) analysis. This difference persisted at 12 months (6 months after explantation) with 7.6% TWL for the Orbera group versus 3.1% TWL for the control group.^13,14

ReShape integrated dual balloon system (ReShape Lifesciences, San Clemente, Calif.) consists of two connected fluid-filled balloons that are endoscopically placed and removed at 6 months. Each balloon is filled with 375-450 cc of saline mixed with methylene blue. The U.S. pivotal trial (REDUCE trial) including 326 subjects (187 ReShape arm versus 139 sham arm) demonstrated 6.8% TWL in the ReShape group compared with 3.3% TWL in the sham group at 6 months based on ITT analysis.^15,16

Obalon balloon system (Obalon Therapeutics, Carlsbad, Calif.) is a swallowable, gas-filled balloon system that requires endoscopy only for removal. During placement, a capsule is swallowed under fluoroscopic guidance. The balloon is then inflated with 250 cc of nitrogen mix gas prior to tube detachment. Up to three balloons may be swallowed sequentially at 1-month intervals. At 6 months from the first balloon placement, all balloons are removed endoscopically. The U.S. pivotal trial (SMART trial) including 366 subjects (185 Obalon arm versus 181 sham capsule arm) demonstrated 6.6% TWL in the Obalon group compared with 3.4% TWL in the sham group at 6 months based on ITT analysis.^17,18

Two other balloons that are currently under investigation in the United States are the Spatz3 adjustable balloon system (Spatz Medical, Great Neck, N.Y.) and Elipse balloon (Allurion Technologies, Wellesley, Mass.). The Spatz3 is a fluid-filled balloon that is placed and removed endoscopically. It consists of a single balloon and a connecting tube that allows volume adjustment for control of symptoms and possible augmentation of weight loss. The U.S. pivotal trial was recently completed and the data are being reviewed by the FDA. The Elipse is a swallowable fluid-filled balloon that does not require endoscopy for placement or removal. At 4 months, the balloon releases fluid allowing it to empty and pass naturally. The U.S. pivotal trial (ENLIGHTEN trial) is currently underway.

A meta-analysis of randomized controlled trials revealed improvement in most metabolic parameters (diastolic blood pressure, fasting glucose, hemoglobin A_1c, and waist circumference) following IGB compared with controls.¹⁹ Nausea and vomiting are seen in approximately 30% and should be addressed appropriately. Pooled serious adverse event (SAE) rate was 1.5%, which included migration, perforation, and death. Since 2016, 14 deaths have been reported according to the FDA MAUDE database. Corporate response was that over 295,000 balloons had been distributed worldwide with a mortality rate of less than 0.01%.²⁰
 

Plication and suturing

Currently, there are two endoscopic devices that are approved for the general indication of tissue apposition. These include the Incisionless Operating Platform (IOP) (USGI Medical, San Clemente, Calif.) and the Overstitch endoscopic suturing system (Apollo Endosurgery, Austin, Tex.). These devices are used to remodel the stomach to create a sleeve-like structure to induce weight loss.

The IOP system consists of a transport, which is a 54-Fr flexible endoscope. It consists of four working channels that accommodate a G-Prox (for tissue approximation), a G-Lix (for tissue grasping), and an ultrathin endoscope (for visualization). In April 2008, Horgan performed the first-in-human primary obesity surgery endoluminal (POSE) procedure in Argentina. The procedure involves the use of the IOP system to place plications primarily in the fundus to modify gastric accommodation.²¹ The U.S. pivotal trial (ESSENTIAL trial) including 332 subjects (221 POSE arm versus 111 sham arm) demonstrated 5.0% TWL in the POSE group compared with 1.4% in the sham group at 12 months based on ITT analysis.²² A European multicenter randomized controlled trial (MILEPOST trial) including 44 subjects (34 POSE arm versus 10 non-sham control arm) demonstrated 13.0% TWL in the POSE group compared with 5.3% TWL in the control group at 12 months.²³ A recent meta-analysis including five studies with 586 subjects showed pooled weight loss of 13.2% at 12-15 months following POSE with a pooled serious adverse event rate of 3.2%.²⁴ These included extraluminal bleeding, minor bleeding at the suture site, hepatic abscess, chest pain, nausea, vomiting, and abdominal pain. A distal POSE procedure with a new plication pattern focusing on the gastric body to augment the effect on gastric emptying has also been described.²⁵

The Overstitch is an endoscopic suturing device that is mounted on a double-channel endoscope. At the tip of the scope, there is a curved suture arm and an anchor exchange that allow the needle to pass back and forth to perform full-thickness bites. The tissue helix may also be placed through the second channel to grasp tissue. In April 2012, Thompson performed the first-in-human endoscopic sutured/sleeve gastroplasty (ESG) procedure in India, which was published together with cases performed in Panama and the Dominican Republic.^26-28 This procedure involves the use of the Overstitch device to place several sets of running sutures along the greater curvature of the stomach to create a sleeve-like structure. It is thought to delay gastric emptying and therefore increase satiety.²⁹ The largest multicenter retrospective study including 248 patients demonstrated 18.6% TWL at 2 years with 2% SAE rate including perigastric fluid collections, extraluminal hemorrhage, pulmonary embolism, pneumoperitoneum, and pneumothorax.³⁰

Aspiration therapy

Aspiration therapy (AT; Aspire Bariatrics, King of Prussia, Pa.) allows patients to remove 25%-30% of ingested calories at approximately 30 minutes after meals. AT consists of an A-tube, which is a 26-Fr gastrostomy tube with a 15-cm fenestrated drainage catheter placed endoscopically via a standard pull technique. At 1-2 weeks after A-tube placement, the tube is cut down to the skin and connected to the port prior to aspiration. AT is approved for patients with a BMI of 35-55 kg/m².³¹ The U.S. pivotal trial (PATHWAY trial) including 207 subjects (137 AT arm versus 70 non-sham control arm) demonstrated 12.1% TWL in the AT group compared to 3.5% in the control group at 12 months based on ITT analysis. The SAE rate was 3.6% including severe abdominal pain, peritonitis, prepyloric ulcer, and A-tube replacement due to skin-port malfunction.³²

Transpyloric shuttle

The transpyloric shuttle (TPS; BAROnova, Goleta, Calif.) consists of a spherical bulb that is attached to a smaller cylindrical bulb by a flexible tether. It is placed and removed endoscopically at 6 months. TPS resides across the pylorus creating intermittent obstruction that may result in delayed gastric emptying. A pilot study including 20 patients demonstrated 14.5% TWL at 6 months.³³ The U.S. pivotal trial (ENDObesity II trial) was recently completed and the data are being reviewed by the FDA.

Revision for weight regain following bariatric surgery

Weight regain is common following RYGB^34,35 and can be associated with dilation of the gastrojejunal anastomosis (GJA).³⁶ Several procedures have been developed to treat this condition by focusing on reduction of GJA size and are available in the United States (Figure 2). These procedures have level I evidence supporting their use and include transoral outlet reduction (TORe) and restorative obesity surgery endoluminal (ROSE).³⁷ TORe involves the use of the Overstitch to place sutures at the GJA. At 1 year, patients had 8.4% TWL with improvement in comorbidities.³⁸ Weight loss remained significant up to 3-5 years.^39,40 The modern ROSE procedure utilizes the IOP system to place plications at the GJA and distal gastric pouch following argon plasma coagulation (APC). A small series showed 12.4% TWL at 6 months.⁴¹ APC is also currently being investigated as a standalone therapy for weight regain in this population.

Small bowel interventions

There are several small bowel interventions, with different mechanisms of action, available internationally. Many of these are under investigation in the United States; however, none are currently FDA approved.

Duodenal-jejunal bypass liner

Duodenal-jejunal bypass liner (DJBL; GI Dynamics, Boston, Mass.) is a 60-cm fluoropolymer liner that is endoscopically placed and removed at 12 months. It is anchored at the duodenal bulb and ends at the jejunum. By excluding direct contact between chyme and the proximal small bowel, DJBL is thought to work via foregut mechanism where there is less inhibition of the incretin effect (greater increase in insulin secretion following oral glucose administration compared to intravenous glucose administration due to gut-derived factors that enhance insulin secretion) leading to improved insulin resistance. In addition, the enteral transit of chyme and bile is altered suggesting the possible role of the hindgut mechanism. The previous U.S. pivotal trial (ENDO trial) met efficacy endpoints. However, the study was stopped early by the company because of a hepatic abscess rate of 3.5%, all of which were treated conservatively.⁴² A new U.S. pivotal study is currently planned. A meta-analysis of 17 published studies, all of which were from outside the United States, demonstrated a significant decrease in hemoglobin A_1c of 1.3% and 18.9% TWL at 1 year following implantation in patients with obesity with concomitant diabetes.⁴³
 

Duodenal mucosal resurfacing

Duodenal mucosal resurfacing (Fractyl, Lexington, Mass.) involves saline lifting of the duodenal mucosa circumferentially prior to thermal ablation using an inflated balloon filled with heated water. It is hypothesized that this may reset the diseased duodenal enteroendocrine cells leading to restoration of the incretin effect. A pilot study including 39 patients with poorly controlled diabetes demonstrated a decrease in hemoglobin A_1c of 1.2%. The SAE rate was 7.7% including duodenal stenosis, all of which were treated with balloon dilation.⁴⁴ The U.S. pivotal trial is currently planned.

Gastroduodenal-jejunal bypass

Gastroduodenal-jejunal bypass (ValenTx., Hopkins, Minn.) is a 120-cm sleeve that is anchored at the gastroesophageal junction to create the anatomic changes of RYGB. It is placed and removed endoscopically with laparoscopic assistance. A pilot study including 12 patients demonstrated 35.9% excess weight loss at 12 months. Two out of 12 patients had early device removal due to intolerance and they were not included in the weight loss analysis.⁴⁵

Incisionless magnetic anastomosis system

The incisionless magnetic anastomosis system (GI Windows, West Bridgewater, Mass.) consists of self-assembling magnets that are deployed under fluoroscopic guidance through the working channel of colonoscopes to form magnetic octagons in the jejunum and ileum. After a week, a compression anastomosis is formed and the coupled magnets pass spontaneously. A pilot study including 10 patients showed 14.6% TWL and a decrease in hemoglobin A_1c of 1.9% (for patients with diabetes) at 1 year.⁴⁶ A randomized study outside the United States is currently underway.

Summary

Endoscopic bariatric and metabolic therapies are emerging as first-line treatments for obesity in many populations. They can serve as a gap therapy for patients who do not qualify for surgery, but also may have a specific role in the treatment of metabolic comorbidities. This field will continue to develop and improve with the introduction of personalized medicine leading to better patient selection, and newer combination therapies. It is time for gastroenterologists to become more involved in the management of this challenging condition.

Dr. Jirapinyo is an advanced and bariatric endoscopy fellow, Brigham and Women’s Hospital, Harvard Medical School, Boston; Dr. Thompson is director of therapeutic endoscopy, Brigham and Women’s Hospital, and associate professor of medicine, Harvard Medical School. Dr. Jirapinyo has served as a consultant for GI Dynamics and holds royalties for Endosim. Dr. Thompson has contracted research for Aspire Bariatrics, USGI Medical, Spatz, and Apollo Endosurgery; has served as a consultant for Boston Scientific, Covidien, USGI Medical, Olympus, and Fractyl; holds stocks and royalties for GI Windows and Endosim, and has served as an expert reviewer for GI Dynamics.
 

References

1. CDC. From https://www.cdc.gov/obesity/data/adult.html. Accessed on 11 September 2018.

2. Aronne LJ et al. Obesity. 2013;21:2163-71.

3. Torgerson JS et al. Diabetes Care. 2004;27:155-61.

4. Allison DB et al. Obesity. 2012;20:330-42.

5. Smith SR et al. N Engl J Med. 2010;363:245-56.

6. Apovian CM et al. Obesity. 2013;21:935-43.

7. Pi-Sunyer X et al. N Engl J Med. 2015;373:11-22.

8. Colguitt JL et al. Cochrane Database Syst Rev. 2014;8(8):CD003641.

9. Ponce J et al. Surg Obes Relat Dis. 2015;11(6):1199-200.

10. Jirapinyo P, Thompson CC et al. Clin Gastroenterol Hepatol. 2017;15(5):619-30.

11. Sullivan S et al.Gastroenterology. 2017;152(7):1791-801.

12. Gomez V et al. Obesity. 2016;24(9):1849-53.

13. Food and Drug Administration. Summary of safety and effectiveness data (SSED) ORBERA Intragastric Balloon System. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf14/P140008b.pdf. 2015:1-32.

14. Abu Dayyeh BK et al. Gastrointest Endosc. 2015;81:AB147.

15. Food and Drug Administration. Summary of safety and effectiveness data (SSED) ReShape Integrated Dual Balloon System. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf14/P140012b.pdf. 2015:1-43.

