Acute kidney injury after hip or knee replacement: Can we lower the risk?

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Acute kidney injury after hip or knee replacement: Can we lower the risk?
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Edward J. Filippone, MD, FASN
Anju Yadav, MD

Total hip or knee replacement (also called total joint arthroplasty) is highly successful at relieving pain and restoring function, but at the risk of acute kidney injury, which is a sudden loss of renal function. Various factors have been associated with this risk, some of which are potentially modifiable, notably, the use of nephrotoxic antibiotics and other drugs.

This review examines the incidence of acute kidney injury using current criteria in total joint arthroplasty of the hip or knee in general, and in the setting of revision surgery for prosthetic joint infection in particular, in which the risk is higher. We identify risk factors for acute kidney injury and propose ways to lower the risk.

MILLIONS OF PROCEDURES ANNUALLY

Total replacement of the hip1,2 or knee3 is being done more and more. Kurtz et al4 estimate that by the year 2030, we will see approximately 3.5 million primary total knee and 500,000 primary total hip replacements every year. In addition, revision total knee procedures are expected to exceed 250,000 per year, and revision total hip procedures are expected to exceed 90,000 per year.4

Chronic infection may complicate up to 2% of these procedures and is associated with significant morbidity, death, and financial costs. Currently, it may be the reason for 25% of total joint arthroplasty revisions,5 but by the year 2030, it is projected to account for 66% of revision total knee arthroplasties and 48% of revision total hip arthroplasties.6

PRIMARY TOTAL JOINT ARTHROPLASTY AND ACUTE KIDNEY INJURY

Table 1. Studies reporting the incidence of acute kidney injury using current diagnostic criteria
We searched Ovid MEDLINE for articles on acute kidney injury and either arthroplasty or antibiotic-loaded cement spacers. We found 22 studies, with a total of 72,850 patients, that assessed the incidence of acute kidney injury after primary or revision total joint arthroplasty of the hip or knee, or both, using current criteria7–28 (Table 1), and 3 additional studies that used discharge diagnosis coding.29–31

Study designs, findings varied widely

The incidence of acute kidney injury varied markedly among the studies of primary total joint arthroplasty or revision for aseptic reasons. Numerous factors explain this heterogeneity.

Designs ranged from single-center studies with relatively small numbers of patients to large regional and national samples based on administrative data.

Table 2. Current criteria for diagnosing and staging acute kidney injury
The definition of acute kidney injury also varied, although many used current criteria, specifically the RIFLE (risk, injury, failure, loss, end-stage renal disease),32 AKIN (Acute Kidney Injury Network),33 and KDIGO (Kidney Disease Improving Global Outcomes)34 creatinine criteria (Table 2). Some studies considered only higher stages of acute kidney injury (equivalent to KDIGO stage 2 or 3), ignoring the most common stage, ie, stage 1. No study considered urine output criteria.

Almost all of the studies were retrospective. We are not aware of any randomized controlled trials.

Discharge diagnosis may miss many cases

Several studies based the diagnosis of acute kidney injury on International Classification of Diseases, Ninth Revision (ICD-9) coding from hospital discharge summaries.

Nadkarni et al,29 in the largest study published to date, used the nationwide inpatient sample database of more than 7 million total joint arthroplasties and found an incidence of acute kidney injury based on ICD-9 coding of 1.3% over the years 2002 to 2012, although this increased to 1.8% to 1.9% from 2010 to 2012.

Lopez-de-Andres et al,30 in a similar study using the Spanish national hospital discharge database, evaluated 20,188 patients who underwent revision total hip or knee arthroplasty and found an overall incidence of acute kidney injury of 0.94%, also using ICD-9 coding.

Gharaibeh et al31 used similar methods to diagnose acute kidney injury in a single-center study of 8,949 patients and found an incidence of 1.1%.

Although these 3 studies suggest that the incidence of acute kidney injury is relatively low, Grams et al35 found the sensitivity of ICD-9 coding from hospital records for the diagnosis of acute kidney injury to be only 11.7% compared with KDIGO serum creatinine and urine output criteria. This suggests that the true incidence in these studies may be many times higher, possibly near 10%.

Do all stages of kidney injury count?

Jafari et al,7 in a large series from a single medical center, used only the “I” (injury) and “F” (failure) levels of the RIFLE criteria (corresponding to stages 2 and 3 of the KDIGO criteria) and found an incidence of 0.55% in more than 17,000 total joint arthroplasties.

Jamsa et al8 used the same criteria for acute kidney injury (only “I” and “F”) and found 58 cases in 5,609 patients in whom postoperative serum creatinine was measured, for an incidence of 1%; the remaining 14,966 patients in their cohort did not have serum creatinine measured, and it was assumed they did not have acute kidney injury. Neither of these studies included the most common “R” (risk) stage of acute kidney injury.

Parr et al36 recently studied a nationwide sample of 657,840 hospitalized veterans and found that of 90,614 who developed acute kidney injury based on KDIGO creatinine criteria, 84% reached only stage R. This suggests that if all stages were considered, the true incidence of acute kidney injury would have been higher—possibly 4% in the Jafari series and possibly 7% in the Jamsa series.

Smaller studies had higher rates

Smaller, single-center series reported much higher incidences of acute kidney injury.

Kimmel et al11 found an incidence of 14.8% in 425 total joint arthroplasties using RIFLE creatinine criteria.

Johansson et al25 found an incidence of 19.9% in 136 total joint arthroplasties using KDIGO creatinine criteria.

Sehgal et al9 found an incidence of 21.9% in 659 total joint arthroplasties using AKIN creatinine criteria.

Challagundla et al24 found an incidence of 23.7% in 198 procedures using RIFLE creatinine criteria.

Weingarten et al,10 in a single-center series of 7,463 total joint arthroplasties, found an incidence of acute kidney injury of only 2.2% using AKIN criteria, although 12% of the patients with acute kidney injury did not return to their baseline serum creatinine levels by 3 months.

Our estimate: Nearly 10%

In total, in the 20 studies in Table 1 that included all stages of acute kidney injury, there were 1,909 cases of acute kidney injury in 34,337 patients, for an incidence of 5.6%. Considering that all studies but one were retrospective and none considered urine output criteria for acute kidney injury, we believe that using current KDIGO criteria, the true incidence of acute kidney injury complicating primary lower-extremity total joint arthroplasties is really closer to 10%.

 

 

RISK FACTORS FOR ACUTE KIDNEY INJURY

Various factors have been associated with development of acute kidney injury by multivariate analysis in these studies. Some are modifiable, while others are not, at least in the short term.

Nonmodifiable risk factors

Older age is often significant in studies assessing primary total joint arthroplasty or revision total joint arthroplasty not specifically for infection.11,12,16,17,26,28

Obesity is also a major factor in the development of acute kidney injury,7,10–12,17,18 and, along with age, is a major factor contributing to the need for joint replacement in the first place.

Male sex may increase risk.29

Diabetes mellitus was identified as a risk factor in several studies,10,12,17,20 and hypertension in a few.7,10,24

Other comorbidities and factors such as cardiovascular disease,7,10 liver disease,7 pulmonary disease,7 high American Society of Anesthesiology score,8,19 and benign heart murmurs preoperatively by routine physical examination have also been linked to acute kidney injury after joint arthroplasty.28

Chronic kidney disease as a risk factor

Chronic kidney disease at baseline was associated with acute kidney injury in several of these series.7,11–13,15,19,29

Warth et al12 studied 1,038 patients and found an incidence of acute kidney injury of 11% in the 135 with chronic kidney disease (defined as serum creatinine > 1.2 mg/dL) and who received acetaminophen or narcotics for pain control, compared with 4.8% in the remaining 903 patients without chronic kidney disease, who received ketorolac or celecoxib.

Perregaard et al13 studied 3,410 patients who underwent total hip arthroplasty and found an incidence of acute kidney injury (per KDIGO creatinine criteria) of 2.2% overall, but 7% in the 134 patients with chronic kidney disease based on KDIGO creatinine criteria.

Nowicka et al15 found an incidence of acute kidney injury of 16.7% in the 48 patients with chronic kidney disease (defined as a glomerular filtration rate estimated by the Cockroft-Gault formula of less than 60 mL/min/1.73 m2), compared with 4.5% in the remaining 289.

Modifiable risk factors

Modifiable risk factors that should be considered in high-risk cases include anemia, perioperative blood transfusion, perioperative use of renin-angiotensin-aldosterone system inhibitors such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), particular antibiotics used for prophylaxis, and nonsteroidal anti-inflammatory drugs used postoperatively.

Anemia and blood transfusion

Preoperative anemia has been associated with postoperative acute kidney injury in various surgical settings such as cardiac surgery.37,38 Perioperative red blood cell transfusions have also been associated with acute kidney injury in cardiac surgery; similar results may apply to total joint arthroplasty.

Choi et al,17 in 2,467 patients undergoing hip replacement, found a significant risk for acute kidney injury if postoperative hemoglobin was consistently below 10 g/dL compared with consistently above this level, with an inverse probability-of-treatment weighted odds ratio of 1.817 (P = .011).

Others have found a significant association of perioperative blood transfusion with acute kidney injury in total joint arthroplasty.10,29

Nadkarni et al,29 for example, used the nationwide inpatient sample database and found by multivariate analysis that perioperative blood transfusion was strongly associated with acute kidney injury, with an adjusted odds ratio of 2.28 (95% confidence interval [CI] 2.15–2.42, P < .0001).

Comment. A higher incidence of acute kidney injury may represent confounding by indication bias, as sicker patients or complicated surgeries may require transfusion, and this risk may not be completely accounted for by multivariate analysis. It is also possible, however, that transfusions per se may contribute to acute kidney injury. Possible direct or indirect mechanisms mediating acute kidney injury include hemolytic reactions, circulatory overload, acute lung injury, and immunomodulatory effects.39

Preoperative transfusion in anemic patients undergoing cardiac surgery may also reduce the incidence of postoperative acute kidney injury both by correcting the anemia and by limiting the need for perioperative transfusions.40 It remains to be determined whether elective preoperative transfusion to correct anemia would reduce postoperative development of acute kidney injury in total joint arthroplasty. As an aside, perioperative transfusion has also been linked to development of periprosthetic joint infection.41

Renin-angiotensin-aldosterone system inhibitors

Several studies found perioperative use of renin-angiotensin-aldosterone system inhibitors to be a risk factor for acute kidney injury.

Kimmel et al11 reported adjusted odds ratios of 2.70 (95% CI 1.12–6.48) for ACE inhibitor use and 2.64 (95% CI 1.18–5.93) for ARB use in a study of 425 primary total joint arthroplasties.

Challagundla et al24 found an odds ratio of 3.07 (95% CI 1.40–6.74) with ACE inhibitor or ARB use by multivariate analysis in 198 total joint arthroplasties.

Nielson et al18 studied 798 patients who underwent total joint arthroplasty and found that preoperative use of renin-angiotensin system inhibitors was associated with a significantly higher rate of postoperative acute kidney injury (8.3% vs 1.7% without inhibition), which was statistically significant by multivariate analysis (odds ratio 2.6, 95% CI 1.04–6.51).

We recommend holding renin-angiotensin-aldosterone system inhibitors 7 days before surgery through the postoperative period in high-risk cases.

Aminoglycoside use as a risk factor

Prophylactic administration of systemic antibiotics is the standard of care. In a systematic review of 26 studies and meta-analysis of 7 studies (3,065 patients), prophylactic antibiotics reduced the relative risk of wound infection by 81% with an absolute risk reduction of 8%.42

A modifiable risk factor for acute kidney injury is the specific antibiotic used for prophylaxis. Multiple studies assessed the risk of acute kidney injury comparing regimens containing an aminoglycoside (typically gentamicin) with regimens lacking these agents.20–26 In general, these studies found a significantly higher risk of acute kidney injury when gentamicin was used.

Challagundla et al24 found an incidence of acute kidney injury of 52% using RIFLE creatinine criteria in 52 patients receiving 8 g total of flucloxacillin plus 160 mg of gentamicin (120 mg if they weighed less than 60 kg) compared with 8% in 48 patients given cefuroxime (3 g total) and 14% in an additional 52 patients also given cefuroxime.

Johansson et al25 found an incidence of KDIGO creatinine-based acute kidney injury of 13% in 70 patients given dicloxacillin alone prophylactically compared with 27% given dicloxacillin and gentamicin, with a relative risk of 3.

Bell et al,21 in a large registry-based analysis from Scotland involving 7,666 elective orthopedic procedures, found that use of flucloxacillin 2 g plus a single dose of gentamicin 4 mg/kg was significantly associated with a 94% higher risk of acute kidney injury (KDIGO creatinine criteria) compared with a cefuroxime-based regimen, with absolute rates increasing from 6.2% to 10.8%.

Dubrovskaya et al20 and Ferguson et al,26 in contrast, found no increased risk with addition of gentamicin.

We recommend avoiding aminoglycosides for prophylaxis in primary lower-extremity total joint arthroplasty in patients at higher risk unless required for specific microbiologic reasons.

Vancomycin may also increase risk

Courtney et al19 assessed the risk of adding vancomycin to cefazolin for routine prophylaxis in a retrospective series of 1,828 total hip or knee arthroplasties and found a significantly higher rate of acute kidney injury, using AKIN criteria (13% vs 8%, odds ratio by multivariate analysis 1.82, P = .002).19

Other agents shown to be effective in treating periprosthetic joint infections or complicated skin and soft-tissue infections with resistant organisms include daptomycin43 and linezolid.44 These nonnephrotoxic alternatives to vancomycin may be a consideration if prophylaxis for methicillin-resistant Staphylococcus aureus is deemed necessary in patients at risk for acute kidney injury.

 

 

PROSTHETIC JOINT INFECTIONS AND ANTIBIOTIC-LOADED CEMENT

Deep infection may complicate nearly 1% of total hip45 and 2% of total knee arthroplasties.46 Kurtz et al4,6 have projected that by 2030, infection will be the cause of two-thirds of the estimated 268,000 revision total knee arthroplasties and about half of the estimated 96,700 revision total hip arthroplasties.

The most common method of treating a chronically infected replacement joint is a 2-stage procedure.5 First, the prosthesis is removed, all infected bone and soft tissue is debrided, and an antibiotic-loaded cement spacer is implanted. Systemic antibiotics are given concurrently, typically for about 6 weeks. After the infection is brought under control, perhaps 2 to 3 months later, the spacer is removed and a new joint is implanted with antibiotic-loaded cement. A 1-stage procedure may be an option in selected cases and would obviate the need for an antibiotic-loaded cement spacer.47,48

Of obvious relevance to development of acute kidney injury is the choice and amount of antibiotics embedded in the cement used for spacers and in implantation. Very high antibiotic levels are achieved within the joint space, usually with little systemic absorption, although significant systemic exposure has been documented in some cases.

The polymethylmethacrylate cement used for these purposes comes in 40-g bags. Multiple bags are typically required per joint, perhaps 2 to 4.49

The rate of elution of antibiotics is determined by several factors, including surface area, porosity, and the number of antibiotics. In general, elution is greatest early on, with exponential decline lasting perhaps 1 week,  followed by slow, sustained release over weeks to months.50 However, several in vitro studies have indicated that only about 5%50,51 of the total antibiotic actually elutes over time.

Initially, multiple antibiotic-laden cement beads were used to fill the joint space, but this significantly limited function and mobility.52 Now, cement spacers are used, and they can be nonarticulating or articulating for maximal joint mobility.53 Although much greater antibiotic elution occurs from beads due to their high surface area-to-volume ratio, spacers still provide an adequate dose.

ANTIBIOTIC-LOADED CEMENT: DOSAGE AND ELUTION CHARACTERISTICS

Antibiotic-loaded cement can be either low-dose or high-dose.

Low-dose cement

Low-dose cement typically consists of 0.5 to 1.0 g of antibiotic per 40-g bag of cement, usually an aminoglycoside (gentamicin or tobramycin) or vancomycin, and can be purchased premixed by the manufacturer. Such cement is only used prophylactically with primary total joint arthroplasty or revision for aseptic reasons, a practice common in Europe but less so in the United States. Some American authors propose antibiotic-loaded cement prophylaxis for patients at high risk, eg, those with immunosuppression, inflammatory cause of arthritis, or diabetes.54

Vrabec et al,55 in a study of low-dose tobramycin-loaded cement used for primary total knee arthroplasty, found a peak median intra-articular tobramycin concentration of 32 mg/L at 6 hours, declining to 6 mg/L at 48 hours with all serum levels 0.3 mg/L or less (unmeasureable) at similar time points.

Sterling et al,56 studying primary total hip arthroplasties with low-dose tobramycin-loaded cement, found mean levels in drainage fluid of 103 mg/L at 6 hours, declining to 15 mg/L at 48 hours. Serum levels peaked at 0.94 mg/L at 3 hours, declining to 0.2 mg/L by 48 hours.

Although most of the antibiotic elution occurs early (within the first week), antibiotic can be found in joint aspirates up to 20 years later.57 We are unaware of any well-documented cases of acute kidney injury ascribable to low-dose antibiotic-loaded cement used prophylactically. One case report making this assertion did not determine serum levels of aminoglycoside.58

High-dose cement

High-dose antibiotic-loaded cement typically contains about 4 to 8 g of antibiotic per 40-g bag of cement and is used in the treatment of prosthetic joint infection to form the spacers. The antibiotic must be mixed into the cement powder by the surgeon in the operating room.

There is no standard combination or dosage. The choice of antibiotic can be tailored to the infecting organism if known. Otherwise, gram-positive organisms are most common, and vancomycin and aminoglycosides are often used together. This particular combination will enhance the elution of both antibiotics when studied in vitro, a process termed “passive opportunism.”59 Other antibiotics in use include aztreonam, piperacillin, teicoplanin, fluoroquinolones, cephalosporins, and daptomycin, among others.

About 8 g of antibiotic total per 40-g bag is the maximum to allow easy molding.52 As an example, this may include 4 g of vancomycin and 3.6 g of tobramycin per 40 g. Given that 3 to 4 such bags are often used per joint, there is significant risk of systemic exposure.

Kalil et al60 studied 8 patients who received high-dose tobramycin-loaded cement to treat periprosthetic joint infections of the hip or knee and found that 7 had detectable serum levels (mean 0.84 mg/L, highest 2.0 mg/L), including 1 with a level of 0.9 mg/L on day 38; 4 of these 8 developed acute kidney injury by AKIN criteria, although other risk factors for acute kidney injury existed. Nearly all had concomitant vancomycin (3 to 8 g) added to the cement as well.

Hsieh et al61 studied 46 patients with infected total hip arthroplasties treated with high-dose antibiotic-loaded cement spacers (vancomycin 4 g and aztreonam 4 g per 40-g bag) and found vancomycin levels in joint drainage higher than 1,500 mg/L on day 1, decreasing to 571 mg/L on day 7; serum levels were low (range 0.1–1.6 mg/L at 24 hours), falling to undetectable by 72 hours.

 

 

ANTIBIOTIC-LOADED CEMENT SPACERS AND ACUTE KIDNEY INJURY

Case reports have associated high-dose antibiotic-loaded cement spacers with acute kidney injury.

Curtis et al62 described an 85-year-old patient with stage 3 chronic kidney disease who was treated for an infected total knee arthroplasty with an antibiotic-loaded cement spacer (containing 3.6 g of tobramycin and 3 g of cefazolin per 40-g bag, 3 bags total) and developed stage 3 acute kidney injury. After 16 days and 3 hemodialysis sessions, the patient’s serum tobramycin level was still 2 mg/L despite receiving no systemic tobramycin.

Wu et al63 reported a case of acute kidney injury that required dialysis after implantation of a tobramycin- and vancomycin-loaded spacer, with persistent serum tobramycin levels despite repeated hemodialysis sessions until the spacer was removed.

Chalmers et al64 described 2 patients with acute kidney injury and persistently elevated serum tobramycin levels (3.9 mg/L on day 39 in 1 patient and 2.0 mg/L on day 24 in the other patient) despite no systemic administration.

In these and other case reports,65–67 dialysis and spacer explantation were usually required. 


Comment. It is intuitive that acute kidney injury would more likely complicate revision total joint arthroplasties for infection than for primary total joint arthroplasties or revisions for aseptic reasons, given the systemic effects of infection and exposure to nephrotoxic or allergenic antibiotics. And the available data suggest that the risk of acute kidney injury is higher with revision for prosthetic joint infection than with revision for aseptic reasons. However, many of the studies were retrospective, relatively small, single-center series and used different definitions of acute kidney injury.

Table 3. Acute kidney injury in patients with antibiotic-loaded cement spacers for treatment of prosthetic joint infection of the hip and knee
We are aware of 17 studies specifically addressing acute kidney injury or postoperative complications in general that may have included acute kidney injury.50,52,61,68–81 Ten of these studies found at least 1 case of acute kidney injury (Table 3). Of note, 7 studies totaling 219 patients reported no cases of acute kidney injury, although acute kidney injury per se was not mentioned and no definition of it was provided.50,61,76,77,79,80,82

Luu et al83 performed a systematic review of studies published between January 1989 and June 2012 reporting systemic complications (including acute kidney injury) of 2-stage revision arthroplasties including placement of an antibiotic-loaded cement spacer for treatment of periprosthetic joint infection. Overall, 10 studies were identified with 544 total patients. Five of these studies, with 409 patients, reported at least 1 case of acute kidney injury for a total of 27 patients, giving an incidence of 6.6% in these studies.68–71 The remaining 5 studies, totaling 135 patients, did not report any cases of acute kidney injury,50,61,76–78 although that was not the primary focus of any of those trials.

