Clinical

ORLANDO – An additional 14% of Americans have been reclassified as having hypertension – an increase from 32% to 46% of adults – under the latest guidelines on management of high blood pressure released by the American College of Cardiology and American Heart Association in 2017. However, this does not mean these patients are mandated for pharmacologic therapy, since most of them have been reclassified as having stage 1 hypertension, said Leslie L. Davis, PhD, RN, ANP-BC, FPCNA, FAANP, FAHA, associate professor of nursing at the University of North Carolina, Greensboro.

According to the new guidelines, normal BP is classified as less than 120 mm Hg systolic and less than 80 mm Hg diastolic. Elevated BP is 120-129 mm Hg systolic and under 80 mm Hg diastolic, while patients are classified as having stage 1 hypertension if their systolic BP is 130-139 mm Hg or diastolic BP is 80-90 mm Hg. Patients now have stage 2 hypertension if their systolic BP is higher than 140 mm Hg or diastolic BP is above 90 mm Hg.

This raises the importance of getting an accurate BP measurement from patients. At least two readings over two or more visits should be used before categorizing a patient. To take an ideal reading, patients should be sitting at rest with their back supported, feet positioned on a flat surface (no crossing legs), and their arm at heart level for at least 5 minutes. Patients should also refrain from tobacco or caffeine use 30 minutes before the reading. “These numbers need to be correct, because we’ve got new [BP] categories, and also for managing blood pressure, you’re making decisions based on these numbers,” said Dr. Davis at the Cardiovascular & Respiratory Summit by Global Academy for Medical Education.

When taking a patient’s BP, neither the patient nor the provider should talk, and constricting clothes on the upper extremity should be removed instead of pushed up. Using a incorrectly sized cuff can artificially raise or lower a patient’s BP level, so clinicians should use one that is 80% of the length and 40% of the width of the patient’s arm circumference. If the BP reading is elevated, confirm the reading in the other arm and use the arm with the higher reading for future measurements. BP measurements taken in different settings, such as ambulatory BP monitoring or home BP monitoring, can help give context to the in-office reading and whether the patient has white-coat hypertension or masked hypertension.

After a patient has their accurate BP reading, they can calculate their atherosclerotic cardiovascular disease (ASCVD) risk using the ACC’s ASCVD Risk Estimator, said Dr. Davis. If a patient has confirmed cardiovascular disease or has a 10% or greater 10-year ASCVD risk, the target to lower BP is 130 based on high-quality evidence, but expert opinion recommends targeting 130/80 for patients with confirmed hypertension as well.

In terms of nonpharmacologic therapies for these patients, the largest benefit is in getting patients to lose weight. “If somebody is overweight or obese, 10 pounds is 10 points,” said Dr. Davis. “Even if you don’t get them to the appropriate body mass index over 3 months’ time, that’s as much as a low or medium dose of antihypertensive therapy. For you to be able to get double-digit reduction, that’s what a med does.”

Other nonpharmacologic interventions for these patients include a heart-healthy diet such as the DASH diet, lowering sodium and increasing potassium, structuring exercise and physical activity, lowering use of or avoiding alcohol, and smoking cessation. The goal of nonpharmacologic therapy is not only to lower BP, but make the medication work better, said Dr. Davis.

Pharmacologic therapy should be initiated when patients exceed or are above the cutoff values for the new BP categories and if a patient has already had a cardiovascular event. “Basically, if you’re above that line in the sand of your goal, that’s when to start medications,” she said.

For stage 1 hypertension, first-line therapy is lifestyle change plus thiazides, calcium-channel blockers, or ACE inhibitors, with stage 1 hypertension therapy consisting of a combination of two first-line therapy therapies to reduce systolic BP by about 20 mm Hg and diastolic BP by 10 mm Hg. Beta-blockers are not first-line antihypertension therapy, but can be considered in patients with coronary artery disease and heart failure with reduced left ventricular ejection fraction.

With regard to follow-up, patients with low ASCVD risk and stage 1 hypertension can be monitored in 3-6 months after lifestyle changes, while patients with high ASCVD risk and stage 1 hypertension should be followed up in 1 month. Patients with stage 2 hypertension should follow up with their primary care provider 1 month after beginning their therapy, and those with very high BP should promptly be started on drug treatment with lifestyle changes, with upward dose adjustments as needed.

In adults aged 65 years or older, the ACC/AHA guidelines also focused on how to prevent cognitive decline and dementia, said Dr. Davis. The goal for ambulatory, community-dwelling adults is still to have a systolic BP of less than 130 mm Hg, but clinical judgment should prevail because of comorbid conditions and limited life expectancy in these patients. Patient preference should also be considered, and clinicians should use a team-based approach with shared decision making to determine goals for each patient.

Dr. Davis reported no relevant financial disclosures. Global Academy for Medical Education and this news organization are owned by the same parent company.

ORLANDO – An additional 14% of Americans have been reclassified as having hypertension – an increase from 32% to 46% of adults – under the latest guidelines on management of high blood pressure released by the American College of Cardiology and American Heart Association in 2017. However, this does not mean these patients are mandated for pharmacologic therapy, since most of them have been reclassified as having stage 1 hypertension, said Leslie L. Davis, PhD, RN, ANP-BC, FPCNA, FAANP, FAHA, associate professor of nursing at the University of North Carolina, Greensboro.

According to the new guidelines, normal BP is classified as less than 120 mm Hg systolic and less than 80 mm Hg diastolic. Elevated BP is 120-129 mm Hg systolic and under 80 mm Hg diastolic, while patients are classified as having stage 1 hypertension if their systolic BP is 130-139 mm Hg or diastolic BP is 80-90 mm Hg. Patients now have stage 2 hypertension if their systolic BP is higher than 140 mm Hg or diastolic BP is above 90 mm Hg.

This raises the importance of getting an accurate BP measurement from patients. At least two readings over two or more visits should be used before categorizing a patient. To take an ideal reading, patients should be sitting at rest with their back supported, feet positioned on a flat surface (no crossing legs), and their arm at heart level for at least 5 minutes. Patients should also refrain from tobacco or caffeine use 30 minutes before the reading. “These numbers need to be correct, because we’ve got new [BP] categories, and also for managing blood pressure, you’re making decisions based on these numbers,” said Dr. Davis at the Cardiovascular & Respiratory Summit by Global Academy for Medical Education.

When taking a patient’s BP, neither the patient nor the provider should talk, and constricting clothes on the upper extremity should be removed instead of pushed up. Using a incorrectly sized cuff can artificially raise or lower a patient’s BP level, so clinicians should use one that is 80% of the length and 40% of the width of the patient’s arm circumference. If the BP reading is elevated, confirm the reading in the other arm and use the arm with the higher reading for future measurements. BP measurements taken in different settings, such as ambulatory BP monitoring or home BP monitoring, can help give context to the in-office reading and whether the patient has white-coat hypertension or masked hypertension.

After a patient has their accurate BP reading, they can calculate their atherosclerotic cardiovascular disease (ASCVD) risk using the ACC’s ASCVD Risk Estimator, said Dr. Davis. If a patient has confirmed cardiovascular disease or has a 10% or greater 10-year ASCVD risk, the target to lower BP is 130 based on high-quality evidence, but expert opinion recommends targeting 130/80 for patients with confirmed hypertension as well.

In terms of nonpharmacologic therapies for these patients, the largest benefit is in getting patients to lose weight. “If somebody is overweight or obese, 10 pounds is 10 points,” said Dr. Davis. “Even if you don’t get them to the appropriate body mass index over 3 months’ time, that’s as much as a low or medium dose of antihypertensive therapy. For you to be able to get double-digit reduction, that’s what a med does.”

Other nonpharmacologic interventions for these patients include a heart-healthy diet such as the DASH diet, lowering sodium and increasing potassium, structuring exercise and physical activity, lowering use of or avoiding alcohol, and smoking cessation. The goal of nonpharmacologic therapy is not only to lower BP, but make the medication work better, said Dr. Davis.

Pharmacologic therapy should be initiated when patients exceed or are above the cutoff values for the new BP categories and if a patient has already had a cardiovascular event. “Basically, if you’re above that line in the sand of your goal, that’s when to start medications,” she said.

For stage 1 hypertension, first-line therapy is lifestyle change plus thiazides, calcium-channel blockers, or ACE inhibitors, with stage 1 hypertension therapy consisting of a combination of two first-line therapy therapies to reduce systolic BP by about 20 mm Hg and diastolic BP by 10 mm Hg. Beta-blockers are not first-line antihypertension therapy, but can be considered in patients with coronary artery disease and heart failure with reduced left ventricular ejection fraction.

With regard to follow-up, patients with low ASCVD risk and stage 1 hypertension can be monitored in 3-6 months after lifestyle changes, while patients with high ASCVD risk and stage 1 hypertension should be followed up in 1 month. Patients with stage 2 hypertension should follow up with their primary care provider 1 month after beginning their therapy, and those with very high BP should promptly be started on drug treatment with lifestyle changes, with upward dose adjustments as needed.

In adults aged 65 years or older, the ACC/AHA guidelines also focused on how to prevent cognitive decline and dementia, said Dr. Davis. The goal for ambulatory, community-dwelling adults is still to have a systolic BP of less than 130 mm Hg, but clinical judgment should prevail because of comorbid conditions and limited life expectancy in these patients. Patient preference should also be considered, and clinicians should use a team-based approach with shared decision making to determine goals for each patient.

Dr. Davis reported no relevant financial disclosures. Global Academy for Medical Education and this news organization are owned by the same parent company.

ORLANDO – An additional 14% of Americans have been reclassified as having hypertension – an increase from 32% to 46% of adults – under the latest guidelines on management of high blood pressure released by the American College of Cardiology and American Heart Association in 2017. However, this does not mean these patients are mandated for pharmacologic therapy, since most of them have been reclassified as having stage 1 hypertension, said Leslie L. Davis, PhD, RN, ANP-BC, FPCNA, FAANP, FAHA, associate professor of nursing at the University of North Carolina, Greensboro.

According to the new guidelines, normal BP is classified as less than 120 mm Hg systolic and less than 80 mm Hg diastolic. Elevated BP is 120-129 mm Hg systolic and under 80 mm Hg diastolic, while patients are classified as having stage 1 hypertension if their systolic BP is 130-139 mm Hg or diastolic BP is 80-90 mm Hg. Patients now have stage 2 hypertension if their systolic BP is higher than 140 mm Hg or diastolic BP is above 90 mm Hg.

This raises the importance of getting an accurate BP measurement from patients. At least two readings over two or more visits should be used before categorizing a patient. To take an ideal reading, patients should be sitting at rest with their back supported, feet positioned on a flat surface (no crossing legs), and their arm at heart level for at least 5 minutes. Patients should also refrain from tobacco or caffeine use 30 minutes before the reading. “These numbers need to be correct, because we’ve got new [BP] categories, and also for managing blood pressure, you’re making decisions based on these numbers,” said Dr. Davis at the Cardiovascular & Respiratory Summit by Global Academy for Medical Education.

When taking a patient’s BP, neither the patient nor the provider should talk, and constricting clothes on the upper extremity should be removed instead of pushed up. Using a incorrectly sized cuff can artificially raise or lower a patient’s BP level, so clinicians should use one that is 80% of the length and 40% of the width of the patient’s arm circumference. If the BP reading is elevated, confirm the reading in the other arm and use the arm with the higher reading for future measurements. BP measurements taken in different settings, such as ambulatory BP monitoring or home BP monitoring, can help give context to the in-office reading and whether the patient has white-coat hypertension or masked hypertension.

After a patient has their accurate BP reading, they can calculate their atherosclerotic cardiovascular disease (ASCVD) risk using the ACC’s ASCVD Risk Estimator, said Dr. Davis. If a patient has confirmed cardiovascular disease or has a 10% or greater 10-year ASCVD risk, the target to lower BP is 130 based on high-quality evidence, but expert opinion recommends targeting 130/80 for patients with confirmed hypertension as well.