16. Ponce J et al. Surg Obes Relat Dis. 2015;11:874-81.

17. Food and Drug Administration. Summary and effectiveness data (SSED): Obalon Balloon System. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf16/P160001b.pdf. 2016:1-46.

18. Sullivan S et al. Gastroenterology. 2016;150:S1267.

19. Popov VB et al. Am J Gastroenterol. 2017;112:429-39.

20. Abu Dayyeh BK et al. Gastrointest Endosc. 2015;82(3):425-38.

21. Espinos JC et al. Obes Surg. 2013;23(9):1375-83.

22. Sullivan S et al. Obesity. 2017;25:294-301.

23. Miller K et al. Obesity Surg. 2017;27(2):310-22.

24. Jirapinyo P et al. Gastrointest Endosc. 2018;87(6):AB604-AB605.

25. Jirapinyo P, Thompson CC. Video GIE. 2018;3(10):296-300.

26. Campos J et al. SAGES 2013 Presentation. Baltimore, MD. 19 April 2013.

27. Kumar N et al. Gastroenterology. 2014;146(5):S571-2.

28. Kumar N et al. Surg Endosc. 2018;32(4):2159-64.

29. Abu Dayyeh BK et al. Clin Gastroenterol Hepatol. 2017;15:37-43.

30. Lopez-Nava G et al. Obes Surg. 2017;27(10):2649-55.

31. Food and Drug Administration. Summary of safety and effectiveness (SSED): AspireAssist. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf15/p150024b.pdf. FDA,ed,2016:1-36.

32. Thompson CC et al. Am J Gastroenterol. 2017;112:447-57.

33. SAGES abstract archives. SAGES. Available from: http://www.sages.org/meetings/annual-meeting/abstracts-archive/first-clinical-experience-with-the-transpyloric-shuttle-tpsr-device-a-non-surgical-endoscopic treatment-for-obesity-results-from-a-3-month-and-6-month-study. Accessed Sept. 12, 2018.

34. Sjostrom L et al. N Engl J Med. 2007;357:741-52.

35. Adams TD et al. N Engl J Med. 2017;377:1143-55.

36. Abu Dayyeh BK et al. Clin Gastroenterol Hepatol. 2011;9:228-33.

37. Thompson CC et al. Gastroenterology. 2013;145(1):129-37.

38. Jirapinyo P et al. Endoscopy. 2018;50(4):371-7.

39. Kumar N, Thompson CC. Gastrointest Endosc. 2016;83(4):776-9.

40. Jirapinyo P et al. Gastrointest Endosc. 2017;85(5):AB93-94.

41. Jirapinyo P, Thompson CC et al. Comparison of a novel plication technique to suturing for endoscopic outlet reduction for the treatment of weight regain after Roux-en-Y gastric bypass. Obesity Week 2018. Poster presentation.

42. Kaplan LM et al. EndoBarrier therapy is associated with glycemic improvement, weight loss and safety issues in patients with obesity and type 2 diabetes on oral anti-hyperglycemic agents (The ENDO Trial). In: Oral Presentation at the 76th American Diabetes Association (ADA) Annual Meeting: 2016 June 10-14: New Orleans. Abstract number 362-LB.

43. Jirapinyo P et al. Diabetes Care. 2018;41(5):1106-15.

44. Rajagopalan H et al. Diabetes Care. 2016;39(12):2254-61.

45. Sandler BJ et al. Surgical Endosc. 2015;29:3298-303.

46. Machytka E et al. Gastrointest Endosc. 2017;86(5):904-12.

Editor's Note

Gastroenterologists are becoming increasingly involved in the management of obesity. While prior therapy for obesity was mainly based on lifestyle changes, medication, or surgery, the new and exciting field of endoscopic bariatric and metabolic therapies has recently garnered incredible attention and momentum.

In this quarter’s In Focus article, brought to you by The New Gastroenterologist, Pichamol Jirapinyo and Christopher Thompson (Brigham and Women’s Hospital) provide an outstanding overview of the gastric and small bowel endoscopic interventions that are either already approved for use in obesity or currently being studied. This field is moving incredibly fast, and knowledge and understanding of these endoscopic therapies for obesity will undoubtedly be important for our field.

Bryson W. Katona, MD, PhD
Editor in Chief, The New Gastroenterologist

Introduction

Obesity is a rising pandemic. As of 2016, 93.3 million U.S. adults had obesity, representing 39.8% of our adult population.¹ It is estimated that approximately $147 billion is spent annually on caring for patients with obesity. Traditionally, the management of obesity includes lifestyle therapy (diet and exercise), pharmacotherapy (six Food and Drug Administration–approved medications for obesity), and bariatric surgery (sleeve gastrectomy [SG] and Roux-en-Y gastric bypass [RYGB]). Nevertheless, intensive lifestyle intervention and pharmacotherapy are associated with approximately 3.1%-6.6% total weight loss (TWL),^2-7 and bariatric surgery is associated with 20%-33.3% TWL.⁸ However, less than 2% of patients who are eligible for bariatric surgery elect to undergo surgery, leaving a large proportion of patients with obesity untreated or undertreated.⁹

Copyright Elsevier and AGA Institute (2017)

Endoscopic bariatric and metabolic therapies (EBMTs) encompass an emerging field for the treatment of obesity. In general, EBMTs are associated with greater weight loss than are lifestyle intervention and pharmacotherapy, but with a less- invasive risk profile than bariatric surgery. EBMTs may be divided into two general categories – gastric and small bowel interventions (Figure 1 and Table 1). Gastric EBMTs are effective at treating obesity, while small bowel EBMTs are effective at treating metabolic diseases with a variable weight loss profile depending on the device.^10,11

Of note, a variety of study designs (including retrospective series, prospective series, and randomized trials with and without shams) have been employed, which can affect outcomes. Therefore, weight loss comparisons among studies are challenging and should be considered in this context.
 

Gastric interventions

Currently, there are three types of EBMTs that are FDA approved and used for the treatment of obesity. These include intragastric balloons (IGBs), plications and suturing, and aspiration therapy (AT). Other technologies that are under investigation also will be briefly covered.

Intragastric balloons

An intragastric balloon is a space-occupying device that is placed in the stomach. The mechanism of action of IGBs involves delaying gastric emptying, which leads to increased satiety.¹² There are several types of IGBs available worldwide differing in techniques of placement and removal (endoscopic versus fluoroscopic versus swallowable), materials used to fill the balloon (fluid-filled versus air-filled), and the number of balloons placed (single versus duo versus three-balloon). At the time of this writing, three IGBs are approved by the FDA (Orbera, ReShape, and Obalon), all for patients with body mass indexes of 30-40 kg/m², and two others are in the process of obtaining FDA approval (Spatz and Elipse).

Orbera gastric balloon (Apollo Endosurgery, Austin, Tex.) is a single fluid-filled IGB that is endoscopically placed and removed at 6 months. The balloon is filled with 400-700 cc of saline with or without methylene blue (to identify leakage or rupture). Recently, Orbera365, which allows the balloon to stay for 12 months instead of 6 months, has become available in Europe; however, it is yet to be approved in the United States. The U.S. pivotal trial (Orbera trial) including 255 subjects (125 Orbera arm versus 130 non-sham control arm) demonstrated 10.2% TWL in the Orbera group compared with 3.3% TWL in the control group at 6 months based on intention-to-treat (ITT) analysis. This difference persisted at 12 months (6 months after explantation) with 7.6% TWL for the Orbera group versus 3.1% TWL for the control group.^13,14

ReShape integrated dual balloon system (ReShape Lifesciences, San Clemente, Calif.) consists of two connected fluid-filled balloons that are endoscopically placed and removed at 6 months. Each balloon is filled with 375-450 cc of saline mixed with methylene blue. The U.S. pivotal trial (REDUCE trial) including 326 subjects (187 ReShape arm versus 139 sham arm) demonstrated 6.8% TWL in the ReShape group compared with 3.3% TWL in the sham group at 6 months based on ITT analysis.^15,16

Obalon balloon system (Obalon Therapeutics, Carlsbad, Calif.) is a swallowable, gas-filled balloon system that requires endoscopy only for removal. During placement, a capsule is swallowed under fluoroscopic guidance. The balloon is then inflated with 250 cc of nitrogen mix gas prior to tube detachment. Up to three balloons may be swallowed sequentially at 1-month intervals. At 6 months from the first balloon placement, all balloons are removed endoscopically. The U.S. pivotal trial (SMART trial) including 366 subjects (185 Obalon arm versus 181 sham capsule arm) demonstrated 6.6% TWL in the Obalon group compared with 3.4% TWL in the sham group at 6 months based on ITT analysis.^17,18

Two other balloons that are currently under investigation in the United States are the Spatz3 adjustable balloon system (Spatz Medical, Great Neck, N.Y.) and Elipse balloon (Allurion Technologies, Wellesley, Mass.). The Spatz3 is a fluid-filled balloon that is placed and removed endoscopically. It consists of a single balloon and a connecting tube that allows volume adjustment for control of symptoms and possible augmentation of weight loss. The U.S. pivotal trial was recently completed and the data are being reviewed by the FDA. The Elipse is a swallowable fluid-filled balloon that does not require endoscopy for placement or removal. At 4 months, the balloon releases fluid allowing it to empty and pass naturally. The U.S. pivotal trial (ENLIGHTEN trial) is currently underway.

A meta-analysis of randomized controlled trials revealed improvement in most metabolic parameters (diastolic blood pressure, fasting glucose, hemoglobin A_1c, and waist circumference) following IGB compared with controls.¹⁹ Nausea and vomiting are seen in approximately 30% and should be addressed appropriately. Pooled serious adverse event (SAE) rate was 1.5%, which included migration, perforation, and death. Since 2016, 14 deaths have been reported according to the FDA MAUDE database. Corporate response was that over 295,000 balloons had been distributed worldwide with a mortality rate of less than 0.01%.²⁰
 

Plication and suturing

Currently, there are two endoscopic devices that are approved for the general indication of tissue apposition. These include the Incisionless Operating Platform (IOP) (USGI Medical, San Clemente, Calif.) and the Overstitch endoscopic suturing system (Apollo Endosurgery, Austin, Tex.). These devices are used to remodel the stomach to create a sleeve-like structure to induce weight loss.

The IOP system consists of a transport, which is a 54-Fr flexible endoscope. It consists of four working channels that accommodate a G-Prox (for tissue approximation), a G-Lix (for tissue grasping), and an ultrathin endoscope (for visualization). In April 2008, Horgan performed the first-in-human primary obesity surgery endoluminal (POSE) procedure in Argentina. The procedure involves the use of the IOP system to place plications primarily in the fundus to modify gastric accommodation.²¹ The U.S. pivotal trial (ESSENTIAL trial) including 332 subjects (221 POSE arm versus 111 sham arm) demonstrated 5.0% TWL in the POSE group compared with 1.4% in the sham group at 12 months based on ITT analysis.²² A European multicenter randomized controlled trial (MILEPOST trial) including 44 subjects (34 POSE arm versus 10 non-sham control arm) demonstrated 13.0% TWL in the POSE group compared with 5.3% TWL in the control group at 12 months.²³ A recent meta-analysis including five studies with 586 subjects showed pooled weight loss of 13.2% at 12-15 months following POSE with a pooled serious adverse event rate of 3.2%.²⁴ These included extraluminal bleeding, minor bleeding at the suture site, hepatic abscess, chest pain, nausea, vomiting, and abdominal pain. A distal POSE procedure with a new plication pattern focusing on the gastric body to augment the effect on gastric emptying has also been described.²⁵

The Overstitch is an endoscopic suturing device that is mounted on a double-channel endoscope. At the tip of the scope, there is a curved suture arm and an anchor exchange that allow the needle to pass back and forth to perform full-thickness bites. The tissue helix may also be placed through the second channel to grasp tissue. In April 2012, Thompson performed the first-in-human endoscopic sutured/sleeve gastroplasty (ESG) procedure in India, which was published together with cases performed in Panama and the Dominican Republic.^26-28 This procedure involves the use of the Overstitch device to place several sets of running sutures along the greater curvature of the stomach to create a sleeve-like structure. It is thought to delay gastric emptying and therefore increase satiety.²⁹ The largest multicenter retrospective study including 248 patients demonstrated 18.6% TWL at 2 years with 2% SAE rate including perigastric fluid collections, extraluminal hemorrhage, pulmonary embolism, pneumoperitoneum, and pneumothorax.³⁰

Aspiration therapy

Aspiration therapy (AT; Aspire Bariatrics, King of Prussia, Pa.) allows patients to remove 25%-30% of ingested calories at approximately 30 minutes after meals. AT consists of an A-tube, which is a 26-Fr gastrostomy tube with a 15-cm fenestrated drainage catheter placed endoscopically via a standard pull technique. At 1-2 weeks after A-tube placement, the tube is cut down to the skin and connected to the port prior to aspiration. AT is approved for patients with a BMI of 35-55 kg/m².³¹ The U.S. pivotal trial (PATHWAY trial) including 207 subjects (137 AT arm versus 70 non-sham control arm) demonstrated 12.1% TWL in the AT group compared to 3.5% in the control group at 12 months based on ITT analysis. The SAE rate was 3.6% including severe abdominal pain, peritonitis, prepyloric ulcer, and A-tube replacement due to skin-port malfunction.³²

Transpyloric shuttle

The transpyloric shuttle (TPS; BAROnova, Goleta, Calif.) consists of a spherical bulb that is attached to a smaller cylindrical bulb by a flexible tether. It is placed and removed endoscopically at 6 months. TPS resides across the pylorus creating intermittent obstruction that may result in delayed gastric emptying. A pilot study including 20 patients demonstrated 14.5% TWL at 6 months.³³ The U.S. pivotal trial (ENDObesity II trial) was recently completed and the data are being reviewed by the FDA.