Most notable from this systematic review, the study of Menge et al69 retrospectively determined the incidence of acute kidney injury (defined as a 50% rise in serum creatinine to > 1.4 mg/dL within 90 days of surgery) to be 17% in 84 patients with infected total knee arthroplasties treated with antibiotic-loaded cement spacers. A mean of 3.5 bags of cement per spacer were used in the 35 articulating spacers, compared with 2.9 per nonarticulating spacer. These spacers contained vancomycin in 82% (median 4.0 g, range 1–16 g) and tobramycin in 94% (median 4.8 g, range 1–12 g), among others in small percentages. The dose of tobramycin in the spacer considered either as a dichotomous variable (> 4.8 g, OR 5.87) or linearly (OR 1.24 per 1-g increase) was significantly associated with acute kidney injury, although systemic administration of aminoglycosides or vancomycin was not.

Additional single-center series that were published subsequent to this review have generally used more current diagnostic criteria.

Noto et al72 found that 10 of 46 patients treated with antibiotic-loaded cement spacers had a greater than 50% rise in serum creatinine (average increase 260%). All spacers contained tobramycin (mean dose 8.2 g), and 9 of 10 also contained vancomycin (mean 7.6 g). All of the 9 patients with acute kidney injury with follow-up data recovered renal function.

Reed et al75 found 26 cases of acute kidney injury (based on RIFLE creatinine criteria) in 306 patients with antibiotic-loaded cement spacers treating various periprosthetic joint infections (including hips, knees, shoulders, and digits) and compared them with 74 controls who did not develop acute kidney injury. By multivariable analysis, receipt of an ACE inhibitor within 7 days of surgery and receipt of piperacillin-tazobactam within 7 days after surgery were both significantly more common in cases with acute kidney injury than in controls without acute kidney injury.

Aeng et al73 prospectively studied 50 consecutive patients receiving antibiotic-loaded spacers containing tobramycin (with or without vancomycin) for treatment of infected hip or knee replacements. Using RIFLE creatinine criteria, they found an incidence of acute kidney injury of 20% (10 of 50). Factors significantly associated with acute kidney injury included cement premixed by the manufacturer with gentamicin (0.5 g per 40-g bag) in addition to the tobramycin they added, intraoperative blood transfusions, and postoperative use of nonsteroidal anti-inflammatory drugs.

Geller et al,74 in a multicenter retrospective study of 247 patients with prosthetic joint infections (156 knees and 91 hips) undergoing antibiotic-loaded cement spacer placement, found an incidence of acute kidney injury of 26% based on KDIGO creatinine criteria. Significant risk factors included higher body mass index, lower preoperative hemoglobin level, drop in hemoglobin after surgery, and comorbidity (hypertension, diabetes, chronic kidney disease, or cardiovascular disease). Most of the spacers contained a combination of vancomycin and either tobramycin (81%) or gentamicin (13%). The spacers contained an average of 5.3 g (range 0.6–18 g) of vancomycin (average 2.65 g per 40-g bag) and an average of 5.2 g (range 0.5–16.4 g) of tobramycin (average 2.6 g per bag).

As in Menge et al,69 this study illustrates the wide range of antibiotic dosages in use and the lack of standardization. In contrast to the study by Menge et al, however, development of acute kidney injury was not related to the amount of vancomycin or tobramycin contained in the spacers. Eventual clearance of infection (at 1 and 2 years) was significantly related to increasing amounts of vancomycin. Multiple different systemic antibiotics were used, most commonly vancomycin (44%), and systemic vancomycin was not associated with acute kidney injury.

Yadav et al,81 in a study of 3,129 consecutive revision procedures of the knee or hip, found an incidence of acute kidney injury by RIFLE creatinine criteria of 29% in the 197 patients who received antibiotic-loaded cement spacers for periprosthetic joint infection compared with 3.4% in the 2,848 who underwent revision for aseptic reasons. In 84 patients with prosthetic joint infection having various surgeries not including placement of a spacer, the acute kidney injury rate at some point in their course was an alarmingly high 82%. In the group that received spacers, only age and comorbidity as assessed by Charlson comorbidity index were independently associated with acute kidney injury by multivariate analysis. Surprisingly, modest renal impairment was protective, possibly because physicians of patients with chronic kidney disease were more vigilant and took appropriate measures to prevent acute kidney injury.

Overall, the risk of acute kidney injury appears to be much higher during treatment of prosthetic joint infection with a 2-stage procedure using an antibiotic-loaded cement spacer than after primary total joint arthroplasty or revision for aseptic reasons, and may complicate up to one-third of cases.

 

 

REDUCING RISK DURING TREATMENT OF INFECTED REPLACEMENT JOINTS

Table 4. Suggestions for practice modifications
Due to lack of appropriate data, how best to mitigate the risk of acute kidney injury is uncertain. In our opinion, however, the following measures should be considered (Table 4).

As in primary total joint arthroplasty in general, higher-risk cases should be identified based on age, body mass index, chronic kidney disease, comorbidities (hypertension, diabetes, established cardiovascular disease), and anemia.

Preoperative transfusion can be considered case by case depending on degree of anemia and associated risk factors.

All renin-angiotensin-aldosterone system inhibitors should be withheld starting 1 week before surgery.

Both nonselective and cyclooxygenase-2 selective nonsteroidal anti-inflammatory drugs should be avoided, if possible.

Strict attention should be paid to adequate intraoperative and postoperative fluid resuscitation.

Kidney function should be monitored closely in the early postoperative period, including urine output and daily creatinine for at least 72 hours.

Systemic administration of potentially nephrotoxic antibiotics should be minimized, especially the combination of vancomycin with piperacillin-tazobactam.84 Daptomycin is a consideration.43

If acute kidney injury should develop, serum levels of vancomycin or aminoglycosides should be measured if the spacer contains these antibiotics. The spacer may need to be removed if toxic serum levels persist.

TAKE-HOME POINTS

Acute kidney injury may complicate up to 10% of primary lower-extremity total joint arthroplasties and up to 25% of periprosthetic joint infections treated with a 2-stage procedure including placement of an antibiotic-loaded cement spacer in the first stage.

Risk factors for acute kidney injury include older age, obesity, chronic kidney disease, and overall comorbidity. Potentially modifiable risk factors include anemia, perioperative transfusions, aminoglycoside prophylaxis, perioperative renin-angiotensin system blockade, and postoperative nonsteroidal anti-inflammatory drugs. These should be mitigated when possible.

In patients with periprosthetic joint infection who receive antibiotic-loaded cement spacers, especially patients  with additional risk factors for acute kidney injury, strict attention should be paid to the dose of antibiotic in the spacer, with levels checked postoperatively if necessary. Nonnephrotoxic antibiotics should be chosen for systemic administration when possible.

Prospective randomized controlled trials are needed to guide therapy after total joint arthroplasty, and to verify the adverse long-term outcomes of acute kidney injury in this setting.

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  58. Lau BP, Kumar VP. Acute kidney injury (AKI) with the use of antibiotic-impregnated bone cement in primary total knee arthroplasty. Ann Acad Med Singapore 2013; 42(12):692–695. pmid:24463833
  59. Penner MJ, Masri BA, Duncan CP. Elution characteristics of vancomycin and tobramycin combined in acrylic bone-cement. J Arthroplasty 1996; 11(8):939–944. pmid:8986572
  60. Kalil GZ, Ernst EJ, Johnson SJ, et al. Systemic exposure to aminoglycosides following knee and hip arthroplasty with aminoglycoside-loaded bone cement implants. Ann Pharmacother 2012; 46(7–8):929–934. doi:10.1345/aph.1R049
  61. Hsieh PH, Chang YH, Chen SH, Ueng SW, Shih CH. High concentration and bioactivity of vancomycin and aztreonam eluted from simplex cement spacers in two-stage revision of infected hip implants: a study of 46 patients at an average follow-up of 107 days. J Orthop Res 2006; 24(8):1615–1621. doi:10.1002/jor.20214
  62. Curtis JM, Sternhagen V, Batts D. Acute renal failure after placement of tobramycin-impregnated bone cement in an infected total knee arthroplasty. Pharmacotherapy 2005; 25(6):876–880. pmid:15927906
  63. Wu IM, Marin EP, Kashgarian M, Brewster UC. A case of an acute kidney injury secondary to an implanted aminoglycoside. Kidney Int 2009; 75(10):1109–1112. doi:10.1038/ki.2008.386
  64. Chalmers PN, Frank J, Sporer SM. Acute postoperative renal failure following insertion of an antibiotic-impregnated cement spacer in revision total joint arthroplasty: two case reports. JBJS Case Connect 2012; 2(1):e12. doi:10.2106/JBJS.CC.K.00094
  65. Patrick BN, Rivey MP, Allington DR. Acute renal failure associated with vancomycin- and tobramycin-laden cement in total hip arthroplasty. Ann Pharmacother 2006; 40(11):2037–2042. doi:10.1345/aph.1H173
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Edward J. Filippone, MD, FASN
Clinical Associate Professor of Medicine, Department of Medicine, Division of Nephrology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA

Anju Yadav, MD
Assistant Professor, Department of Medicine, Division of Nephrology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA

Address: Edward J. Filippone, MD, FASN, Department of Medicine, Division of Nephrology, Sidney Kimmel Medical College, Thomas Jefferson University, 2228 South Broad Street, Philadelphia, PA 19145; [email protected]

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Cleveland Clinic Journal of Medicine - 86(4)
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Cleveland Clinic Journal of Medicine
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Nephrology
Infectious Diseases
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263-276
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acute kidney injury, AKI, total joint arthroplasty, TJA, hip replacement, knee replacement, antibiotic, aminoglycoside, cement, prosthetic joint infections, antibiotic-loaded cement, gentamicin, tobramycin, vancomycin, Edward Filippone, Anju Yadav
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Edward J. Filippone, MD, FASN
Anju Yadav, MD
Author(s)
Edward J. Filippone, MD, FASN
Anju Yadav, MD
Author and Disclosure Information

Edward J. Filippone, MD, FASN
Clinical Associate Professor of Medicine, Department of Medicine, Division of Nephrology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA

Anju Yadav, MD
Assistant Professor, Department of Medicine, Division of Nephrology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA

Address: Edward J. Filippone, MD, FASN, Department of Medicine, Division of Nephrology, Sidney Kimmel Medical College, Thomas Jefferson University, 2228 South Broad Street, Philadelphia, PA 19145; [email protected]

Author and Disclosure Information

Edward J. Filippone, MD, FASN
Clinical Associate Professor of Medicine, Department of Medicine, Division of Nephrology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA

Anju Yadav, MD
Assistant Professor, Department of Medicine, Division of Nephrology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA

Address: Edward J. Filippone, MD, FASN, Department of Medicine, Division of Nephrology, Sidney Kimmel Medical College, Thomas Jefferson University, 2228 South Broad Street, Philadelphia, PA 19145; [email protected]

Article PDF
filippone_acutekidneyinjuryafterarthroplasty.pdf
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filippone_acutekidneyinjuryafterarthroplasty.pdf
Related Articles
Predictors of acute kidney injury in patients undergoing total knee replacement surgery
Acute renal failure in hospitalized patients
Finding the cause of acute kidney injury: Which index of fractional excretion is better?

Total hip or knee replacement (also called total joint arthroplasty) is highly successful at relieving pain and restoring function, but at the risk of acute kidney injury, which is a sudden loss of renal function. Various factors have been associated with this risk, some of which are potentially modifiable, notably, the use of nephrotoxic antibiotics and other drugs.

This review examines the incidence of acute kidney injury using current criteria in total joint arthroplasty of the hip or knee in general, and in the setting of revision surgery for prosthetic joint infection in particular, in which the risk is higher. We identify risk factors for acute kidney injury and propose ways to lower the risk.

MILLIONS OF PROCEDURES ANNUALLY

Total replacement of the hip1,2 or knee3 is being done more and more. Kurtz et al4 estimate that by the year 2030, we will see approximately 3.5 million primary total knee and 500,000 primary total hip replacements every year. In addition, revision total knee procedures are expected to exceed 250,000 per year, and revision total hip procedures are expected to exceed 90,000 per year.4

Chronic infection may complicate up to 2% of these procedures and is associated with significant morbidity, death, and financial costs. Currently, it may be the reason for 25% of total joint arthroplasty revisions,5 but by the year 2030, it is projected to account for 66% of revision total knee arthroplasties and 48% of revision total hip arthroplasties.6

PRIMARY TOTAL JOINT ARTHROPLASTY AND ACUTE KIDNEY INJURY

Table 1. Studies reporting the incidence of acute kidney injury using current diagnostic criteria
We searched Ovid MEDLINE for articles on acute kidney injury and either arthroplasty or antibiotic-loaded cement spacers. We found 22 studies, with a total of 72,850 patients, that assessed the incidence of acute kidney injury after primary or revision total joint arthroplasty of the hip or knee, or both, using current criteria7–28 (Table 1), and 3 additional studies that used discharge diagnosis coding.29–31

Study designs, findings varied widely

The incidence of acute kidney injury varied markedly among the studies of primary total joint arthroplasty or revision for aseptic reasons. Numerous factors explain this heterogeneity.

Designs ranged from single-center studies with relatively small numbers of patients to large regional and national samples based on administrative data.

Table 2. Current criteria for diagnosing and staging acute kidney injury
The definition of acute kidney injury also varied, although many used current criteria, specifically the RIFLE (risk, injury, failure, loss, end-stage renal disease),32 AKIN (Acute Kidney Injury Network),33 and KDIGO (Kidney Disease Improving Global Outcomes)34 creatinine criteria (Table 2). Some studies considered only higher stages of acute kidney injury (equivalent to KDIGO stage 2 or 3), ignoring the most common stage, ie, stage 1. No study considered urine output criteria.

Almost all of the studies were retrospective. We are not aware of any randomized controlled trials.

Discharge diagnosis may miss many cases

Several studies based the diagnosis of acute kidney injury on International Classification of Diseases, Ninth Revision (ICD-9) coding from hospital discharge summaries.

Nadkarni et al,29 in the largest study published to date, used the nationwide inpatient sample database of more than 7 million total joint arthroplasties and found an incidence of acute kidney injury based on ICD-9 coding of 1.3% over the years 2002 to 2012, although this increased to 1.8% to 1.9% from 2010 to 2012.

Lopez-de-Andres et al,30 in a similar study using the Spanish national hospital discharge database, evaluated 20,188 patients who underwent revision total hip or knee arthroplasty and found an overall incidence of acute kidney injury of 0.94%, also using ICD-9 coding.

Gharaibeh et al31 used similar methods to diagnose acute kidney injury in a single-center study of 8,949 patients and found an incidence of 1.1%.

Although these 3 studies suggest that the incidence of acute kidney injury is relatively low, Grams et al35 found the sensitivity of ICD-9 coding from hospital records for the diagnosis of acute kidney injury to be only 11.7% compared with KDIGO serum creatinine and urine output criteria. This suggests that the true incidence in these studies may be many times higher, possibly near 10%.

Do all stages of kidney injury count?

Jafari et al,7 in a large series from a single medical center, used only the “I” (injury) and “F” (failure) levels of the RIFLE criteria (corresponding to stages 2 and 3 of the KDIGO criteria) and found an incidence of 0.55% in more than 17,000 total joint arthroplasties.

Jamsa et al8 used the same criteria for acute kidney injury (only “I” and “F”) and found 58 cases in 5,609 patients in whom postoperative serum creatinine was measured, for an incidence of 1%; the remaining 14,966 patients in their cohort did not have serum creatinine measured, and it was assumed they did not have acute kidney injury. Neither of these studies included the most common “R” (risk) stage of acute kidney injury.

Parr et al36 recently studied a nationwide sample of 657,840 hospitalized veterans and found that of 90,614 who developed acute kidney injury based on KDIGO creatinine criteria, 84% reached only stage R. This suggests that if all stages were considered, the true incidence of acute kidney injury would have been higher—possibly 4% in the Jafari series and possibly 7% in the Jamsa series.

Smaller studies had higher rates

Smaller, single-center series reported much higher incidences of acute kidney injury.

Kimmel et al11 found an incidence of 14.8% in 425 total joint arthroplasties using RIFLE creatinine criteria.

Johansson et al25 found an incidence of 19.9% in 136 total joint arthroplasties using KDIGO creatinine criteria.

Sehgal et al9 found an incidence of 21.9% in 659 total joint arthroplasties using AKIN creatinine criteria.

Challagundla et al24 found an incidence of 23.7% in 198 procedures using RIFLE creatinine criteria.

Weingarten et al,10 in a single-center series of 7,463 total joint arthroplasties, found an incidence of acute kidney injury of only 2.2% using AKIN criteria, although 12% of the patients with acute kidney injury did not return to their baseline serum creatinine levels by 3 months.

Our estimate: Nearly 10%

In total, in the 20 studies in Table 1 that included all stages of acute kidney injury, there were 1,909 cases of acute kidney injury in 34,337 patients, for an incidence of 5.6%. Considering that all studies but one were retrospective and none considered urine output criteria for acute kidney injury, we believe that using current KDIGO criteria, the true incidence of acute kidney injury complicating primary lower-extremity total joint arthroplasties is really closer to 10%.

 

 

RISK FACTORS FOR ACUTE KIDNEY INJURY

Various factors have been associated with development of acute kidney injury by multivariate analysis in these studies. Some are modifiable, while others are not, at least in the short term.

Nonmodifiable risk factors

Older age is often significant in studies assessing primary total joint arthroplasty or revision total joint arthroplasty not specifically for infection.11,12,16,17,26,28

Obesity is also a major factor in the development of acute kidney injury,7,10–12,17,18 and, along with age, is a major factor contributing to the need for joint replacement in the first place.

Male sex may increase risk.29

Diabetes mellitus was identified as a risk factor in several studies,10,12,17,20 and hypertension in a few.7,10,24

Other comorbidities and factors such as cardiovascular disease,7,10 liver disease,7 pulmonary disease,7 high American Society of Anesthesiology score,8,19 and benign heart murmurs preoperatively by routine physical examination have also been linked to acute kidney injury after joint arthroplasty.28

Chronic kidney disease as a risk factor

Chronic kidney disease at baseline was associated with acute kidney injury in several of these series.7,11–13,15,19,29

Warth et al12 studied 1,038 patients and found an incidence of acute kidney injury of 11% in the 135 with chronic kidney disease (defined as serum creatinine > 1.2 mg/dL) and who received acetaminophen or narcotics for pain control, compared with 4.8% in the remaining 903 patients without chronic kidney disease, who received ketorolac or celecoxib.

Perregaard et al13 studied 3,410 patients who underwent total hip arthroplasty and found an incidence of acute kidney injury (per KDIGO creatinine criteria) of 2.2% overall, but 7% in the 134 patients with chronic kidney disease based on KDIGO creatinine criteria.

Nowicka et al15 found an incidence of acute kidney injury of 16.7% in the 48 patients with chronic kidney disease (defined as a glomerular filtration rate estimated by the Cockroft-Gault formula of less than 60 mL/min/1.73 m2), compared with 4.5% in the remaining 289.

Modifiable risk factors

Modifiable risk factors that should be considered in high-risk cases include anemia, perioperative blood transfusion, perioperative use of renin-angiotensin-aldosterone system inhibitors such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), particular antibiotics used for prophylaxis, and nonsteroidal anti-inflammatory drugs used postoperatively.

Anemia and blood transfusion

Preoperative anemia has been associated with postoperative acute kidney injury in various surgical settings such as cardiac surgery.37,38 Perioperative red blood cell transfusions have also been associated with acute kidney injury in cardiac surgery; similar results may apply to total joint arthroplasty.

Choi et al,17 in 2,467 patients undergoing hip replacement, found a significant risk for acute kidney injury if postoperative hemoglobin was consistently below 10 g/dL compared with consistently above this level, with an inverse probability-of-treatment weighted odds ratio of 1.817 (P = .011).

Others have found a significant association of perioperative blood transfusion with acute kidney injury in total joint arthroplasty.10,29

Nadkarni et al,29 for example, used the nationwide inpatient sample database and found by multivariate analysis that perioperative blood transfusion was strongly associated with acute kidney injury, with an adjusted odds ratio of 2.28 (95% confidence interval [CI] 2.15–2.42, P < .0001).

Comment. A higher incidence of acute kidney injury may represent confounding by indication bias, as sicker patients or complicated surgeries may require transfusion, and this risk may not be completely accounted for by multivariate analysis. It is also possible, however, that transfusions per se may contribute to acute kidney injury. Possible direct or indirect mechanisms mediating acute kidney injury include hemolytic reactions, circulatory overload, acute lung injury, and immunomodulatory effects.39

Preoperative transfusion in anemic patients undergoing cardiac surgery may also reduce the incidence of postoperative acute kidney injury both by correcting the anemia and by limiting the need for perioperative transfusions.40 It remains to be determined whether elective preoperative transfusion to correct anemia would reduce postoperative development of acute kidney injury in total joint arthroplasty. As an aside, perioperative transfusion has also been linked to development of periprosthetic joint infection.41

Renin-angiotensin-aldosterone system inhibitors

Several studies found perioperative use of renin-angiotensin-aldosterone system inhibitors to be a risk factor for acute kidney injury.