In terms of nonpharmacologic therapies for these patients, the largest benefit is in getting patients to lose weight. “If somebody is overweight or obese, 10 pounds is 10 points,” said Dr. Davis. “Even if you don’t get them to the appropriate body mass index over 3 months’ time, that’s as much as a low or medium dose of antihypertensive therapy. For you to be able to get double-digit reduction, that’s what a med does.”

Other nonpharmacologic interventions for these patients include a heart-healthy diet such as the DASH diet, lowering sodium and increasing potassium, structuring exercise and physical activity, lowering use of or avoiding alcohol, and smoking cessation. The goal of nonpharmacologic therapy is not only to lower BP, but make the medication work better, said Dr. Davis.

Pharmacologic therapy should be initiated when patients exceed or are above the cutoff values for the new BP categories and if a patient has already had a cardiovascular event. “Basically, if you’re above that line in the sand of your goal, that’s when to start medications,” she said.

For stage 1 hypertension, first-line therapy is lifestyle change plus thiazides, calcium-channel blockers, or ACE inhibitors, with stage 1 hypertension therapy consisting of a combination of two first-line therapy therapies to reduce systolic BP by about 20 mm Hg and diastolic BP by 10 mm Hg. Beta-blockers are not first-line antihypertension therapy, but can be considered in patients with coronary artery disease and heart failure with reduced left ventricular ejection fraction.

With regard to follow-up, patients with low ASCVD risk and stage 1 hypertension can be monitored in 3-6 months after lifestyle changes, while patients with high ASCVD risk and stage 1 hypertension should be followed up in 1 month. Patients with stage 2 hypertension should follow up with their primary care provider 1 month after beginning their therapy, and those with very high BP should promptly be started on drug treatment with lifestyle changes, with upward dose adjustments as needed.

In adults aged 65 years or older, the ACC/AHA guidelines also focused on how to prevent cognitive decline and dementia, said Dr. Davis. The goal for ambulatory, community-dwelling adults is still to have a systolic BP of less than 130 mm Hg, but clinical judgment should prevail because of comorbid conditions and limited life expectancy in these patients. Patient preference should also be considered, and clinicians should use a team-based approach with shared decision making to determine goals for each patient.

Dr. Davis reported no relevant financial disclosures. Global Academy for Medical Education and this news organization are owned by the same parent company.

Case

A 42-year-old woman with uncontrolled diabetes presents to the ED with fever, chills, dysuria, and flank pain for 3 days. On exam, she is febrile and tachycardic. Lab results show leukocytosis and urinalysis is consistent with infection. CT scan shows acute pyelonephritis without complication. She is admitted to the hospital and started on ceftriaxone 2 g/24 hrs. On hospital day 2, her blood cultures show gram-negative bacteria.

Brief overview

Management of gram-negative (GN) bacteremia remains a challenging clinical situation for inpatient providers. With the push for high-value care and reductions in length of stay, recent literature has focused on reviewing current practices and attempting to standardize care. Despite this, no overarching guidelines exist to direct practice and clinicians are left to make decisions based on prior experience and expert opinion. Three key clinical questions exist when caring for a hospitalized patient with GN bacteremia: Should blood cultures be repeated? When is transition to oral antibiotics appropriate? And for what duration should antibiotics be given?

Overview of the data

When considering repeating blood cultures, it is important to understand that current literature does not support the practice for all GN bacteremias.

Canzoneri et al. retrospectively studied GN bacteremia and found that it took 17 repeat blood cultures being drawn to yield 1 positive result, which suggests that they are not necessary in all cases.¹ Furthermore, repeat blood cultures increase cost of hospitalization, length of stay, and inconvenience to patients.²

However, Mushtaq et al. noted that repeating blood cultures can provide valuable information to confirm the response to treatment in patients with endovascular infection. Furthermore, they found that repeated blood cultures are also reasonable when the following scenarios are suspected: endocarditis or central line–associated infection, concern for multidrug resistant GN bacilli, and ongoing evidence of sepsis or patient decompensation.³

Consideration of a transition from intravenous to oral antibiotics is a key decision point in the care of GN bacteremia. Without guidelines, clinicians are left to evaluate patients on a case-by-case basis.⁴ Studies have suggested that the transition should be guided by the condition of the patient, the type of infection, and the culture-derived sensitivities.⁵ Additionally, bioavailability of antibiotics (see Table 1) is an important consideration and a recent examination of oral antibiotic failure rates demonstrated that lower bioavailability antibiotics have an increased risk of failure (2% vs. 16%).⁶

In their study, Kutob et al. highlighted the importance of choosing not only an antibiotic of high bioavailability, but also an antibiotic dose which will support a high concentration of the antibiotic in the bloodstream.⁶ For example, they identify ciprofloxacin as a moderate bioavailability medication, but note that most cases they examined utilized 500 mg b.i.d., where the concentration-dependent killing and dose-dependent bioavailability would advocate for the use of 750 mg b.i.d. or 500 mg every 8 hours.

The heterogeneity of GN bloodstream infections also creates difficulty in standardization of care. The literature suggests that infection source plays a significant role in the type of GN bacteria isolated.^6,7 The best data for the transition to oral antibiotics exists with urologic sources and it remains unclear whether bacteria from other sources have higher risks of oral antibiotic failure.⁸

One recent study of 66 patients examined bacteremia in the setting of cholangitis and found that, once patients had stabilized, a switch from intravenous to oral antibiotics was noninferior, but randomized, prospective trials have not been performed. Notably, patients were transitioned to orals only after they were found to have a fluoroquinolone-sensitive infection, allowing the study authors to use higher-bioavailability agents for the transition to orals.⁹ Multiple studies have highlighted the unique care required for certain infections, such as pseudomonal infections, which most experts agree requires a more conservative approach.^5,6

Fluoroquinolones are the bedrock of therapy for GN bacteremia because of historic in vivo experience and in vitro findings about bioavailability and dose-dependent killing, but they are also the antibiotic class associated with the highest hospitalization rates for antibiotic-associated adverse events.⁸ A recent noninferiority trial comparing the use of beta-lactams with fluoroquinolones found that beta-lactams were noninferior, though the study was flawed by the limited number of beta-lactam–using patients identified.⁸ It is clear that more investigation is needed before recommendations can be made regarding ideal oral antibiotics for GN bacteremia.

The transition to oral is reasonable given the following criteria: the patient has improved on intravenous antibiotics and source control has been achieved; the culture data have demonstrated sensitivity to the oral antibiotic of choice, with special care given to higher-risk bacteria such as Pseudomonas; the patient is able to take the oral antibiotic; and the oral antibiotic of choice has the highest bioavailability possible and is given at an appropriate dose to reach its highest killing and bioavailability concentrations.⁷

After evaluating the appropriateness of transition to oral antibiotics, the final decision is about duration of antibiotic therapy. Current Infectious Disease Society of America guidelines are based on expert opinion and recommend 7-14 days of therapy. As with many common infections, recent studies have focused on evaluating reduction in antibiotic durations.

Chotiprasitsakul et al. demonstrated no difference in mortality or morbidity in 385 propensity-matched pairs with treatment of Enterobacteriaceae bacteremia for 8 versus 15 days.¹⁰ A mixed meta-analysis performed in 2011 evaluated 24 randomized, controlled trials and found shorter durations (5-7 days) had similar outcomes to prolonged durations (7-21 days).¹¹ Recently, Yahav et al. performed a randomized control trial comparing 7- and 14-day regimens for uncomplicated GN bacteremia and found a 7-day course to be noninferior if patients were clinically stable by day 5 and had source control.¹²

It should be noted that not all studies have found that reduced durations are without harm. Nelson et al. performed a retrospective cohort analysis and found that reduced durations of antibiotics (7-10 days) increased mortality and recurrent infection when compared with a longer course (greater than 10 days).¹³ These contrary findings highlight the need for provider discretion in selecting a course of antibiotics as well as the need for further studies about optimal duration of antibiotics.
 

Application of the data

Returning to our case, on day 3, the patient’s fever had resolved and leukocytosis improved. In the absence of concern for persistent infection, repeat blood cultures were not performed. On day 4 initial blood cultures showed pan-sensitive Escherichia coli. The patient was transitioned to 750 mg oral ciprofloxacin b.i.d. to complete a 10-day course from first dose of ceftriaxone and was discharged from the hospital.

Bottom line

Management of GN bacteremia requires individualized care based on clinical presentation, but the data presented above can be used as broad guidelines to help reduce excess blood cultures, avoid prolonged use of intravenous antibiotics, and limit the duration of antibiotic exposure.

Dr. Imber is an assistant professor in the division of hospital medicine at the University of New Mexico, Albuquerque, and director of the Internal Medicine Simulation Education and Hospitalist Procedural Certification. Dr. Burns is an assistant professor in the division of hospital medicine at the University of New Mexico. Dr. Chan is currently a chief resident in the department of internal medicine at the University of New Mexico.

References

1. Canzoneri CN et al. Follow-up blood cultures in gram-negative bacteremia: Are they needed? Clin Infect Dis. 2017;65(11):1776-9. doi: 10.1093/cid/cix648.

2. Kang CK et al. Can a routine follow-up blood culture be justified in Klebsiella pneumoniae bacteremia? A retrospective case-control study. BMC Infect Dis. 2013;13:365. doi: 10.1186/1471-2334-13-365.

3. Mushtaq A et al. Repeating blood cultures after an initial bacteremia: When and how often? Cleve Clin J Med. 2019;86(2):89-92. doi: 10.3949/ccjm.86a.18001.

4. Nimmich EB et al. Development of institutional guidelines for management of gram-negative bloodstream infections: Incorporating local evidence. Hosp Pharm. 2017;52(10):691-7. doi: 10.1177/0018578717720506.

5. Hale AJ et al. When are oral antibiotics a safe and effective choice for bacterial bloodstream infections? An evidence-based narrative review. J Hosp Med. 2018 May. doi: 10.12788/jhm.2949.

6. Kutob LF et al. Effectiveness of oral antibiotics for definitive therapy of gram-negative bloodstream infections. Int J Antimicrob Agents. 2016. doi: 10.1016/j.ijantimicag.2016.07.013.

7. Tamma PD et al. Association of 30-day mortality with oral step-down vs. continued intravenous therapy in patients hospitalized with Enterobacteriaceae bacteremia. JAMA Intern Med. 2019. doi: 10.1001/jamainternmed.2018.6226.

8. Mercuro NJ et al. Retrospective analysis comparing oral stepdown therapy for enterobacteriaceae bloodstream infections: fluoroquinolones vs. B-lactams. Int J Antimicrob Agents. 2017. doi: 10.1016/j.ijantimicag.2017.12.007.

9. Park TY et al. Early oral antibiotic switch compared with conventional intravenous antibiotic therapy for acute cholangitis with bacteremia. Dig Dis Sci. 2014;59:2790-6. doi: 10.1007/s10620-014-3233-0.

10. Chotiprasitsakul D et al. Comparing the outcomes of adults with Enterobacteriaceae bacteremia receiving short-course versus prolonged-course antibiotic therapy in a multicenter, propensity score-matched cohort. Clin Infect Dis. 2018;66(2):172-7. doi:10.1093/cid/cix767.

11. Havey TC et al. Duration of antibiotic therapy for bacteremia: a systematic review and meta-analysis. Crit Care. 2011;15(6):R267. doi:10.1186/cc10545.

12. Yahav D et al. Seven versus fourteen days of antibiotic therapy for uncomplicated gram-negative bacteremia: A noninferiority randomized controlled trial. Clin Infect Dis. 2018 Dec. doi:10.1093/cid/ciy1054.

13. Nelson AN et al. Optimal duration of antimicrobial therapy for uncomplicated gram-negative bloodstream infections. Infection. 2017;45(5):613-20. doi:10.1007/s15010-017-1020-5.