Revision for weight regain following bariatric surgery

Weight regain is common following RYGB^34,35 and can be associated with dilation of the gastrojejunal anastomosis (GJA).³⁶ Several procedures have been developed to treat this condition by focusing on reduction of GJA size and are available in the United States (Figure 2). These procedures have level I evidence supporting their use and include transoral outlet reduction (TORe) and restorative obesity surgery endoluminal (ROSE).³⁷ TORe involves the use of the Overstitch to place sutures at the GJA. At 1 year, patients had 8.4% TWL with improvement in comorbidities.³⁸ Weight loss remained significant up to 3-5 years.^39,40 The modern ROSE procedure utilizes the IOP system to place plications at the GJA and distal gastric pouch following argon plasma coagulation (APC). A small series showed 12.4% TWL at 6 months.⁴¹ APC is also currently being investigated as a standalone therapy for weight regain in this population.

Small bowel interventions

There are several small bowel interventions, with different mechanisms of action, available internationally. Many of these are under investigation in the United States; however, none are currently FDA approved.

Duodenal-jejunal bypass liner

Duodenal-jejunal bypass liner (DJBL; GI Dynamics, Boston, Mass.) is a 60-cm fluoropolymer liner that is endoscopically placed and removed at 12 months. It is anchored at the duodenal bulb and ends at the jejunum. By excluding direct contact between chyme and the proximal small bowel, DJBL is thought to work via foregut mechanism where there is less inhibition of the incretin effect (greater increase in insulin secretion following oral glucose administration compared to intravenous glucose administration due to gut-derived factors that enhance insulin secretion) leading to improved insulin resistance. In addition, the enteral transit of chyme and bile is altered suggesting the possible role of the hindgut mechanism. The previous U.S. pivotal trial (ENDO trial) met efficacy endpoints. However, the study was stopped early by the company because of a hepatic abscess rate of 3.5%, all of which were treated conservatively.⁴² A new U.S. pivotal study is currently planned. A meta-analysis of 17 published studies, all of which were from outside the United States, demonstrated a significant decrease in hemoglobin A_1c of 1.3% and 18.9% TWL at 1 year following implantation in patients with obesity with concomitant diabetes.⁴³
 

Duodenal mucosal resurfacing

Duodenal mucosal resurfacing (Fractyl, Lexington, Mass.) involves saline lifting of the duodenal mucosa circumferentially prior to thermal ablation using an inflated balloon filled with heated water. It is hypothesized that this may reset the diseased duodenal enteroendocrine cells leading to restoration of the incretin effect. A pilot study including 39 patients with poorly controlled diabetes demonstrated a decrease in hemoglobin A_1c of 1.2%. The SAE rate was 7.7% including duodenal stenosis, all of which were treated with balloon dilation.⁴⁴ The U.S. pivotal trial is currently planned.

Gastroduodenal-jejunal bypass

Gastroduodenal-jejunal bypass (ValenTx., Hopkins, Minn.) is a 120-cm sleeve that is anchored at the gastroesophageal junction to create the anatomic changes of RYGB. It is placed and removed endoscopically with laparoscopic assistance. A pilot study including 12 patients demonstrated 35.9% excess weight loss at 12 months. Two out of 12 patients had early device removal due to intolerance and they were not included in the weight loss analysis.⁴⁵

Incisionless magnetic anastomosis system

The incisionless magnetic anastomosis system (GI Windows, West Bridgewater, Mass.) consists of self-assembling magnets that are deployed under fluoroscopic guidance through the working channel of colonoscopes to form magnetic octagons in the jejunum and ileum. After a week, a compression anastomosis is formed and the coupled magnets pass spontaneously. A pilot study including 10 patients showed 14.6% TWL and a decrease in hemoglobin A_1c of 1.9% (for patients with diabetes) at 1 year.⁴⁶ A randomized study outside the United States is currently underway.

Summary

Endoscopic bariatric and metabolic therapies are emerging as first-line treatments for obesity in many populations. They can serve as a gap therapy for patients who do not qualify for surgery, but also may have a specific role in the treatment of metabolic comorbidities. This field will continue to develop and improve with the introduction of personalized medicine leading to better patient selection, and newer combination therapies. It is time for gastroenterologists to become more involved in the management of this challenging condition.

Dr. Jirapinyo is an advanced and bariatric endoscopy fellow, Brigham and Women’s Hospital, Harvard Medical School, Boston; Dr. Thompson is director of therapeutic endoscopy, Brigham and Women’s Hospital, and associate professor of medicine, Harvard Medical School. Dr. Jirapinyo has served as a consultant for GI Dynamics and holds royalties for Endosim. Dr. Thompson has contracted research for Aspire Bariatrics, USGI Medical, Spatz, and Apollo Endosurgery; has served as a consultant for Boston Scientific, Covidien, USGI Medical, Olympus, and Fractyl; holds stocks and royalties for GI Windows and Endosim, and has served as an expert reviewer for GI Dynamics.
 

References

1. CDC. From https://www.cdc.gov/obesity/data/adult.html. Accessed on 11 September 2018.

2. Aronne LJ et al. Obesity. 2013;21:2163-71.

3. Torgerson JS et al. Diabetes Care. 2004;27:155-61.

4. Allison DB et al. Obesity. 2012;20:330-42.

5. Smith SR et al. N Engl J Med. 2010;363:245-56.

6. Apovian CM et al. Obesity. 2013;21:935-43.

7. Pi-Sunyer X et al. N Engl J Med. 2015;373:11-22.

8. Colguitt JL et al. Cochrane Database Syst Rev. 2014;8(8):CD003641.

9. Ponce J et al. Surg Obes Relat Dis. 2015;11(6):1199-200.

10. Jirapinyo P, Thompson CC et al. Clin Gastroenterol Hepatol. 2017;15(5):619-30.

11. Sullivan S et al.Gastroenterology. 2017;152(7):1791-801.

12. Gomez V et al. Obesity. 2016;24(9):1849-53.

13. Food and Drug Administration. Summary of safety and effectiveness data (SSED) ORBERA Intragastric Balloon System. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf14/P140008b.pdf. 2015:1-32.

14. Abu Dayyeh BK et al. Gastrointest Endosc. 2015;81:AB147.

15. Food and Drug Administration. Summary of safety and effectiveness data (SSED) ReShape Integrated Dual Balloon System. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf14/P140012b.pdf. 2015:1-43.

16. Ponce J et al. Surg Obes Relat Dis. 2015;11:874-81.

17. Food and Drug Administration. Summary and effectiveness data (SSED): Obalon Balloon System. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf16/P160001b.pdf. 2016:1-46.

18. Sullivan S et al. Gastroenterology. 2016;150:S1267.

19. Popov VB et al. Am J Gastroenterol. 2017;112:429-39.

20. Abu Dayyeh BK et al. Gastrointest Endosc. 2015;82(3):425-38.

21. Espinos JC et al. Obes Surg. 2013;23(9):1375-83.

22. Sullivan S et al. Obesity. 2017;25:294-301.

23. Miller K et al. Obesity Surg. 2017;27(2):310-22.

24. Jirapinyo P et al. Gastrointest Endosc. 2018;87(6):AB604-AB605.

25. Jirapinyo P, Thompson CC. Video GIE. 2018;3(10):296-300.

26. Campos J et al. SAGES 2013 Presentation. Baltimore, MD. 19 April 2013.

27. Kumar N et al. Gastroenterology. 2014;146(5):S571-2.

28. Kumar N et al. Surg Endosc. 2018;32(4):2159-64.

29. Abu Dayyeh BK et al. Clin Gastroenterol Hepatol. 2017;15:37-43.

30. Lopez-Nava G et al. Obes Surg. 2017;27(10):2649-55.

31. Food and Drug Administration. Summary of safety and effectiveness (SSED): AspireAssist. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf15/p150024b.pdf. FDA,ed,2016:1-36.

32. Thompson CC et al. Am J Gastroenterol. 2017;112:447-57.

33. SAGES abstract archives. SAGES. Available from: http://www.sages.org/meetings/annual-meeting/abstracts-archive/first-clinical-experience-with-the-transpyloric-shuttle-tpsr-device-a-non-surgical-endoscopic treatment-for-obesity-results-from-a-3-month-and-6-month-study. Accessed Sept. 12, 2018.

34. Sjostrom L et al. N Engl J Med. 2007;357:741-52.

35. Adams TD et al. N Engl J Med. 2017;377:1143-55.

36. Abu Dayyeh BK et al. Clin Gastroenterol Hepatol. 2011;9:228-33.

37. Thompson CC et al. Gastroenterology. 2013;145(1):129-37.

38. Jirapinyo P et al. Endoscopy. 2018;50(4):371-7.

39. Kumar N, Thompson CC. Gastrointest Endosc. 2016;83(4):776-9.

40. Jirapinyo P et al. Gastrointest Endosc. 2017;85(5):AB93-94.

41. Jirapinyo P, Thompson CC et al. Comparison of a novel plication technique to suturing for endoscopic outlet reduction for the treatment of weight regain after Roux-en-Y gastric bypass. Obesity Week 2018. Poster presentation.

42. Kaplan LM et al. EndoBarrier therapy is associated with glycemic improvement, weight loss and safety issues in patients with obesity and type 2 diabetes on oral anti-hyperglycemic agents (The ENDO Trial). In: Oral Presentation at the 76th American Diabetes Association (ADA) Annual Meeting: 2016 June 10-14: New Orleans. Abstract number 362-LB.

43. Jirapinyo P et al. Diabetes Care. 2018;41(5):1106-15.

44. Rajagopalan H et al. Diabetes Care. 2016;39(12):2254-61.

45. Sandler BJ et al. Surgical Endosc. 2015;29:3298-303.

46. Machytka E et al. Gastrointest Endosc. 2017;86(5):904-12.

Editor's Note

Gastroenterologists are becoming increasingly involved in the management of obesity. While prior therapy for obesity was mainly based on lifestyle changes, medication, or surgery, the new and exciting field of endoscopic bariatric and metabolic therapies has recently garnered incredible attention and momentum.

In this quarter’s In Focus article, brought to you by The New Gastroenterologist, Pichamol Jirapinyo and Christopher Thompson (Brigham and Women’s Hospital) provide an outstanding overview of the gastric and small bowel endoscopic interventions that are either already approved for use in obesity or currently being studied. This field is moving incredibly fast, and knowledge and understanding of these endoscopic therapies for obesity will undoubtedly be important for our field.

Bryson W. Katona, MD, PhD
Editor in Chief, The New Gastroenterologist

Introduction

Obesity is a rising pandemic. As of 2016, 93.3 million U.S. adults had obesity, representing 39.8% of our adult population.¹ It is estimated that approximately $147 billion is spent annually on caring for patients with obesity. Traditionally, the management of obesity includes lifestyle therapy (diet and exercise), pharmacotherapy (six Food and Drug Administration–approved medications for obesity), and bariatric surgery (sleeve gastrectomy [SG] and Roux-en-Y gastric bypass [RYGB]). Nevertheless, intensive lifestyle intervention and pharmacotherapy are associated with approximately 3.1%-6.6% total weight loss (TWL),^2-7 and bariatric surgery is associated with 20%-33.3% TWL.⁸ However, less than 2% of patients who are eligible for bariatric surgery elect to undergo surgery, leaving a large proportion of patients with obesity untreated or undertreated.⁹

Copyright Elsevier and AGA Institute (2017)

Endoscopic bariatric and metabolic therapies (EBMTs) encompass an emerging field for the treatment of obesity. In general, EBMTs are associated with greater weight loss than are lifestyle intervention and pharmacotherapy, but with a less- invasive risk profile than bariatric surgery. EBMTs may be divided into two general categories – gastric and small bowel interventions (Figure 1 and Table 1). Gastric EBMTs are effective at treating obesity, while small bowel EBMTs are effective at treating metabolic diseases with a variable weight loss profile depending on the device.^10,11

Of note, a variety of study designs (including retrospective series, prospective series, and randomized trials with and without shams) have been employed, which can affect outcomes. Therefore, weight loss comparisons among studies are challenging and should be considered in this context.
 