Kimmel et al11 reported adjusted odds ratios of 2.70 (95% CI 1.12–6.48) for ACE inhibitor use and 2.64 (95% CI 1.18–5.93) for ARB use in a study of 425 primary total joint arthroplasties.

Challagundla et al24 found an odds ratio of 3.07 (95% CI 1.40–6.74) with ACE inhibitor or ARB use by multivariate analysis in 198 total joint arthroplasties.

Nielson et al18 studied 798 patients who underwent total joint arthroplasty and found that preoperative use of renin-angiotensin system inhibitors was associated with a significantly higher rate of postoperative acute kidney injury (8.3% vs 1.7% without inhibition), which was statistically significant by multivariate analysis (odds ratio 2.6, 95% CI 1.04–6.51).

We recommend holding renin-angiotensin-aldosterone system inhibitors 7 days before surgery through the postoperative period in high-risk cases.

Aminoglycoside use as a risk factor

Prophylactic administration of systemic antibiotics is the standard of care. In a systematic review of 26 studies and meta-analysis of 7 studies (3,065 patients), prophylactic antibiotics reduced the relative risk of wound infection by 81% with an absolute risk reduction of 8%.42

A modifiable risk factor for acute kidney injury is the specific antibiotic used for prophylaxis. Multiple studies assessed the risk of acute kidney injury comparing regimens containing an aminoglycoside (typically gentamicin) with regimens lacking these agents.20–26 In general, these studies found a significantly higher risk of acute kidney injury when gentamicin was used.

Challagundla et al24 found an incidence of acute kidney injury of 52% using RIFLE creatinine criteria in 52 patients receiving 8 g total of flucloxacillin plus 160 mg of gentamicin (120 mg if they weighed less than 60 kg) compared with 8% in 48 patients given cefuroxime (3 g total) and 14% in an additional 52 patients also given cefuroxime.

Johansson et al25 found an incidence of KDIGO creatinine-based acute kidney injury of 13% in 70 patients given dicloxacillin alone prophylactically compared with 27% given dicloxacillin and gentamicin, with a relative risk of 3.

Bell et al,21 in a large registry-based analysis from Scotland involving 7,666 elective orthopedic procedures, found that use of flucloxacillin 2 g plus a single dose of gentamicin 4 mg/kg was significantly associated with a 94% higher risk of acute kidney injury (KDIGO creatinine criteria) compared with a cefuroxime-based regimen, with absolute rates increasing from 6.2% to 10.8%.

Dubrovskaya et al20 and Ferguson et al,26 in contrast, found no increased risk with addition of gentamicin.

We recommend avoiding aminoglycosides for prophylaxis in primary lower-extremity total joint arthroplasty in patients at higher risk unless required for specific microbiologic reasons.

Vancomycin may also increase risk

Courtney et al19 assessed the risk of adding vancomycin to cefazolin for routine prophylaxis in a retrospective series of 1,828 total hip or knee arthroplasties and found a significantly higher rate of acute kidney injury, using AKIN criteria (13% vs 8%, odds ratio by multivariate analysis 1.82, P = .002).19

Other agents shown to be effective in treating periprosthetic joint infections or complicated skin and soft-tissue infections with resistant organisms include daptomycin43 and linezolid.44 These nonnephrotoxic alternatives to vancomycin may be a consideration if prophylaxis for methicillin-resistant Staphylococcus aureus is deemed necessary in patients at risk for acute kidney injury.

 

 

PROSTHETIC JOINT INFECTIONS AND ANTIBIOTIC-LOADED CEMENT

Deep infection may complicate nearly 1% of total hip45 and 2% of total knee arthroplasties.46 Kurtz et al4,6 have projected that by 2030, infection will be the cause of two-thirds of the estimated 268,000 revision total knee arthroplasties and about half of the estimated 96,700 revision total hip arthroplasties.

The most common method of treating a chronically infected replacement joint is a 2-stage procedure.5 First, the prosthesis is removed, all infected bone and soft tissue is debrided, and an antibiotic-loaded cement spacer is implanted. Systemic antibiotics are given concurrently, typically for about 6 weeks. After the infection is brought under control, perhaps 2 to 3 months later, the spacer is removed and a new joint is implanted with antibiotic-loaded cement. A 1-stage procedure may be an option in selected cases and would obviate the need for an antibiotic-loaded cement spacer.47,48

Of obvious relevance to development of acute kidney injury is the choice and amount of antibiotics embedded in the cement used for spacers and in implantation. Very high antibiotic levels are achieved within the joint space, usually with little systemic absorption, although significant systemic exposure has been documented in some cases.

The polymethylmethacrylate cement used for these purposes comes in 40-g bags. Multiple bags are typically required per joint, perhaps 2 to 4.49

The rate of elution of antibiotics is determined by several factors, including surface area, porosity, and the number of antibiotics. In general, elution is greatest early on, with exponential decline lasting perhaps 1 week,  followed by slow, sustained release over weeks to months.50 However, several in vitro studies have indicated that only about 5%50,51 of the total antibiotic actually elutes over time.

Initially, multiple antibiotic-laden cement beads were used to fill the joint space, but this significantly limited function and mobility.52 Now, cement spacers are used, and they can be nonarticulating or articulating for maximal joint mobility.53 Although much greater antibiotic elution occurs from beads due to their high surface area-to-volume ratio, spacers still provide an adequate dose.

ANTIBIOTIC-LOADED CEMENT: DOSAGE AND ELUTION CHARACTERISTICS

Antibiotic-loaded cement can be either low-dose or high-dose.

Low-dose cement

Low-dose cement typically consists of 0.5 to 1.0 g of antibiotic per 40-g bag of cement, usually an aminoglycoside (gentamicin or tobramycin) or vancomycin, and can be purchased premixed by the manufacturer. Such cement is only used prophylactically with primary total joint arthroplasty or revision for aseptic reasons, a practice common in Europe but less so in the United States. Some American authors propose antibiotic-loaded cement prophylaxis for patients at high risk, eg, those with immunosuppression, inflammatory cause of arthritis, or diabetes.54

Vrabec et al,55 in a study of low-dose tobramycin-loaded cement used for primary total knee arthroplasty, found a peak median intra-articular tobramycin concentration of 32 mg/L at 6 hours, declining to 6 mg/L at 48 hours with all serum levels 0.3 mg/L or less (unmeasureable) at similar time points.

Sterling et al,56 studying primary total hip arthroplasties with low-dose tobramycin-loaded cement, found mean levels in drainage fluid of 103 mg/L at 6 hours, declining to 15 mg/L at 48 hours. Serum levels peaked at 0.94 mg/L at 3 hours, declining to 0.2 mg/L by 48 hours.

Although most of the antibiotic elution occurs early (within the first week), antibiotic can be found in joint aspirates up to 20 years later.57 We are unaware of any well-documented cases of acute kidney injury ascribable to low-dose antibiotic-loaded cement used prophylactically. One case report making this assertion did not determine serum levels of aminoglycoside.58

High-dose cement

High-dose antibiotic-loaded cement typically contains about 4 to 8 g of antibiotic per 40-g bag of cement and is used in the treatment of prosthetic joint infection to form the spacers. The antibiotic must be mixed into the cement powder by the surgeon in the operating room.

There is no standard combination or dosage. The choice of antibiotic can be tailored to the infecting organism if known. Otherwise, gram-positive organisms are most common, and vancomycin and aminoglycosides are often used together. This particular combination will enhance the elution of both antibiotics when studied in vitro, a process termed “passive opportunism.”59 Other antibiotics in use include aztreonam, piperacillin, teicoplanin, fluoroquinolones, cephalosporins, and daptomycin, among others.

About 8 g of antibiotic total per 40-g bag is the maximum to allow easy molding.52 As an example, this may include 4 g of vancomycin and 3.6 g of tobramycin per 40 g. Given that 3 to 4 such bags are often used per joint, there is significant risk of systemic exposure.

Kalil et al60 studied 8 patients who received high-dose tobramycin-loaded cement to treat periprosthetic joint infections of the hip or knee and found that 7 had detectable serum levels (mean 0.84 mg/L, highest 2.0 mg/L), including 1 with a level of 0.9 mg/L on day 38; 4 of these 8 developed acute kidney injury by AKIN criteria, although other risk factors for acute kidney injury existed. Nearly all had concomitant vancomycin (3 to 8 g) added to the cement as well.

Hsieh et al61 studied 46 patients with infected total hip arthroplasties treated with high-dose antibiotic-loaded cement spacers (vancomycin 4 g and aztreonam 4 g per 40-g bag) and found vancomycin levels in joint drainage higher than 1,500 mg/L on day 1, decreasing to 571 mg/L on day 7; serum levels were low (range 0.1–1.6 mg/L at 24 hours), falling to undetectable by 72 hours.

 

 

ANTIBIOTIC-LOADED CEMENT SPACERS AND ACUTE KIDNEY INJURY

Case reports have associated high-dose antibiotic-loaded cement spacers with acute kidney injury.

Curtis et al62 described an 85-year-old patient with stage 3 chronic kidney disease who was treated for an infected total knee arthroplasty with an antibiotic-loaded cement spacer (containing 3.6 g of tobramycin and 3 g of cefazolin per 40-g bag, 3 bags total) and developed stage 3 acute kidney injury. After 16 days and 3 hemodialysis sessions, the patient’s serum tobramycin level was still 2 mg/L despite receiving no systemic tobramycin.

Wu et al63 reported a case of acute kidney injury that required dialysis after implantation of a tobramycin- and vancomycin-loaded spacer, with persistent serum tobramycin levels despite repeated hemodialysis sessions until the spacer was removed.

Chalmers et al64 described 2 patients with acute kidney injury and persistently elevated serum tobramycin levels (3.9 mg/L on day 39 in 1 patient and 2.0 mg/L on day 24 in the other patient) despite no systemic administration.

In these and other case reports,65–67 dialysis and spacer explantation were usually required. 


Comment. It is intuitive that acute kidney injury would more likely complicate revision total joint arthroplasties for infection than for primary total joint arthroplasties or revisions for aseptic reasons, given the systemic effects of infection and exposure to nephrotoxic or allergenic antibiotics. And the available data suggest that the risk of acute kidney injury is higher with revision for prosthetic joint infection than with revision for aseptic reasons. However, many of the studies were retrospective, relatively small, single-center series and used different definitions of acute kidney injury.

Table 3. Acute kidney injury in patients with antibiotic-loaded cement spacers for treatment of prosthetic joint infection of the hip and knee
We are aware of 17 studies specifically addressing acute kidney injury or postoperative complications in general that may have included acute kidney injury.50,52,61,68–81 Ten of these studies found at least 1 case of acute kidney injury (Table 3). Of note, 7 studies totaling 219 patients reported no cases of acute kidney injury, although acute kidney injury per se was not mentioned and no definition of it was provided.50,61,76,77,79,80,82

Luu et al83 performed a systematic review of studies published between January 1989 and June 2012 reporting systemic complications (including acute kidney injury) of 2-stage revision arthroplasties including placement of an antibiotic-loaded cement spacer for treatment of periprosthetic joint infection. Overall, 10 studies were identified with 544 total patients. Five of these studies, with 409 patients, reported at least 1 case of acute kidney injury for a total of 27 patients, giving an incidence of 6.6% in these studies.68–71 The remaining 5 studies, totaling 135 patients, did not report any cases of acute kidney injury,50,61,76–78 although that was not the primary focus of any of those trials.

Most notable from this systematic review, the study of Menge et al69 retrospectively determined the incidence of acute kidney injury (defined as a 50% rise in serum creatinine to > 1.4 mg/dL within 90 days of surgery) to be 17% in 84 patients with infected total knee arthroplasties treated with antibiotic-loaded cement spacers. A mean of 3.5 bags of cement per spacer were used in the 35 articulating spacers, compared with 2.9 per nonarticulating spacer. These spacers contained vancomycin in 82% (median 4.0 g, range 1–16 g) and tobramycin in 94% (median 4.8 g, range 1–12 g), among others in small percentages. The dose of tobramycin in the spacer considered either as a dichotomous variable (> 4.8 g, OR 5.87) or linearly (OR 1.24 per 1-g increase) was significantly associated with acute kidney injury, although systemic administration of aminoglycosides or vancomycin was not.

Additional single-center series that were published subsequent to this review have generally used more current diagnostic criteria.

Noto et al72 found that 10 of 46 patients treated with antibiotic-loaded cement spacers had a greater than 50% rise in serum creatinine (average increase 260%). All spacers contained tobramycin (mean dose 8.2 g), and 9 of 10 also contained vancomycin (mean 7.6 g). All of the 9 patients with acute kidney injury with follow-up data recovered renal function.

Reed et al75 found 26 cases of acute kidney injury (based on RIFLE creatinine criteria) in 306 patients with antibiotic-loaded cement spacers treating various periprosthetic joint infections (including hips, knees, shoulders, and digits) and compared them with 74 controls who did not develop acute kidney injury. By multivariable analysis, receipt of an ACE inhibitor within 7 days of surgery and receipt of piperacillin-tazobactam within 7 days after surgery were both significantly more common in cases with acute kidney injury than in controls without acute kidney injury.

Aeng et al73 prospectively studied 50 consecutive patients receiving antibiotic-loaded spacers containing tobramycin (with or without vancomycin) for treatment of infected hip or knee replacements. Using RIFLE creatinine criteria, they found an incidence of acute kidney injury of 20% (10 of 50). Factors significantly associated with acute kidney injury included cement premixed by the manufacturer with gentamicin (0.5 g per 40-g bag) in addition to the tobramycin they added, intraoperative blood transfusions, and postoperative use of nonsteroidal anti-inflammatory drugs.

Geller et al,74 in a multicenter retrospective study of 247 patients with prosthetic joint infections (156 knees and 91 hips) undergoing antibiotic-loaded cement spacer placement, found an incidence of acute kidney injury of 26% based on KDIGO creatinine criteria. Significant risk factors included higher body mass index, lower preoperative hemoglobin level, drop in hemoglobin after surgery, and comorbidity (hypertension, diabetes, chronic kidney disease, or cardiovascular disease). Most of the spacers contained a combination of vancomycin and either tobramycin (81%) or gentamicin (13%). The spacers contained an average of 5.3 g (range 0.6–18 g) of vancomycin (average 2.65 g per 40-g bag) and an average of 5.2 g (range 0.5–16.4 g) of tobramycin (average 2.6 g per bag).

As in Menge et al,69 this study illustrates the wide range of antibiotic dosages in use and the lack of standardization. In contrast to the study by Menge et al, however, development of acute kidney injury was not related to the amount of vancomycin or tobramycin contained in the spacers. Eventual clearance of infection (at 1 and 2 years) was significantly related to increasing amounts of vancomycin. Multiple different systemic antibiotics were used, most commonly vancomycin (44%), and systemic vancomycin was not associated with acute kidney injury.

Yadav et al,81 in a study of 3,129 consecutive revision procedures of the knee or hip, found an incidence of acute kidney injury by RIFLE creatinine criteria of 29% in the 197 patients who received antibiotic-loaded cement spacers for periprosthetic joint infection compared with 3.4% in the 2,848 who underwent revision for aseptic reasons. In 84 patients with prosthetic joint infection having various surgeries not including placement of a spacer, the acute kidney injury rate at some point in their course was an alarmingly high 82%. In the group that received spacers, only age and comorbidity as assessed by Charlson comorbidity index were independently associated with acute kidney injury by multivariate analysis. Surprisingly, modest renal impairment was protective, possibly because physicians of patients with chronic kidney disease were more vigilant and took appropriate measures to prevent acute kidney injury.

Overall, the risk of acute kidney injury appears to be much higher during treatment of prosthetic joint infection with a 2-stage procedure using an antibiotic-loaded cement spacer than after primary total joint arthroplasty or revision for aseptic reasons, and may complicate up to one-third of cases.

 

 

REDUCING RISK DURING TREATMENT OF INFECTED REPLACEMENT JOINTS

Table 4. Suggestions for practice modifications
Due to lack of appropriate data, how best to mitigate the risk of acute kidney injury is uncertain. In our opinion, however, the following measures should be considered (Table 4).

As in primary total joint arthroplasty in general, higher-risk cases should be identified based on age, body mass index, chronic kidney disease, comorbidities (hypertension, diabetes, established cardiovascular disease), and anemia.

Preoperative transfusion can be considered case by case depending on degree of anemia and associated risk factors.

All renin-angiotensin-aldosterone system inhibitors should be withheld starting 1 week before surgery.

Both nonselective and cyclooxygenase-2 selective nonsteroidal anti-inflammatory drugs should be avoided, if possible.

Strict attention should be paid to adequate intraoperative and postoperative fluid resuscitation.

Kidney function should be monitored closely in the early postoperative period, including urine output and daily creatinine for at least 72 hours.

Systemic administration of potentially nephrotoxic antibiotics should be minimized, especially the combination of vancomycin with piperacillin-tazobactam.84 Daptomycin is a consideration.43

If acute kidney injury should develop, serum levels of vancomycin or aminoglycosides should be measured if the spacer contains these antibiotics. The spacer may need to be removed if toxic serum levels persist.

TAKE-HOME POINTS

Acute kidney injury may complicate up to 10% of primary lower-extremity total joint arthroplasties and up to 25% of periprosthetic joint infections treated with a 2-stage procedure including placement of an antibiotic-loaded cement spacer in the first stage.

Risk factors for acute kidney injury include older age, obesity, chronic kidney disease, and overall comorbidity. Potentially modifiable risk factors include anemia, perioperative transfusions, aminoglycoside prophylaxis, perioperative renin-angiotensin system blockade, and postoperative nonsteroidal anti-inflammatory drugs. These should be mitigated when possible.

In patients with periprosthetic joint infection who receive antibiotic-loaded cement spacers, especially patients  with additional risk factors for acute kidney injury, strict attention should be paid to the dose of antibiotic in the spacer, with levels checked postoperatively if necessary. Nonnephrotoxic antibiotics should be chosen for systemic administration when possible.

Prospective randomized controlled trials are needed to guide therapy after total joint arthroplasty, and to verify the adverse long-term outcomes of acute kidney injury in this setting.

Total hip or knee replacement (also called total joint arthroplasty) is highly successful at relieving pain and restoring function, but at the risk of acute kidney injury, which is a sudden loss of renal function. Various factors have been associated with this risk, some of which are potentially modifiable, notably, the use of nephrotoxic antibiotics and other drugs.

This review examines the incidence of acute kidney injury using current criteria in total joint arthroplasty of the hip or knee in general, and in the setting of revision surgery for prosthetic joint infection in particular, in which the risk is higher. We identify risk factors for acute kidney injury and propose ways to lower the risk.

MILLIONS OF PROCEDURES ANNUALLY

Total replacement of the hip1,2 or knee3 is being done more and more. Kurtz et al4 estimate that by the year 2030, we will see approximately 3.5 million primary total knee and 500,000 primary total hip replacements every year. In addition, revision total knee procedures are expected to exceed 250,000 per year, and revision total hip procedures are expected to exceed 90,000 per year.4

Chronic infection may complicate up to 2% of these procedures and is associated with significant morbidity, death, and financial costs. Currently, it may be the reason for 25% of total joint arthroplasty revisions,5 but by the year 2030, it is projected to account for 66% of revision total knee arthroplasties and 48% of revision total hip arthroplasties.6

PRIMARY TOTAL JOINT ARTHROPLASTY AND ACUTE KIDNEY INJURY

Table 1. Studies reporting the incidence of acute kidney injury using current diagnostic criteria
We searched Ovid MEDLINE for articles on acute kidney injury and either arthroplasty or antibiotic-loaded cement spacers. We found 22 studies, with a total of 72,850 patients, that assessed the incidence of acute kidney injury after primary or revision total joint arthroplasty of the hip or knee, or both, using current criteria7–28 (Table 1), and 3 additional studies that used discharge diagnosis coding.29–31

Study designs, findings varied widely

The incidence of acute kidney injury varied markedly among the studies of primary total joint arthroplasty or revision for aseptic reasons. Numerous factors explain this heterogeneity.

Designs ranged from single-center studies with relatively small numbers of patients to large regional and national samples based on administrative data.

Table 2. Current criteria for diagnosing and staging acute kidney injury
The definition of acute kidney injury also varied, although many used current criteria, specifically the RIFLE (risk, injury, failure, loss, end-stage renal disease),32 AKIN (Acute Kidney Injury Network),33 and KDIGO (Kidney Disease Improving Global Outcomes)34 creatinine criteria (Table 2). Some studies considered only higher stages of acute kidney injury (equivalent to KDIGO stage 2 or 3), ignoring the most common stage, ie, stage 1. No study considered urine output criteria.

Almost all of the studies were retrospective. We are not aware of any randomized controlled trials.

Discharge diagnosis may miss many cases

Several studies based the diagnosis of acute kidney injury on International Classification of Diseases, Ninth Revision (ICD-9) coding from hospital discharge summaries.