Case

A 42-year-old woman with uncontrolled diabetes presents to the ED with fever, chills, dysuria, and flank pain for 3 days. On exam, she is febrile and tachycardic. Lab results show leukocytosis and urinalysis is consistent with infection. CT scan shows acute pyelonephritis without complication. She is admitted to the hospital and started on ceftriaxone 2 g/24 hrs. On hospital day 2, her blood cultures show gram-negative bacteria.

Brief overview

Management of gram-negative (GN) bacteremia remains a challenging clinical situation for inpatient providers. With the push for high-value care and reductions in length of stay, recent literature has focused on reviewing current practices and attempting to standardize care. Despite this, no overarching guidelines exist to direct practice and clinicians are left to make decisions based on prior experience and expert opinion. Three key clinical questions exist when caring for a hospitalized patient with GN bacteremia: Should blood cultures be repeated? When is transition to oral antibiotics appropriate? And for what duration should antibiotics be given?

Overview of the data

When considering repeating blood cultures, it is important to understand that current literature does not support the practice for all GN bacteremias.

Canzoneri et al. retrospectively studied GN bacteremia and found that it took 17 repeat blood cultures being drawn to yield 1 positive result, which suggests that they are not necessary in all cases.¹ Furthermore, repeat blood cultures increase cost of hospitalization, length of stay, and inconvenience to patients.²

However, Mushtaq et al. noted that repeating blood cultures can provide valuable information to confirm the response to treatment in patients with endovascular infection. Furthermore, they found that repeated blood cultures are also reasonable when the following scenarios are suspected: endocarditis or central line–associated infection, concern for multidrug resistant GN bacilli, and ongoing evidence of sepsis or patient decompensation.³

Consideration of a transition from intravenous to oral antibiotics is a key decision point in the care of GN bacteremia. Without guidelines, clinicians are left to evaluate patients on a case-by-case basis.⁴ Studies have suggested that the transition should be guided by the condition of the patient, the type of infection, and the culture-derived sensitivities.⁵ Additionally, bioavailability of antibiotics (see Table 1) is an important consideration and a recent examination of oral antibiotic failure rates demonstrated that lower bioavailability antibiotics have an increased risk of failure (2% vs. 16%).⁶

In their study, Kutob et al. highlighted the importance of choosing not only an antibiotic of high bioavailability, but also an antibiotic dose which will support a high concentration of the antibiotic in the bloodstream.⁶ For example, they identify ciprofloxacin as a moderate bioavailability medication, but note that most cases they examined utilized 500 mg b.i.d., where the concentration-dependent killing and dose-dependent bioavailability would advocate for the use of 750 mg b.i.d. or 500 mg every 8 hours.

The heterogeneity of GN bloodstream infections also creates difficulty in standardization of care. The literature suggests that infection source plays a significant role in the type of GN bacteria isolated.^6,7 The best data for the transition to oral antibiotics exists with urologic sources and it remains unclear whether bacteria from other sources have higher risks of oral antibiotic failure.⁸

One recent study of 66 patients examined bacteremia in the setting of cholangitis and found that, once patients had stabilized, a switch from intravenous to oral antibiotics was noninferior, but randomized, prospective trials have not been performed. Notably, patients were transitioned to orals only after they were found to have a fluoroquinolone-sensitive infection, allowing the study authors to use higher-bioavailability agents for the transition to orals.⁹ Multiple studies have highlighted the unique care required for certain infections, such as pseudomonal infections, which most experts agree requires a more conservative approach.^5,6

Fluoroquinolones are the bedrock of therapy for GN bacteremia because of historic in vivo experience and in vitro findings about bioavailability and dose-dependent killing, but they are also the antibiotic class associated with the highest hospitalization rates for antibiotic-associated adverse events.⁸ A recent noninferiority trial comparing the use of beta-lactams with fluoroquinolones found that beta-lactams were noninferior, though the study was flawed by the limited number of beta-lactam–using patients identified.⁸ It is clear that more investigation is needed before recommendations can be made regarding ideal oral antibiotics for GN bacteremia.

The transition to oral is reasonable given the following criteria: the patient has improved on intravenous antibiotics and source control has been achieved; the culture data have demonstrated sensitivity to the oral antibiotic of choice, with special care given to higher-risk bacteria such as Pseudomonas; the patient is able to take the oral antibiotic; and the oral antibiotic of choice has the highest bioavailability possible and is given at an appropriate dose to reach its highest killing and bioavailability concentrations.⁷

After evaluating the appropriateness of transition to oral antibiotics, the final decision is about duration of antibiotic therapy. Current Infectious Disease Society of America guidelines are based on expert opinion and recommend 7-14 days of therapy. As with many common infections, recent studies have focused on evaluating reduction in antibiotic durations.

Chotiprasitsakul et al. demonstrated no difference in mortality or morbidity in 385 propensity-matched pairs with treatment of Enterobacteriaceae bacteremia for 8 versus 15 days.¹⁰ A mixed meta-analysis performed in 2011 evaluated 24 randomized, controlled trials and found shorter durations (5-7 days) had similar outcomes to prolonged durations (7-21 days).¹¹ Recently, Yahav et al. performed a randomized control trial comparing 7- and 14-day regimens for uncomplicated GN bacteremia and found a 7-day course to be noninferior if patients were clinically stable by day 5 and had source control.¹²

It should be noted that not all studies have found that reduced durations are without harm. Nelson et al. performed a retrospective cohort analysis and found that reduced durations of antibiotics (7-10 days) increased mortality and recurrent infection when compared with a longer course (greater than 10 days).¹³ These contrary findings highlight the need for provider discretion in selecting a course of antibiotics as well as the need for further studies about optimal duration of antibiotics.
 

Application of the data

Returning to our case, on day 3, the patient’s fever had resolved and leukocytosis improved. In the absence of concern for persistent infection, repeat blood cultures were not performed. On day 4 initial blood cultures showed pan-sensitive Escherichia coli. The patient was transitioned to 750 mg oral ciprofloxacin b.i.d. to complete a 10-day course from first dose of ceftriaxone and was discharged from the hospital.

Bottom line

Management of GN bacteremia requires individualized care based on clinical presentation, but the data presented above can be used as broad guidelines to help reduce excess blood cultures, avoid prolonged use of intravenous antibiotics, and limit the duration of antibiotic exposure.

Dr. Imber is an assistant professor in the division of hospital medicine at the University of New Mexico, Albuquerque, and director of the Internal Medicine Simulation Education and Hospitalist Procedural Certification. Dr. Burns is an assistant professor in the division of hospital medicine at the University of New Mexico. Dr. Chan is currently a chief resident in the department of internal medicine at the University of New Mexico.

References

1. Canzoneri CN et al. Follow-up blood cultures in gram-negative bacteremia: Are they needed? Clin Infect Dis. 2017;65(11):1776-9. doi: 10.1093/cid/cix648.

2. Kang CK et al. Can a routine follow-up blood culture be justified in Klebsiella pneumoniae bacteremia? A retrospective case-control study. BMC Infect Dis. 2013;13:365. doi: 10.1186/1471-2334-13-365.

3. Mushtaq A et al. Repeating blood cultures after an initial bacteremia: When and how often? Cleve Clin J Med. 2019;86(2):89-92. doi: 10.3949/ccjm.86a.18001.

4. Nimmich EB et al. Development of institutional guidelines for management of gram-negative bloodstream infections: Incorporating local evidence. Hosp Pharm. 2017;52(10):691-7. doi: 10.1177/0018578717720506.

5. Hale AJ et al. When are oral antibiotics a safe and effective choice for bacterial bloodstream infections? An evidence-based narrative review. J Hosp Med. 2018 May. doi: 10.12788/jhm.2949.

6. Kutob LF et al. Effectiveness of oral antibiotics for definitive therapy of gram-negative bloodstream infections. Int J Antimicrob Agents. 2016. doi: 10.1016/j.ijantimicag.2016.07.013.

7. Tamma PD et al. Association of 30-day mortality with oral step-down vs. continued intravenous therapy in patients hospitalized with Enterobacteriaceae bacteremia. JAMA Intern Med. 2019. doi: 10.1001/jamainternmed.2018.6226.

8. Mercuro NJ et al. Retrospective analysis comparing oral stepdown therapy for enterobacteriaceae bloodstream infections: fluoroquinolones vs. B-lactams. Int J Antimicrob Agents. 2017. doi: 10.1016/j.ijantimicag.2017.12.007.

9. Park TY et al. Early oral antibiotic switch compared with conventional intravenous antibiotic therapy for acute cholangitis with bacteremia. Dig Dis Sci. 2014;59:2790-6. doi: 10.1007/s10620-014-3233-0.

10. Chotiprasitsakul D et al. Comparing the outcomes of adults with Enterobacteriaceae bacteremia receiving short-course versus prolonged-course antibiotic therapy in a multicenter, propensity score-matched cohort. Clin Infect Dis. 2018;66(2):172-7. doi:10.1093/cid/cix767.

11. Havey TC et al. Duration of antibiotic therapy for bacteremia: a systematic review and meta-analysis. Crit Care. 2011;15(6):R267. doi:10.1186/cc10545.

12. Yahav D et al. Seven versus fourteen days of antibiotic therapy for uncomplicated gram-negative bacteremia: A noninferiority randomized controlled trial. Clin Infect Dis. 2018 Dec. doi:10.1093/cid/ciy1054.

13. Nelson AN et al. Optimal duration of antimicrobial therapy for uncomplicated gram-negative bloodstream infections. Infection. 2017;45(5):613-20. doi:10.1007/s15010-017-1020-5.

Case

A 42-year-old woman with uncontrolled diabetes presents to the ED with fever, chills, dysuria, and flank pain for 3 days. On exam, she is febrile and tachycardic. Lab results show leukocytosis and urinalysis is consistent with infection. CT scan shows acute pyelonephritis without complication. She is admitted to the hospital and started on ceftriaxone 2 g/24 hrs. On hospital day 2, her blood cultures show gram-negative bacteria.

Brief overview

Management of gram-negative (GN) bacteremia remains a challenging clinical situation for inpatient providers. With the push for high-value care and reductions in length of stay, recent literature has focused on reviewing current practices and attempting to standardize care. Despite this, no overarching guidelines exist to direct practice and clinicians are left to make decisions based on prior experience and expert opinion. Three key clinical questions exist when caring for a hospitalized patient with GN bacteremia: Should blood cultures be repeated? When is transition to oral antibiotics appropriate? And for what duration should antibiotics be given?

Overview of the data

When considering repeating blood cultures, it is important to understand that current literature does not support the practice for all GN bacteremias.

Canzoneri et al. retrospectively studied GN bacteremia and found that it took 17 repeat blood cultures being drawn to yield 1 positive result, which suggests that they are not necessary in all cases.¹ Furthermore, repeat blood cultures increase cost of hospitalization, length of stay, and inconvenience to patients.²

However, Mushtaq et al. noted that repeating blood cultures can provide valuable information to confirm the response to treatment in patients with endovascular infection. Furthermore, they found that repeated blood cultures are also reasonable when the following scenarios are suspected: endocarditis or central line–associated infection, concern for multidrug resistant GN bacilli, and ongoing evidence of sepsis or patient decompensation.³

Consideration of a transition from intravenous to oral antibiotics is a key decision point in the care of GN bacteremia. Without guidelines, clinicians are left to evaluate patients on a case-by-case basis.⁴ Studies have suggested that the transition should be guided by the condition of the patient, the type of infection, and the culture-derived sensitivities.⁵ Additionally, bioavailability of antibiotics (see Table 1) is an important consideration and a recent examination of oral antibiotic failure rates demonstrated that lower bioavailability antibiotics have an increased risk of failure (2% vs. 16%).⁶

In their study, Kutob et al. highlighted the importance of choosing not only an antibiotic of high bioavailability, but also an antibiotic dose which will support a high concentration of the antibiotic in the bloodstream.⁶ For example, they identify ciprofloxacin as a moderate bioavailability medication, but note that most cases they examined utilized 500 mg b.i.d., where the concentration-dependent killing and dose-dependent bioavailability would advocate for the use of 750 mg b.i.d. or 500 mg every 8 hours.