Gastric interventions

Currently, there are three types of EBMTs that are FDA approved and used for the treatment of obesity. These include intragastric balloons (IGBs), plications and suturing, and aspiration therapy (AT). Other technologies that are under investigation also will be briefly covered.

Intragastric balloons

An intragastric balloon is a space-occupying device that is placed in the stomach. The mechanism of action of IGBs involves delaying gastric emptying, which leads to increased satiety.¹² There are several types of IGBs available worldwide differing in techniques of placement and removal (endoscopic versus fluoroscopic versus swallowable), materials used to fill the balloon (fluid-filled versus air-filled), and the number of balloons placed (single versus duo versus three-balloon). At the time of this writing, three IGBs are approved by the FDA (Orbera, ReShape, and Obalon), all for patients with body mass indexes of 30-40 kg/m², and two others are in the process of obtaining FDA approval (Spatz and Elipse).

Orbera gastric balloon (Apollo Endosurgery, Austin, Tex.) is a single fluid-filled IGB that is endoscopically placed and removed at 6 months. The balloon is filled with 400-700 cc of saline with or without methylene blue (to identify leakage or rupture). Recently, Orbera365, which allows the balloon to stay for 12 months instead of 6 months, has become available in Europe; however, it is yet to be approved in the United States. The U.S. pivotal trial (Orbera trial) including 255 subjects (125 Orbera arm versus 130 non-sham control arm) demonstrated 10.2% TWL in the Orbera group compared with 3.3% TWL in the control group at 6 months based on intention-to-treat (ITT) analysis. This difference persisted at 12 months (6 months after explantation) with 7.6% TWL for the Orbera group versus 3.1% TWL for the control group.^13,14

ReShape integrated dual balloon system (ReShape Lifesciences, San Clemente, Calif.) consists of two connected fluid-filled balloons that are endoscopically placed and removed at 6 months. Each balloon is filled with 375-450 cc of saline mixed with methylene blue. The U.S. pivotal trial (REDUCE trial) including 326 subjects (187 ReShape arm versus 139 sham arm) demonstrated 6.8% TWL in the ReShape group compared with 3.3% TWL in the sham group at 6 months based on ITT analysis.^15,16

Obalon balloon system (Obalon Therapeutics, Carlsbad, Calif.) is a swallowable, gas-filled balloon system that requires endoscopy only for removal. During placement, a capsule is swallowed under fluoroscopic guidance. The balloon is then inflated with 250 cc of nitrogen mix gas prior to tube detachment. Up to three balloons may be swallowed sequentially at 1-month intervals. At 6 months from the first balloon placement, all balloons are removed endoscopically. The U.S. pivotal trial (SMART trial) including 366 subjects (185 Obalon arm versus 181 sham capsule arm) demonstrated 6.6% TWL in the Obalon group compared with 3.4% TWL in the sham group at 6 months based on ITT analysis.^17,18

Two other balloons that are currently under investigation in the United States are the Spatz3 adjustable balloon system (Spatz Medical, Great Neck, N.Y.) and Elipse balloon (Allurion Technologies, Wellesley, Mass.). The Spatz3 is a fluid-filled balloon that is placed and removed endoscopically. It consists of a single balloon and a connecting tube that allows volume adjustment for control of symptoms and possible augmentation of weight loss. The U.S. pivotal trial was recently completed and the data are being reviewed by the FDA. The Elipse is a swallowable fluid-filled balloon that does not require endoscopy for placement or removal. At 4 months, the balloon releases fluid allowing it to empty and pass naturally. The U.S. pivotal trial (ENLIGHTEN trial) is currently underway.

A meta-analysis of randomized controlled trials revealed improvement in most metabolic parameters (diastolic blood pressure, fasting glucose, hemoglobin A_1c, and waist circumference) following IGB compared with controls.¹⁹ Nausea and vomiting are seen in approximately 30% and should be addressed appropriately. Pooled serious adverse event (SAE) rate was 1.5%, which included migration, perforation, and death. Since 2016, 14 deaths have been reported according to the FDA MAUDE database. Corporate response was that over 295,000 balloons had been distributed worldwide with a mortality rate of less than 0.01%.²⁰
 

Plication and suturing

Currently, there are two endoscopic devices that are approved for the general indication of tissue apposition. These include the Incisionless Operating Platform (IOP) (USGI Medical, San Clemente, Calif.) and the Overstitch endoscopic suturing system (Apollo Endosurgery, Austin, Tex.). These devices are used to remodel the stomach to create a sleeve-like structure to induce weight loss.

The IOP system consists of a transport, which is a 54-Fr flexible endoscope. It consists of four working channels that accommodate a G-Prox (for tissue approximation), a G-Lix (for tissue grasping), and an ultrathin endoscope (for visualization). In April 2008, Horgan performed the first-in-human primary obesity surgery endoluminal (POSE) procedure in Argentina. The procedure involves the use of the IOP system to place plications primarily in the fundus to modify gastric accommodation.²¹ The U.S. pivotal trial (ESSENTIAL trial) including 332 subjects (221 POSE arm versus 111 sham arm) demonstrated 5.0% TWL in the POSE group compared with 1.4% in the sham group at 12 months based on ITT analysis.²² A European multicenter randomized controlled trial (MILEPOST trial) including 44 subjects (34 POSE arm versus 10 non-sham control arm) demonstrated 13.0% TWL in the POSE group compared with 5.3% TWL in the control group at 12 months.²³ A recent meta-analysis including five studies with 586 subjects showed pooled weight loss of 13.2% at 12-15 months following POSE with a pooled serious adverse event rate of 3.2%.²⁴ These included extraluminal bleeding, minor bleeding at the suture site, hepatic abscess, chest pain, nausea, vomiting, and abdominal pain. A distal POSE procedure with a new plication pattern focusing on the gastric body to augment the effect on gastric emptying has also been described.²⁵

The Overstitch is an endoscopic suturing device that is mounted on a double-channel endoscope. At the tip of the scope, there is a curved suture arm and an anchor exchange that allow the needle to pass back and forth to perform full-thickness bites. The tissue helix may also be placed through the second channel to grasp tissue. In April 2012, Thompson performed the first-in-human endoscopic sutured/sleeve gastroplasty (ESG) procedure in India, which was published together with cases performed in Panama and the Dominican Republic.^26-28 This procedure involves the use of the Overstitch device to place several sets of running sutures along the greater curvature of the stomach to create a sleeve-like structure. It is thought to delay gastric emptying and therefore increase satiety.²⁹ The largest multicenter retrospective study including 248 patients demonstrated 18.6% TWL at 2 years with 2% SAE rate including perigastric fluid collections, extraluminal hemorrhage, pulmonary embolism, pneumoperitoneum, and pneumothorax.³⁰

Aspiration therapy

Aspiration therapy (AT; Aspire Bariatrics, King of Prussia, Pa.) allows patients to remove 25%-30% of ingested calories at approximately 30 minutes after meals. AT consists of an A-tube, which is a 26-Fr gastrostomy tube with a 15-cm fenestrated drainage catheter placed endoscopically via a standard pull technique. At 1-2 weeks after A-tube placement, the tube is cut down to the skin and connected to the port prior to aspiration. AT is approved for patients with a BMI of 35-55 kg/m².³¹ The U.S. pivotal trial (PATHWAY trial) including 207 subjects (137 AT arm versus 70 non-sham control arm) demonstrated 12.1% TWL in the AT group compared to 3.5% in the control group at 12 months based on ITT analysis. The SAE rate was 3.6% including severe abdominal pain, peritonitis, prepyloric ulcer, and A-tube replacement due to skin-port malfunction.³²

Transpyloric shuttle

The transpyloric shuttle (TPS; BAROnova, Goleta, Calif.) consists of a spherical bulb that is attached to a smaller cylindrical bulb by a flexible tether. It is placed and removed endoscopically at 6 months. TPS resides across the pylorus creating intermittent obstruction that may result in delayed gastric emptying. A pilot study including 20 patients demonstrated 14.5% TWL at 6 months.³³ The U.S. pivotal trial (ENDObesity II trial) was recently completed and the data are being reviewed by the FDA.

Revision for weight regain following bariatric surgery

Weight regain is common following RYGB^34,35 and can be associated with dilation of the gastrojejunal anastomosis (GJA).³⁶ Several procedures have been developed to treat this condition by focusing on reduction of GJA size and are available in the United States (Figure 2). These procedures have level I evidence supporting their use and include transoral outlet reduction (TORe) and restorative obesity surgery endoluminal (ROSE).³⁷ TORe involves the use of the Overstitch to place sutures at the GJA. At 1 year, patients had 8.4% TWL with improvement in comorbidities.³⁸ Weight loss remained significant up to 3-5 years.^39,40 The modern ROSE procedure utilizes the IOP system to place plications at the GJA and distal gastric pouch following argon plasma coagulation (APC). A small series showed 12.4% TWL at 6 months.⁴¹ APC is also currently being investigated as a standalone therapy for weight regain in this population.

Small bowel interventions

There are several small bowel interventions, with different mechanisms of action, available internationally. Many of these are under investigation in the United States; however, none are currently FDA approved.

Duodenal-jejunal bypass liner

Duodenal-jejunal bypass liner (DJBL; GI Dynamics, Boston, Mass.) is a 60-cm fluoropolymer liner that is endoscopically placed and removed at 12 months. It is anchored at the duodenal bulb and ends at the jejunum. By excluding direct contact between chyme and the proximal small bowel, DJBL is thought to work via foregut mechanism where there is less inhibition of the incretin effect (greater increase in insulin secretion following oral glucose administration compared to intravenous glucose administration due to gut-derived factors that enhance insulin secretion) leading to improved insulin resistance. In addition, the enteral transit of chyme and bile is altered suggesting the possible role of the hindgut mechanism. The previous U.S. pivotal trial (ENDO trial) met efficacy endpoints. However, the study was stopped early by the company because of a hepatic abscess rate of 3.5%, all of which were treated conservatively.⁴² A new U.S. pivotal study is currently planned. A meta-analysis of 17 published studies, all of which were from outside the United States, demonstrated a significant decrease in hemoglobin A_1c of 1.3% and 18.9% TWL at 1 year following implantation in patients with obesity with concomitant diabetes.⁴³
 

Duodenal mucosal resurfacing

Duodenal mucosal resurfacing (Fractyl, Lexington, Mass.) involves saline lifting of the duodenal mucosa circumferentially prior to thermal ablation using an inflated balloon filled with heated water. It is hypothesized that this may reset the diseased duodenal enteroendocrine cells leading to restoration of the incretin effect. A pilot study including 39 patients with poorly controlled diabetes demonstrated a decrease in hemoglobin A_1c of 1.2%. The SAE rate was 7.7% including duodenal stenosis, all of which were treated with balloon dilation.⁴⁴ The U.S. pivotal trial is currently planned.

Gastroduodenal-jejunal bypass

Gastroduodenal-jejunal bypass (ValenTx., Hopkins, Minn.) is a 120-cm sleeve that is anchored at the gastroesophageal junction to create the anatomic changes of RYGB. It is placed and removed endoscopically with laparoscopic assistance. A pilot study including 12 patients demonstrated 35.9% excess weight loss at 12 months. Two out of 12 patients had early device removal due to intolerance and they were not included in the weight loss analysis.⁴⁵

Incisionless magnetic anastomosis system

The incisionless magnetic anastomosis system (GI Windows, West Bridgewater, Mass.) consists of self-assembling magnets that are deployed under fluoroscopic guidance through the working channel of colonoscopes to form magnetic octagons in the jejunum and ileum. After a week, a compression anastomosis is formed and the coupled magnets pass spontaneously. A pilot study including 10 patients showed 14.6% TWL and a decrease in hemoglobin A_1c of 1.9% (for patients with diabetes) at 1 year.⁴⁶ A randomized study outside the United States is currently underway.

Summary

Endoscopic bariatric and metabolic therapies are emerging as first-line treatments for obesity in many populations. They can serve as a gap therapy for patients who do not qualify for surgery, but also may have a specific role in the treatment of metabolic comorbidities. This field will continue to develop and improve with the introduction of personalized medicine leading to better patient selection, and newer combination therapies. It is time for gastroenterologists to become more involved in the management of this challenging condition.