Nadkarni et al,29 in the largest study published to date, used the nationwide inpatient sample database of more than 7 million total joint arthroplasties and found an incidence of acute kidney injury based on ICD-9 coding of 1.3% over the years 2002 to 2012, although this increased to 1.8% to 1.9% from 2010 to 2012.

Lopez-de-Andres et al,30 in a similar study using the Spanish national hospital discharge database, evaluated 20,188 patients who underwent revision total hip or knee arthroplasty and found an overall incidence of acute kidney injury of 0.94%, also using ICD-9 coding.

Gharaibeh et al31 used similar methods to diagnose acute kidney injury in a single-center study of 8,949 patients and found an incidence of 1.1%.

Although these 3 studies suggest that the incidence of acute kidney injury is relatively low, Grams et al35 found the sensitivity of ICD-9 coding from hospital records for the diagnosis of acute kidney injury to be only 11.7% compared with KDIGO serum creatinine and urine output criteria. This suggests that the true incidence in these studies may be many times higher, possibly near 10%.

Do all stages of kidney injury count?

Jafari et al,7 in a large series from a single medical center, used only the “I” (injury) and “F” (failure) levels of the RIFLE criteria (corresponding to stages 2 and 3 of the KDIGO criteria) and found an incidence of 0.55% in more than 17,000 total joint arthroplasties.

Jamsa et al8 used the same criteria for acute kidney injury (only “I” and “F”) and found 58 cases in 5,609 patients in whom postoperative serum creatinine was measured, for an incidence of 1%; the remaining 14,966 patients in their cohort did not have serum creatinine measured, and it was assumed they did not have acute kidney injury. Neither of these studies included the most common “R” (risk) stage of acute kidney injury.

Parr et al36 recently studied a nationwide sample of 657,840 hospitalized veterans and found that of 90,614 who developed acute kidney injury based on KDIGO creatinine criteria, 84% reached only stage R. This suggests that if all stages were considered, the true incidence of acute kidney injury would have been higher—possibly 4% in the Jafari series and possibly 7% in the Jamsa series.

Smaller studies had higher rates

Smaller, single-center series reported much higher incidences of acute kidney injury.

Kimmel et al11 found an incidence of 14.8% in 425 total joint arthroplasties using RIFLE creatinine criteria.

Johansson et al25 found an incidence of 19.9% in 136 total joint arthroplasties using KDIGO creatinine criteria.

Sehgal et al9 found an incidence of 21.9% in 659 total joint arthroplasties using AKIN creatinine criteria.

Challagundla et al24 found an incidence of 23.7% in 198 procedures using RIFLE creatinine criteria.

Weingarten et al,10 in a single-center series of 7,463 total joint arthroplasties, found an incidence of acute kidney injury of only 2.2% using AKIN criteria, although 12% of the patients with acute kidney injury did not return to their baseline serum creatinine levels by 3 months.

Our estimate: Nearly 10%

In total, in the 20 studies in Table 1 that included all stages of acute kidney injury, there were 1,909 cases of acute kidney injury in 34,337 patients, for an incidence of 5.6%. Considering that all studies but one were retrospective and none considered urine output criteria for acute kidney injury, we believe that using current KDIGO criteria, the true incidence of acute kidney injury complicating primary lower-extremity total joint arthroplasties is really closer to 10%.

 

 

RISK FACTORS FOR ACUTE KIDNEY INJURY

Various factors have been associated with development of acute kidney injury by multivariate analysis in these studies. Some are modifiable, while others are not, at least in the short term.

Nonmodifiable risk factors

Older age is often significant in studies assessing primary total joint arthroplasty or revision total joint arthroplasty not specifically for infection.11,12,16,17,26,28

Obesity is also a major factor in the development of acute kidney injury,7,10–12,17,18 and, along with age, is a major factor contributing to the need for joint replacement in the first place.

Male sex may increase risk.29

Diabetes mellitus was identified as a risk factor in several studies,10,12,17,20 and hypertension in a few.7,10,24

Other comorbidities and factors such as cardiovascular disease,7,10 liver disease,7 pulmonary disease,7 high American Society of Anesthesiology score,8,19 and benign heart murmurs preoperatively by routine physical examination have also been linked to acute kidney injury after joint arthroplasty.28

Chronic kidney disease as a risk factor

Chronic kidney disease at baseline was associated with acute kidney injury in several of these series.7,11–13,15,19,29

Warth et al12 studied 1,038 patients and found an incidence of acute kidney injury of 11% in the 135 with chronic kidney disease (defined as serum creatinine > 1.2 mg/dL) and who received acetaminophen or narcotics for pain control, compared with 4.8% in the remaining 903 patients without chronic kidney disease, who received ketorolac or celecoxib.

Perregaard et al13 studied 3,410 patients who underwent total hip arthroplasty and found an incidence of acute kidney injury (per KDIGO creatinine criteria) of 2.2% overall, but 7% in the 134 patients with chronic kidney disease based on KDIGO creatinine criteria.

Nowicka et al15 found an incidence of acute kidney injury of 16.7% in the 48 patients with chronic kidney disease (defined as a glomerular filtration rate estimated by the Cockroft-Gault formula of less than 60 mL/min/1.73 m2), compared with 4.5% in the remaining 289.

Modifiable risk factors

Modifiable risk factors that should be considered in high-risk cases include anemia, perioperative blood transfusion, perioperative use of renin-angiotensin-aldosterone system inhibitors such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), particular antibiotics used for prophylaxis, and nonsteroidal anti-inflammatory drugs used postoperatively.

Anemia and blood transfusion

Preoperative anemia has been associated with postoperative acute kidney injury in various surgical settings such as cardiac surgery.37,38 Perioperative red blood cell transfusions have also been associated with acute kidney injury in cardiac surgery; similar results may apply to total joint arthroplasty.

Choi et al,17 in 2,467 patients undergoing hip replacement, found a significant risk for acute kidney injury if postoperative hemoglobin was consistently below 10 g/dL compared with consistently above this level, with an inverse probability-of-treatment weighted odds ratio of 1.817 (P = .011).

Others have found a significant association of perioperative blood transfusion with acute kidney injury in total joint arthroplasty.10,29

Nadkarni et al,29 for example, used the nationwide inpatient sample database and found by multivariate analysis that perioperative blood transfusion was strongly associated with acute kidney injury, with an adjusted odds ratio of 2.28 (95% confidence interval [CI] 2.15–2.42, P < .0001).

Comment. A higher incidence of acute kidney injury may represent confounding by indication bias, as sicker patients or complicated surgeries may require transfusion, and this risk may not be completely accounted for by multivariate analysis. It is also possible, however, that transfusions per se may contribute to acute kidney injury. Possible direct or indirect mechanisms mediating acute kidney injury include hemolytic reactions, circulatory overload, acute lung injury, and immunomodulatory effects.39

Preoperative transfusion in anemic patients undergoing cardiac surgery may also reduce the incidence of postoperative acute kidney injury both by correcting the anemia and by limiting the need for perioperative transfusions.40 It remains to be determined whether elective preoperative transfusion to correct anemia would reduce postoperative development of acute kidney injury in total joint arthroplasty. As an aside, perioperative transfusion has also been linked to development of periprosthetic joint infection.41

Renin-angiotensin-aldosterone system inhibitors

Several studies found perioperative use of renin-angiotensin-aldosterone system inhibitors to be a risk factor for acute kidney injury.

Kimmel et al11 reported adjusted odds ratios of 2.70 (95% CI 1.12–6.48) for ACE inhibitor use and 2.64 (95% CI 1.18–5.93) for ARB use in a study of 425 primary total joint arthroplasties.

Challagundla et al24 found an odds ratio of 3.07 (95% CI 1.40–6.74) with ACE inhibitor or ARB use by multivariate analysis in 198 total joint arthroplasties.

Nielson et al18 studied 798 patients who underwent total joint arthroplasty and found that preoperative use of renin-angiotensin system inhibitors was associated with a significantly higher rate of postoperative acute kidney injury (8.3% vs 1.7% without inhibition), which was statistically significant by multivariate analysis (odds ratio 2.6, 95% CI 1.04–6.51).

We recommend holding renin-angiotensin-aldosterone system inhibitors 7 days before surgery through the postoperative period in high-risk cases.

Aminoglycoside use as a risk factor

Prophylactic administration of systemic antibiotics is the standard of care. In a systematic review of 26 studies and meta-analysis of 7 studies (3,065 patients), prophylactic antibiotics reduced the relative risk of wound infection by 81% with an absolute risk reduction of 8%.42

A modifiable risk factor for acute kidney injury is the specific antibiotic used for prophylaxis. Multiple studies assessed the risk of acute kidney injury comparing regimens containing an aminoglycoside (typically gentamicin) with regimens lacking these agents.20–26 In general, these studies found a significantly higher risk of acute kidney injury when gentamicin was used.

Challagundla et al24 found an incidence of acute kidney injury of 52% using RIFLE creatinine criteria in 52 patients receiving 8 g total of flucloxacillin plus 160 mg of gentamicin (120 mg if they weighed less than 60 kg) compared with 8% in 48 patients given cefuroxime (3 g total) and 14% in an additional 52 patients also given cefuroxime.

Johansson et al25 found an incidence of KDIGO creatinine-based acute kidney injury of 13% in 70 patients given dicloxacillin alone prophylactically compared with 27% given dicloxacillin and gentamicin, with a relative risk of 3.

Bell et al,21 in a large registry-based analysis from Scotland involving 7,666 elective orthopedic procedures, found that use of flucloxacillin 2 g plus a single dose of gentamicin 4 mg/kg was significantly associated with a 94% higher risk of acute kidney injury (KDIGO creatinine criteria) compared with a cefuroxime-based regimen, with absolute rates increasing from 6.2% to 10.8%.

Dubrovskaya et al20 and Ferguson et al,26 in contrast, found no increased risk with addition of gentamicin.

We recommend avoiding aminoglycosides for prophylaxis in primary lower-extremity total joint arthroplasty in patients at higher risk unless required for specific microbiologic reasons.

Vancomycin may also increase risk

Courtney et al19 assessed the risk of adding vancomycin to cefazolin for routine prophylaxis in a retrospective series of 1,828 total hip or knee arthroplasties and found a significantly higher rate of acute kidney injury, using AKIN criteria (13% vs 8%, odds ratio by multivariate analysis 1.82, P = .002).19

Other agents shown to be effective in treating periprosthetic joint infections or complicated skin and soft-tissue infections with resistant organisms include daptomycin43 and linezolid.44 These nonnephrotoxic alternatives to vancomycin may be a consideration if prophylaxis for methicillin-resistant Staphylococcus aureus is deemed necessary in patients at risk for acute kidney injury.

 

 

PROSTHETIC JOINT INFECTIONS AND ANTIBIOTIC-LOADED CEMENT

Deep infection may complicate nearly 1% of total hip45 and 2% of total knee arthroplasties.46 Kurtz et al4,6 have projected that by 2030, infection will be the cause of two-thirds of the estimated 268,000 revision total knee arthroplasties and about half of the estimated 96,700 revision total hip arthroplasties.

The most common method of treating a chronically infected replacement joint is a 2-stage procedure.5 First, the prosthesis is removed, all infected bone and soft tissue is debrided, and an antibiotic-loaded cement spacer is implanted. Systemic antibiotics are given concurrently, typically for about 6 weeks. After the infection is brought under control, perhaps 2 to 3 months later, the spacer is removed and a new joint is implanted with antibiotic-loaded cement. A 1-stage procedure may be an option in selected cases and would obviate the need for an antibiotic-loaded cement spacer.47,48

Of obvious relevance to development of acute kidney injury is the choice and amount of antibiotics embedded in the cement used for spacers and in implantation. Very high antibiotic levels are achieved within the joint space, usually with little systemic absorption, although significant systemic exposure has been documented in some cases.

The polymethylmethacrylate cement used for these purposes comes in 40-g bags. Multiple bags are typically required per joint, perhaps 2 to 4.49

The rate of elution of antibiotics is determined by several factors, including surface area, porosity, and the number of antibiotics. In general, elution is greatest early on, with exponential decline lasting perhaps 1 week,  followed by slow, sustained release over weeks to months.50 However, several in vitro studies have indicated that only about 5%50,51 of the total antibiotic actually elutes over time.

Initially, multiple antibiotic-laden cement beads were used to fill the joint space, but this significantly limited function and mobility.52 Now, cement spacers are used, and they can be nonarticulating or articulating for maximal joint mobility.53 Although much greater antibiotic elution occurs from beads due to their high surface area-to-volume ratio, spacers still provide an adequate dose.

ANTIBIOTIC-LOADED CEMENT: DOSAGE AND ELUTION CHARACTERISTICS

Antibiotic-loaded cement can be either low-dose or high-dose.

Low-dose cement

Low-dose cement typically consists of 0.5 to 1.0 g of antibiotic per 40-g bag of cement, usually an aminoglycoside (gentamicin or tobramycin) or vancomycin, and can be purchased premixed by the manufacturer. Such cement is only used prophylactically with primary total joint arthroplasty or revision for aseptic reasons, a practice common in Europe but less so in the United States. Some American authors propose antibiotic-loaded cement prophylaxis for patients at high risk, eg, those with immunosuppression, inflammatory cause of arthritis, or diabetes.54

Vrabec et al,55 in a study of low-dose tobramycin-loaded cement used for primary total knee arthroplasty, found a peak median intra-articular tobramycin concentration of 32 mg/L at 6 hours, declining to 6 mg/L at 48 hours with all serum levels 0.3 mg/L or less (unmeasureable) at similar time points.

Sterling et al,56 studying primary total hip arthroplasties with low-dose tobramycin-loaded cement, found mean levels in drainage fluid of 103 mg/L at 6 hours, declining to 15 mg/L at 48 hours. Serum levels peaked at 0.94 mg/L at 3 hours, declining to 0.2 mg/L by 48 hours.

Although most of the antibiotic elution occurs early (within the first week), antibiotic can be found in joint aspirates up to 20 years later.57 We are unaware of any well-documented cases of acute kidney injury ascribable to low-dose antibiotic-loaded cement used prophylactically. One case report making this assertion did not determine serum levels of aminoglycoside.58

High-dose cement

High-dose antibiotic-loaded cement typically contains about 4 to 8 g of antibiotic per 40-g bag of cement and is used in the treatment of prosthetic joint infection to form the spacers. The antibiotic must be mixed into the cement powder by the surgeon in the operating room.

There is no standard combination or dosage. The choice of antibiotic can be tailored to the infecting organism if known. Otherwise, gram-positive organisms are most common, and vancomycin and aminoglycosides are often used together. This particular combination will enhance the elution of both antibiotics when studied in vitro, a process termed “passive opportunism.”59 Other antibiotics in use include aztreonam, piperacillin, teicoplanin, fluoroquinolones, cephalosporins, and daptomycin, among others.

About 8 g of antibiotic total per 40-g bag is the maximum to allow easy molding.52 As an example, this may include 4 g of vancomycin and 3.6 g of tobramycin per 40 g. Given that 3 to 4 such bags are often used per joint, there is significant risk of systemic exposure.

Kalil et al60 studied 8 patients who received high-dose tobramycin-loaded cement to treat periprosthetic joint infections of the hip or knee and found that 7 had detectable serum levels (mean 0.84 mg/L, highest 2.0 mg/L), including 1 with a level of 0.9 mg/L on day 38; 4 of these 8 developed acute kidney injury by AKIN criteria, although other risk factors for acute kidney injury existed. Nearly all had concomitant vancomycin (3 to 8 g) added to the cement as well.

Hsieh et al61 studied 46 patients with infected total hip arthroplasties treated with high-dose antibiotic-loaded cement spacers (vancomycin 4 g and aztreonam 4 g per 40-g bag) and found vancomycin levels in joint drainage higher than 1,500 mg/L on day 1, decreasing to 571 mg/L on day 7; serum levels were low (range 0.1–1.6 mg/L at 24 hours), falling to undetectable by 72 hours.

 

 

ANTIBIOTIC-LOADED CEMENT SPACERS AND ACUTE KIDNEY INJURY

Case reports have associated high-dose antibiotic-loaded cement spacers with acute kidney injury.

Curtis et al62 described an 85-year-old patient with stage 3 chronic kidney disease who was treated for an infected total knee arthroplasty with an antibiotic-loaded cement spacer (containing 3.6 g of tobramycin and 3 g of cefazolin per 40-g bag, 3 bags total) and developed stage 3 acute kidney injury. After 16 days and 3 hemodialysis sessions, the patient’s serum tobramycin level was still 2 mg/L despite receiving no systemic tobramycin.

Wu et al63 reported a case of acute kidney injury that required dialysis after implantation of a tobramycin- and vancomycin-loaded spacer, with persistent serum tobramycin levels despite repeated hemodialysis sessions until the spacer was removed.

Chalmers et al64 described 2 patients with acute kidney injury and persistently elevated serum tobramycin levels (3.9 mg/L on day 39 in 1 patient and 2.0 mg/L on day 24 in the other patient) despite no systemic administration.

In these and other case reports,65–67 dialysis and spacer explantation were usually required. 


Comment. It is intuitive that acute kidney injury would more likely complicate revision total joint arthroplasties for infection than for primary total joint arthroplasties or revisions for aseptic reasons, given the systemic effects of infection and exposure to nephrotoxic or allergenic antibiotics. And the available data suggest that the risk of acute kidney injury is higher with revision for prosthetic joint infection than with revision for aseptic reasons. However, many of the studies were retrospective, relatively small, single-center series and used different definitions of acute kidney injury.

Table 3. Acute kidney injury in patients with antibiotic-loaded cement spacers for treatment of prosthetic joint infection of the hip and knee
We are aware of 17 studies specifically addressing acute kidney injury or postoperative complications in general that may have included acute kidney injury.50,52,61,68–81 Ten of these studies found at least 1 case of acute kidney injury (Table 3). Of note, 7 studies totaling 219 patients reported no cases of acute kidney injury, although acute kidney injury per se was not mentioned and no definition of it was provided.50,61,76,77,79,80,82

Luu et al83 performed a systematic review of studies published between January 1989 and June 2012 reporting systemic complications (including acute kidney injury) of 2-stage revision arthroplasties including placement of an antibiotic-loaded cement spacer for treatment of periprosthetic joint infection. Overall, 10 studies were identified with 544 total patients. Five of these studies, with 409 patients, reported at least 1 case of acute kidney injury for a total of 27 patients, giving an incidence of 6.6% in these studies.68–71 The remaining 5 studies, totaling 135 patients, did not report any cases of acute kidney injury,50,61,76–78 although that was not the primary focus of any of those trials.

Most notable from this systematic review, the study of Menge et al69 retrospectively determined the incidence of acute kidney injury (defined as a 50% rise in serum creatinine to > 1.4 mg/dL within 90 days of surgery) to be 17% in 84 patients with infected total knee arthroplasties treated with antibiotic-loaded cement spacers. A mean of 3.5 bags of cement per spacer were used in the 35 articulating spacers, compared with 2.9 per nonarticulating spacer. These spacers contained vancomycin in 82% (median 4.0 g, range 1–16 g) and tobramycin in 94% (median 4.8 g, range 1–12 g), among others in small percentages. The dose of tobramycin in the spacer considered either as a dichotomous variable (> 4.8 g, OR 5.87) or linearly (OR 1.24 per 1-g increase) was significantly associated with acute kidney injury, although systemic administration of aminoglycosides or vancomycin was not.

Additional single-center series that were published subsequent to this review have generally used more current diagnostic criteria.

Noto et al72 found that 10 of 46 patients treated with antibiotic-loaded cement spacers had a greater than 50% rise in serum creatinine (average increase 260%). All spacers contained tobramycin (mean dose 8.2 g), and 9 of 10 also contained vancomycin (mean 7.6 g). All of the 9 patients with acute kidney injury with follow-up data recovered renal function.

Reed et al75 found 26 cases of acute kidney injury (based on RIFLE creatinine criteria) in 306 patients with antibiotic-loaded cement spacers treating various periprosthetic joint infections (including hips, knees, shoulders, and digits) and compared them with 74 controls who did not develop acute kidney injury. By multivariable analysis, receipt of an ACE inhibitor within 7 days of surgery and receipt of piperacillin-tazobactam within 7 days after surgery were both significantly more common in cases with acute kidney injury than in controls without acute kidney injury.

Aeng et al73 prospectively studied 50 consecutive patients receiving antibiotic-loaded spacers containing tobramycin (with or without vancomycin) for treatment of infected hip or knee replacements. Using RIFLE creatinine criteria, they found an incidence of acute kidney injury of 20% (10 of 50). Factors significantly associated with acute kidney injury included cement premixed by the manufacturer with gentamicin (0.5 g per 40-g bag) in addition to the tobramycin they added, intraoperative blood transfusions, and postoperative use of nonsteroidal anti-inflammatory drugs.