The heterogeneity of GN bloodstream infections also creates difficulty in standardization of care. The literature suggests that infection source plays a significant role in the type of GN bacteria isolated.^6,7 The best data for the transition to oral antibiotics exists with urologic sources and it remains unclear whether bacteria from other sources have higher risks of oral antibiotic failure.⁸

One recent study of 66 patients examined bacteremia in the setting of cholangitis and found that, once patients had stabilized, a switch from intravenous to oral antibiotics was noninferior, but randomized, prospective trials have not been performed. Notably, patients were transitioned to orals only after they were found to have a fluoroquinolone-sensitive infection, allowing the study authors to use higher-bioavailability agents for the transition to orals.⁹ Multiple studies have highlighted the unique care required for certain infections, such as pseudomonal infections, which most experts agree requires a more conservative approach.^5,6

Fluoroquinolones are the bedrock of therapy for GN bacteremia because of historic in vivo experience and in vitro findings about bioavailability and dose-dependent killing, but they are also the antibiotic class associated with the highest hospitalization rates for antibiotic-associated adverse events.⁸ A recent noninferiority trial comparing the use of beta-lactams with fluoroquinolones found that beta-lactams were noninferior, though the study was flawed by the limited number of beta-lactam–using patients identified.⁸ It is clear that more investigation is needed before recommendations can be made regarding ideal oral antibiotics for GN bacteremia.

The transition to oral is reasonable given the following criteria: the patient has improved on intravenous antibiotics and source control has been achieved; the culture data have demonstrated sensitivity to the oral antibiotic of choice, with special care given to higher-risk bacteria such as Pseudomonas; the patient is able to take the oral antibiotic; and the oral antibiotic of choice has the highest bioavailability possible and is given at an appropriate dose to reach its highest killing and bioavailability concentrations.⁷

After evaluating the appropriateness of transition to oral antibiotics, the final decision is about duration of antibiotic therapy. Current Infectious Disease Society of America guidelines are based on expert opinion and recommend 7-14 days of therapy. As with many common infections, recent studies have focused on evaluating reduction in antibiotic durations.

Chotiprasitsakul et al. demonstrated no difference in mortality or morbidity in 385 propensity-matched pairs with treatment of Enterobacteriaceae bacteremia for 8 versus 15 days.¹⁰ A mixed meta-analysis performed in 2011 evaluated 24 randomized, controlled trials and found shorter durations (5-7 days) had similar outcomes to prolonged durations (7-21 days).¹¹ Recently, Yahav et al. performed a randomized control trial comparing 7- and 14-day regimens for uncomplicated GN bacteremia and found a 7-day course to be noninferior if patients were clinically stable by day 5 and had source control.¹²

It should be noted that not all studies have found that reduced durations are without harm. Nelson et al. performed a retrospective cohort analysis and found that reduced durations of antibiotics (7-10 days) increased mortality and recurrent infection when compared with a longer course (greater than 10 days).¹³ These contrary findings highlight the need for provider discretion in selecting a course of antibiotics as well as the need for further studies about optimal duration of antibiotics.
 

Application of the data

Returning to our case, on day 3, the patient’s fever had resolved and leukocytosis improved. In the absence of concern for persistent infection, repeat blood cultures were not performed. On day 4 initial blood cultures showed pan-sensitive Escherichia coli. The patient was transitioned to 750 mg oral ciprofloxacin b.i.d. to complete a 10-day course from first dose of ceftriaxone and was discharged from the hospital.

Bottom line

Management of GN bacteremia requires individualized care based on clinical presentation, but the data presented above can be used as broad guidelines to help reduce excess blood cultures, avoid prolonged use of intravenous antibiotics, and limit the duration of antibiotic exposure.

Dr. Imber is an assistant professor in the division of hospital medicine at the University of New Mexico, Albuquerque, and director of the Internal Medicine Simulation Education and Hospitalist Procedural Certification. Dr. Burns is an assistant professor in the division of hospital medicine at the University of New Mexico. Dr. Chan is currently a chief resident in the department of internal medicine at the University of New Mexico.

References

1. Canzoneri CN et al. Follow-up blood cultures in gram-negative bacteremia: Are they needed? Clin Infect Dis. 2017;65(11):1776-9. doi: 10.1093/cid/cix648.

2. Kang CK et al. Can a routine follow-up blood culture be justified in Klebsiella pneumoniae bacteremia? A retrospective case-control study. BMC Infect Dis. 2013;13:365. doi: 10.1186/1471-2334-13-365.

3. Mushtaq A et al. Repeating blood cultures after an initial bacteremia: When and how often? Cleve Clin J Med. 2019;86(2):89-92. doi: 10.3949/ccjm.86a.18001.

4. Nimmich EB et al. Development of institutional guidelines for management of gram-negative bloodstream infections: Incorporating local evidence. Hosp Pharm. 2017;52(10):691-7. doi: 10.1177/0018578717720506.

5. Hale AJ et al. When are oral antibiotics a safe and effective choice for bacterial bloodstream infections? An evidence-based narrative review. J Hosp Med. 2018 May. doi: 10.12788/jhm.2949.

6. Kutob LF et al. Effectiveness of oral antibiotics for definitive therapy of gram-negative bloodstream infections. Int J Antimicrob Agents. 2016. doi: 10.1016/j.ijantimicag.2016.07.013.

7. Tamma PD et al. Association of 30-day mortality with oral step-down vs. continued intravenous therapy in patients hospitalized with Enterobacteriaceae bacteremia. JAMA Intern Med. 2019. doi: 10.1001/jamainternmed.2018.6226.

8. Mercuro NJ et al. Retrospective analysis comparing oral stepdown therapy for enterobacteriaceae bloodstream infections: fluoroquinolones vs. B-lactams. Int J Antimicrob Agents. 2017. doi: 10.1016/j.ijantimicag.2017.12.007.

9. Park TY et al. Early oral antibiotic switch compared with conventional intravenous antibiotic therapy for acute cholangitis with bacteremia. Dig Dis Sci. 2014;59:2790-6. doi: 10.1007/s10620-014-3233-0.

10. Chotiprasitsakul D et al. Comparing the outcomes of adults with Enterobacteriaceae bacteremia receiving short-course versus prolonged-course antibiotic therapy in a multicenter, propensity score-matched cohort. Clin Infect Dis. 2018;66(2):172-7. doi:10.1093/cid/cix767.

11. Havey TC et al. Duration of antibiotic therapy for bacteremia: a systematic review and meta-analysis. Crit Care. 2011;15(6):R267. doi:10.1186/cc10545.

12. Yahav D et al. Seven versus fourteen days of antibiotic therapy for uncomplicated gram-negative bacteremia: A noninferiority randomized controlled trial. Clin Infect Dis. 2018 Dec. doi:10.1093/cid/ciy1054.

13. Nelson AN et al. Optimal duration of antimicrobial therapy for uncomplicated gram-negative bloodstream infections. Infection. 2017;45(5):613-20. doi:10.1007/s15010-017-1020-5.

SAN DIEGO – Two leading figures in microbiome research took time during the annual Digestive Disease Week to share their perspective with members of the press. Identifying key research presented at the meeting and painting a broader picture of trends and challenges in research on the interplay with the microbiota with gut health, Colleen Kelly, MD, of Brown University, Providence, R.I., cochair and principal investigator, AGA FMT Registry Steering Committee, led off the round table with a discussion of human research on fecal microbial transplantation (FMT) and obesity.

Purna Kashyap, MBBS, of the Mayo Clinic, Rochester, Minn., member, AGA Center for Gut Microbiome Research and Education Scientific Advisory Board, delved into the potential for donor microbiota transplant to address small bowel disorders, such as small intestinal bacterial overgrowth, and provided commentary regarding the potential – and limitations – of using FMT in functional bowel disorders such as irritable bowel syndrome (IBS).

Obesity

Dr. Kelly noted that two abstracts at the conference presented data about FMT in obesity. The first study was presented by Jessica Allegretti, MD, a gastroenterologist at Brigham and Women’s Hospital, Boston; the second study was presented by Elaine Yu, MD, an endocrinologist at Massachusetts General Hospital, Boston.

The two studies shared some similarities, but had some differences, said Dr. Kelly. “They both used lean donor encapsulated FMT ... and they both were placebo controlled, using placebo capsules.” The first study looked at metabolically healthy obese patients, while the second study included patients with mild to moderate insulin resistance.

Dr. Allegretti’s work looked at the effect that FMT from lean donors had on levels of a satiety peptide, glucagonlike peptide–1 (GLP-1), while also looking at changes in weight and microbiota, as well as safety. Patients received an initial 30-capsule dose as well as two later doses of 12 capsules each. The 22-patient study, in which individuals were randomized 1:1 to FMT or placebo capsules, didn’t show statistically significant changes in GLP-1 levels or body mass index with FMT over the 12-week study period. “But they were able to show engraftment, which I think is an important thing that you do wonder about – over this period of time, the bacteria that came from the lean donor actually engrafted into the recipient and affected the diversity. The recipient became more similar to the donor,” said Dr. Kelly.

There were some clues among the findings that engraftment was effecting metabolic change in the recipient, she said, including differences in bile acid conversion among gut bacteria; also, lower levels of the primary bile acid taurocholic acid in recipients after FMT. “So it was a negative study in what she was looking for, but an example of these smaller studies kind of pushing the field along.”

In discussing the study presented by Dr. Yu that examined lean donor FMT in individuals with insulin resistance, Dr. Kelly said, “It was actually pretty sophisticated.” By using hyperinsulinemic euglycemic clamping, the investigators were able to measure insulin sensitivity based on glucose load. In this study of 24 individuals randomized 1:1 to receive FMT or placebo capsules, recipients received weekly doses over a period of 6 weeks. Here again, though Dr. Yu and colleagues again found engraftment, “they did not find the big changes in metabolic parameters that they hoped that they would,” said Dr. Kelly.

These two studies furthered previous work completed in the Netherlands examining lean donor FMT for individuals with metabolic syndrome. “Those [studies] did show both engraftment and some changes in insulin resistance,” but they were also small studies, noted Dr. Kelly. Dr. Kashyap pointed out that the earlier studies had shown in a subgroup analysis that response to FMT was limited to those patients who lacked microbial diversity pretransplant.

This makes some mechanistic sense when thinking about FMT’s greatest success to date: Treating Clostridioides difficile infection, a condition whose very hallmark is dysbiosis characterized by monospecies gut domination, noted Dr. Kashyap.

Added Dr. Kelly, “I think everyone’s hoping there’s going to be this pill that’s going to make us skinny, but I don’t think we’re going to find that with FMT and obesity. I do think these studies are important, because there’s so much animal data already, and we’re kind of like, ‘How much more can you do in mice?’ ” By translating this preclinical work into humans, the mechanisms of obesity and the role of the microbiome can be better understood.

IBS

Turning to functional bowel disorders, Dr. Kelly pointed out a new study examining FMT for IBS. “So far, the research has been pretty disappointing,” she noted. The study, presented by Prashant Singh, MBBS, a gastroenterology fellow at Beth Israel Deaconess Medical Center, Boston, examined FMT for patients with moderate to severe diarrhea-predominant IBS. The study had four arms, randomizing the 44 participants to FMT alone; pretreatment with metronidazole and ciprofloxacin or rifaximin, each followed by FMT; or placebo. “It really didn’t show any differences in their severity of IBS in any group; so no effect: a negative study,” said Dr. Kelly.

“It’s challenging. FMT is an appealing strategy because we don’t have to put a lot of thought process into it,” said Dr. Kashyap, but it’s no panacea. “We aren’t going to be able to treat everybody with FMT.

“The challenge with IBS is that if we look at all the compositional studies, the majority of them show that at least a big subset of patients with IBS already have a normal-appearing microbiome,” said Dr. Kashyap. In those patients, “It’s very hard to know what FMT is doing.” He noted that IBS subclassifications are made by pathophysiology, without regard to the intestinal microbiome, so these classifications may not be useful for determining who may benefit from FMT.