Dr. Jirapinyo is an advanced and bariatric endoscopy fellow, Brigham and Women’s Hospital, Harvard Medical School, Boston; Dr. Thompson is director of therapeutic endoscopy, Brigham and Women’s Hospital, and associate professor of medicine, Harvard Medical School. Dr. Jirapinyo has served as a consultant for GI Dynamics and holds royalties for Endosim. Dr. Thompson has contracted research for Aspire Bariatrics, USGI Medical, Spatz, and Apollo Endosurgery; has served as a consultant for Boston Scientific, Covidien, USGI Medical, Olympus, and Fractyl; holds stocks and royalties for GI Windows and Endosim, and has served as an expert reviewer for GI Dynamics.
 

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2. Aronne LJ et al. Obesity. 2013;21:2163-71.

3. Torgerson JS et al. Diabetes Care. 2004;27:155-61.

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12. Gomez V et al. Obesity. 2016;24(9):1849-53.

13. Food and Drug Administration. Summary of safety and effectiveness data (SSED) ORBERA Intragastric Balloon System. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf14/P140008b.pdf. 2015:1-32.

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15. Food and Drug Administration. Summary of safety and effectiveness data (SSED) ReShape Integrated Dual Balloon System. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf14/P140012b.pdf. 2015:1-43.

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Over the past decade, Helicobacter pylori strains have reached “alarming levels” of antimicrobial resistance worldwide, investigators reported in the November issue of Gastroenterology.

In a large meta-analysis spanning 2007-2017, H. pylori isolates showed a 15% or higher pooled prevalence of primary and secondary resistance to clarithromycin, metronidazole, and levofloxacin in almost all World Health Organization (WHO) regions. “Local surveillance networks are required to select appropriate eradication regimens for each region,” concluded Alessia Savoldi, MD, of the University of Tübingen (Germany) and her associates.

Typically, the threshold of antimicrobial resistance for choosing empiric regimens is 15%, Dr. Savoldi and her associates noted. Their systematic review and meta-analysis included 178 studies comprising 66,142 isolates from 65 countries. They defined H. pylori infection as a positive histology, serology, stool antigen, urea breath test, or rapid urease test. They excluded studies of fewer than 50 isolates, studies that only reported resistance as a percentage with no denominator, studies that failed to specify time frames or clustered data over more than 3 years, and data reported in guidelines, conference presentations, or letters without formal publication.

Patho/Wikimedia Commons/CC BY-SA 3.0

SOURCE: Savoldi A et al. Gastroenterology. 2018 Nov. doi: 10.1053/j.gastro.2018.07.007.

Over the past decade, Helicobacter pylori strains have reached “alarming levels” of antimicrobial resistance worldwide, investigators reported in the November issue of Gastroenterology.

In a large meta-analysis spanning 2007-2017, H. pylori isolates showed a 15% or higher pooled prevalence of primary and secondary resistance to clarithromycin, metronidazole, and levofloxacin in almost all World Health Organization (WHO) regions. “Local surveillance networks are required to select appropriate eradication regimens for each region,” concluded Alessia Savoldi, MD, of the University of Tübingen (Germany) and her associates.

Typically, the threshold of antimicrobial resistance for choosing empiric regimens is 15%, Dr. Savoldi and her associates noted. Their systematic review and meta-analysis included 178 studies comprising 66,142 isolates from 65 countries. They defined H. pylori infection as a positive histology, serology, stool antigen, urea breath test, or rapid urease test. They excluded studies of fewer than 50 isolates, studies that only reported resistance as a percentage with no denominator, studies that failed to specify time frames or clustered data over more than 3 years, and data reported in guidelines, conference presentations, or letters without formal publication.

Patho/Wikimedia Commons/CC BY-SA 3.0

SOURCE: Savoldi A et al. Gastroenterology. 2018 Nov. doi: 10.1053/j.gastro.2018.07.007.

Over the past decade, Helicobacter pylori strains have reached “alarming levels” of antimicrobial resistance worldwide, investigators reported in the November issue of Gastroenterology.

In a large meta-analysis spanning 2007-2017, H. pylori isolates showed a 15% or higher pooled prevalence of primary and secondary resistance to clarithromycin, metronidazole, and levofloxacin in almost all World Health Organization (WHO) regions. “Local surveillance networks are required to select appropriate eradication regimens for each region,” concluded Alessia Savoldi, MD, of the University of Tübingen (Germany) and her associates.

Typically, the threshold of antimicrobial resistance for choosing empiric regimens is 15%, Dr. Savoldi and her associates noted. Their systematic review and meta-analysis included 178 studies comprising 66,142 isolates from 65 countries. They defined H. pylori infection as a positive histology, serology, stool antigen, urea breath test, or rapid urease test. They excluded studies of fewer than 50 isolates, studies that only reported resistance as a percentage with no denominator, studies that failed to specify time frames or clustered data over more than 3 years, and data reported in guidelines, conference presentations, or letters without formal publication.

Patho/Wikimedia Commons/CC BY-SA 3.0

SOURCE: Savoldi A et al. Gastroenterology. 2018 Nov. doi: 10.1053/j.gastro.2018.07.007.

Cervical cancer was more likely to recur and overall survival was lower among patients who underwent minimally invasive vs. open abdominal radical hysterectomy, based on findings from the randomized, controlled phase 3 Laparoscopic Approach to Cervical Cancer (LACC) trial of more than 600 women.

U.S. Air Force photo by Staff Sgt. Ciara Gosier

The alarming findings, which led to early study termination, also were supported by results from a second population-based study. Both studies were published concurrently in the Oct. 31 issue of the New England Journal of Medicine.

The disease-free survival at 4.5 years among 319 patients who underwent minimally invasive surgery in the LACC trial was 86.0% vs. 96.5% in 312 patients who underwent open surgery, Pedro T. Ramirez, MD, of the University of Texas MD Anderson Cancer Center, Houston, and his colleagues reported (N Engl J Med. 2018 Oct 31. doi: 10.1056/NEJMoa1806395).

At 3 years, the disease-free survival rates were 91.2% in the minimally invasive surgery group and 97.1% in open surgery group (hazard ratio for disease recurrence or death from cervical cancer, 3.74).

The differences between the groups persisted after adjustment for age, body mass index, disease stage, lymphovascular invasion, and lymph-node involvement. In the minimally invasive surgery group, the findings were comparable for those who underwent laparoscopic vs. robot-assisted surgery, the investigators found.

Further, at 3 years, overall survival was 93.8% vs. 99.0% (HR for death from any cause, 6.00), death from cervical cancer was 4.4% vs. 0.6% (HR, 6.56), and the rate of locoregional recurrence-free survival was 94.3 vs. 98.3 (HR, 4.26) in the minimally invasive and open surgery groups, respectively.

Study participants were women with a mean age of 46 years with stage IA1, IA2, or IB1 cervical cancer, with most (91.9%) having IB1 disease, and either squamous-cell carcinoma, adenocarcinoma, or adenosquamous carcinoma. They were recruited from 33 centers worldwide between June 2008 and June 2017. Most of those assigned to minimally invasive surgery underwent laparoscopic surgery (84.4%), and the remaining patients underwent robot-assisted surgery.

The treatment groups were balanced with respect to baseline characteristics, they noted.

The minimally invasive approach is widely used given that guidelines from the National Comprehensive Cancer Network and European Society of Gynecological Oncology consider both surgical approaches acceptable, and since retrospective studies suggest laparoscopic radical hysterectomy is associated with lower complication rates and comparable outcomes. However, there are limited prospective data regarding survival outcomes in early stage disease with the two approaches, the researchers said.

“Our results call into question the findings in the literature suggesting that minimally invasive radical hysterectomy is associated with no difference in oncologic outcomes as compared with the open approach,” they wrote, noting that a number of factors may explain the differences, such as concurrent vs. sequential analyses in the current studies vs. prior studies (in sequential analyses, earlier procedures may have been performed under broader indications and less clearly defined radiotherapy guidelines), and the possibility that “routine use of a uterine manipulator might increase the propensity for tumor spillage” in minimally invasive surgery.

Strengths of the study include its prospective, randomized, international multicenter design and inclusion of a per-protocol analysis that was consistent with the intention-to-treat analysis, and limitations include the fact that intended enrollment wasn’t reached because of the “safety alert raised by the data and safety monitoring committee on the basis of the higher recurrence and death in the minimally invasive surgery groups,” as well as the inability to generalize the results to patients with low-risk disease as there was lack of power to evaluate outcomes in that context.

Justin Chura, MD, director of gynecologic oncology and robotic surgery at Cancer Treatment Center of America’s Eastern Regional Medical Center in Philadelphia, said in an interview, “The results of the study by Ramirez et al. are certainly disappointing for those among us who are advocates of minimally invasive surgery (MIS). In my own practice, I transitioned to minimally invasive radical hysterectomy approximately 10 years ago. Now that approach has to be reconsidered. While there are likely subsets of patients who will still benefit from a MIS approach without worsening oncologic outcomes, we do not have robust data to reliably identify those patients. 

“One factor that warrants further investigation is the use of a uterine manipulator. While I do not use a manipulator out of personal preference (one less step in the operating room), the idea of placing a device through the tumor or adjacent to it, has biologic plausibility in terms of displacing tumor cells into lymphatic channels,” he said. “Until we have more data, an open approach appears to be preferred.”*

Dr. Ramirez and Dr. Melamed each reported having no relevant disclosures. Dr. Salani and Dr. Chura are members of the Ob.Gyn. News editorial board, but reported having no other relevant disclosures.* 

[email protected]

SOURCE: Ramirez P. N Engl J Med. 2018 Oct 31. doi: 10.1056/NEJMoa1806395.

*This article was updated 11/9/2018.

Cervical cancer was more likely to recur and overall survival was lower among patients who underwent minimally invasive vs. open abdominal radical hysterectomy, based on findings from the randomized, controlled phase 3 Laparoscopic Approach to Cervical Cancer (LACC) trial of more than 600 women.

U.S. Air Force photo by Staff Sgt. Ciara Gosier

The alarming findings, which led to early study termination, also were supported by results from a second population-based study. Both studies were published concurrently in the Oct. 31 issue of the New England Journal of Medicine.

The disease-free survival at 4.5 years among 319 patients who underwent minimally invasive surgery in the LACC trial was 86.0% vs. 96.5% in 312 patients who underwent open surgery, Pedro T. Ramirez, MD, of the University of Texas MD Anderson Cancer Center, Houston, and his colleagues reported (N Engl J Med. 2018 Oct 31. doi: 10.1056/NEJMoa1806395).

At 3 years, the disease-free survival rates were 91.2% in the minimally invasive surgery group and 97.1% in open surgery group (hazard ratio for disease recurrence or death from cervical cancer, 3.74).

The differences between the groups persisted after adjustment for age, body mass index, disease stage, lymphovascular invasion, and lymph-node involvement. In the minimally invasive surgery group, the findings were comparable for those who underwent laparoscopic vs. robot-assisted surgery, the investigators found.

Further, at 3 years, overall survival was 93.8% vs. 99.0% (HR for death from any cause, 6.00), death from cervical cancer was 4.4% vs. 0.6% (HR, 6.56), and the rate of locoregional recurrence-free survival was 94.3 vs. 98.3 (HR, 4.26) in the minimally invasive and open surgery groups, respectively.

Study participants were women with a mean age of 46 years with stage IA1, IA2, or IB1 cervical cancer, with most (91.9%) having IB1 disease, and either squamous-cell carcinoma, adenocarcinoma, or adenosquamous carcinoma. They were recruited from 33 centers worldwide between June 2008 and June 2017. Most of those assigned to minimally invasive surgery underwent laparoscopic surgery (84.4%), and the remaining patients underwent robot-assisted surgery.

The treatment groups were balanced with respect to baseline characteristics, they noted.

The minimally invasive approach is widely used given that guidelines from the National Comprehensive Cancer Network and European Society of Gynecological Oncology consider both surgical approaches acceptable, and since retrospective studies suggest laparoscopic radical hysterectomy is associated with lower complication rates and comparable outcomes. However, there are limited prospective data regarding survival outcomes in early stage disease with the two approaches, the researchers said.

“Our results call into question the findings in the literature suggesting that minimally invasive radical hysterectomy is associated with no difference in oncologic outcomes as compared with the open approach,” they wrote, noting that a number of factors may explain the differences, such as concurrent vs. sequential analyses in the current studies vs. prior studies (in sequential analyses, earlier procedures may have been performed under broader indications and less clearly defined radiotherapy guidelines), and the possibility that “routine use of a uterine manipulator might increase the propensity for tumor spillage” in minimally invasive surgery.

Strengths of the study include its prospective, randomized, international multicenter design and inclusion of a per-protocol analysis that was consistent with the intention-to-treat analysis, and limitations include the fact that intended enrollment wasn’t reached because of the “safety alert raised by the data and safety monitoring committee on the basis of the higher recurrence and death in the minimally invasive surgery groups,” as well as the inability to generalize the results to patients with low-risk disease as there was lack of power to evaluate outcomes in that context.