Geller et al,74 in a multicenter retrospective study of 247 patients with prosthetic joint infections (156 knees and 91 hips) undergoing antibiotic-loaded cement spacer placement, found an incidence of acute kidney injury of 26% based on KDIGO creatinine criteria. Significant risk factors included higher body mass index, lower preoperative hemoglobin level, drop in hemoglobin after surgery, and comorbidity (hypertension, diabetes, chronic kidney disease, or cardiovascular disease). Most of the spacers contained a combination of vancomycin and either tobramycin (81%) or gentamicin (13%). The spacers contained an average of 5.3 g (range 0.6–18 g) of vancomycin (average 2.65 g per 40-g bag) and an average of 5.2 g (range 0.5–16.4 g) of tobramycin (average 2.6 g per bag).

As in Menge et al,69 this study illustrates the wide range of antibiotic dosages in use and the lack of standardization. In contrast to the study by Menge et al, however, development of acute kidney injury was not related to the amount of vancomycin or tobramycin contained in the spacers. Eventual clearance of infection (at 1 and 2 years) was significantly related to increasing amounts of vancomycin. Multiple different systemic antibiotics were used, most commonly vancomycin (44%), and systemic vancomycin was not associated with acute kidney injury.

Yadav et al,81 in a study of 3,129 consecutive revision procedures of the knee or hip, found an incidence of acute kidney injury by RIFLE creatinine criteria of 29% in the 197 patients who received antibiotic-loaded cement spacers for periprosthetic joint infection compared with 3.4% in the 2,848 who underwent revision for aseptic reasons. In 84 patients with prosthetic joint infection having various surgeries not including placement of a spacer, the acute kidney injury rate at some point in their course was an alarmingly high 82%. In the group that received spacers, only age and comorbidity as assessed by Charlson comorbidity index were independently associated with acute kidney injury by multivariate analysis. Surprisingly, modest renal impairment was protective, possibly because physicians of patients with chronic kidney disease were more vigilant and took appropriate measures to prevent acute kidney injury.

Overall, the risk of acute kidney injury appears to be much higher during treatment of prosthetic joint infection with a 2-stage procedure using an antibiotic-loaded cement spacer than after primary total joint arthroplasty or revision for aseptic reasons, and may complicate up to one-third of cases.

 

 

REDUCING RISK DURING TREATMENT OF INFECTED REPLACEMENT JOINTS

Table 4. Suggestions for practice modifications
Due to lack of appropriate data, how best to mitigate the risk of acute kidney injury is uncertain. In our opinion, however, the following measures should be considered (Table 4).

As in primary total joint arthroplasty in general, higher-risk cases should be identified based on age, body mass index, chronic kidney disease, comorbidities (hypertension, diabetes, established cardiovascular disease), and anemia.

Preoperative transfusion can be considered case by case depending on degree of anemia and associated risk factors.

All renin-angiotensin-aldosterone system inhibitors should be withheld starting 1 week before surgery.

Both nonselective and cyclooxygenase-2 selective nonsteroidal anti-inflammatory drugs should be avoided, if possible.

Strict attention should be paid to adequate intraoperative and postoperative fluid resuscitation.

Kidney function should be monitored closely in the early postoperative period, including urine output and daily creatinine for at least 72 hours.

Systemic administration of potentially nephrotoxic antibiotics should be minimized, especially the combination of vancomycin with piperacillin-tazobactam.84 Daptomycin is a consideration.43

If acute kidney injury should develop, serum levels of vancomycin or aminoglycosides should be measured if the spacer contains these antibiotics. The spacer may need to be removed if toxic serum levels persist.

TAKE-HOME POINTS

Acute kidney injury may complicate up to 10% of primary lower-extremity total joint arthroplasties and up to 25% of periprosthetic joint infections treated with a 2-stage procedure including placement of an antibiotic-loaded cement spacer in the first stage.

Risk factors for acute kidney injury include older age, obesity, chronic kidney disease, and overall comorbidity. Potentially modifiable risk factors include anemia, perioperative transfusions, aminoglycoside prophylaxis, perioperative renin-angiotensin system blockade, and postoperative nonsteroidal anti-inflammatory drugs. These should be mitigated when possible.

In patients with periprosthetic joint infection who receive antibiotic-loaded cement spacers, especially patients  with additional risk factors for acute kidney injury, strict attention should be paid to the dose of antibiotic in the spacer, with levels checked postoperatively if necessary. Nonnephrotoxic antibiotics should be chosen for systemic administration when possible.

Prospective randomized controlled trials are needed to guide therapy after total joint arthroplasty, and to verify the adverse long-term outcomes of acute kidney injury in this setting.

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  75. Reed EE, Johnston J, Severing J, Stevenson KB, Deutscher M. Nephrotoxicity risk factors and intravenous vancomycin dosing in the immediate postoperative period following antibiotic-impregnated cement spacer placement. Ann Pharmacother 2014; 48(8):962–969. doi:10.1177/1060028014535360
  76. Koo KH, Yang JW, Cho SH, et al. Impregnation of vancomycin, gentamicin, and cefotaxime in a cement spacer for two-stage cementless reconstruction in infected total hip arthroplasty. J Arthroplasty 2001; 16(7):882–892. doi:10.1054/arth.2001.24444
  77. Forsythe ME, Crawford S, Sterling GJ, Whitehouse SL, Crawford R. Safeness of simplex-tobramycin bone cement in patients with renal dysfunction undergoing total hip replacement. J Orthop Surg (Hong Kong) 2006; 14(1):38–42. doi:10.1177/230949900601400109
  78. Hsieh PH, Huang KC, Tai CL. Liquid gentamicin in bone cement spacers: in vivo antibiotic release and systemic safety in two-stage revision of infected hip arthroplasty. J Trauma 2009; 66(3):804–808. doi:10.1097/TA.0b013e31818896cc
  79. Hofmann AA, Goldberg T, Tanner AM, Kurtin SM. Treatment of infected total knee arthroplasty using an articulating spacer: 2- to 12-year experience. Clin Orthop Relat Res 2005; 430:125–131. pmid:15662313
  80. Evans RP. Successful treatment of total hip and knee infection with articulating antibiotic components: a modified treatment method. Clin Orthop Relat Res 2004; 427:37–46. pmid:15552134
  81. Yadav A, Alijanipour P, Ackerman CT, Karanth S, Hozack WJ, Filippone EJ. Acute kidney injury following failed total hip and knee arthroplasty. J Arthroplasty 2018; 33(10):3297–3303. doi:10.1016/j.arth.2018.06.019
  82. Hsieh PH, Huang KC, Lee PC, Lee MS. Two-stage revision of infected hip arthroplasty using an antibiotic-loaded spacer: retrospective comparison between short-term and prolonged antibiotic therapy. J Antimicrob Chemother 2009; 64(2):392–397. doi:10.1093/jac/dkp177
  83. Luu A, Syed F, Raman G, et al. Two-stage arthroplasty for prosthetic joint infection: a systematic review of acute kidney injury, systemic toxicity and infection control. J Arthroplasty 2013; 28(9):1490–1498.e1. doi:10.1016/j.arth.2013.02.035
  84. Filippone EJ, Kraft WK, Farber JL. The nephrotoxicity of vancomycin. Clin Pharmacol Ther 2017; 102(3):459–469. doi:10.1002/cpt.726
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Acute kidney injury after hip or knee replacement: Can we lower the risk?
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Acute kidney injury after hip or knee replacement: Can we lower the risk?
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acute kidney injury, AKI, total joint arthroplasty, TJA, hip replacement, knee replacement, antibiotic, aminoglycoside, cement, prosthetic joint infections, antibiotic-loaded cement, gentamicin, tobramycin, vancomycin, Edward Filippone, Anju Yadav
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acute kidney injury, AKI, total joint arthroplasty, TJA, hip replacement, knee replacement, antibiotic, aminoglycoside, cement, prosthetic joint infections, antibiotic-loaded cement, gentamicin, tobramycin, vancomycin, Edward Filippone, Anju Yadav
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  • Using current diagnostic criteria, the incidence of acute kidney injury complicating primary total joint arthroplasty may be nearly 10%, and 25% after placement of an antibiotic-loaded cement spacer to treat infection.
  • In primary total joint arthroplasty, significant risk factors include older age, higher body mass index, chronic kidney disease, comorbidity, anemia, perioperative transfusion, aminoglycoside prophylaxis and treatment, preoperative heart murmur, and renin-angiotensin-aldosterone system blockade.
  • Acute kidney injury may arise from infection, systemic administration of nephrotoxic antibiotics, and elution of antibiotics from antibiotic-loaded cement.
  • No randomized controlled trial aimed at reducing acute kidney injury in these settings has been published; however, suggestions for practice modification are made based on the available data.
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Unusual effects of common antibiotics

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Unusual effects of common antibiotics
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Maria Elena Ruiz, MD
Glenn W. Wortmann, MD

A 60-year-old man is admitted for respiratory failure following a massive myocardial infarction. He develops ventilator-associated pneumonia and is treated with cefepime and vancomycin. Three days later, he develops prolonged atypical absence seizures.

What caused these seizures? The neurologist thinks it might be the cefepime. Do you agree?

Antibiotics are widely used in the United States, with 269 million courses of oral therapy prescribed in 2011.1 Adverse effects such as rash are well known, but rare effects such as seizure, hypoglycemia, and hypoxemia may not be immediately attributed to these drugs.

In this article, we review less-recognized but potentially serious adverse effects of antibiotics commonly prescribed in the United States. We have structured our discussion by organ system for ease of reference.

NERVOUS SYSTEM

The potential adverse effects of antibiotics on the nervous system range from encephalopathy and seizure to nonconvulsive status epilepticus.

Encephalopathy and seizure

Encephalopathy has been reported with penicillins, cephalosporins, sulfamethoxazole-trimethoprim, quinolones, and oxazolidinones such as linezolid.2,3

Seizures are known to occur with penicillins, cephalosporins, carbapenems, and quinolones.2–4 For cephalosporins, these effects are more common at higher doses, in elderly patients, and in patients with renal impairment. Carbapenems are associated with seizure activity in elderly patients.2–4

Encephalopathy and seizure can also occur on a continuum, as is the case with piperacillin-induced encephalopathy, with progressive dysarthria, tremor, and progressive confusion culminating in tonic-clonic seizures.2

Nonconvulsive status epilepticus

Nonconvulsive status epilepticus, marked by prolonged atypical absence seizures, has complicated the use of penicillins, quinolones, clarithromycin, and cephalosporins, specifically cefepime.2,3,5 Diagnosis can be difficult and requires clinical awareness and confirmation with electroencephalography.

Class-specific neurologic effects

Certain antibiotics have class-specific effects:

Tetracyclines: cranial nerve toxicity, neuromuscular blockade, and intracranial hypertension.2

Sulfamethoxazole-trimethoprim: tremors and psychosis, with visual and auditory hallucinations.6

Macrolides: dysequilibrium and potentially irreversible hearing loss.2

Quinolones: orofacial dyskinesia and a Tourette-like syndrome, with a higher incidence reported with newer quinolones.7

Linezolid: optic and peripheral neuropathy2; neuropathy can be persistent and can lead to loss of vision. The package insert recommends monitoring visual function in patients taking linezolid for more than 3 months and in any patient reporting visual symptoms.8

Linezolid is also associated with serotonin syndrome when combined with a drug that potentiates serotonergic activity, most commonly selective serotonin reuptake inhibitors. The syndrome is characterized by a triad of cognitive or behavioral changes, autonomic instability, and neuromuscular excitability such as spontaneous clonus.9

Metronidazole: optic and peripheral neuropathy, in addition to cerebellar toxicity and central nervous system lesions on magnetic resonance imaging of the brain. In a series of 11 cases of cerebellar toxicity, most patients presented with ataxia and dysarthria associated with high total doses of metronidazole, and in most cases, magnetic resonance imaging showed resolution of the lesions upon discontinuation of metronidazole.10

 

 

HEMATOLOGIC AND RHEUMATOLOGIC EFFECTS

Agranulocytosis has been associated with beta-lactams, in most cases with prolonged exposure. In one report, the average exposure before onset of agranulocytosis was 22 days for nafcillin and 25 days for penicillin. For penicillins, more than 50% of cases involved high daily doses.11

Likewise, most episodes of vancomycin-induced neutropenia were reported to occur after 20 days of therapy.12

In another study, most cases of drug-induced anemia were due to ceftriaxone and piperacillin.13

Drug-induced thrombocytopenia has been described with penicillins, cephalo­sporins, sulfonamides, and vancomycin14 and is a well-recognized effect of linezolid. The syndrome of drug reaction with eosinophilia and systemic symptoms, a severe and rare adverse reaction, has been reported with minocycline, sulfamethoxazole, and vancomycin.15

The tetracycline minocycline has been reported to cause drug-induced lupus and polyarteritis nodosa-like vasculitis.16 Drug-induced lupus presents as myalgias and arthralgias, serositis, constitutional symptoms, and positive antinuclear antibody titers. The effect is not dose-dependent. Penicillin, cefuroxime, and nitrofurantoin have also been implicated.16

Kermani et al17 described 9 cases of polyarteritis nodosa, in which 5 patients (56%) had systemic involvement including renal artery microaneurysm, mononeuritis multiplex, and mesenteric vasculitis, and some of these patients also had cutaneous involvement. All patients had positive antineutrophil cytoplasmic antibody in a perinuclear pattern. The median time from start of the minocycline to symptom onset was 9 months, and the median duration of use was 2 years.

Quinolones have also been reported to cause fatal hypersensitivity vasculitis.18,19

CARDIOVASCULAR SYSTEM

Macrolides and quinolones have been reported to cause QT-interval prolongation and torsades de pointes. The risk is greatest when a  macrolide is co-administered with a CYP3A4 inhibitor.

Of the macrolides, azithromycin is the safest, as clarithromycin and erythromycin are more likely to cause QT prolongation.

While QT prolongation is a class effect of quinolones, there is variability within the class. Ciprofloxacin is thought to be the safest in terms of cardiovascular adverse effects.20 In addition, Owens and Nolin20 reported that quinolone-associated QT prolongation was more likely to occur in patients with pre-existing QT prolongation, electrolyte abnormalities, organic heart disease, and bradycardia, and especially in women. Other risk factors for QT prolongation with quinolone use include underlying cardiac disease and advanced age.21

Quinolones have also been associated with an increased risk of aortic dissection. The US Food and Drug Administration has issued a warning advising clinicians to avoid quinolones in patients who have aneurysms or are at risk for aneurysms, such as patients with advanced age, peripheral atherosclerotic vascular disease, hypertension and conditions such as Marfan and Ehlers-Danlos syndrome.22

DIGESTIVE SYSTEM

Tetracyclines are known to cause esophagitis from direct contact with and disruption of the mucosal lining. Doxycycline is the most frequent offender.23

Amoxicillin-clavulanate is the antibiotic most commonly associated with drug-induced liver injury, mainly attributable to the clavulanate component.24 It is more common in men over age 50 and with prolonged and repeated dosing and is sometimes fatal. Other adverse effects include Stevens-Johnson syndrome, interstitial nephritis, and thrombotic thrombocytopenic purpura.25

Cholestatic hepatitis has been reported with penicillins, particularly dicloxacillin, oxacillin, and amoxicillin-clavulanate; cephalosporins; doxycycline; sulfamethoxazole-trimethoprim; macrolides; and ciprofloxacin.24–26 Hepatocellular injury is linked to amoxicillin-clavulanate and doxycycline. Drug-induced mixed liver injury has been observed with amoxicillin-clavulanate, sulfamethoxazole-trimethoprim and, rarely, cephalosporins.

Liver injury is classified as cholestatic if the alkaline phosphatase level is more than 2 times higher than normal, or if the ratio of alanine aminotransferase to alkaline phosphatase is less than 2; if the ratio is greater than 5, the injury is considered hepatocellular.24 Mixed liver injury, the most common, is defined as a ratio from 2 to 5.

Nitrofurantoin has also been linked to hepatotoxicity, cirrhosis, and end-stage liver disease, and to death if the drug is continued after the onset of jaundice.26 Death from liver injury has been reported with amoxicillin-clavulanate, sulfamethoxazole-trimethoprim, and erythromycin, and jaundice indicates a poor prognosis, associated with a 10% mortality rate or need for liver transplant in all patients.24

 

 

ENDOCRINE SYSTEM

Clarithromycin, sulfonamides, and quinolones are known to precipitate hypoglycemia by interacting with sulfonylureas. A study of Medicare patients age 66 or older who were taking glipizide or glyburide reported that female sex, older age, and a history of hypoglycemic episodes were associated with antibiotic-related hypoglycemia.27 The odds ratio for hypoglycemia was highest for clarithromycin (3.96), sulfamethoxazole-trimethoprim (2.56), metronidazole (2.11), and ciprofloxacin (1.62) when compared with antibiotics that do not cause hypoglycemia. There was no signal for levofloxacin-mediated hypoglycemia in this series.27

RESPIRATORY SYSTEM

Hypersensitivity lung disease has been reported with penicillin, ampicillin, cephalosporins, ciprofloxacin, and sulfonamides including sulfamethoxazole-trimethoprim.28 The lipopeptide daptomycin has been reported to cause acute eosinophilic pneumonia defined as fever for less than 5 days, pulmonary infiltrates, hypoxemia, and a bronchoalveolar lavage or biopsy study with eosinophils. Daptomycin should be stopped early in these cases, and the patient should not be rechallenged, as the reaction can be deadly.29

Nitrofurantoin has a long history of hypersensitivity pneumonitis in its acute form and a chronic allergic response. While more widely recognized, nitrofurantoin pulmonary toxicity is rare, occurring in 1 in 5,000 patients.30

RENAL SYSTEM

Acute interstitial nephritis has been reported with penicillins, cephalosporins, macrolides, quinolones, sulfonamides, and vancomycin.31–33 Acute tubular necrosis has been linked to cephalosporins and tetracyclines. Crystal nephropathy has been seen with quinolones and sulfonamides.

Advanced age is an important risk factor for renal dysfunction from quinolones,18 and penicillin G has been reported to cause glomerulonephritis.31

MUSCULOSKELETAL SYSTEM

Quinolones have been associated with arthropathy or tendinitis at a rate of 1%, including cases of Achilles tendon rupture.18 The US Food and Drug Administration announced in 2016 that the serious adverse events with fluoroquinolones outweigh the benefits in patients with acute sinusitis, acute bronchitis, and uncomplicated urinary tract infection, and that they should be used only if there are no other options.34

Daptomycin is known to cause elevations of creatine kinase.34 Weekly monitoring is recommended based on postmarketing data reports of elevations in 2.5% of patients; myopathy is a rarer effect, occurring in 0.2% of patients.35

REPRODUCTIVE SYSTEM

Antibiotics have long been reported to interact with oral contraceptives, but the data are not compelling for commonly used antibiotics. The strongest association is with rifampicin, which reduces oral contraceptive efficacy and warrants an alternative mode of contraception.36

BACK TO OUR PATIENT

Antibiotics can have serious adverse effects, and it is important for clinicians to be cognizant of this. Our 60-year-old patient who was taking cefepime and vancomycin for pneumonia developed prolonged atypical absence seizures. When the cefepime was discontinued, his mental status improved, and no other seizures were observed.