“Again, there’s always an opportunity to learn from these studies,” whether they’re positive or negative, as long as they’re well done, said Dr. Kashyap. “There’s always an opportunity to go back and see, was there a specific subgroup of patients who responded, where there might be one or more causes which might be more amenable” to FMT.

Small intestine

And most intestinal microbial research to date, noted Dr. Kelly, has focused on the colon. “Most of our knowledge is of fecal microbiota.” New techniques including double-balloon enteroscopy of the small bowel have promise to “provide completely new information about patterns of bacteria throughout the small bowel,” and of the role of small bowel bacteria in overall gut health, she said.

“The role of the small bowel has been ignored because of accessibility,” agreed Dr. Kashyap. There’s a current focus on research into enteroscopy and other techniques to sample small intestine microbiota, he said.

In a podium presentation, Eugene Chang, MD, Martin Boyer Professor in the University of Chicago’s department of medicine, gave a broad overview of how the small intestine microbiome modulates lipid regulation. This choice of topic for the Charles M. Mansbach Memorial Lecture shows that gastroenterologists are recognizing the importance of microbiome along the entire span of the gut, said Dr. Kashyap. Dr. Chang’s approach, he added, represents a departure in that “it’s not simply just looking at what’s present and what’s not, but seeing what’s functionally relevant to metabolism.”

“We always have known that the small intestine is the workhorse; that’s where everything happens” in terms of motility, absorption, and digestion, said Dr. Kashyap. “But because of our inability to reach it easily we’ve always chosen to ignore it; we always go after the low-hanging fruit.” Despite challenges, more microbiome research should be small-bowel focused. “Eventually, it’s no pain, no gain.”

Dr. Kashyap is on the advisory board of uBiome, and is an ad hoc advisory board member for Salix Pharmaceuticals. Dr. Kelly reported no conflicts of interest.

This story was updated on July 30, 2019.

[email protected]

SAN DIEGO – Two leading figures in microbiome research took time during the annual Digestive Disease Week to share their perspective with members of the press. Identifying key research presented at the meeting and painting a broader picture of trends and challenges in research on the interplay with the microbiota with gut health, Colleen Kelly, MD, of Brown University, Providence, R.I., cochair and principal investigator, AGA FMT Registry Steering Committee, led off the round table with a discussion of human research on fecal microbial transplantation (FMT) and obesity.

Purna Kashyap, MBBS, of the Mayo Clinic, Rochester, Minn., member, AGA Center for Gut Microbiome Research and Education Scientific Advisory Board, delved into the potential for donor microbiota transplant to address small bowel disorders, such as small intestinal bacterial overgrowth, and provided commentary regarding the potential – and limitations – of using FMT in functional bowel disorders such as irritable bowel syndrome (IBS).

Obesity

Dr. Kelly noted that two abstracts at the conference presented data about FMT in obesity. The first study was presented by Jessica Allegretti, MD, a gastroenterologist at Brigham and Women’s Hospital, Boston; the second study was presented by Elaine Yu, MD, an endocrinologist at Massachusetts General Hospital, Boston.

The two studies shared some similarities, but had some differences, said Dr. Kelly. “They both used lean donor encapsulated FMT ... and they both were placebo controlled, using placebo capsules.” The first study looked at metabolically healthy obese patients, while the second study included patients with mild to moderate insulin resistance.

Dr. Allegretti’s work looked at the effect that FMT from lean donors had on levels of a satiety peptide, glucagonlike peptide–1 (GLP-1), while also looking at changes in weight and microbiota, as well as safety. Patients received an initial 30-capsule dose as well as two later doses of 12 capsules each. The 22-patient study, in which individuals were randomized 1:1 to FMT or placebo capsules, didn’t show statistically significant changes in GLP-1 levels or body mass index with FMT over the 12-week study period. “But they were able to show engraftment, which I think is an important thing that you do wonder about – over this period of time, the bacteria that came from the lean donor actually engrafted into the recipient and affected the diversity. The recipient became more similar to the donor,” said Dr. Kelly.

There were some clues among the findings that engraftment was effecting metabolic change in the recipient, she said, including differences in bile acid conversion among gut bacteria; also, lower levels of the primary bile acid taurocholic acid in recipients after FMT. “So it was a negative study in what she was looking for, but an example of these smaller studies kind of pushing the field along.”

In discussing the study presented by Dr. Yu that examined lean donor FMT in individuals with insulin resistance, Dr. Kelly said, “It was actually pretty sophisticated.” By using hyperinsulinemic euglycemic clamping, the investigators were able to measure insulin sensitivity based on glucose load. In this study of 24 individuals randomized 1:1 to receive FMT or placebo capsules, recipients received weekly doses over a period of 6 weeks. Here again, though Dr. Yu and colleagues again found engraftment, “they did not find the big changes in metabolic parameters that they hoped that they would,” said Dr. Kelly.

These two studies furthered previous work completed in the Netherlands examining lean donor FMT for individuals with metabolic syndrome. “Those [studies] did show both engraftment and some changes in insulin resistance,” but they were also small studies, noted Dr. Kelly. Dr. Kashyap pointed out that the earlier studies had shown in a subgroup analysis that response to FMT was limited to those patients who lacked microbial diversity pretransplant.

This makes some mechanistic sense when thinking about FMT’s greatest success to date: Treating Clostridioides difficile infection, a condition whose very hallmark is dysbiosis characterized by monospecies gut domination, noted Dr. Kashyap.

Added Dr. Kelly, “I think everyone’s hoping there’s going to be this pill that’s going to make us skinny, but I don’t think we’re going to find that with FMT and obesity. I do think these studies are important, because there’s so much animal data already, and we’re kind of like, ‘How much more can you do in mice?’ ” By translating this preclinical work into humans, the mechanisms of obesity and the role of the microbiome can be better understood.

IBS

Turning to functional bowel disorders, Dr. Kelly pointed out a new study examining FMT for IBS. “So far, the research has been pretty disappointing,” she noted. The study, presented by Prashant Singh, MBBS, a gastroenterology fellow at Beth Israel Deaconess Medical Center, Boston, examined FMT for patients with moderate to severe diarrhea-predominant IBS. The study had four arms, randomizing the 44 participants to FMT alone; pretreatment with metronidazole and ciprofloxacin or rifaximin, each followed by FMT; or placebo. “It really didn’t show any differences in their severity of IBS in any group; so no effect: a negative study,” said Dr. Kelly.

“It’s challenging. FMT is an appealing strategy because we don’t have to put a lot of thought process into it,” said Dr. Kashyap, but it’s no panacea. “We aren’t going to be able to treat everybody with FMT.

“The challenge with IBS is that if we look at all the compositional studies, the majority of them show that at least a big subset of patients with IBS already have a normal-appearing microbiome,” said Dr. Kashyap. In those patients, “It’s very hard to know what FMT is doing.” He noted that IBS subclassifications are made by pathophysiology, without regard to the intestinal microbiome, so these classifications may not be useful for determining who may benefit from FMT.

“Again, there’s always an opportunity to learn from these studies,” whether they’re positive or negative, as long as they’re well done, said Dr. Kashyap. “There’s always an opportunity to go back and see, was there a specific subgroup of patients who responded, where there might be one or more causes which might be more amenable” to FMT.

Small intestine

And most intestinal microbial research to date, noted Dr. Kelly, has focused on the colon. “Most of our knowledge is of fecal microbiota.” New techniques including double-balloon enteroscopy of the small bowel have promise to “provide completely new information about patterns of bacteria throughout the small bowel,” and of the role of small bowel bacteria in overall gut health, she said.

“The role of the small bowel has been ignored because of accessibility,” agreed Dr. Kashyap. There’s a current focus on research into enteroscopy and other techniques to sample small intestine microbiota, he said.

In a podium presentation, Eugene Chang, MD, Martin Boyer Professor in the University of Chicago’s department of medicine, gave a broad overview of how the small intestine microbiome modulates lipid regulation. This choice of topic for the Charles M. Mansbach Memorial Lecture shows that gastroenterologists are recognizing the importance of microbiome along the entire span of the gut, said Dr. Kashyap. Dr. Chang’s approach, he added, represents a departure in that “it’s not simply just looking at what’s present and what’s not, but seeing what’s functionally relevant to metabolism.”

“We always have known that the small intestine is the workhorse; that’s where everything happens” in terms of motility, absorption, and digestion, said Dr. Kashyap. “But because of our inability to reach it easily we’ve always chosen to ignore it; we always go after the low-hanging fruit.” Despite challenges, more microbiome research should be small-bowel focused. “Eventually, it’s no pain, no gain.”

Dr. Kashyap is on the advisory board of uBiome, and is an ad hoc advisory board member for Salix Pharmaceuticals. Dr. Kelly reported no conflicts of interest.

This story was updated on July 30, 2019.

[email protected]

SAN DIEGO – Two leading figures in microbiome research took time during the annual Digestive Disease Week to share their perspective with members of the press. Identifying key research presented at the meeting and painting a broader picture of trends and challenges in research on the interplay with the microbiota with gut health, Colleen Kelly, MD, of Brown University, Providence, R.I., cochair and principal investigator, AGA FMT Registry Steering Committee, led off the round table with a discussion of human research on fecal microbial transplantation (FMT) and obesity.

Purna Kashyap, MBBS, of the Mayo Clinic, Rochester, Minn., member, AGA Center for Gut Microbiome Research and Education Scientific Advisory Board, delved into the potential for donor microbiota transplant to address small bowel disorders, such as small intestinal bacterial overgrowth, and provided commentary regarding the potential – and limitations – of using FMT in functional bowel disorders such as irritable bowel syndrome (IBS).

Obesity

Dr. Kelly noted that two abstracts at the conference presented data about FMT in obesity. The first study was presented by Jessica Allegretti, MD, a gastroenterologist at Brigham and Women’s Hospital, Boston; the second study was presented by Elaine Yu, MD, an endocrinologist at Massachusetts General Hospital, Boston.

The two studies shared some similarities, but had some differences, said Dr. Kelly. “They both used lean donor encapsulated FMT ... and they both were placebo controlled, using placebo capsules.” The first study looked at metabolically healthy obese patients, while the second study included patients with mild to moderate insulin resistance.

Dr. Allegretti’s work looked at the effect that FMT from lean donors had on levels of a satiety peptide, glucagonlike peptide–1 (GLP-1), while also looking at changes in weight and microbiota, as well as safety. Patients received an initial 30-capsule dose as well as two later doses of 12 capsules each. The 22-patient study, in which individuals were randomized 1:1 to FMT or placebo capsules, didn’t show statistically significant changes in GLP-1 levels or body mass index with FMT over the 12-week study period. “But they were able to show engraftment, which I think is an important thing that you do wonder about – over this period of time, the bacteria that came from the lean donor actually engrafted into the recipient and affected the diversity. The recipient became more similar to the donor,” said Dr. Kelly.

There were some clues among the findings that engraftment was effecting metabolic change in the recipient, she said, including differences in bile acid conversion among gut bacteria; also, lower levels of the primary bile acid taurocholic acid in recipients after FMT. “So it was a negative study in what she was looking for, but an example of these smaller studies kind of pushing the field along.”

In discussing the study presented by Dr. Yu that examined lean donor FMT in individuals with insulin resistance, Dr. Kelly said, “It was actually pretty sophisticated.” By using hyperinsulinemic euglycemic clamping, the investigators were able to measure insulin sensitivity based on glucose load. In this study of 24 individuals randomized 1:1 to receive FMT or placebo capsules, recipients received weekly doses over a period of 6 weeks. Here again, though Dr. Yu and colleagues again found engraftment, “they did not find the big changes in metabolic parameters that they hoped that they would,” said Dr. Kelly.