Justin Chura, MD, director of gynecologic oncology and robotic surgery at Cancer Treatment Center of America’s Eastern Regional Medical Center in Philadelphia, said in an interview, “The results of the study by Ramirez et al. are certainly disappointing for those among us who are advocates of minimally invasive surgery (MIS). In my own practice, I transitioned to minimally invasive radical hysterectomy approximately 10 years ago. Now that approach has to be reconsidered. While there are likely subsets of patients who will still benefit from a MIS approach without worsening oncologic outcomes, we do not have robust data to reliably identify those patients. 

“One factor that warrants further investigation is the use of a uterine manipulator. While I do not use a manipulator out of personal preference (one less step in the operating room), the idea of placing a device through the tumor or adjacent to it, has biologic plausibility in terms of displacing tumor cells into lymphatic channels,” he said. “Until we have more data, an open approach appears to be preferred.”*

Dr. Ramirez and Dr. Melamed each reported having no relevant disclosures. Dr. Salani and Dr. Chura are members of the Ob.Gyn. News editorial board, but reported having no other relevant disclosures.* 

[email protected]

SOURCE: Ramirez P. N Engl J Med. 2018 Oct 31. doi: 10.1056/NEJMoa1806395.

*This article was updated 11/9/2018.

Cervical cancer was more likely to recur and overall survival was lower among patients who underwent minimally invasive vs. open abdominal radical hysterectomy, based on findings from the randomized, controlled phase 3 Laparoscopic Approach to Cervical Cancer (LACC) trial of more than 600 women.

U.S. Air Force photo by Staff Sgt. Ciara Gosier

The alarming findings, which led to early study termination, also were supported by results from a second population-based study. Both studies were published concurrently in the Oct. 31 issue of the New England Journal of Medicine.

The disease-free survival at 4.5 years among 319 patients who underwent minimally invasive surgery in the LACC trial was 86.0% vs. 96.5% in 312 patients who underwent open surgery, Pedro T. Ramirez, MD, of the University of Texas MD Anderson Cancer Center, Houston, and his colleagues reported (N Engl J Med. 2018 Oct 31. doi: 10.1056/NEJMoa1806395).

At 3 years, the disease-free survival rates were 91.2% in the minimally invasive surgery group and 97.1% in open surgery group (hazard ratio for disease recurrence or death from cervical cancer, 3.74).

The differences between the groups persisted after adjustment for age, body mass index, disease stage, lymphovascular invasion, and lymph-node involvement. In the minimally invasive surgery group, the findings were comparable for those who underwent laparoscopic vs. robot-assisted surgery, the investigators found.

Further, at 3 years, overall survival was 93.8% vs. 99.0% (HR for death from any cause, 6.00), death from cervical cancer was 4.4% vs. 0.6% (HR, 6.56), and the rate of locoregional recurrence-free survival was 94.3 vs. 98.3 (HR, 4.26) in the minimally invasive and open surgery groups, respectively.

Study participants were women with a mean age of 46 years with stage IA1, IA2, or IB1 cervical cancer, with most (91.9%) having IB1 disease, and either squamous-cell carcinoma, adenocarcinoma, or adenosquamous carcinoma. They were recruited from 33 centers worldwide between June 2008 and June 2017. Most of those assigned to minimally invasive surgery underwent laparoscopic surgery (84.4%), and the remaining patients underwent robot-assisted surgery.

The treatment groups were balanced with respect to baseline characteristics, they noted.

The minimally invasive approach is widely used given that guidelines from the National Comprehensive Cancer Network and European Society of Gynecological Oncology consider both surgical approaches acceptable, and since retrospective studies suggest laparoscopic radical hysterectomy is associated with lower complication rates and comparable outcomes. However, there are limited prospective data regarding survival outcomes in early stage disease with the two approaches, the researchers said.

“Our results call into question the findings in the literature suggesting that minimally invasive radical hysterectomy is associated with no difference in oncologic outcomes as compared with the open approach,” they wrote, noting that a number of factors may explain the differences, such as concurrent vs. sequential analyses in the current studies vs. prior studies (in sequential analyses, earlier procedures may have been performed under broader indications and less clearly defined radiotherapy guidelines), and the possibility that “routine use of a uterine manipulator might increase the propensity for tumor spillage” in minimally invasive surgery.

Strengths of the study include its prospective, randomized, international multicenter design and inclusion of a per-protocol analysis that was consistent with the intention-to-treat analysis, and limitations include the fact that intended enrollment wasn’t reached because of the “safety alert raised by the data and safety monitoring committee on the basis of the higher recurrence and death in the minimally invasive surgery groups,” as well as the inability to generalize the results to patients with low-risk disease as there was lack of power to evaluate outcomes in that context.

Justin Chura, MD, director of gynecologic oncology and robotic surgery at Cancer Treatment Center of America’s Eastern Regional Medical Center in Philadelphia, said in an interview, “The results of the study by Ramirez et al. are certainly disappointing for those among us who are advocates of minimally invasive surgery (MIS). In my own practice, I transitioned to minimally invasive radical hysterectomy approximately 10 years ago. Now that approach has to be reconsidered. While there are likely subsets of patients who will still benefit from a MIS approach without worsening oncologic outcomes, we do not have robust data to reliably identify those patients. 

“One factor that warrants further investigation is the use of a uterine manipulator. While I do not use a manipulator out of personal preference (one less step in the operating room), the idea of placing a device through the tumor or adjacent to it, has biologic plausibility in terms of displacing tumor cells into lymphatic channels,” he said. “Until we have more data, an open approach appears to be preferred.”*

Dr. Ramirez and Dr. Melamed each reported having no relevant disclosures. Dr. Salani and Dr. Chura are members of the Ob.Gyn. News editorial board, but reported having no other relevant disclosures.* 

[email protected]

SOURCE: Ramirez P. N Engl J Med. 2018 Oct 31. doi: 10.1056/NEJMoa1806395.

*This article was updated 11/9/2018.

A macrophage-activating immune checkpoint inhibitor, combined with rituximab therapy, was safe and produced durable complete responses in patients with relapsed or refractory non-Hodgkin lymphoma, according to results of a phase 1b study.

Courtesy Stanford Medicine

Mainly low-grade toxic effects were seen on treatment with Hu5F9-G4 (5F9) and rituximab, which induced responses in more than half of patients, of which more than one-third were complete responses, the study investigators reported.

Most of the responses were ongoing at the time of data cutoff, suggesting durable responses with the combination of rituximab and 5F9 – a humanized monoclonal antibody that blocks CD47, an antiphagocytic or “do not eat me” signal overexpressed by most cancers, Ranjana Advani, MD, of Stanford (Calif.) University, and her coauthors wrote.

“The macrophage-mediated activity of 5F9 plus rituximab may serve as an effective new immunotherapy for stimulating the innate immune system,” Dr. Advani and her colleagues reported in the New England Journal of Medicine.

The study included 22 patients, including 15 with diffuse large B-cell lymphoma (DLBCL) and 7 with follicular lymphoma, who had received a median of four prior therapies. Almost all of the non-Hodgkin lymphomas (21, or 95%) were refractory to rituximab.

All patients received intravenous 5F9 starting with a priming dose of 1 mg/kg followed by weekly maintenance doses of 10-30 mg/kg in three dose-escalation cohorts, given until disease progression or lack of clinical benefit. Intravenous rituximab at 375 mg/m² weekly was started on the second week of the first cycle, and then monthly for cycles 2 through 6.

“Substantial antitumor activity” was seen with this chemotherapy-free regimen in a group of heavily pretreated, largely rituximab-refractory patients, Dr. Advani and her coauthors wrote in their report.

The objective response rate was 50%, including a 36% complete response rate in the intent-to-treat analysis. For DLBCL, the rates of objective and complete responses were 40% and 33%, while for follicular lymphoma, they were 71% and 43%.

The median duration of response was not reached in either disease cohort with a median follow-up of 6.2 months for DLBCL and 8.1 months for follicular lymphoma. Of the 11 patients who responded, 10 (91%) were still in response at the time of data cutoff. “Longer follow-up is needed,” the investigators wrote.

Most adverse events were seen within the first few weeks of treatment and mainly included anemia and infusion-related reactions. The anemia was an expected, on-target effect of 5F9 because of selective clearance of older red cells, which was predictable, transient, and mitigated by the maintenance dosing strategy employed in this phase 1b trial.

“As red cells age, they lose CD47 expression and gain expression of prophagocytic signals, leading to homeostatic clearance,” they wrote.

The activity of 5F9 and rituximab is “synergistic” based on the results of previous, preclinical investigations in models of lymphoma, Dr. Advani and her coauthors added.

A phase 2 trial of 5F9 plus rituximab in relapsed or refractory B-cell non-Hodgkin lymphoma is ongoing, according to their report.

The study was supported by Forty Seven and the Leukemia & Lymphoma Society. Dr. Advani reported disclosures related to Forty Seven, Bristol-Myers Squibb, Pharmacyclics, Seattle Genetics, and Roche/Genentech, among others.

SOURCE: Advani R et al. N Engl J Med. 2018;379:1711-21.

A macrophage-activating immune checkpoint inhibitor, combined with rituximab therapy, was safe and produced durable complete responses in patients with relapsed or refractory non-Hodgkin lymphoma, according to results of a phase 1b study.

Courtesy Stanford Medicine

Mainly low-grade toxic effects were seen on treatment with Hu5F9-G4 (5F9) and rituximab, which induced responses in more than half of patients, of which more than one-third were complete responses, the study investigators reported.

Most of the responses were ongoing at the time of data cutoff, suggesting durable responses with the combination of rituximab and 5F9 – a humanized monoclonal antibody that blocks CD47, an antiphagocytic or “do not eat me” signal overexpressed by most cancers, Ranjana Advani, MD, of Stanford (Calif.) University, and her coauthors wrote.

“The macrophage-mediated activity of 5F9 plus rituximab may serve as an effective new immunotherapy for stimulating the innate immune system,” Dr. Advani and her colleagues reported in the New England Journal of Medicine.

The study included 22 patients, including 15 with diffuse large B-cell lymphoma (DLBCL) and 7 with follicular lymphoma, who had received a median of four prior therapies. Almost all of the non-Hodgkin lymphomas (21, or 95%) were refractory to rituximab.

All patients received intravenous 5F9 starting with a priming dose of 1 mg/kg followed by weekly maintenance doses of 10-30 mg/kg in three dose-escalation cohorts, given until disease progression or lack of clinical benefit. Intravenous rituximab at 375 mg/m² weekly was started on the second week of the first cycle, and then monthly for cycles 2 through 6.

“Substantial antitumor activity” was seen with this chemotherapy-free regimen in a group of heavily pretreated, largely rituximab-refractory patients, Dr. Advani and her coauthors wrote in their report.

The objective response rate was 50%, including a 36% complete response rate in the intent-to-treat analysis. For DLBCL, the rates of objective and complete responses were 40% and 33%, while for follicular lymphoma, they were 71% and 43%.

The median duration of response was not reached in either disease cohort with a median follow-up of 6.2 months for DLBCL and 8.1 months for follicular lymphoma. Of the 11 patients who responded, 10 (91%) were still in response at the time of data cutoff. “Longer follow-up is needed,” the investigators wrote.

Most adverse events were seen within the first few weeks of treatment and mainly included anemia and infusion-related reactions. The anemia was an expected, on-target effect of 5F9 because of selective clearance of older red cells, which was predictable, transient, and mitigated by the maintenance dosing strategy employed in this phase 1b trial.

“As red cells age, they lose CD47 expression and gain expression of prophagocytic signals, leading to homeostatic clearance,” they wrote.

The activity of 5F9 and rituximab is “synergistic” based on the results of previous, preclinical investigations in models of lymphoma, Dr. Advani and her coauthors added.

A phase 2 trial of 5F9 plus rituximab in relapsed or refractory B-cell non-Hodgkin lymphoma is ongoing, according to their report.

The study was supported by Forty Seven and the Leukemia & Lymphoma Society. Dr. Advani reported disclosures related to Forty Seven, Bristol-Myers Squibb, Pharmacyclics, Seattle Genetics, and Roche/Genentech, among others.

SOURCE: Advani R et al. N Engl J Med. 2018;379:1711-21.

A macrophage-activating immune checkpoint inhibitor, combined with rituximab therapy, was safe and produced durable complete responses in patients with relapsed or refractory non-Hodgkin lymphoma, according to results of a phase 1b study.

Courtesy Stanford Medicine

Mainly low-grade toxic effects were seen on treatment with Hu5F9-G4 (5F9) and rituximab, which induced responses in more than half of patients, of which more than one-third were complete responses, the study investigators reported.