References
  1. Fleming-Dutra KE, Hersh AL, Shapiro DJ, et al. Prevalence of inappropriate antibiotic prescriptions among US ambulatory care visits, 2010–2011. JAMA 2016; 315(17):1864–1873. doi:10.1001/jama.2016.4151
  2. Grill MF, Maganti RK. Neurotoxic effects associated with antibiotic use: management considerations. Br J Clin Pharmacol 2011; 72(3):381–393. doi:10.1111/j.1365-2125.2011.03991.x
  3. Dakdouki GK, Al-Awar GN. Cefepime-induced encephalopathy. Int J Infect Dis 2004; 8(1):59–61. pmid:14690782
  4. Bazan JA, Martin SI, Kaye KM. Newer beta-lactam antiobiotics: doripenem, ceftobiprole, and cefepime. Infect Dis Clin North Am 2009; 23(4):983–999. doi:10.1016/j.idc.2009.06.007
  5. Bandettini di Poggio M, Anfosso S, Audenino D, Primavera A. Clarithromycin-induced neurotoxicity in adults. J Clin Neurosci 2011; 18(3):313–318. doi:10.1016/j.jocn.2010.08.014
  6. Saidinejad M, Ewald MB, Shannon MW. Transient psychosis in an immune-competent patient after oral trimethoprim-sulfamethoxazole administration. Pediatrics 2005; 115(6):e739–e741. doi:10.1542/peds.2004-1352
  7. Thomas RJ, Reagan DR. Association of a Tourette-like syndrome with ofloxacin. Ann Pharmacother 1996; 30(2):138–141. doi:10.1177/106002809603000205
  8. Pharmacia and Upjohn Company LLC. Zyvox® Package Insert. http://labeling.pfizer.com/showlabeling.aspx?id=649. Accessed March 5, 2019.
  9. Lawrence KR, Adra M, Gillman PK. Serotonin toxicity associated with the use of linezolid: a review of postmarketing data. Clin Infect Dis 2006; 42(11):1578–1583. doi:10.1086/503839
  10. Patel K, Green-Hopkins I, Lu S, Tunkel AR. Cerebellar ataxia following prolonged use of metronidazole: case report and literature review. Int J Infect Dis 2008; 12(6):e111–e114. doi:10.1016/j.ijid.2008.03.006
  11. Andersohn F, Konzen C, Garbe E. Systematic review: agranulocytosis induced by nonchemotherapy drugs. Ann Intern Med 2007; 146(9):657–665. pmid:17470834
  12. Black E, Lau TT, Ensom MH. Vancomycin-induced neutropenia: is it dose- or duration-related? Ann Pharmacother 2011; 45(5):629–638. doi:10.1345/aph.1P583
  13. Garratty G. Drug-induced immune hemolytic anemia. Hematology Am Soc Hematol Educ Program 2009: 73–79. doi:10.1182/asheducation-2009.1.73
  14. Chong Bh, Choi PY, Khachigian L, Perdomo J. Drug-induced immune thrombocytopenia. Hematol Oncol Clin North Am 2013; 27(3):521–540. doi:10.1016/j.hoc.2013.02.003
  15. Cacoub P, Musette P, Descamps V, et al. The DRESS syndrome: a literature review. Am J Med 2011; 124(7):588–597. doi:10.1016/j.amjmed.2011.01.017
  16. Chang C, Gershwin ME. Drugs and autoimmunity—a contemporary review and mechanistic approach. J Autoimmun 2010; 34(3):J266–J275. doi:10.1016/j.jaut.2009.11.012
  17. Kermani TA, Ham EK, Camilleri MJ, Warrington KJ. Polyarteritis nodosa-like vasculitis in association with minocycline use: a single-center case series. Semin Arthritis Rheum 2012; 42(2):213–221. doi:10.1016/j.semarthrit.2012.03.006
  18. Mandell LA, Ball P, Tillotson G. Antimicrobial safety and tolerability: differences and dilemmas. Clin Infect Dis 2001; 32(suppl 1):S72–S79. doi:10.1086/319379
  19. Christ W, Esch B. Session III: safety. Adverse reactions to fluoroquinolones in adults and children. Infect Dis Clin Pract 1994; 3(3 suppl 3):S168–S176.
  20. Owens RC, Nolin TD. Antimicrobial-associated QT interval prolongation: pointes of interest. Clin Infect Dis 2006; 43(12):1603–1611. doi:10.1086/508873
  21. Rubinstein E, Camm J. Cardiotoxicity of fluoroquinolones. J Antimicrob Chemother 2002; 49(4):593–596. pmid:11909831
  22. US Food and Drug Administration (FDA). FDA drug safety communication: FDA warns about increased risk of ruptures or tears in the aorta blood vessel with fluoroquinolones antibiotics in certain patients. https://www.fda.gov/Drugs/DrugSafety/ucm628753.htm.   Accessed March 15, 2019.
  23. Seminerio J, McGrath K, Arnold CA, Voltaggio L, Singhi AD. Medication-associated lesions of the GI tract. Gastrointest Endosc 2014; 79(1):140–150. doi:10.1016/j.gie.2013.08.027
  24. Bjornsson ES, Jonasson JG. Drug-induced cholestasis. Clin Liver Dis 2013; 17(2):191–209. doi:10.1016/j.cld.2012.11.002
  25. Fontana RJ, Shakil AO, Greenson JK, Boyd I, Lee WM. Acute liver failure due to amoxicillin and amoxicillin/clavulanate. Dig Dis Sci 2005; 50(10):1785–1790. doi:10.1007/s10620-005-2938-5
  26. Sakaan SA, Twilla JD, Usery JB, Winton JC, Self TH. Nitrofurantoin-induced hepatotoxicity: a rare yet serious complication. South Med J 2014; 107(2):107–113. doi:10.1097/SMJ.0000000000000059
  27. Parekh TM, Raji M, Lin YL, Tan A, Kuo YF, Goodwin JS. Hypoglycemia after antimicrobial drug prescription for older patients using sulfonylureas. JAMA Intern Med 2014; 174(10):1605–1612. doi:10.1001/jamainternmed.2014.3293
  28. Prasad R, Gupta P, Singh A, Goel N. Drug induced pulmonary parenchymal disease. Drug Discov Ther 2014; 8(6):232–237. doi:10.5582/ddt.2014.01046
  29. Miller BA, Gray A, Leblanc TW, Sexton DJ, Martin AR, Slama TG. Acute eosinophilic pneumonia secondary to daptomycin: a report of three cases. Clin Infect Dis 2010; 50(11):e63–e68. doi:10.1086/652656
  30. Kabbara WK, Kordahi MC. Nitrofurantoin-induced pulmonary toxicity: a case report and review of the literature. J Infect Public Health 2015; 8(4):309–313. doi:10.1016/j.jiph.2015.01.007
  31. Ghane Shahrbaf F, Assadi F. Drug-induced renal disorders. J Renal Inj Prev 2015; 4(3):57–60. doi:10.12861/jrip.2015.12
  32. Mac K, Chavada R, Paull S, Howlin K, Wong J. Cefepime induced acute interstitial nephritis—a case report. BMC Nephrol 2015; 16:15. doi:10.1186/s12882-015-0004-x
  33. Woodruff AE, Meaney CJ, Hansen EA, Prescott GM. Azithromycin-induced, biopsy-proven cute interstitial nephritis in an adult successfully treated with low-dose corticosteroids. Pharmacotherapy 2015; 35(11):e169–e174. doi:10.1002/phar.1660
  34. US Food and Drug Administration (FDA). FDA drug safety communication: FDA advises restricting fluoroquinolone antibiotic use for certain uncomplicated infections; warns about disabling side effects that can occur together. https://www.fda.gov/Drugs/DrugSafety/ucm500143.htm. Accessed March 7, 2019.
  35. Hawkey PM. Pre-clinical experience with daptomycin. J Antimicrob Chemother 2008; 62(suppl 3):iii7–iii14. doi:10.1093/jac/dkn367
  36. ACOG Committee on Practice Bulletins–Gynecology. ACOG practice bulletin. No. 73: Use of hormonal contraception in women with coexisting medical conditions. Obstet Gynecol 2006; 107(6):1453–1472. pmid:16738183
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Section of Infectious Diseases, Department of Medicine, MedStar Washington Hospital Center, Washington, DC

Glenn W. Wortmann, MD
Section of Infectious Diseases, Department of Medicine, MedStar Washington Hospital Center, Washington, DC; Professor of Clinical Medicine (Infectious Diseases), Georgetown University, Washington, DC

Address: Maria Elena Ruiz, MD, Section of Infectious Diseases, Department of Medicine, MedStar Washington Hospital Center, 110 Irving Street NW 2A38C, Washington, DC 20010; [email protected]

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antibiotics, side effects, piperacillin encephalopathy, seizure, minocycline lupus, acute tubular necrosis, cephalosporin, tetracycline, crystal nephropathy, quinolones, sulfonamides, QT prolongation, agranulocytosis, beta-lactams, thrombocytopenia, aortic aneurysm, esophagitis, hepatitis, Maria Ruiz, Glenn Wortmann
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Section of Infectious Diseases, Department of Medicine, MedStar Washington Hospital Center, Washington, DC

Glenn W. Wortmann, MD
Section of Infectious Diseases, Department of Medicine, MedStar Washington Hospital Center, Washington, DC; Professor of Clinical Medicine (Infectious Diseases), Georgetown University, Washington, DC

Address: Maria Elena Ruiz, MD, Section of Infectious Diseases, Department of Medicine, MedStar Washington Hospital Center, 110 Irving Street NW 2A38C, Washington, DC 20010; [email protected]

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Glenn W. Wortmann, MD
Section of Infectious Diseases, Department of Medicine, MedStar Washington Hospital Center, Washington, DC; Professor of Clinical Medicine (Infectious Diseases), Georgetown University, Washington, DC

Address: Maria Elena Ruiz, MD, Section of Infectious Diseases, Department of Medicine, MedStar Washington Hospital Center, 110 Irving Street NW 2A38C, Washington, DC 20010; [email protected]

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Related Articles
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Adverse effects of antimicrobial agents on major organ systems

A 60-year-old man is admitted for respiratory failure following a massive myocardial infarction. He develops ventilator-associated pneumonia and is treated with cefepime and vancomycin. Three days later, he develops prolonged atypical absence seizures.

What caused these seizures? The neurologist thinks it might be the cefepime. Do you agree?

Antibiotics are widely used in the United States, with 269 million courses of oral therapy prescribed in 2011.1 Adverse effects such as rash are well known, but rare effects such as seizure, hypoglycemia, and hypoxemia may not be immediately attributed to these drugs.

In this article, we review less-recognized but potentially serious adverse effects of antibiotics commonly prescribed in the United States. We have structured our discussion by organ system for ease of reference.

NERVOUS SYSTEM

The potential adverse effects of antibiotics on the nervous system range from encephalopathy and seizure to nonconvulsive status epilepticus.

Encephalopathy and seizure

Encephalopathy has been reported with penicillins, cephalosporins, sulfamethoxazole-trimethoprim, quinolones, and oxazolidinones such as linezolid.2,3

Seizures are known to occur with penicillins, cephalosporins, carbapenems, and quinolones.2–4 For cephalosporins, these effects are more common at higher doses, in elderly patients, and in patients with renal impairment. Carbapenems are associated with seizure activity in elderly patients.2–4

Encephalopathy and seizure can also occur on a continuum, as is the case with piperacillin-induced encephalopathy, with progressive dysarthria, tremor, and progressive confusion culminating in tonic-clonic seizures.2

Nonconvulsive status epilepticus

Nonconvulsive status epilepticus, marked by prolonged atypical absence seizures, has complicated the use of penicillins, quinolones, clarithromycin, and cephalosporins, specifically cefepime.2,3,5 Diagnosis can be difficult and requires clinical awareness and confirmation with electroencephalography.

Class-specific neurologic effects

Certain antibiotics have class-specific effects:

Tetracyclines: cranial nerve toxicity, neuromuscular blockade, and intracranial hypertension.2

Sulfamethoxazole-trimethoprim: tremors and psychosis, with visual and auditory hallucinations.6

Macrolides: dysequilibrium and potentially irreversible hearing loss.2

Quinolones: orofacial dyskinesia and a Tourette-like syndrome, with a higher incidence reported with newer quinolones.7

Linezolid: optic and peripheral neuropathy2; neuropathy can be persistent and can lead to loss of vision. The package insert recommends monitoring visual function in patients taking linezolid for more than 3 months and in any patient reporting visual symptoms.8

Linezolid is also associated with serotonin syndrome when combined with a drug that potentiates serotonergic activity, most commonly selective serotonin reuptake inhibitors. The syndrome is characterized by a triad of cognitive or behavioral changes, autonomic instability, and neuromuscular excitability such as spontaneous clonus.9

Metronidazole: optic and peripheral neuropathy, in addition to cerebellar toxicity and central nervous system lesions on magnetic resonance imaging of the brain. In a series of 11 cases of cerebellar toxicity, most patients presented with ataxia and dysarthria associated with high total doses of metronidazole, and in most cases, magnetic resonance imaging showed resolution of the lesions upon discontinuation of metronidazole.10

 

 

HEMATOLOGIC AND RHEUMATOLOGIC EFFECTS

Agranulocytosis has been associated with beta-lactams, in most cases with prolonged exposure. In one report, the average exposure before onset of agranulocytosis was 22 days for nafcillin and 25 days for penicillin. For penicillins, more than 50% of cases involved high daily doses.11

Likewise, most episodes of vancomycin-induced neutropenia were reported to occur after 20 days of therapy.12

In another study, most cases of drug-induced anemia were due to ceftriaxone and piperacillin.13

Drug-induced thrombocytopenia has been described with penicillins, cephalo­sporins, sulfonamides, and vancomycin14 and is a well-recognized effect of linezolid. The syndrome of drug reaction with eosinophilia and systemic symptoms, a severe and rare adverse reaction, has been reported with minocycline, sulfamethoxazole, and vancomycin.15

The tetracycline minocycline has been reported to cause drug-induced lupus and polyarteritis nodosa-like vasculitis.16 Drug-induced lupus presents as myalgias and arthralgias, serositis, constitutional symptoms, and positive antinuclear antibody titers. The effect is not dose-dependent. Penicillin, cefuroxime, and nitrofurantoin have also been implicated.16

Kermani et al17 described 9 cases of polyarteritis nodosa, in which 5 patients (56%) had systemic involvement including renal artery microaneurysm, mononeuritis multiplex, and mesenteric vasculitis, and some of these patients also had cutaneous involvement. All patients had positive antineutrophil cytoplasmic antibody in a perinuclear pattern. The median time from start of the minocycline to symptom onset was 9 months, and the median duration of use was 2 years.

Quinolones have also been reported to cause fatal hypersensitivity vasculitis.18,19

CARDIOVASCULAR SYSTEM

Macrolides and quinolones have been reported to cause QT-interval prolongation and torsades de pointes. The risk is greatest when a  macrolide is co-administered with a CYP3A4 inhibitor.

Of the macrolides, azithromycin is the safest, as clarithromycin and erythromycin are more likely to cause QT prolongation.

While QT prolongation is a class effect of quinolones, there is variability within the class. Ciprofloxacin is thought to be the safest in terms of cardiovascular adverse effects.20 In addition, Owens and Nolin20 reported that quinolone-associated QT prolongation was more likely to occur in patients with pre-existing QT prolongation, electrolyte abnormalities, organic heart disease, and bradycardia, and especially in women. Other risk factors for QT prolongation with quinolone use include underlying cardiac disease and advanced age.21

Quinolones have also been associated with an increased risk of aortic dissection. The US Food and Drug Administration has issued a warning advising clinicians to avoid quinolones in patients who have aneurysms or are at risk for aneurysms, such as patients with advanced age, peripheral atherosclerotic vascular disease, hypertension and conditions such as Marfan and Ehlers-Danlos syndrome.22

DIGESTIVE SYSTEM

Tetracyclines are known to cause esophagitis from direct contact with and disruption of the mucosal lining. Doxycycline is the most frequent offender.23

Amoxicillin-clavulanate is the antibiotic most commonly associated with drug-induced liver injury, mainly attributable to the clavulanate component.24 It is more common in men over age 50 and with prolonged and repeated dosing and is sometimes fatal. Other adverse effects include Stevens-Johnson syndrome, interstitial nephritis, and thrombotic thrombocytopenic purpura.25

Cholestatic hepatitis has been reported with penicillins, particularly dicloxacillin, oxacillin, and amoxicillin-clavulanate; cephalosporins; doxycycline; sulfamethoxazole-trimethoprim; macrolides; and ciprofloxacin.24–26 Hepatocellular injury is linked to amoxicillin-clavulanate and doxycycline. Drug-induced mixed liver injury has been observed with amoxicillin-clavulanate, sulfamethoxazole-trimethoprim and, rarely, cephalosporins.

Liver injury is classified as cholestatic if the alkaline phosphatase level is more than 2 times higher than normal, or if the ratio of alanine aminotransferase to alkaline phosphatase is less than 2; if the ratio is greater than 5, the injury is considered hepatocellular.24 Mixed liver injury, the most common, is defined as a ratio from 2 to 5.

Nitrofurantoin has also been linked to hepatotoxicity, cirrhosis, and end-stage liver disease, and to death if the drug is continued after the onset of jaundice.26 Death from liver injury has been reported with amoxicillin-clavulanate, sulfamethoxazole-trimethoprim, and erythromycin, and jaundice indicates a poor prognosis, associated with a 10% mortality rate or need for liver transplant in all patients.24

 

 

ENDOCRINE SYSTEM

Clarithromycin, sulfonamides, and quinolones are known to precipitate hypoglycemia by interacting with sulfonylureas. A study of Medicare patients age 66 or older who were taking glipizide or glyburide reported that female sex, older age, and a history of hypoglycemic episodes were associated with antibiotic-related hypoglycemia.27 The odds ratio for hypoglycemia was highest for clarithromycin (3.96), sulfamethoxazole-trimethoprim (2.56), metronidazole (2.11), and ciprofloxacin (1.62) when compared with antibiotics that do not cause hypoglycemia. There was no signal for levofloxacin-mediated hypoglycemia in this series.27

RESPIRATORY SYSTEM

Hypersensitivity lung disease has been reported with penicillin, ampicillin, cephalosporins, ciprofloxacin, and sulfonamides including sulfamethoxazole-trimethoprim.28 The lipopeptide daptomycin has been reported to cause acute eosinophilic pneumonia defined as fever for less than 5 days, pulmonary infiltrates, hypoxemia, and a bronchoalveolar lavage or biopsy study with eosinophils. Daptomycin should be stopped early in these cases, and the patient should not be rechallenged, as the reaction can be deadly.29

Nitrofurantoin has a long history of hypersensitivity pneumonitis in its acute form and a chronic allergic response. While more widely recognized, nitrofurantoin pulmonary toxicity is rare, occurring in 1 in 5,000 patients.30

RENAL SYSTEM

Acute interstitial nephritis has been reported with penicillins, cephalosporins, macrolides, quinolones, sulfonamides, and vancomycin.31–33 Acute tubular necrosis has been linked to cephalosporins and tetracyclines. Crystal nephropathy has been seen with quinolones and sulfonamides.

Advanced age is an important risk factor for renal dysfunction from quinolones,18 and penicillin G has been reported to cause glomerulonephritis.31

MUSCULOSKELETAL SYSTEM

Quinolones have been associated with arthropathy or tendinitis at a rate of 1%, including cases of Achilles tendon rupture.18 The US Food and Drug Administration announced in 2016 that the serious adverse events with fluoroquinolones outweigh the benefits in patients with acute sinusitis, acute bronchitis, and uncomplicated urinary tract infection, and that they should be used only if there are no other options.34

Daptomycin is known to cause elevations of creatine kinase.34 Weekly monitoring is recommended based on postmarketing data reports of elevations in 2.5% of patients; myopathy is a rarer effect, occurring in 0.2% of patients.35

REPRODUCTIVE SYSTEM

Antibiotics have long been reported to interact with oral contraceptives, but the data are not compelling for commonly used antibiotics. The strongest association is with rifampicin, which reduces oral contraceptive efficacy and warrants an alternative mode of contraception.36

BACK TO OUR PATIENT

Antibiotics can have serious adverse effects, and it is important for clinicians to be cognizant of this. Our 60-year-old patient who was taking cefepime and vancomycin for pneumonia developed prolonged atypical absence seizures. When the cefepime was discontinued, his mental status improved, and no other seizures were observed.

A 60-year-old man is admitted for respiratory failure following a massive myocardial infarction. He develops ventilator-associated pneumonia and is treated with cefepime and vancomycin. Three days later, he develops prolonged atypical absence seizures.

What caused these seizures? The neurologist thinks it might be the cefepime. Do you agree?

Antibiotics are widely used in the United States, with 269 million courses of oral therapy prescribed in 2011.1 Adverse effects such as rash are well known, but rare effects such as seizure, hypoglycemia, and hypoxemia may not be immediately attributed to these drugs.

In this article, we review less-recognized but potentially serious adverse effects of antibiotics commonly prescribed in the United States. We have structured our discussion by organ system for ease of reference.

NERVOUS SYSTEM

The potential adverse effects of antibiotics on the nervous system range from encephalopathy and seizure to nonconvulsive status epilepticus.

Encephalopathy and seizure

Encephalopathy has been reported with penicillins, cephalosporins, sulfamethoxazole-trimethoprim, quinolones, and oxazolidinones such as linezolid.2,3

Seizures are known to occur with penicillins, cephalosporins, carbapenems, and quinolones.2–4 For cephalosporins, these effects are more common at higher doses, in elderly patients, and in patients with renal impairment. Carbapenems are associated with seizure activity in elderly patients.2–4

Encephalopathy and seizure can also occur on a continuum, as is the case with piperacillin-induced encephalopathy, with progressive dysarthria, tremor, and progressive confusion culminating in tonic-clonic seizures.2

Nonconvulsive status epilepticus

Nonconvulsive status epilepticus, marked by prolonged atypical absence seizures, has complicated the use of penicillins, quinolones, clarithromycin, and cephalosporins, specifically cefepime.2,3,5 Diagnosis can be difficult and requires clinical awareness and confirmation with electroencephalography.