These two studies furthered previous work completed in the Netherlands examining lean donor FMT for individuals with metabolic syndrome. “Those [studies] did show both engraftment and some changes in insulin resistance,” but they were also small studies, noted Dr. Kelly. Dr. Kashyap pointed out that the earlier studies had shown in a subgroup analysis that response to FMT was limited to those patients who lacked microbial diversity pretransplant.

This makes some mechanistic sense when thinking about FMT’s greatest success to date: Treating Clostridioides difficile infection, a condition whose very hallmark is dysbiosis characterized by monospecies gut domination, noted Dr. Kashyap.

Added Dr. Kelly, “I think everyone’s hoping there’s going to be this pill that’s going to make us skinny, but I don’t think we’re going to find that with FMT and obesity. I do think these studies are important, because there’s so much animal data already, and we’re kind of like, ‘How much more can you do in mice?’ ” By translating this preclinical work into humans, the mechanisms of obesity and the role of the microbiome can be better understood.

IBS

Turning to functional bowel disorders, Dr. Kelly pointed out a new study examining FMT for IBS. “So far, the research has been pretty disappointing,” she noted. The study, presented by Prashant Singh, MBBS, a gastroenterology fellow at Beth Israel Deaconess Medical Center, Boston, examined FMT for patients with moderate to severe diarrhea-predominant IBS. The study had four arms, randomizing the 44 participants to FMT alone; pretreatment with metronidazole and ciprofloxacin or rifaximin, each followed by FMT; or placebo. “It really didn’t show any differences in their severity of IBS in any group; so no effect: a negative study,” said Dr. Kelly.

“It’s challenging. FMT is an appealing strategy because we don’t have to put a lot of thought process into it,” said Dr. Kashyap, but it’s no panacea. “We aren’t going to be able to treat everybody with FMT.

“The challenge with IBS is that if we look at all the compositional studies, the majority of them show that at least a big subset of patients with IBS already have a normal-appearing microbiome,” said Dr. Kashyap. In those patients, “It’s very hard to know what FMT is doing.” He noted that IBS subclassifications are made by pathophysiology, without regard to the intestinal microbiome, so these classifications may not be useful for determining who may benefit from FMT.

“Again, there’s always an opportunity to learn from these studies,” whether they’re positive or negative, as long as they’re well done, said Dr. Kashyap. “There’s always an opportunity to go back and see, was there a specific subgroup of patients who responded, where there might be one or more causes which might be more amenable” to FMT.

Small intestine

And most intestinal microbial research to date, noted Dr. Kelly, has focused on the colon. “Most of our knowledge is of fecal microbiota.” New techniques including double-balloon enteroscopy of the small bowel have promise to “provide completely new information about patterns of bacteria throughout the small bowel,” and of the role of small bowel bacteria in overall gut health, she said.

“The role of the small bowel has been ignored because of accessibility,” agreed Dr. Kashyap. There’s a current focus on research into enteroscopy and other techniques to sample small intestine microbiota, he said.

In a podium presentation, Eugene Chang, MD, Martin Boyer Professor in the University of Chicago’s department of medicine, gave a broad overview of how the small intestine microbiome modulates lipid regulation. This choice of topic for the Charles M. Mansbach Memorial Lecture shows that gastroenterologists are recognizing the importance of microbiome along the entire span of the gut, said Dr. Kashyap. Dr. Chang’s approach, he added, represents a departure in that “it’s not simply just looking at what’s present and what’s not, but seeing what’s functionally relevant to metabolism.”

“We always have known that the small intestine is the workhorse; that’s where everything happens” in terms of motility, absorption, and digestion, said Dr. Kashyap. “But because of our inability to reach it easily we’ve always chosen to ignore it; we always go after the low-hanging fruit.” Despite challenges, more microbiome research should be small-bowel focused. “Eventually, it’s no pain, no gain.”

Dr. Kashyap is on the advisory board of uBiome, and is an ad hoc advisory board member for Salix Pharmaceuticals. Dr. Kelly reported no conflicts of interest.

This story was updated on July 30, 2019.

[email protected]

Clinical question: Among older adults, what attitudes exist toward deprescribing?

Background: Polypharmacy in older adults is common and can be associated with increased hospitalizations and reduced quality of life.

Study design: Population-based survey study.

Setting: Medicare beneficiaries in the United States.

Dr. Stanley is assistant professor of medicine at Northwestern University Feinberg School of Medicine and a hospitalist at Northwestern Memorial Hospital, both in Chicago.

Clinical question: Among older adults, what attitudes exist toward deprescribing?

Background: Polypharmacy in older adults is common and can be associated with increased hospitalizations and reduced quality of life.

Study design: Population-based survey study.

Setting: Medicare beneficiaries in the United States.

Dr. Stanley is assistant professor of medicine at Northwestern University Feinberg School of Medicine and a hospitalist at Northwestern Memorial Hospital, both in Chicago.

Clinical question: Among older adults, what attitudes exist toward deprescribing?

Background: Polypharmacy in older adults is common and can be associated with increased hospitalizations and reduced quality of life.

Study design: Population-based survey study.

Setting: Medicare beneficiaries in the United States.

Dr. Stanley is assistant professor of medicine at Northwestern University Feinberg School of Medicine and a hospitalist at Northwestern Memorial Hospital, both in Chicago.

Clinical question: In patients with hypertension, chronic kidney disease, or heart failure presenting with a musculoskeletal disorder, how frequently are prescription NSAIDs dispensed and are there associated short-term (between 7-38 days of visit) safety-related outcomes?

Background: Multiple expert panels recommend against the use of NSAIDs in patients with hypertension (HTN), chronic kidney disease (CKD), or heart failure (HF). Previous studies have demonstrated an increased risk of cardiovascular events and renal injury with long-term NSAID use.

Study design: Retrospective cohort study.

Setting: Population-based administrative claims database identified primary care visits in Ontario.

Dr. Stanley is assistant professor of medicine at Northwestern University Feinberg School of Medicine and a hospitalist at Northwestern Memorial Hospital, both in Chicago.

Clinical question: In patients with hypertension, chronic kidney disease, or heart failure presenting with a musculoskeletal disorder, how frequently are prescription NSAIDs dispensed and are there associated short-term (between 7-38 days of visit) safety-related outcomes?

Background: Multiple expert panels recommend against the use of NSAIDs in patients with hypertension (HTN), chronic kidney disease (CKD), or heart failure (HF). Previous studies have demonstrated an increased risk of cardiovascular events and renal injury with long-term NSAID use.

Study design: Retrospective cohort study.

Setting: Population-based administrative claims database identified primary care visits in Ontario.

Dr. Stanley is assistant professor of medicine at Northwestern University Feinberg School of Medicine and a hospitalist at Northwestern Memorial Hospital, both in Chicago.

Clinical question: In patients with hypertension, chronic kidney disease, or heart failure presenting with a musculoskeletal disorder, how frequently are prescription NSAIDs dispensed and are there associated short-term (between 7-38 days of visit) safety-related outcomes?

Background: Multiple expert panels recommend against the use of NSAIDs in patients with hypertension (HTN), chronic kidney disease (CKD), or heart failure (HF). Previous studies have demonstrated an increased risk of cardiovascular events and renal injury with long-term NSAID use.

Study design: Retrospective cohort study.

Setting: Population-based administrative claims database identified primary care visits in Ontario.

Dr. Stanley is assistant professor of medicine at Northwestern University Feinberg School of Medicine and a hospitalist at Northwestern Memorial Hospital, both in Chicago.

Background: DOACs have been shown to be efficacious in randomized, controlled trials, but these trials did not include high-risk patients. This trial studies the efficacy and safety of DOACs in elderly patients with new-onset atrial fibrillation who are at high risk of both ischemic stroke and major bleeding.

Researchers then used three-way propensity matching, accounting for each morbidity category and anticoagulation medication to compare outcomes. Cox proportion regression models were used to adjust for risk and compare outcomes of ischemic stroke and major hemorrhage in matched participants in each anticoagulant group.

Primary outcomes of the study were ischemic stroke and major hemorrhage, which were determined based on ICD-9 codes. The investigators did not find a significant difference among anticoagulants regardless of the morbidity level for risk-adjusted ischemic stroke rates. Participants in the dabigatran group had lower rates of risk-adjusted major hemorrhage, compared with the warfarin group, regardless of morbidity category. The dabigatran group also had lower major hemorrhage risk, compared with the rivaroxaban group, especially in moderate- and high-morbidity category. Lastly, risk-adjusted rates of mortality were lower in the dabigatran and rivaroxaban groups, compared with the warfarin group, and there was no difference between the dabigatran and rivaroxaban groups with regards to mortality.

Bottom line: Rivaroxaban and dabigatran are each equally effective, compared with warfarin, in preventing ischemic strokes in elderly patients with new-onset atrial fibrillation and multiple comorbidities. However, patients on dabigatran appear to be at less risk of major bleeding, compared with warfarin and rivaroxaban.

Citation: Mentias A et al. Assessment of outcomes of treatment with oral anticoagulants in patients with atrial fibrillation and multiple chronic conditions. JAMA Netw Open. 2018 Sep 28;1(5):e182870.

Dr. Puri is assistant professor of medicine at Northwestern University Feinberg School of Medicine and a hospitalist at Northwestern Memorial Hospital, both in Chicago.

Background: DOACs have been shown to be efficacious in randomized, controlled trials, but these trials did not include high-risk patients. This trial studies the efficacy and safety of DOACs in elderly patients with new-onset atrial fibrillation who are at high risk of both ischemic stroke and major bleeding.

Researchers then used three-way propensity matching, accounting for each morbidity category and anticoagulation medication to compare outcomes. Cox proportion regression models were used to adjust for risk and compare outcomes of ischemic stroke and major hemorrhage in matched participants in each anticoagulant group.

Primary outcomes of the study were ischemic stroke and major hemorrhage, which were determined based on ICD-9 codes. The investigators did not find a significant difference among anticoagulants regardless of the morbidity level for risk-adjusted ischemic stroke rates. Participants in the dabigatran group had lower rates of risk-adjusted major hemorrhage, compared with the warfarin group, regardless of morbidity category. The dabigatran group also had lower major hemorrhage risk, compared with the rivaroxaban group, especially in moderate- and high-morbidity category. Lastly, risk-adjusted rates of mortality were lower in the dabigatran and rivaroxaban groups, compared with the warfarin group, and there was no difference between the dabigatran and rivaroxaban groups with regards to mortality.

Bottom line: Rivaroxaban and dabigatran are each equally effective, compared with warfarin, in preventing ischemic strokes in elderly patients with new-onset atrial fibrillation and multiple comorbidities. However, patients on dabigatran appear to be at less risk of major bleeding, compared with warfarin and rivaroxaban.

Citation: Mentias A et al. Assessment of outcomes of treatment with oral anticoagulants in patients with atrial fibrillation and multiple chronic conditions. JAMA Netw Open. 2018 Sep 28;1(5):e182870.

Dr. Puri is assistant professor of medicine at Northwestern University Feinberg School of Medicine and a hospitalist at Northwestern Memorial Hospital, both in Chicago.

Background: DOACs have been shown to be efficacious in randomized, controlled trials, but these trials did not include high-risk patients. This trial studies the efficacy and safety of DOACs in elderly patients with new-onset atrial fibrillation who are at high risk of both ischemic stroke and major bleeding.

Researchers then used three-way propensity matching, accounting for each morbidity category and anticoagulation medication to compare outcomes. Cox proportion regression models were used to adjust for risk and compare outcomes of ischemic stroke and major hemorrhage in matched participants in each anticoagulant group.

Primary outcomes of the study were ischemic stroke and major hemorrhage, which were determined based on ICD-9 codes. The investigators did not find a significant difference among anticoagulants regardless of the morbidity level for risk-adjusted ischemic stroke rates. Participants in the dabigatran group had lower rates of risk-adjusted major hemorrhage, compared with the warfarin group, regardless of morbidity category. The dabigatran group also had lower major hemorrhage risk, compared with the rivaroxaban group, especially in moderate- and high-morbidity category. Lastly, risk-adjusted rates of mortality were lower in the dabigatran and rivaroxaban groups, compared with the warfarin group, and there was no difference between the dabigatran and rivaroxaban groups with regards to mortality.