Most of the responses were ongoing at the time of data cutoff, suggesting durable responses with the combination of rituximab and 5F9 – a humanized monoclonal antibody that blocks CD47, an antiphagocytic or “do not eat me” signal overexpressed by most cancers, Ranjana Advani, MD, of Stanford (Calif.) University, and her coauthors wrote.

“The macrophage-mediated activity of 5F9 plus rituximab may serve as an effective new immunotherapy for stimulating the innate immune system,” Dr. Advani and her colleagues reported in the New England Journal of Medicine.

The study included 22 patients, including 15 with diffuse large B-cell lymphoma (DLBCL) and 7 with follicular lymphoma, who had received a median of four prior therapies. Almost all of the non-Hodgkin lymphomas (21, or 95%) were refractory to rituximab.

All patients received intravenous 5F9 starting with a priming dose of 1 mg/kg followed by weekly maintenance doses of 10-30 mg/kg in three dose-escalation cohorts, given until disease progression or lack of clinical benefit. Intravenous rituximab at 375 mg/m² weekly was started on the second week of the first cycle, and then monthly for cycles 2 through 6.

“Substantial antitumor activity” was seen with this chemotherapy-free regimen in a group of heavily pretreated, largely rituximab-refractory patients, Dr. Advani and her coauthors wrote in their report.

The objective response rate was 50%, including a 36% complete response rate in the intent-to-treat analysis. For DLBCL, the rates of objective and complete responses were 40% and 33%, while for follicular lymphoma, they were 71% and 43%.

The median duration of response was not reached in either disease cohort with a median follow-up of 6.2 months for DLBCL and 8.1 months for follicular lymphoma. Of the 11 patients who responded, 10 (91%) were still in response at the time of data cutoff. “Longer follow-up is needed,” the investigators wrote.

Most adverse events were seen within the first few weeks of treatment and mainly included anemia and infusion-related reactions. The anemia was an expected, on-target effect of 5F9 because of selective clearance of older red cells, which was predictable, transient, and mitigated by the maintenance dosing strategy employed in this phase 1b trial.

“As red cells age, they lose CD47 expression and gain expression of prophagocytic signals, leading to homeostatic clearance,” they wrote.

The activity of 5F9 and rituximab is “synergistic” based on the results of previous, preclinical investigations in models of lymphoma, Dr. Advani and her coauthors added.

A phase 2 trial of 5F9 plus rituximab in relapsed or refractory B-cell non-Hodgkin lymphoma is ongoing, according to their report.

The study was supported by Forty Seven and the Leukemia & Lymphoma Society. Dr. Advani reported disclosures related to Forty Seven, Bristol-Myers Squibb, Pharmacyclics, Seattle Genetics, and Roche/Genentech, among others.

SOURCE: Advani R et al. N Engl J Med. 2018;379:1711-21.

While adjuvant axitinib failed to improve disease-free survival in a recent phase 3 renal cell carcinoma (RCC) trial, the highest-risk subgroup appeared to benefit, according to a report on the study.

The phase 3 ATLAS trial was stopped early because of a lack of benefit for axitinib versus placebo in the study, which included patients with locoregional RCC at risk of recurrence after nephrectomy.

However, a prespecified analysis showed that axitinib reduced risk of disease-free survival events by about one-third in the highest-risk subset of patients, according to investigator David I. Quinn, MD, USC Norris Comprehensive Cancer Center, Los Angeles, and colleagues.

That finding tracks with results of the earlier S-TRAC trial, in which patients at high risk of tumor recurrence after nephrectomy had significantly longer disease-free survival with sunitinib versus placebo, Dr. Quinn and coauthors said.

“Taken together, these results support that patients at highest risk for RCC recurrence benefit from adjuvant treatment,” they wrote in Annals of Oncology.

In the ATLAS trial, Dr. Quinn and coinvestigators at 137 centers in eight countries enrolled 724 adults with newly diagnosed renal cell carcinoma (greater than or equal to pT2 and/or N+, any Fuhrman grade) with Eastern Cooperative Oncology Group status of 0 or 1 and prior nephrectomy.

Patients were randomly assigned to oral, twice-daily axitinib 5 mg or placebo for up to 3 years of treatment, and at least 1 year of treatment provided there was no recurrence, substantial toxicity, or withdrawal of consent.

For the primary endpoint, disease-free survival per independent review committee assessment, the hazard ratio was 0.870 (95% confidence interval, 0.660-1.147; P = .3211), according to the report. Disease-free survival as rated by investigators showed a somewhat larger but still not statistically significant reduction in risk of an event, Dr. Quinn and colleagues said.

However, in the prespecified subgroup analyses, the patients at highest risk (pT3 with Fuhrman grade greater than or equal to 3 or pT4 and/or N+, any T, any Fuhrman grade) had a reduction of risk with hazard ratios of 0.735 per independent review committee (P = .0704) and 0.641 per investigator (P = .0051).

The ATLAS study was designed before results of the S-TRAC study were known, and so patients at lower risk of recurrence were included, said Dr. Quinn and coauthors.

Ongoing trials are looking at sorafenib, everolimus, and immune checkpoint inhibitors in the adjuvant RCC setting, they noted in their discussion of ATLAS, S-TRAC, and other investigations.

Results from these trials may provide clarification on the future of adjuvant treatment for RCC, and whether angiogenesis inhibition is the key mechanism to obtain a reduction in risk of relapse after nephrectomy,” they said.

The study was sponsored by Pfizer and SFJ Pharmaceuticals. Dr. Quinn reported providing advisory board services for Pfizer, Bayer, Novartis, Bristol-Myers Squibb, Merck, Exelixis, Genentech, Roche, AstraZeneca, and Astellas. Coauthors reported disclosures related to Bristol-Myers Squibb, Ipsen, MSD, Novartis, Pfizer, and Roche, among others.

SOURCE: Quinn DI et al. Ann Oncol. 2018 Oct 20. doi: 10.1093/annonc/mdy454.

While adjuvant axitinib failed to improve disease-free survival in a recent phase 3 renal cell carcinoma (RCC) trial, the highest-risk subgroup appeared to benefit, according to a report on the study.

The phase 3 ATLAS trial was stopped early because of a lack of benefit for axitinib versus placebo in the study, which included patients with locoregional RCC at risk of recurrence after nephrectomy.

However, a prespecified analysis showed that axitinib reduced risk of disease-free survival events by about one-third in the highest-risk subset of patients, according to investigator David I. Quinn, MD, USC Norris Comprehensive Cancer Center, Los Angeles, and colleagues.

That finding tracks with results of the earlier S-TRAC trial, in which patients at high risk of tumor recurrence after nephrectomy had significantly longer disease-free survival with sunitinib versus placebo, Dr. Quinn and coauthors said.

“Taken together, these results support that patients at highest risk for RCC recurrence benefit from adjuvant treatment,” they wrote in Annals of Oncology.

In the ATLAS trial, Dr. Quinn and coinvestigators at 137 centers in eight countries enrolled 724 adults with newly diagnosed renal cell carcinoma (greater than or equal to pT2 and/or N+, any Fuhrman grade) with Eastern Cooperative Oncology Group status of 0 or 1 and prior nephrectomy.

Patients were randomly assigned to oral, twice-daily axitinib 5 mg or placebo for up to 3 years of treatment, and at least 1 year of treatment provided there was no recurrence, substantial toxicity, or withdrawal of consent.

For the primary endpoint, disease-free survival per independent review committee assessment, the hazard ratio was 0.870 (95% confidence interval, 0.660-1.147; P = .3211), according to the report. Disease-free survival as rated by investigators showed a somewhat larger but still not statistically significant reduction in risk of an event, Dr. Quinn and colleagues said.

However, in the prespecified subgroup analyses, the patients at highest risk (pT3 with Fuhrman grade greater than or equal to 3 or pT4 and/or N+, any T, any Fuhrman grade) had a reduction of risk with hazard ratios of 0.735 per independent review committee (P = .0704) and 0.641 per investigator (P = .0051).

The ATLAS study was designed before results of the S-TRAC study were known, and so patients at lower risk of recurrence were included, said Dr. Quinn and coauthors.

Ongoing trials are looking at sorafenib, everolimus, and immune checkpoint inhibitors in the adjuvant RCC setting, they noted in their discussion of ATLAS, S-TRAC, and other investigations.

Results from these trials may provide clarification on the future of adjuvant treatment for RCC, and whether angiogenesis inhibition is the key mechanism to obtain a reduction in risk of relapse after nephrectomy,” they said.

The study was sponsored by Pfizer and SFJ Pharmaceuticals. Dr. Quinn reported providing advisory board services for Pfizer, Bayer, Novartis, Bristol-Myers Squibb, Merck, Exelixis, Genentech, Roche, AstraZeneca, and Astellas. Coauthors reported disclosures related to Bristol-Myers Squibb, Ipsen, MSD, Novartis, Pfizer, and Roche, among others.

SOURCE: Quinn DI et al. Ann Oncol. 2018 Oct 20. doi: 10.1093/annonc/mdy454.

While adjuvant axitinib failed to improve disease-free survival in a recent phase 3 renal cell carcinoma (RCC) trial, the highest-risk subgroup appeared to benefit, according to a report on the study.

The phase 3 ATLAS trial was stopped early because of a lack of benefit for axitinib versus placebo in the study, which included patients with locoregional RCC at risk of recurrence after nephrectomy.

However, a prespecified analysis showed that axitinib reduced risk of disease-free survival events by about one-third in the highest-risk subset of patients, according to investigator David I. Quinn, MD, USC Norris Comprehensive Cancer Center, Los Angeles, and colleagues.

That finding tracks with results of the earlier S-TRAC trial, in which patients at high risk of tumor recurrence after nephrectomy had significantly longer disease-free survival with sunitinib versus placebo, Dr. Quinn and coauthors said.

“Taken together, these results support that patients at highest risk for RCC recurrence benefit from adjuvant treatment,” they wrote in Annals of Oncology.

In the ATLAS trial, Dr. Quinn and coinvestigators at 137 centers in eight countries enrolled 724 adults with newly diagnosed renal cell carcinoma (greater than or equal to pT2 and/or N+, any Fuhrman grade) with Eastern Cooperative Oncology Group status of 0 or 1 and prior nephrectomy.

Patients were randomly assigned to oral, twice-daily axitinib 5 mg or placebo for up to 3 years of treatment, and at least 1 year of treatment provided there was no recurrence, substantial toxicity, or withdrawal of consent.

For the primary endpoint, disease-free survival per independent review committee assessment, the hazard ratio was 0.870 (95% confidence interval, 0.660-1.147; P = .3211), according to the report. Disease-free survival as rated by investigators showed a somewhat larger but still not statistically significant reduction in risk of an event, Dr. Quinn and colleagues said.

However, in the prespecified subgroup analyses, the patients at highest risk (pT3 with Fuhrman grade greater than or equal to 3 or pT4 and/or N+, any T, any Fuhrman grade) had a reduction of risk with hazard ratios of 0.735 per independent review committee (P = .0704) and 0.641 per investigator (P = .0051).

The ATLAS study was designed before results of the S-TRAC study were known, and so patients at lower risk of recurrence were included, said Dr. Quinn and coauthors.

Ongoing trials are looking at sorafenib, everolimus, and immune checkpoint inhibitors in the adjuvant RCC setting, they noted in their discussion of ATLAS, S-TRAC, and other investigations.

Results from these trials may provide clarification on the future of adjuvant treatment for RCC, and whether angiogenesis inhibition is the key mechanism to obtain a reduction in risk of relapse after nephrectomy,” they said.

The study was sponsored by Pfizer and SFJ Pharmaceuticals. Dr. Quinn reported providing advisory board services for Pfizer, Bayer, Novartis, Bristol-Myers Squibb, Merck, Exelixis, Genentech, Roche, AstraZeneca, and Astellas. Coauthors reported disclosures related to Bristol-Myers Squibb, Ipsen, MSD, Novartis, Pfizer, and Roche, among others.

SOURCE: Quinn DI et al. Ann Oncol. 2018 Oct 20. doi: 10.1093/annonc/mdy454.

On Sept. 14 of this year, Apple executives took to the stage to tout the incredible benefits of their new Apple Watch Series 4. While impressively presented in typical Apple fashion, the watch appeared to be only an evolution – not a revolution – in wearable technology. Still, there were a few noteworthy aspects of the new model that seemed to shine a light on the direction of the industry as a whole, and these were all focused on health care.

Like products from FitBit, Garmin, and others, the new Apple Watch can monitor a user’s heart rate and notify if it goes too high or too low. In addition, the watch now includes “fall detection,” and can automatically call for help if its wearer has taken a spill and become unresponsive. Soon it will even be capable of recording a single-lead ECG and detecting atrial fibrillation. While this all sounds fantastic, it also raises an important question in the minds of many physicians (including us): What do we do with all of these new data?