Class-specific neurologic effects

Certain antibiotics have class-specific effects:

Tetracyclines: cranial nerve toxicity, neuromuscular blockade, and intracranial hypertension.2

Sulfamethoxazole-trimethoprim: tremors and psychosis, with visual and auditory hallucinations.6

Macrolides: dysequilibrium and potentially irreversible hearing loss.2

Quinolones: orofacial dyskinesia and a Tourette-like syndrome, with a higher incidence reported with newer quinolones.7

Linezolid: optic and peripheral neuropathy2; neuropathy can be persistent and can lead to loss of vision. The package insert recommends monitoring visual function in patients taking linezolid for more than 3 months and in any patient reporting visual symptoms.8

Linezolid is also associated with serotonin syndrome when combined with a drug that potentiates serotonergic activity, most commonly selective serotonin reuptake inhibitors. The syndrome is characterized by a triad of cognitive or behavioral changes, autonomic instability, and neuromuscular excitability such as spontaneous clonus.9

Metronidazole: optic and peripheral neuropathy, in addition to cerebellar toxicity and central nervous system lesions on magnetic resonance imaging of the brain. In a series of 11 cases of cerebellar toxicity, most patients presented with ataxia and dysarthria associated with high total doses of metronidazole, and in most cases, magnetic resonance imaging showed resolution of the lesions upon discontinuation of metronidazole.10

 

 

HEMATOLOGIC AND RHEUMATOLOGIC EFFECTS

Agranulocytosis has been associated with beta-lactams, in most cases with prolonged exposure. In one report, the average exposure before onset of agranulocytosis was 22 days for nafcillin and 25 days for penicillin. For penicillins, more than 50% of cases involved high daily doses.11

Likewise, most episodes of vancomycin-induced neutropenia were reported to occur after 20 days of therapy.12

In another study, most cases of drug-induced anemia were due to ceftriaxone and piperacillin.13

Drug-induced thrombocytopenia has been described with penicillins, cephalo­sporins, sulfonamides, and vancomycin14 and is a well-recognized effect of linezolid. The syndrome of drug reaction with eosinophilia and systemic symptoms, a severe and rare adverse reaction, has been reported with minocycline, sulfamethoxazole, and vancomycin.15

The tetracycline minocycline has been reported to cause drug-induced lupus and polyarteritis nodosa-like vasculitis.16 Drug-induced lupus presents as myalgias and arthralgias, serositis, constitutional symptoms, and positive antinuclear antibody titers. The effect is not dose-dependent. Penicillin, cefuroxime, and nitrofurantoin have also been implicated.16

Kermani et al17 described 9 cases of polyarteritis nodosa, in which 5 patients (56%) had systemic involvement including renal artery microaneurysm, mononeuritis multiplex, and mesenteric vasculitis, and some of these patients also had cutaneous involvement. All patients had positive antineutrophil cytoplasmic antibody in a perinuclear pattern. The median time from start of the minocycline to symptom onset was 9 months, and the median duration of use was 2 years.

Quinolones have also been reported to cause fatal hypersensitivity vasculitis.18,19

CARDIOVASCULAR SYSTEM

Macrolides and quinolones have been reported to cause QT-interval prolongation and torsades de pointes. The risk is greatest when a  macrolide is co-administered with a CYP3A4 inhibitor.

Of the macrolides, azithromycin is the safest, as clarithromycin and erythromycin are more likely to cause QT prolongation.

While QT prolongation is a class effect of quinolones, there is variability within the class. Ciprofloxacin is thought to be the safest in terms of cardiovascular adverse effects.20 In addition, Owens and Nolin20 reported that quinolone-associated QT prolongation was more likely to occur in patients with pre-existing QT prolongation, electrolyte abnormalities, organic heart disease, and bradycardia, and especially in women. Other risk factors for QT prolongation with quinolone use include underlying cardiac disease and advanced age.21

Quinolones have also been associated with an increased risk of aortic dissection. The US Food and Drug Administration has issued a warning advising clinicians to avoid quinolones in patients who have aneurysms or are at risk for aneurysms, such as patients with advanced age, peripheral atherosclerotic vascular disease, hypertension and conditions such as Marfan and Ehlers-Danlos syndrome.22

DIGESTIVE SYSTEM

Tetracyclines are known to cause esophagitis from direct contact with and disruption of the mucosal lining. Doxycycline is the most frequent offender.23

Amoxicillin-clavulanate is the antibiotic most commonly associated with drug-induced liver injury, mainly attributable to the clavulanate component.24 It is more common in men over age 50 and with prolonged and repeated dosing and is sometimes fatal. Other adverse effects include Stevens-Johnson syndrome, interstitial nephritis, and thrombotic thrombocytopenic purpura.25

Cholestatic hepatitis has been reported with penicillins, particularly dicloxacillin, oxacillin, and amoxicillin-clavulanate; cephalosporins; doxycycline; sulfamethoxazole-trimethoprim; macrolides; and ciprofloxacin.24–26 Hepatocellular injury is linked to amoxicillin-clavulanate and doxycycline. Drug-induced mixed liver injury has been observed with amoxicillin-clavulanate, sulfamethoxazole-trimethoprim and, rarely, cephalosporins.

Liver injury is classified as cholestatic if the alkaline phosphatase level is more than 2 times higher than normal, or if the ratio of alanine aminotransferase to alkaline phosphatase is less than 2; if the ratio is greater than 5, the injury is considered hepatocellular.24 Mixed liver injury, the most common, is defined as a ratio from 2 to 5.

Nitrofurantoin has also been linked to hepatotoxicity, cirrhosis, and end-stage liver disease, and to death if the drug is continued after the onset of jaundice.26 Death from liver injury has been reported with amoxicillin-clavulanate, sulfamethoxazole-trimethoprim, and erythromycin, and jaundice indicates a poor prognosis, associated with a 10% mortality rate or need for liver transplant in all patients.24

 

 

ENDOCRINE SYSTEM

Clarithromycin, sulfonamides, and quinolones are known to precipitate hypoglycemia by interacting with sulfonylureas. A study of Medicare patients age 66 or older who were taking glipizide or glyburide reported that female sex, older age, and a history of hypoglycemic episodes were associated with antibiotic-related hypoglycemia.27 The odds ratio for hypoglycemia was highest for clarithromycin (3.96), sulfamethoxazole-trimethoprim (2.56), metronidazole (2.11), and ciprofloxacin (1.62) when compared with antibiotics that do not cause hypoglycemia. There was no signal for levofloxacin-mediated hypoglycemia in this series.27

RESPIRATORY SYSTEM

Hypersensitivity lung disease has been reported with penicillin, ampicillin, cephalosporins, ciprofloxacin, and sulfonamides including sulfamethoxazole-trimethoprim.28 The lipopeptide daptomycin has been reported to cause acute eosinophilic pneumonia defined as fever for less than 5 days, pulmonary infiltrates, hypoxemia, and a bronchoalveolar lavage or biopsy study with eosinophils. Daptomycin should be stopped early in these cases, and the patient should not be rechallenged, as the reaction can be deadly.29

Nitrofurantoin has a long history of hypersensitivity pneumonitis in its acute form and a chronic allergic response. While more widely recognized, nitrofurantoin pulmonary toxicity is rare, occurring in 1 in 5,000 patients.30

RENAL SYSTEM

Acute interstitial nephritis has been reported with penicillins, cephalosporins, macrolides, quinolones, sulfonamides, and vancomycin.31–33 Acute tubular necrosis has been linked to cephalosporins and tetracyclines. Crystal nephropathy has been seen with quinolones and sulfonamides.

Advanced age is an important risk factor for renal dysfunction from quinolones,18 and penicillin G has been reported to cause glomerulonephritis.31

MUSCULOSKELETAL SYSTEM

Quinolones have been associated with arthropathy or tendinitis at a rate of 1%, including cases of Achilles tendon rupture.18 The US Food and Drug Administration announced in 2016 that the serious adverse events with fluoroquinolones outweigh the benefits in patients with acute sinusitis, acute bronchitis, and uncomplicated urinary tract infection, and that they should be used only if there are no other options.34

Daptomycin is known to cause elevations of creatine kinase.34 Weekly monitoring is recommended based on postmarketing data reports of elevations in 2.5% of patients; myopathy is a rarer effect, occurring in 0.2% of patients.35

REPRODUCTIVE SYSTEM

Antibiotics have long been reported to interact with oral contraceptives, but the data are not compelling for commonly used antibiotics. The strongest association is with rifampicin, which reduces oral contraceptive efficacy and warrants an alternative mode of contraception.36

BACK TO OUR PATIENT

Antibiotics can have serious adverse effects, and it is important for clinicians to be cognizant of this. Our 60-year-old patient who was taking cefepime and vancomycin for pneumonia developed prolonged atypical absence seizures. When the cefepime was discontinued, his mental status improved, and no other seizures were observed.

References
  1. Fleming-Dutra KE, Hersh AL, Shapiro DJ, et al. Prevalence of inappropriate antibiotic prescriptions among US ambulatory care visits, 2010–2011. JAMA 2016; 315(17):1864–1873. doi:10.1001/jama.2016.4151
  2. Grill MF, Maganti RK. Neurotoxic effects associated with antibiotic use: management considerations. Br J Clin Pharmacol 2011; 72(3):381–393. doi:10.1111/j.1365-2125.2011.03991.x
  3. Dakdouki GK, Al-Awar GN. Cefepime-induced encephalopathy. Int J Infect Dis 2004; 8(1):59–61. pmid:14690782
  4. Bazan JA, Martin SI, Kaye KM. Newer beta-lactam antiobiotics: doripenem, ceftobiprole, and cefepime. Infect Dis Clin North Am 2009; 23(4):983–999. doi:10.1016/j.idc.2009.06.007
  5. Bandettini di Poggio M, Anfosso S, Audenino D, Primavera A. Clarithromycin-induced neurotoxicity in adults. J Clin Neurosci 2011; 18(3):313–318. doi:10.1016/j.jocn.2010.08.014
  6. Saidinejad M, Ewald MB, Shannon MW. Transient psychosis in an immune-competent patient after oral trimethoprim-sulfamethoxazole administration. Pediatrics 2005; 115(6):e739–e741. doi:10.1542/peds.2004-1352
  7. Thomas RJ, Reagan DR. Association of a Tourette-like syndrome with ofloxacin. Ann Pharmacother 1996; 30(2):138–141. doi:10.1177/106002809603000205
  8. Pharmacia and Upjohn Company LLC. Zyvox® Package Insert. http://labeling.pfizer.com/showlabeling.aspx?id=649. Accessed March 5, 2019.
  9. Lawrence KR, Adra M, Gillman PK. Serotonin toxicity associated with the use of linezolid: a review of postmarketing data. Clin Infect Dis 2006; 42(11):1578–1583. doi:10.1086/503839
  10. Patel K, Green-Hopkins I, Lu S, Tunkel AR. Cerebellar ataxia following prolonged use of metronidazole: case report and literature review. Int J Infect Dis 2008; 12(6):e111–e114. doi:10.1016/j.ijid.2008.03.006
  11. Andersohn F, Konzen C, Garbe E. Systematic review: agranulocytosis induced by nonchemotherapy drugs. Ann Intern Med 2007; 146(9):657–665. pmid:17470834
  12. Black E, Lau TT, Ensom MH. Vancomycin-induced neutropenia: is it dose- or duration-related? Ann Pharmacother 2011; 45(5):629–638. doi:10.1345/aph.1P583
  13. Garratty G. Drug-induced immune hemolytic anemia. Hematology Am Soc Hematol Educ Program 2009: 73–79. doi:10.1182/asheducation-2009.1.73
  14. Chong Bh, Choi PY, Khachigian L, Perdomo J. Drug-induced immune thrombocytopenia. Hematol Oncol Clin North Am 2013; 27(3):521–540. doi:10.1016/j.hoc.2013.02.003
  15. Cacoub P, Musette P, Descamps V, et al. The DRESS syndrome: a literature review. Am J Med 2011; 124(7):588–597. doi:10.1016/j.amjmed.2011.01.017
  16. Chang C, Gershwin ME. Drugs and autoimmunity—a contemporary review and mechanistic approach. J Autoimmun 2010; 34(3):J266–J275. doi:10.1016/j.jaut.2009.11.012
  17. Kermani TA, Ham EK, Camilleri MJ, Warrington KJ. Polyarteritis nodosa-like vasculitis in association with minocycline use: a single-center case series. Semin Arthritis Rheum 2012; 42(2):213–221. doi:10.1016/j.semarthrit.2012.03.006
  18. Mandell LA, Ball P, Tillotson G. Antimicrobial safety and tolerability: differences and dilemmas. Clin Infect Dis 2001; 32(suppl 1):S72–S79. doi:10.1086/319379
  19. Christ W, Esch B. Session III: safety. Adverse reactions to fluoroquinolones in adults and children. Infect Dis Clin Pract 1994; 3(3 suppl 3):S168–S176.
  20. Owens RC, Nolin TD. Antimicrobial-associated QT interval prolongation: pointes of interest. Clin Infect Dis 2006; 43(12):1603–1611. doi:10.1086/508873
  21. Rubinstein E, Camm J. Cardiotoxicity of fluoroquinolones. J Antimicrob Chemother 2002; 49(4):593–596. pmid:11909831
  22. US Food and Drug Administration (FDA). FDA drug safety communication: FDA warns about increased risk of ruptures or tears in the aorta blood vessel with fluoroquinolones antibiotics in certain patients. https://www.fda.gov/Drugs/DrugSafety/ucm628753.htm.   Accessed March 15, 2019.
  23. Seminerio J, McGrath K, Arnold CA, Voltaggio L, Singhi AD. Medication-associated lesions of the GI tract. Gastrointest Endosc 2014; 79(1):140–150. doi:10.1016/j.gie.2013.08.027
  24. Bjornsson ES, Jonasson JG. Drug-induced cholestasis. Clin Liver Dis 2013; 17(2):191–209. doi:10.1016/j.cld.2012.11.002
  25. Fontana RJ, Shakil AO, Greenson JK, Boyd I, Lee WM. Acute liver failure due to amoxicillin and amoxicillin/clavulanate. Dig Dis Sci 2005; 50(10):1785–1790. doi:10.1007/s10620-005-2938-5
  26. Sakaan SA, Twilla JD, Usery JB, Winton JC, Self TH. Nitrofurantoin-induced hepatotoxicity: a rare yet serious complication. South Med J 2014; 107(2):107–113. doi:10.1097/SMJ.0000000000000059
  27. Parekh TM, Raji M, Lin YL, Tan A, Kuo YF, Goodwin JS. Hypoglycemia after antimicrobial drug prescription for older patients using sulfonylureas. JAMA Intern Med 2014; 174(10):1605–1612. doi:10.1001/jamainternmed.2014.3293
  28. Prasad R, Gupta P, Singh A, Goel N. Drug induced pulmonary parenchymal disease. Drug Discov Ther 2014; 8(6):232–237. doi:10.5582/ddt.2014.01046
  29. Miller BA, Gray A, Leblanc TW, Sexton DJ, Martin AR, Slama TG. Acute eosinophilic pneumonia secondary to daptomycin: a report of three cases. Clin Infect Dis 2010; 50(11):e63–e68. doi:10.1086/652656
  30. Kabbara WK, Kordahi MC. Nitrofurantoin-induced pulmonary toxicity: a case report and review of the literature. J Infect Public Health 2015; 8(4):309–313. doi:10.1016/j.jiph.2015.01.007
  31. Ghane Shahrbaf F, Assadi F. Drug-induced renal disorders. J Renal Inj Prev 2015; 4(3):57–60. doi:10.12861/jrip.2015.12
  32. Mac K, Chavada R, Paull S, Howlin K, Wong J. Cefepime induced acute interstitial nephritis—a case report. BMC Nephrol 2015; 16:15. doi:10.1186/s12882-015-0004-x
  33. Woodruff AE, Meaney CJ, Hansen EA, Prescott GM. Azithromycin-induced, biopsy-proven cute interstitial nephritis in an adult successfully treated with low-dose corticosteroids. Pharmacotherapy 2015; 35(11):e169–e174. doi:10.1002/phar.1660
  34. US Food and Drug Administration (FDA). FDA drug safety communication: FDA advises restricting fluoroquinolone antibiotic use for certain uncomplicated infections; warns about disabling side effects that can occur together. https://www.fda.gov/Drugs/DrugSafety/ucm500143.htm. Accessed March 7, 2019.
  35. Hawkey PM. Pre-clinical experience with daptomycin. J Antimicrob Chemother 2008; 62(suppl 3):iii7–iii14. doi:10.1093/jac/dkn367
  36. ACOG Committee on Practice Bulletins–Gynecology. ACOG practice bulletin. No. 73: Use of hormonal contraception in women with coexisting medical conditions. Obstet Gynecol 2006; 107(6):1453–1472. pmid:16738183
References
  1. Fleming-Dutra KE, Hersh AL, Shapiro DJ, et al. Prevalence of inappropriate antibiotic prescriptions among US ambulatory care visits, 2010–2011. JAMA 2016; 315(17):1864–1873. doi:10.1001/jama.2016.4151
  2. Grill MF, Maganti RK. Neurotoxic effects associated with antibiotic use: management considerations. Br J Clin Pharmacol 2011; 72(3):381–393. doi:10.1111/j.1365-2125.2011.03991.x
  3. Dakdouki GK, Al-Awar GN. Cefepime-induced encephalopathy. Int J Infect Dis 2004; 8(1):59–61. pmid:14690782
  4. Bazan JA, Martin SI, Kaye KM. Newer beta-lactam antiobiotics: doripenem, ceftobiprole, and cefepime. Infect Dis Clin North Am 2009; 23(4):983–999. doi:10.1016/j.idc.2009.06.007
  5. Bandettini di Poggio M, Anfosso S, Audenino D, Primavera A. Clarithromycin-induced neurotoxicity in adults. J Clin Neurosci 2011; 18(3):313–318. doi:10.1016/j.jocn.2010.08.014
  6. Saidinejad M, Ewald MB, Shannon MW. Transient psychosis in an immune-competent patient after oral trimethoprim-sulfamethoxazole administration. Pediatrics 2005; 115(6):e739–e741. doi:10.1542/peds.2004-1352
  7. Thomas RJ, Reagan DR. Association of a Tourette-like syndrome with ofloxacin. Ann Pharmacother 1996; 30(2):138–141. doi:10.1177/106002809603000205
  8. Pharmacia and Upjohn Company LLC. Zyvox® Package Insert. http://labeling.pfizer.com/showlabeling.aspx?id=649. Accessed March 5, 2019.
  9. Lawrence KR, Adra M, Gillman PK. Serotonin toxicity associated with the use of linezolid: a review of postmarketing data. Clin Infect Dis 2006; 42(11):1578–1583. doi:10.1086/503839
  10. Patel K, Green-Hopkins I, Lu S, Tunkel AR. Cerebellar ataxia following prolonged use of metronidazole: case report and literature review. Int J Infect Dis 2008; 12(6):e111–e114. doi:10.1016/j.ijid.2008.03.006
  11. Andersohn F, Konzen C, Garbe E. Systematic review: agranulocytosis induced by nonchemotherapy drugs. Ann Intern Med 2007; 146(9):657–665. pmid:17470834
  12. Black E, Lau TT, Ensom MH. Vancomycin-induced neutropenia: is it dose- or duration-related? Ann Pharmacother 2011; 45(5):629–638. doi:10.1345/aph.1P583
  13. Garratty G. Drug-induced immune hemolytic anemia. Hematology Am Soc Hematol Educ Program 2009: 73–79. doi:10.1182/asheducation-2009.1.73
  14. Chong Bh, Choi PY, Khachigian L, Perdomo J. Drug-induced immune thrombocytopenia. Hematol Oncol Clin North Am 2013; 27(3):521–540. doi:10.1016/j.hoc.2013.02.003
  15. Cacoub P, Musette P, Descamps V, et al. The DRESS syndrome: a literature review. Am J Med 2011; 124(7):588–597. doi:10.1016/j.amjmed.2011.01.017
  16. Chang C, Gershwin ME. Drugs and autoimmunity—a contemporary review and mechanistic approach. J Autoimmun 2010; 34(3):J266–J275. doi:10.1016/j.jaut.2009.11.012
  17. Kermani TA, Ham EK, Camilleri MJ, Warrington KJ. Polyarteritis nodosa-like vasculitis in association with minocycline use: a single-center case series. Semin Arthritis Rheum 2012; 42(2):213–221. doi:10.1016/j.semarthrit.2012.03.006
  18. Mandell LA, Ball P, Tillotson G. Antimicrobial safety and tolerability: differences and dilemmas. Clin Infect Dis 2001; 32(suppl 1):S72–S79. doi:10.1086/319379
  19. Christ W, Esch B. Session III: safety. Adverse reactions to fluoroquinolones in adults and children. Infect Dis Clin Pract 1994; 3(3 suppl 3):S168–S176.
  20. Owens RC, Nolin TD. Antimicrobial-associated QT interval prolongation: pointes of interest. Clin Infect Dis 2006; 43(12):1603–1611. doi:10.1086/508873
  21. Rubinstein E, Camm J. Cardiotoxicity of fluoroquinolones. J Antimicrob Chemother 2002; 49(4):593–596. pmid:11909831
  22. US Food and Drug Administration (FDA). FDA drug safety communication: FDA warns about increased risk of ruptures or tears in the aorta blood vessel with fluoroquinolones antibiotics in certain patients. https://www.fda.gov/Drugs/DrugSafety/ucm628753.htm.   Accessed March 15, 2019.
  23. Seminerio J, McGrath K, Arnold CA, Voltaggio L, Singhi AD. Medication-associated lesions of the GI tract. Gastrointest Endosc 2014; 79(1):140–150. doi:10.1016/j.gie.2013.08.027
  24. Bjornsson ES, Jonasson JG. Drug-induced cholestasis. Clin Liver Dis 2013; 17(2):191–209. doi:10.1016/j.cld.2012.11.002
  25. Fontana RJ, Shakil AO, Greenson JK, Boyd I, Lee WM. Acute liver failure due to amoxicillin and amoxicillin/clavulanate. Dig Dis Sci 2005; 50(10):1785–1790. doi:10.1007/s10620-005-2938-5
  26. Sakaan SA, Twilla JD, Usery JB, Winton JC, Self TH. Nitrofurantoin-induced hepatotoxicity: a rare yet serious complication. South Med J 2014; 107(2):107–113. doi:10.1097/SMJ.0000000000000059
  27. Parekh TM, Raji M, Lin YL, Tan A, Kuo YF, Goodwin JS. Hypoglycemia after antimicrobial drug prescription for older patients using sulfonylureas. JAMA Intern Med 2014; 174(10):1605–1612. doi:10.1001/jamainternmed.2014.3293
  28. Prasad R, Gupta P, Singh A, Goel N. Drug induced pulmonary parenchymal disease. Drug Discov Ther 2014; 8(6):232–237. doi:10.5582/ddt.2014.01046
  29. Miller BA, Gray A, Leblanc TW, Sexton DJ, Martin AR, Slama TG. Acute eosinophilic pneumonia secondary to daptomycin: a report of three cases. Clin Infect Dis 2010; 50(11):e63–e68. doi:10.1086/652656
  30. Kabbara WK, Kordahi MC. Nitrofurantoin-induced pulmonary toxicity: a case report and review of the literature. J Infect Public Health 2015; 8(4):309–313. doi:10.1016/j.jiph.2015.01.007
  31. Ghane Shahrbaf F, Assadi F. Drug-induced renal disorders. J Renal Inj Prev 2015; 4(3):57–60. doi:10.12861/jrip.2015.12
  32. Mac K, Chavada R, Paull S, Howlin K, Wong J. Cefepime induced acute interstitial nephritis—a case report. BMC Nephrol 2015; 16:15. doi:10.1186/s12882-015-0004-x
  33. Woodruff AE, Meaney CJ, Hansen EA, Prescott GM. Azithromycin-induced, biopsy-proven cute interstitial nephritis in an adult successfully treated with low-dose corticosteroids. Pharmacotherapy 2015; 35(11):e169–e174. doi:10.1002/phar.1660
  34. US Food and Drug Administration (FDA). FDA drug safety communication: FDA advises restricting fluoroquinolone antibiotic use for certain uncomplicated infections; warns about disabling side effects that can occur together. https://www.fda.gov/Drugs/DrugSafety/ucm500143.htm. Accessed March 7, 2019.
  35. Hawkey PM. Pre-clinical experience with daptomycin. J Antimicrob Chemother 2008; 62(suppl 3):iii7–iii14. doi:10.1093/jac/dkn367
  36. ACOG Committee on Practice Bulletins–Gynecology. ACOG practice bulletin. No. 73: Use of hormonal contraception in women with coexisting medical conditions. Obstet Gynecol 2006; 107(6):1453–1472. pmid:16738183
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antibiotics, side effects, piperacillin encephalopathy, seizure, minocycline lupus, acute tubular necrosis, cephalosporin, tetracycline, crystal nephropathy, quinolones, sulfonamides, QT prolongation, agranulocytosis, beta-lactams, thrombocytopenia, aortic aneurysm, esophagitis, hepatitis, Maria Ruiz, Glenn Wortmann
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antibiotics, side effects, piperacillin encephalopathy, seizure, minocycline lupus, acute tubular necrosis, cephalosporin, tetracycline, crystal nephropathy, quinolones, sulfonamides, QT prolongation, agranulocytosis, beta-lactams, thrombocytopenia, aortic aneurysm, esophagitis, hepatitis, Maria Ruiz, Glenn Wortmann
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  • Piperacillin-induced encephalopathy and seizure can occur on a continuum, with progressive dysarthria, tremor, and confusion culminating in tonic-clonic seizures.
  • Monocycline-induced lupus can present as myalgia, arthralgia, serositis, constitutional symptoms, and a positive antinuclear antibody titer. The effect is not dose-dependent.
  • Acute tubular necrosis has been linked to cephalosporins and tetracyclines. Crystal nephropathy has been reported with quinolones and sulfonamides.
  • QT-interval prolongation is a class effect of quinolones and is more likely to occur in patients with pre-existing QT prolongation, electrolyte abnormalities, organic heart disease, or bradycardia, or in women.
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Flu shot can be given irrespective of the time of last methotrexate dose