Bottom line: Rivaroxaban and dabigatran are each equally effective, compared with warfarin, in preventing ischemic strokes in elderly patients with new-onset atrial fibrillation and multiple comorbidities. However, patients on dabigatran appear to be at less risk of major bleeding, compared with warfarin and rivaroxaban.

Citation: Mentias A et al. Assessment of outcomes of treatment with oral anticoagulants in patients with atrial fibrillation and multiple chronic conditions. JAMA Netw Open. 2018 Sep 28;1(5):e182870.

Dr. Puri is assistant professor of medicine at Northwestern University Feinberg School of Medicine and a hospitalist at Northwestern Memorial Hospital, both in Chicago.

The Food and Drug Administration has approved Baqsimi nasal powder, the first glucagon therapy approved for the treatment of severe hypoglycemia that is administrable without an injection, in patients aged 4 years and older.

Olivier Le Moal/Getty Images

Injectable glucagon has been approved in the United States for several decades.

The safety and efficacy of the Baqsimi powder was assessed in two studies with adults with diabetes and one with pediatric patients. In all three studies, a single dose of Baqsimi was compared with a single dose of glucagon injection, and Baqsimi adequately raised blood sugar levels in response to insulin-induced hypoglycemia.

The most common adverse events associated with Baqsimi include nausea, vomiting, headache, upper respiratory tract irritation, watery eyes, redness of eyes, and itchiness. The safety profile is similar to that of injectable glucagon, with the addition of nasal- and eye-related symptoms because of the method of delivery.

“There are many products on the market for those who need insulin, but until now, people suffering from a severe hypoglycemic episode had to be treated with a glucagon injection that first had to be mixed in a several-step process. This new way to administer glucagon may simplify the process, which can be critical during an episode, especially since the patient may have lost consciousness or may be having a seizure. In those situations, we want the process to treat the suffering person to be as simple as possible,” Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said in the press release.

Find the full press release on the FDA website.

[email protected]

The Food and Drug Administration has approved Baqsimi nasal powder, the first glucagon therapy approved for the treatment of severe hypoglycemia that is administrable without an injection, in patients aged 4 years and older.

Olivier Le Moal/Getty Images

Injectable glucagon has been approved in the United States for several decades.

The safety and efficacy of the Baqsimi powder was assessed in two studies with adults with diabetes and one with pediatric patients. In all three studies, a single dose of Baqsimi was compared with a single dose of glucagon injection, and Baqsimi adequately raised blood sugar levels in response to insulin-induced hypoglycemia.

The most common adverse events associated with Baqsimi include nausea, vomiting, headache, upper respiratory tract irritation, watery eyes, redness of eyes, and itchiness. The safety profile is similar to that of injectable glucagon, with the addition of nasal- and eye-related symptoms because of the method of delivery.

“There are many products on the market for those who need insulin, but until now, people suffering from a severe hypoglycemic episode had to be treated with a glucagon injection that first had to be mixed in a several-step process. This new way to administer glucagon may simplify the process, which can be critical during an episode, especially since the patient may have lost consciousness or may be having a seizure. In those situations, we want the process to treat the suffering person to be as simple as possible,” Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said in the press release.

Find the full press release on the FDA website.

[email protected]

The Food and Drug Administration has approved Baqsimi nasal powder, the first glucagon therapy approved for the treatment of severe hypoglycemia that is administrable without an injection, in patients aged 4 years and older.

Olivier Le Moal/Getty Images

Injectable glucagon has been approved in the United States for several decades.

The safety and efficacy of the Baqsimi powder was assessed in two studies with adults with diabetes and one with pediatric patients. In all three studies, a single dose of Baqsimi was compared with a single dose of glucagon injection, and Baqsimi adequately raised blood sugar levels in response to insulin-induced hypoglycemia.

The most common adverse events associated with Baqsimi include nausea, vomiting, headache, upper respiratory tract irritation, watery eyes, redness of eyes, and itchiness. The safety profile is similar to that of injectable glucagon, with the addition of nasal- and eye-related symptoms because of the method of delivery.

“There are many products on the market for those who need insulin, but until now, people suffering from a severe hypoglycemic episode had to be treated with a glucagon injection that first had to be mixed in a several-step process. This new way to administer glucagon may simplify the process, which can be critical during an episode, especially since the patient may have lost consciousness or may be having a seizure. In those situations, we want the process to treat the suffering person to be as simple as possible,” Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said in the press release.

Find the full press release on the FDA website.

[email protected]

Background: Prophylactic proton pump inhibitors (PPIs) are used frequently in an ICU setting for acid suppression, but this is an off-label use and the evidence in support of using PPI prophylactically is limited. In fact, PPIs have been associated with adverse effects in recent literature including Clostridium difficile infection, myocardial ischemia, and pneumonia.

The researchers also used a composite outcome comprising clinically important gastrointestinal bleeding, Clostridium difficile infection, new onset pneumonia, and acute myocardial ischemia. Overall, 21.9% in the pantoprazole group and 22.6% participants in the placebo group had the composite outcome – a relative risk of 0.96 (95% CI, 0.83-1.11). Clinically important gastrointestinal bleeding was the only component of the composite outcome that was significantly different between groups, occurring less often in the pantoprazole group – the relative risk was 0.58 (95% CI, 0.40-0.86).

Bottom line: Pantoprazole does not differ significantly, compared with placebo, with regard to 90-day mortality and a composite outcome of clinically significant events.

Citation: Krag M et al. Pantoprazole in patients at risk of gastrointestinal bleeding in the ICU. N Eng J Med. 2018 Dec 6;379(23):2199-208.

Dr. Puri is assistant professor of medicine at Northwestern University Feinberg School of Medicine and a hospitalist at Northwestern Memorial Hospital, both in Chicago.

Background: Prophylactic proton pump inhibitors (PPIs) are used frequently in an ICU setting for acid suppression, but this is an off-label use and the evidence in support of using PPI prophylactically is limited. In fact, PPIs have been associated with adverse effects in recent literature including Clostridium difficile infection, myocardial ischemia, and pneumonia.

The researchers also used a composite outcome comprising clinically important gastrointestinal bleeding, Clostridium difficile infection, new onset pneumonia, and acute myocardial ischemia. Overall, 21.9% in the pantoprazole group and 22.6% participants in the placebo group had the composite outcome – a relative risk of 0.96 (95% CI, 0.83-1.11). Clinically important gastrointestinal bleeding was the only component of the composite outcome that was significantly different between groups, occurring less often in the pantoprazole group – the relative risk was 0.58 (95% CI, 0.40-0.86).

Bottom line: Pantoprazole does not differ significantly, compared with placebo, with regard to 90-day mortality and a composite outcome of clinically significant events.

Citation: Krag M et al. Pantoprazole in patients at risk of gastrointestinal bleeding in the ICU. N Eng J Med. 2018 Dec 6;379(23):2199-208.

Dr. Puri is assistant professor of medicine at Northwestern University Feinberg School of Medicine and a hospitalist at Northwestern Memorial Hospital, both in Chicago.

Background: Prophylactic proton pump inhibitors (PPIs) are used frequently in an ICU setting for acid suppression, but this is an off-label use and the evidence in support of using PPI prophylactically is limited. In fact, PPIs have been associated with adverse effects in recent literature including Clostridium difficile infection, myocardial ischemia, and pneumonia.

The researchers also used a composite outcome comprising clinically important gastrointestinal bleeding, Clostridium difficile infection, new onset pneumonia, and acute myocardial ischemia. Overall, 21.9% in the pantoprazole group and 22.6% participants in the placebo group had the composite outcome – a relative risk of 0.96 (95% CI, 0.83-1.11). Clinically important gastrointestinal bleeding was the only component of the composite outcome that was significantly different between groups, occurring less often in the pantoprazole group – the relative risk was 0.58 (95% CI, 0.40-0.86).

Bottom line: Pantoprazole does not differ significantly, compared with placebo, with regard to 90-day mortality and a composite outcome of clinically significant events.

Citation: Krag M et al. Pantoprazole in patients at risk of gastrointestinal bleeding in the ICU. N Eng J Med. 2018 Dec 6;379(23):2199-208.

Dr. Puri is assistant professor of medicine at Northwestern University Feinberg School of Medicine and a hospitalist at Northwestern Memorial Hospital, both in Chicago.

Clinical question: Is a low-dose tricyclic antidepressant effective in the treatment of chronic low back pain?

Background: Lower back pain is the leading cause of disability globally and effective treatments are limited. Furthermore, opioid usage for lower back pain is a large contributor to the current opioid epidemic. A recent Cochrane review showed no clear evidence that antidepressant use in the treatment of back pain is effective, but it did note a lack of high-quality trials of sufficient rigor or length.

Study design: Double-blind, randomized controlled trial.

Setting: Single center trial in Melbourne.

Synopsis: Overall, 146 patients aged 18-75 with chronic lower back pain of no specific cause for more than 3 months were included. Exclusions included pathological cause, major coexisting illness, psychosis, or diagnosed depression. Patients were given amitriptyline 25 mg daily or benztropine mesylate 1 mg daily. Benztropine has similar anticholinergic side effects, without the antidepressant effect. Participants were assessed and followed by calls at 2 weeks, 1-2 months, 3 months, 4-5 months, and 6 months. Adherence was noted by the return of empty medication bottles at 6 months. Six-month surveys were completed by 81% and found that 70% of each group was adherent and 12% in each group withdrew because of adverse effects.

The primary outcome was level of pain at 6 months using a visual analog and descriptor scales. Secondary outcomes were measurement of disability, work missed, global improvement, general health, fear of movement, and depression.

The primary outcome was reduction in pain intensity of 12.6 (standard error, 2.7) with amitriptyline at 6 months, compared with 4.8 (SE 2.9) with benztropine, which did not meet statistical significance. There was a statistically significant difference in disability at 3 months, but not at 6 months.

Bottom line: This trial suggests that there may be a place for prescribed amitriptyline for chronic lower back pain, but it failed to show statistical significance. The study may not have been sufficiently powered to detect the difference.

Citations: Urquhart DM et al. Efficacy of low-dose amitriptyline for chronic low back pain: A randomized clinical trial. JAMA Intern Med. 2018;178(11):1474-81.

Dr. Lennon is an instructor of medicine at Northwestern University Feinberg School of Medicine and a hospitalist at Northwestern Memorial Hospital, both in Chicago.

Clinical question: Is a low-dose tricyclic antidepressant effective in the treatment of chronic low back pain?

Background: Lower back pain is the leading cause of disability globally and effective treatments are limited. Furthermore, opioid usage for lower back pain is a large contributor to the current opioid epidemic. A recent Cochrane review showed no clear evidence that antidepressant use in the treatment of back pain is effective, but it did note a lack of high-quality trials of sufficient rigor or length.

Study design: Double-blind, randomized controlled trial.

Setting: Single center trial in Melbourne.

Synopsis: Overall, 146 patients aged 18-75 with chronic lower back pain of no specific cause for more than 3 months were included. Exclusions included pathological cause, major coexisting illness, psychosis, or diagnosed depression. Patients were given amitriptyline 25 mg daily or benztropine mesylate 1 mg daily. Benztropine has similar anticholinergic side effects, without the antidepressant effect. Participants were assessed and followed by calls at 2 weeks, 1-2 months, 3 months, 4-5 months, and 6 months. Adherence was noted by the return of empty medication bottles at 6 months. Six-month surveys were completed by 81% and found that 70% of each group was adherent and 12% in each group withdrew because of adverse effects.

The primary outcome was level of pain at 6 months using a visual analog and descriptor scales. Secondary outcomes were measurement of disability, work missed, global improvement, general health, fear of movement, and depression.