Findings from a Digital Health Study published by the American Medical Association in 2016¹ reveal that most doctors are aware of growing advances in Mobile Health (mHealth). Interestingly, however, while 85% see potential advantages in mHealth, less than 30% have begun employing it in their practices. This speaks to an adoption divide and highlights the many barriers to overcome before we can bridge it.

First and foremost, providers need confidence in the accuracy of the monitoring equipment, and, thus far, that accuracy has been questionable. Heart rate measurement, for example, is a staple of all currently available fitness wearables, yet is replete with technological pitfalls. This is because most consumer devices rely on optical sensors to measure heart rate. While inexpensive and noninvasive, the accuracy of these sensors can be affected by the interference of sweat, movement, and even the patient’s skin conditions – so much so that FitBit is currently embroiled in a class action lawsuit² over the issue, in spite of providing disclaimers that a FitBit is “not a medical device.” To improve heart-monitoring capability, Apple has changed to a new sensor technology for this latest generation of Apple Watch. So far its accuracy has yet to be proven, and Apple’s delay in releasing the ECG features until “later this year” suggests there may still be bugs to work out.

Another significant concern raised by the onslaught of wearable health data is how to incorporate it into the electronic health record. Physicians care about efficient data integration, and, when asked in the aforementioned AMA study, physicians named this as their No. 1 functional requirement. EHR vendors have made some strides to allow patients to upload monitoring data directly through an online portal, but the large variety of available consumer devices has made standardizing this process difficult. Doctors have also made it clear that they want it to be straightforward to access and use the information provided by patients, and don’t want it to require special training. These are considerable challenges that will require collaboration between EHR vendors and wearable manufacturers to solve.

The introduction of additional players into the health care space also evokes questions of who owns this new health data set, and who is accountable for its integrity. If history is any indicator, device manufacturers will try their best to eschew any liability, and shift culpability onto patients and physicians. This is causing malpractice insurers to rethink policy coverage and forcing doctors to face a new reality of having “too much information.” While we are excited about the potential for better access to patient monitoring data, we agree that physicians need to understand where their responsibility for these data begins and ends.

Likewise, patients need to understand who has access to their personal health information, and how it’s being used. Privacy concerns will only become more evident as our society becomes ever more connected and as technologies become more invasive. The term “wearable” may soon become antiquated, as more products are coming to market that cross the skin barrier to collect samples directly from the blood or interstitial fluid. Devices such as Abbott’s new FreeStyle Libre continuous blood glucose monitor can be worn for weeks at a time, with its tiny sensor placed just under the skin. It constantly monitors trends in blood sugar and produces enough data points to determine the eating, sleeping, and activity habits of its wearer. This is all uploadable to Abbott’s servers, allowing patients and their providers to review it, thereby further expanding their personal health information footprint.

One encouraging aspect of the expansion mobile health technology is its organic, patient-led adoption. This is quite different from the epoch of electronic health records, which was motivated largely by government financial incentives and resulted in expensive, inefficient software. Patients are expressing a greater desire to take ownership of their health and have a growing interest in personal fitness. Also, the size of the consumer marketplace is forcing vendors to create competitive, high-value, and user-friendly mHealth devices. These products may seem to offer endless possibilities, but patients, vendors, and providers must fully acknowledge existing limitations in order to truly spark a revolution in wearable technology and actually improve patient care.

Dr. Notte is a family physician and clinical informaticist for Abington (Pa.) Memorial Hospital. He is a partner in EHR Practice Consultants, a firm that aids physicians in adopting electronic health records. Dr. Skolnik is a professor of family and community medicine at Jefferson Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington Jefferson Health.

References

1. Digital Health Study: Physicians’ motivations and requirements for adopting digital clinical tools. (2016) American Medical Association.

2. Kate Mclellan et al. v. Fitbit Inc. Fitbit Heart Rate Monitors Fraud & Defects Lawsuit.

On Sept. 14 of this year, Apple executives took to the stage to tout the incredible benefits of their new Apple Watch Series 4. While impressively presented in typical Apple fashion, the watch appeared to be only an evolution – not a revolution – in wearable technology. Still, there were a few noteworthy aspects of the new model that seemed to shine a light on the direction of the industry as a whole, and these were all focused on health care.

Like products from FitBit, Garmin, and others, the new Apple Watch can monitor a user’s heart rate and notify if it goes too high or too low. In addition, the watch now includes “fall detection,” and can automatically call for help if its wearer has taken a spill and become unresponsive. Soon it will even be capable of recording a single-lead ECG and detecting atrial fibrillation. While this all sounds fantastic, it also raises an important question in the minds of many physicians (including us): What do we do with all of these new data?

Findings from a Digital Health Study published by the American Medical Association in 2016¹ reveal that most doctors are aware of growing advances in Mobile Health (mHealth). Interestingly, however, while 85% see potential advantages in mHealth, less than 30% have begun employing it in their practices. This speaks to an adoption divide and highlights the many barriers to overcome before we can bridge it.

First and foremost, providers need confidence in the accuracy of the monitoring equipment, and, thus far, that accuracy has been questionable. Heart rate measurement, for example, is a staple of all currently available fitness wearables, yet is replete with technological pitfalls. This is because most consumer devices rely on optical sensors to measure heart rate. While inexpensive and noninvasive, the accuracy of these sensors can be affected by the interference of sweat, movement, and even the patient’s skin conditions – so much so that FitBit is currently embroiled in a class action lawsuit² over the issue, in spite of providing disclaimers that a FitBit is “not a medical device.” To improve heart-monitoring capability, Apple has changed to a new sensor technology for this latest generation of Apple Watch. So far its accuracy has yet to be proven, and Apple’s delay in releasing the ECG features until “later this year” suggests there may still be bugs to work out.

Another significant concern raised by the onslaught of wearable health data is how to incorporate it into the electronic health record. Physicians care about efficient data integration, and, when asked in the aforementioned AMA study, physicians named this as their No. 1 functional requirement. EHR vendors have made some strides to allow patients to upload monitoring data directly through an online portal, but the large variety of available consumer devices has made standardizing this process difficult. Doctors have also made it clear that they want it to be straightforward to access and use the information provided by patients, and don’t want it to require special training. These are considerable challenges that will require collaboration between EHR vendors and wearable manufacturers to solve.

The introduction of additional players into the health care space also evokes questions of who owns this new health data set, and who is accountable for its integrity. If history is any indicator, device manufacturers will try their best to eschew any liability, and shift culpability onto patients and physicians. This is causing malpractice insurers to rethink policy coverage and forcing doctors to face a new reality of having “too much information.” While we are excited about the potential for better access to patient monitoring data, we agree that physicians need to understand where their responsibility for these data begins and ends.

Likewise, patients need to understand who has access to their personal health information, and how it’s being used. Privacy concerns will only become more evident as our society becomes ever more connected and as technologies become more invasive. The term “wearable” may soon become antiquated, as more products are coming to market that cross the skin barrier to collect samples directly from the blood or interstitial fluid. Devices such as Abbott’s new FreeStyle Libre continuous blood glucose monitor can be worn for weeks at a time, with its tiny sensor placed just under the skin. It constantly monitors trends in blood sugar and produces enough data points to determine the eating, sleeping, and activity habits of its wearer. This is all uploadable to Abbott’s servers, allowing patients and their providers to review it, thereby further expanding their personal health information footprint.

One encouraging aspect of the expansion mobile health technology is its organic, patient-led adoption. This is quite different from the epoch of electronic health records, which was motivated largely by government financial incentives and resulted in expensive, inefficient software. Patients are expressing a greater desire to take ownership of their health and have a growing interest in personal fitness. Also, the size of the consumer marketplace is forcing vendors to create competitive, high-value, and user-friendly mHealth devices. These products may seem to offer endless possibilities, but patients, vendors, and providers must fully acknowledge existing limitations in order to truly spark a revolution in wearable technology and actually improve patient care.

Dr. Notte is a family physician and clinical informaticist for Abington (Pa.) Memorial Hospital. He is a partner in EHR Practice Consultants, a firm that aids physicians in adopting electronic health records. Dr. Skolnik is a professor of family and community medicine at Jefferson Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington Jefferson Health.

References

1. Digital Health Study: Physicians’ motivations and requirements for adopting digital clinical tools. (2016) American Medical Association.

2. Kate Mclellan et al. v. Fitbit Inc. Fitbit Heart Rate Monitors Fraud & Defects Lawsuit.

On Sept. 14 of this year, Apple executives took to the stage to tout the incredible benefits of their new Apple Watch Series 4. While impressively presented in typical Apple fashion, the watch appeared to be only an evolution – not a revolution – in wearable technology. Still, there were a few noteworthy aspects of the new model that seemed to shine a light on the direction of the industry as a whole, and these were all focused on health care.

Like products from FitBit, Garmin, and others, the new Apple Watch can monitor a user’s heart rate and notify if it goes too high or too low. In addition, the watch now includes “fall detection,” and can automatically call for help if its wearer has taken a spill and become unresponsive. Soon it will even be capable of recording a single-lead ECG and detecting atrial fibrillation. While this all sounds fantastic, it also raises an important question in the minds of many physicians (including us): What do we do with all of these new data?

Findings from a Digital Health Study published by the American Medical Association in 2016¹ reveal that most doctors are aware of growing advances in Mobile Health (mHealth). Interestingly, however, while 85% see potential advantages in mHealth, less than 30% have begun employing it in their practices. This speaks to an adoption divide and highlights the many barriers to overcome before we can bridge it.

First and foremost, providers need confidence in the accuracy of the monitoring equipment, and, thus far, that accuracy has been questionable. Heart rate measurement, for example, is a staple of all currently available fitness wearables, yet is replete with technological pitfalls. This is because most consumer devices rely on optical sensors to measure heart rate. While inexpensive and noninvasive, the accuracy of these sensors can be affected by the interference of sweat, movement, and even the patient’s skin conditions – so much so that FitBit is currently embroiled in a class action lawsuit² over the issue, in spite of providing disclaimers that a FitBit is “not a medical device.” To improve heart-monitoring capability, Apple has changed to a new sensor technology for this latest generation of Apple Watch. So far its accuracy has yet to be proven, and Apple’s delay in releasing the ECG features until “later this year” suggests there may still be bugs to work out.

Another significant concern raised by the onslaught of wearable health data is how to incorporate it into the electronic health record. Physicians care about efficient data integration, and, when asked in the aforementioned AMA study, physicians named this as their No. 1 functional requirement. EHR vendors have made some strides to allow patients to upload monitoring data directly through an online portal, but the large variety of available consumer devices has made standardizing this process difficult. Doctors have also made it clear that they want it to be straightforward to access and use the information provided by patients, and don’t want it to require special training. These are considerable challenges that will require collaboration between EHR vendors and wearable manufacturers to solve.

The introduction of additional players into the health care space also evokes questions of who owns this new health data set, and who is accountable for its integrity. If history is any indicator, device manufacturers will try their best to eschew any liability, and shift culpability onto patients and physicians. This is causing malpractice insurers to rethink policy coverage and forcing doctors to face a new reality of having “too much information.” While we are excited about the potential for better access to patient monitoring data, we agree that physicians need to understand where their responsibility for these data begins and ends.

Likewise, patients need to understand who has access to their personal health information, and how it’s being used. Privacy concerns will only become more evident as our society becomes ever more connected and as technologies become more invasive. The term “wearable” may soon become antiquated, as more products are coming to market that cross the skin barrier to collect samples directly from the blood or interstitial fluid. Devices such as Abbott’s new FreeStyle Libre continuous blood glucose monitor can be worn for weeks at a time, with its tiny sensor placed just under the skin. It constantly monitors trends in blood sugar and produces enough data points to determine the eating, sleeping, and activity habits of its wearer. This is all uploadable to Abbott’s servers, allowing patients and their providers to review it, thereby further expanding their personal health information footprint.

One encouraging aspect of the expansion mobile health technology is its organic, patient-led adoption. This is quite different from the epoch of electronic health records, which was motivated largely by government financial incentives and resulted in expensive, inefficient software. Patients are expressing a greater desire to take ownership of their health and have a growing interest in personal fitness. Also, the size of the consumer marketplace is forcing vendors to create competitive, high-value, and user-friendly mHealth devices. These products may seem to offer endless possibilities, but patients, vendors, and providers must fully acknowledge existing limitations in order to truly spark a revolution in wearable technology and actually improve patient care.

Dr. Notte is a family physician and clinical informaticist for Abington (Pa.) Memorial Hospital. He is a partner in EHR Practice Consultants, a firm that aids physicians in adopting electronic health records. Dr. Skolnik is a professor of family and community medicine at Jefferson Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington Jefferson Health.

References

1. Digital Health Study: Physicians’ motivations and requirements for adopting digital clinical tools. (2016) American Medical Association.

2. Kate Mclellan et al. v. Fitbit Inc. Fitbit Heart Rate Monitors Fraud & Defects Lawsuit.