The primary outcome was reduction in pain intensity of 12.6 (standard error, 2.7) with amitriptyline at 6 months, compared with 4.8 (SE 2.9) with benztropine, which did not meet statistical significance. There was a statistically significant difference in disability at 3 months, but not at 6 months.

Bottom line: This trial suggests that there may be a place for prescribed amitriptyline for chronic lower back pain, but it failed to show statistical significance. The study may not have been sufficiently powered to detect the difference.

Citations: Urquhart DM et al. Efficacy of low-dose amitriptyline for chronic low back pain: A randomized clinical trial. JAMA Intern Med. 2018;178(11):1474-81.

Dr. Lennon is an instructor of medicine at Northwestern University Feinberg School of Medicine and a hospitalist at Northwestern Memorial Hospital, both in Chicago.

Clinical question: Is a low-dose tricyclic antidepressant effective in the treatment of chronic low back pain?

Background: Lower back pain is the leading cause of disability globally and effective treatments are limited. Furthermore, opioid usage for lower back pain is a large contributor to the current opioid epidemic. A recent Cochrane review showed no clear evidence that antidepressant use in the treatment of back pain is effective, but it did note a lack of high-quality trials of sufficient rigor or length.

Study design: Double-blind, randomized controlled trial.

Setting: Single center trial in Melbourne.

Synopsis: Overall, 146 patients aged 18-75 with chronic lower back pain of no specific cause for more than 3 months were included. Exclusions included pathological cause, major coexisting illness, psychosis, or diagnosed depression. Patients were given amitriptyline 25 mg daily or benztropine mesylate 1 mg daily. Benztropine has similar anticholinergic side effects, without the antidepressant effect. Participants were assessed and followed by calls at 2 weeks, 1-2 months, 3 months, 4-5 months, and 6 months. Adherence was noted by the return of empty medication bottles at 6 months. Six-month surveys were completed by 81% and found that 70% of each group was adherent and 12% in each group withdrew because of adverse effects.

The primary outcome was level of pain at 6 months using a visual analog and descriptor scales. Secondary outcomes were measurement of disability, work missed, global improvement, general health, fear of movement, and depression.

The primary outcome was reduction in pain intensity of 12.6 (standard error, 2.7) with amitriptyline at 6 months, compared with 4.8 (SE 2.9) with benztropine, which did not meet statistical significance. There was a statistically significant difference in disability at 3 months, but not at 6 months.

Bottom line: This trial suggests that there may be a place for prescribed amitriptyline for chronic lower back pain, but it failed to show statistical significance. The study may not have been sufficiently powered to detect the difference.

Citations: Urquhart DM et al. Efficacy of low-dose amitriptyline for chronic low back pain: A randomized clinical trial. JAMA Intern Med. 2018;178(11):1474-81.

Dr. Lennon is an instructor of medicine at Northwestern University Feinberg School of Medicine and a hospitalist at Northwestern Memorial Hospital, both in Chicago.

Clinical question: Is 6 months of dual antiplatelet therapy (DAPT) therapy noninferior to 12 months, following ST-elevation myocardial infarction (STEMI) with placement of second-generation drug-eluting stents?

Background: DAPT has been the standard of care to prevent abrupt thrombotic closure of vessels following percutaneous coronary intervention (PCI) and placement of stents. The recommended duration of DAPT was lengthened from at least 30 days in bare metal stents to at least 12 months in earlier-generation drug-eluting stents after observation of high rates of in-stent thrombosis of drug-eluting stents.

Trials have shown that there is no difference in outcomes comparing 6 month vs. 12 months in DAPT for PCI in the cases of non-ST-elevation MI and unstable angina. However, there are no randomized controlled studies comparing 6 vs. 12 months of DAPT with newer drug-eluting stents following STEMI. Newer drug-eluting stents are made of biocompatible polymers with thinner struts and are thought to be fully absorbed by 3 months. International guidelines still recommend 12 months of DAPT following drug-eluting stent placement following STEMI.

Study design: Prospective, unblinded, randomized, multicenter noninferiority trial.

Setting: The study was performed at 17 sites in the Netherlands, Norway, Poland, and Switzerland.

Synopsis: This study enrolled 1100 patients with STEMI started on DAPT during December 2011-June 2015. Overall, 870 patients were randomized to continue DAPT or to change to single antiplatelet therapy (SAPT) at 6 months. Exclusions included embolic events, cardiogenic shock, revascularization, bleeding, or being on anticoagulation. Patients were followed for 24 months.

The primary endpoint was a composite of all-cause mortality, any MI, any revascularization, stroke, or thrombolysis. Incidence of the composite endpoint was 4.8% of SAPT cases, and 6.6% of DAPT cases. Noninferiority was met (P = .004) because the upper 95% confidence interval of 1.27 was smaller than the prespecified noninferiority margin of 1.66. The secondary endpoint of safety and bleeding at 18 months was 3.2% for SAPT, and 4.3% for DAPT with HR of 0.75.

Medtronic’s new stent was used in 92% of the cases of this industry-sponsored study. Despite usage of a composite endpoint, there was no difference in the individual elements of the composite in subgroup analyses. There was a low event rate in both arms likely because of the exclusions that led to a lower-risk population. The individual operators were able to choose the P2Y12 inhibitor.

Bottom line: This industry-sponsored randomized, control trial showed noninferiority of 6 months of DAPT to 12 months of therapy following STEMI to prevent in-stent thrombosis with newer second- generation drug-eluting stents. However, the study’s results may be limited to lower-risk patients, without need for revascularization, oral anticoagulation, or with stroke or cardiogenic shock.

Citation: Kedhi E et al. Six months versus 12 months of dual antiplatelet therapy after drug-eluting stent implantation in ST-elevation myocardial infarction (DAPT-STEMI): Randomised, multicenter, noninferiority trial. BMJ. 2018;363:k3793.

Dr. Lennon is an instructor of medicine at Northwestern University Feinberg School of Medicine and a hospitalist at Northwestern Memorial Hospital, both in Chicago.

Clinical question: Is 6 months of dual antiplatelet therapy (DAPT) therapy noninferior to 12 months, following ST-elevation myocardial infarction (STEMI) with placement of second-generation drug-eluting stents?

Background: DAPT has been the standard of care to prevent abrupt thrombotic closure of vessels following percutaneous coronary intervention (PCI) and placement of stents. The recommended duration of DAPT was lengthened from at least 30 days in bare metal stents to at least 12 months in earlier-generation drug-eluting stents after observation of high rates of in-stent thrombosis of drug-eluting stents.

Trials have shown that there is no difference in outcomes comparing 6 month vs. 12 months in DAPT for PCI in the cases of non-ST-elevation MI and unstable angina. However, there are no randomized controlled studies comparing 6 vs. 12 months of DAPT with newer drug-eluting stents following STEMI. Newer drug-eluting stents are made of biocompatible polymers with thinner struts and are thought to be fully absorbed by 3 months. International guidelines still recommend 12 months of DAPT following drug-eluting stent placement following STEMI.

Study design: Prospective, unblinded, randomized, multicenter noninferiority trial.

Setting: The study was performed at 17 sites in the Netherlands, Norway, Poland, and Switzerland.

Synopsis: This study enrolled 1100 patients with STEMI started on DAPT during December 2011-June 2015. Overall, 870 patients were randomized to continue DAPT or to change to single antiplatelet therapy (SAPT) at 6 months. Exclusions included embolic events, cardiogenic shock, revascularization, bleeding, or being on anticoagulation. Patients were followed for 24 months.

The primary endpoint was a composite of all-cause mortality, any MI, any revascularization, stroke, or thrombolysis. Incidence of the composite endpoint was 4.8% of SAPT cases, and 6.6% of DAPT cases. Noninferiority was met (P = .004) because the upper 95% confidence interval of 1.27 was smaller than the prespecified noninferiority margin of 1.66. The secondary endpoint of safety and bleeding at 18 months was 3.2% for SAPT, and 4.3% for DAPT with HR of 0.75.

Medtronic’s new stent was used in 92% of the cases of this industry-sponsored study. Despite usage of a composite endpoint, there was no difference in the individual elements of the composite in subgroup analyses. There was a low event rate in both arms likely because of the exclusions that led to a lower-risk population. The individual operators were able to choose the P2Y12 inhibitor.

Bottom line: This industry-sponsored randomized, control trial showed noninferiority of 6 months of DAPT to 12 months of therapy following STEMI to prevent in-stent thrombosis with newer second- generation drug-eluting stents. However, the study’s results may be limited to lower-risk patients, without need for revascularization, oral anticoagulation, or with stroke or cardiogenic shock.

Citation: Kedhi E et al. Six months versus 12 months of dual antiplatelet therapy after drug-eluting stent implantation in ST-elevation myocardial infarction (DAPT-STEMI): Randomised, multicenter, noninferiority trial. BMJ. 2018;363:k3793.

Dr. Lennon is an instructor of medicine at Northwestern University Feinberg School of Medicine and a hospitalist at Northwestern Memorial Hospital, both in Chicago.

Clinical question: Is 6 months of dual antiplatelet therapy (DAPT) therapy noninferior to 12 months, following ST-elevation myocardial infarction (STEMI) with placement of second-generation drug-eluting stents?

Background: DAPT has been the standard of care to prevent abrupt thrombotic closure of vessels following percutaneous coronary intervention (PCI) and placement of stents. The recommended duration of DAPT was lengthened from at least 30 days in bare metal stents to at least 12 months in earlier-generation drug-eluting stents after observation of high rates of in-stent thrombosis of drug-eluting stents.

Trials have shown that there is no difference in outcomes comparing 6 month vs. 12 months in DAPT for PCI in the cases of non-ST-elevation MI and unstable angina. However, there are no randomized controlled studies comparing 6 vs. 12 months of DAPT with newer drug-eluting stents following STEMI. Newer drug-eluting stents are made of biocompatible polymers with thinner struts and are thought to be fully absorbed by 3 months. International guidelines still recommend 12 months of DAPT following drug-eluting stent placement following STEMI.

Study design: Prospective, unblinded, randomized, multicenter noninferiority trial.

Setting: The study was performed at 17 sites in the Netherlands, Norway, Poland, and Switzerland.

Synopsis: This study enrolled 1100 patients with STEMI started on DAPT during December 2011-June 2015. Overall, 870 patients were randomized to continue DAPT or to change to single antiplatelet therapy (SAPT) at 6 months. Exclusions included embolic events, cardiogenic shock, revascularization, bleeding, or being on anticoagulation. Patients were followed for 24 months.

The primary endpoint was a composite of all-cause mortality, any MI, any revascularization, stroke, or thrombolysis. Incidence of the composite endpoint was 4.8% of SAPT cases, and 6.6% of DAPT cases. Noninferiority was met (P = .004) because the upper 95% confidence interval of 1.27 was smaller than the prespecified noninferiority margin of 1.66. The secondary endpoint of safety and bleeding at 18 months was 3.2% for SAPT, and 4.3% for DAPT with HR of 0.75.

Medtronic’s new stent was used in 92% of the cases of this industry-sponsored study. Despite usage of a composite endpoint, there was no difference in the individual elements of the composite in subgroup analyses. There was a low event rate in both arms likely because of the exclusions that led to a lower-risk population. The individual operators were able to choose the P2Y12 inhibitor.

Bottom line: This industry-sponsored randomized, control trial showed noninferiority of 6 months of DAPT to 12 months of therapy following STEMI to prevent in-stent thrombosis with newer second- generation drug-eluting stents. However, the study’s results may be limited to lower-risk patients, without need for revascularization, oral anticoagulation, or with stroke or cardiogenic shock.

Citation: Kedhi E et al. Six months versus 12 months of dual antiplatelet therapy after drug-eluting stent implantation in ST-elevation myocardial infarction (DAPT-STEMI): Randomised, multicenter, noninferiority trial. BMJ. 2018;363:k3793.

Dr. Lennon is an instructor of medicine at Northwestern University Feinberg School of Medicine and a hospitalist at Northwestern Memorial Hospital, both in Chicago.