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Nicola Garrett

Immune response to influenza vaccination in rheumatoid arthritis patients taking methotrexate appears to depend most on stopping the next two weekly doses of the drug rather than any effect from the timing of the last dose, new research concludes.

Esben H/iStock/Getty Images

The new finding, reported in Annals of the Rheumatic Diseases, stems from a post hoc analysis of a randomized, controlled trial that Jin Kyun Park, MD, of Seoul (Korea) National University, and his colleagues had conducted earlier on immune response when patients stopped methotrexate for either 2 or 4 weeks after vaccination. While the main endpoint of that study showed no difference in the improvement in vaccine response with either stopping methotrexate for 2 or 4 weeks and no increase in disease activity with stopping for 2 weeks, it was unclear whether the timing of the last dose mattered when stopping for 2 weeks.



In a bid to identify the optimal time between the last dose of methotrexate and administration of a flu vaccine, Dr. Park and his colleagues conducted a post hoc analysis of the trial, which involved 316 patients with RA receiving methotrexate for 6 weeks or longer to continue (n = 156) or to hold methotrexate (n = 160) for 2 weeks after receiving a quadrivalent influenza vaccine containing H1N1, H3N2, B-Yamagata, and B-Victoria.

The study authors defined a positive vaccine response as a fourfold or greater increase in hemagglutination inhibition (HI) antibody titer. A satisfactory vaccine response was a positive response to two or more of four vaccine antigens.

Patients who stopped taking methotrexate were divided into eight subgroups according to the number of days between their last dose and their vaccination.

 

 


The research team reported that response to vaccine, fold increase in HI antibody titers, and postvaccination seroprotection rates were not associated with the time between the last methotrexate dose and the time of vaccination.

However, they conceded that “the absence of impact of the number of days between the last methotrexate dose and vaccination could be due to the small patient numbers in eight subgroups.”

Vaccine response also did not differ between patients who received the influenza vaccination within 3 days of the last methotrexate dose (n = 65) and those who received it between 4-7 days of the last methotrexate dose (n = 95).

Furthermore, RA disease activity, seropositivity, or use of conventional or biologic disease-modifying antirheumatic drugs did not have an impact on methotrexate discontinuation.

The authors concluded that vaccinations could be given irrespective of the time of the last methotrexate dose, and patients should be advised to skip two weekly doses following vaccination.

“This supports the notion that the effects of methotrexate on humeral immunity occur rapidly, despite the delayed effects on arthritis; therefore, the absence of methotrexate during the first 2 weeks postvaccination is critical for humoral immunity,” they wrote.

The study was sponsored by GC Pharma. One author disclosed serving as a consultant to Pfizer and receiving research grants from GC Pharma and Hanmi Pharma.

SOURCE: Park JK et al. Ann Rheum Dis. 2019 Mar 23. doi: 10.1136/annrheumdis-2019-215187.

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Immune response to influenza vaccination in rheumatoid arthritis patients taking methotrexate appears to depend most on stopping the next two weekly doses of the drug rather than any effect from the timing of the last dose, new research concludes.

Esben H/iStock/Getty Images

The new finding, reported in Annals of the Rheumatic Diseases, stems from a post hoc analysis of a randomized, controlled trial that Jin Kyun Park, MD, of Seoul (Korea) National University, and his colleagues had conducted earlier on immune response when patients stopped methotrexate for either 2 or 4 weeks after vaccination. While the main endpoint of that study showed no difference in the improvement in vaccine response with either stopping methotrexate for 2 or 4 weeks and no increase in disease activity with stopping for 2 weeks, it was unclear whether the timing of the last dose mattered when stopping for 2 weeks.



In a bid to identify the optimal time between the last dose of methotrexate and administration of a flu vaccine, Dr. Park and his colleagues conducted a post hoc analysis of the trial, which involved 316 patients with RA receiving methotrexate for 6 weeks or longer to continue (n = 156) or to hold methotrexate (n = 160) for 2 weeks after receiving a quadrivalent influenza vaccine containing H1N1, H3N2, B-Yamagata, and B-Victoria.

The study authors defined a positive vaccine response as a fourfold or greater increase in hemagglutination inhibition (HI) antibody titer. A satisfactory vaccine response was a positive response to two or more of four vaccine antigens.

Patients who stopped taking methotrexate were divided into eight subgroups according to the number of days between their last dose and their vaccination.

 

 


The research team reported that response to vaccine, fold increase in HI antibody titers, and postvaccination seroprotection rates were not associated with the time between the last methotrexate dose and the time of vaccination.

However, they conceded that “the absence of impact of the number of days between the last methotrexate dose and vaccination could be due to the small patient numbers in eight subgroups.”

Vaccine response also did not differ between patients who received the influenza vaccination within 3 days of the last methotrexate dose (n = 65) and those who received it between 4-7 days of the last methotrexate dose (n = 95).

Furthermore, RA disease activity, seropositivity, or use of conventional or biologic disease-modifying antirheumatic drugs did not have an impact on methotrexate discontinuation.

The authors concluded that vaccinations could be given irrespective of the time of the last methotrexate dose, and patients should be advised to skip two weekly doses following vaccination.

“This supports the notion that the effects of methotrexate on humeral immunity occur rapidly, despite the delayed effects on arthritis; therefore, the absence of methotrexate during the first 2 weeks postvaccination is critical for humoral immunity,” they wrote.

The study was sponsored by GC Pharma. One author disclosed serving as a consultant to Pfizer and receiving research grants from GC Pharma and Hanmi Pharma.

SOURCE: Park JK et al. Ann Rheum Dis. 2019 Mar 23. doi: 10.1136/annrheumdis-2019-215187.

Immune response to influenza vaccination in rheumatoid arthritis patients taking methotrexate appears to depend most on stopping the next two weekly doses of the drug rather than any effect from the timing of the last dose, new research concludes.

Esben H/iStock/Getty Images

The new finding, reported in Annals of the Rheumatic Diseases, stems from a post hoc analysis of a randomized, controlled trial that Jin Kyun Park, MD, of Seoul (Korea) National University, and his colleagues had conducted earlier on immune response when patients stopped methotrexate for either 2 or 4 weeks after vaccination. While the main endpoint of that study showed no difference in the improvement in vaccine response with either stopping methotrexate for 2 or 4 weeks and no increase in disease activity with stopping for 2 weeks, it was unclear whether the timing of the last dose mattered when stopping for 2 weeks.



In a bid to identify the optimal time between the last dose of methotrexate and administration of a flu vaccine, Dr. Park and his colleagues conducted a post hoc analysis of the trial, which involved 316 patients with RA receiving methotrexate for 6 weeks or longer to continue (n = 156) or to hold methotrexate (n = 160) for 2 weeks after receiving a quadrivalent influenza vaccine containing H1N1, H3N2, B-Yamagata, and B-Victoria.

The study authors defined a positive vaccine response as a fourfold or greater increase in hemagglutination inhibition (HI) antibody titer. A satisfactory vaccine response was a positive response to two or more of four vaccine antigens.

Patients who stopped taking methotrexate were divided into eight subgroups according to the number of days between their last dose and their vaccination.

 

 


The research team reported that response to vaccine, fold increase in HI antibody titers, and postvaccination seroprotection rates were not associated with the time between the last methotrexate dose and the time of vaccination.

However, they conceded that “the absence of impact of the number of days between the last methotrexate dose and vaccination could be due to the small patient numbers in eight subgroups.”

Vaccine response also did not differ between patients who received the influenza vaccination within 3 days of the last methotrexate dose (n = 65) and those who received it between 4-7 days of the last methotrexate dose (n = 95).

Furthermore, RA disease activity, seropositivity, or use of conventional or biologic disease-modifying antirheumatic drugs did not have an impact on methotrexate discontinuation.

The authors concluded that vaccinations could be given irrespective of the time of the last methotrexate dose, and patients should be advised to skip two weekly doses following vaccination.

“This supports the notion that the effects of methotrexate on humeral immunity occur rapidly, despite the delayed effects on arthritis; therefore, the absence of methotrexate during the first 2 weeks postvaccination is critical for humoral immunity,” they wrote.

The study was sponsored by GC Pharma. One author disclosed serving as a consultant to Pfizer and receiving research grants from GC Pharma and Hanmi Pharma.

SOURCE: Park JK et al. Ann Rheum Dis. 2019 Mar 23. doi: 10.1136/annrheumdis-2019-215187.

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Key clinical point: Patients with RA should stop methotrexate for 2 weeks after receiving an influenza vaccination, regardless of the time of their last dose prior to vaccination.

Major finding: Response to vaccine, fold increase in HI antibody titers, and postvaccination seroprotection rates were not associated with the time between the last methotrexate dose and the time of vaccination.

Study details: A post hoc analysis of a randomized, controlled trial involving 316 patients with rheumatoid arthritis who continued or stopped methotrexate for 2 weeks following influenza vaccination.

Disclosures: The study was sponsored by GC Pharma. One author disclosed serving as a consultant to Pfizer and receiving research grants from GC Pharma and Hanmi Pharma.

Source: Park JK et al. Ann Rheum Dis. 2019 Mar 23. doi: 10.1136/annrheumdis-2019-215187

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2018-2019 flu season: Going but not gone yet

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Richard Franki

The 2018-2019 flu season again showed real signs of ending as influenza activity levels dropped during the week ending March 23, according to the Centers for Disease Control and Prevention.

Despite those declines, however, current levels of influenza-like illness (ILI) activity are still elevated enough that the CDC issued a health advisory on March 28 to inform clinicians about the “increasing proportion of activity due to influenza A(H3N2) viruses, continued circulation of influenza A(H1N1) viruses, and low levels of influenza B viruses.”



The CDC’s weekly flu report, released March 29, does show that the overall burden is improving. The national proportion of outpatient visits for ILI dropped from 4.3% for the week ending March 16 to 3.8% for the latest reporting week, the CDC’s influenza division reported. The figure for March 16 was originally reported to be 4.4% but was revised in the new report.

The length of this years’ flu season, when measured as the number of weeks at or above the baseline level of 2.2%, is now 18 weeks. By this measure, the last five seasons have averaged 16 weeks, the CDC noted.

Influenza was considered widespread in 34 states and Puerto Rico for the week ending March 23, down from 44 states the previous week. The number of states at the highest level of ILI activity on the CDC’s 1-10 scale dropped from 20 to 11, and those in the high range (8-10) dropped from 26 to 20, data from the CDC’s Outpatient ILI Surveillance Network show.

There was one flu-related pediatric death during the week of March 23 but none reported from earlier weeks, which brings the total to 77 for the 2018-2019 season, the CDC said.

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The 2018-2019 flu season again showed real signs of ending as influenza activity levels dropped during the week ending March 23, according to the Centers for Disease Control and Prevention.

Despite those declines, however, current levels of influenza-like illness (ILI) activity are still elevated enough that the CDC issued a health advisory on March 28 to inform clinicians about the “increasing proportion of activity due to influenza A(H3N2) viruses, continued circulation of influenza A(H1N1) viruses, and low levels of influenza B viruses.”



The CDC’s weekly flu report, released March 29, does show that the overall burden is improving. The national proportion of outpatient visits for ILI dropped from 4.3% for the week ending March 16 to 3.8% for the latest reporting week, the CDC’s influenza division reported. The figure for March 16 was originally reported to be 4.4% but was revised in the new report.

The length of this years’ flu season, when measured as the number of weeks at or above the baseline level of 2.2%, is now 18 weeks. By this measure, the last five seasons have averaged 16 weeks, the CDC noted.

Influenza was considered widespread in 34 states and Puerto Rico for the week ending March 23, down from 44 states the previous week. The number of states at the highest level of ILI activity on the CDC’s 1-10 scale dropped from 20 to 11, and those in the high range (8-10) dropped from 26 to 20, data from the CDC’s Outpatient ILI Surveillance Network show.

There was one flu-related pediatric death during the week of March 23 but none reported from earlier weeks, which brings the total to 77 for the 2018-2019 season, the CDC said.

The 2018-2019 flu season again showed real signs of ending as influenza activity levels dropped during the week ending March 23, according to the Centers for Disease Control and Prevention.

Despite those declines, however, current levels of influenza-like illness (ILI) activity are still elevated enough that the CDC issued a health advisory on March 28 to inform clinicians about the “increasing proportion of activity due to influenza A(H3N2) viruses, continued circulation of influenza A(H1N1) viruses, and low levels of influenza B viruses.”



The CDC’s weekly flu report, released March 29, does show that the overall burden is improving. The national proportion of outpatient visits for ILI dropped from 4.3% for the week ending March 16 to 3.8% for the latest reporting week, the CDC’s influenza division reported. The figure for March 16 was originally reported to be 4.4% but was revised in the new report.

The length of this years’ flu season, when measured as the number of weeks at or above the baseline level of 2.2%, is now 18 weeks. By this measure, the last five seasons have averaged 16 weeks, the CDC noted.

Influenza was considered widespread in 34 states and Puerto Rico for the week ending March 23, down from 44 states the previous week. The number of states at the highest level of ILI activity on the CDC’s 1-10 scale dropped from 20 to 11, and those in the high range (8-10) dropped from 26 to 20, data from the CDC’s Outpatient ILI Surveillance Network show.

There was one flu-related pediatric death during the week of March 23 but none reported from earlier weeks, which brings the total to 77 for the 2018-2019 season, the CDC said.

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Anti-infective update addresses SSSI choices

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Kari Oakes

 

ORLANDO – What’s new in infectious disease therapeutics for dermatologists? More topical choices, antiparasitics, and some “big guns” to target skin and skin structure infections, according to Justin Finch, MD. He ran through an array of updates at the Orlando Dermatology Aesthetic and Clinical Conference.

Kari Oakes/MDedge News
Dr. Justin Finch

While naturally occurring smallpox was globally eradicated in 1980, small research stores are held in the United States and Russia, and effective antivirals are part of a strategy to combat bioweapons. Tecovirimat (TPOXX) is an antiviral that inhibits a major envelope protein that poxviruses need to produce extracellular virus. Approved by the Food and Drug Administration in mid-2018, it is currently the only antiviral for treating variola virus infection approved in the United States, noted Dr. Finch of the University of Connecticut, Farmington. He added that 2 million doses are currently held in the U.S. Strategic National Stockpile.

Another anti-infective agent that won’t be used by those practicing in the United States, but which promises to alleviate a significant source of suffering in the developing world, is moxidectin. The anthelmintic had previously been approved for veterinary uses, but in June 2018, the FDA approved moxidectin to treat onchocerciasis, also known as river blindness. The drug defeats the parasitic worm by binding to glutamate-gated chloride ion channels; it is licensed by the nonprofit Medicines Development for Global Health.

Another antiparasitic drug, benznidazole, was approved to treat children aged 2-12 years with Chagas disease in 2017, Dr. Finch said.



Also in 2017, a topical quinolone, ozenoxacin (Xepi) was approved to treat impetigo in adults and children aged at least 2 months. Formulated as a 1% cream, ozenoxacin is applied twice daily for 5 days. In clinical trials, ozenoxacin was shown to be noninferior to retapamulin, he said.

A new topical choice is important as mupirocin resistance climbs, Dr. Finch added. A recent Greek study showed that 20% (437) of 2,137 staph infections studied were mupirocin resistant. Of the 20%, all but one were skin and skin structure infections (SSSIs), with 88% of these being impetigo.

In the United States, mupirocin resistance has been seen in one in three outpatients in a Florida study and in 31% of patients in a New York City sample. Other studies have shown mupirocin resistance in Staphylococcus aureus isolates with resistance in the 10%-15% range among children with SSSIs, Dr. Finch said.

Two other new antibiotics to fight SSSIs can each be administered orally or intravenously. One, omadacycline (Nuzyra), is a novel tetracycline that maintains efficacy against bacteria that express tetracycline resistance through efflux and ribosomal protection. Approved in late 2018 for acute bacterial SSSIs, omadacycline treats not just methicillin-sensitive and methicillin-resistant S. aureus, but also Streptococcus species and gram-negative rods such as Enterobacter and Klebsiella pneumoniae, Dr. Finch noted.

Another new fluorinated quinolone, approved in 2017, delafloxacin (Baxdela) has broad spectrum activity against gram-negative and gram-positive bacteria.

Dr. Finch reported that he has no relevant conflicts of interest.

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ORLANDO – What’s new in infectious disease therapeutics for dermatologists? More topical choices, antiparasitics, and some “big guns” to target skin and skin structure infections, according to Justin Finch, MD. He ran through an array of updates at the Orlando Dermatology Aesthetic and Clinical Conference.

Kari Oakes/MDedge News
Dr. Justin Finch

While naturally occurring smallpox was globally eradicated in 1980, small research stores are held in the United States and Russia, and effective antivirals are part of a strategy to combat bioweapons. Tecovirimat (TPOXX) is an antiviral that inhibits a major envelope protein that poxviruses need to produce extracellular virus. Approved by the Food and Drug Administration in mid-2018, it is currently the only antiviral for treating variola virus infection approved in the United States, noted Dr. Finch of the University of Connecticut, Farmington. He added that 2 million doses are currently held in the U.S. Strategic National Stockpile.

Another anti-infective agent that won’t be used by those practicing in the United States, but which promises to alleviate a significant source of suffering in the developing world, is moxidectin. The anthelmintic had previously been approved for veterinary uses, but in June 2018, the FDA approved moxidectin to treat onchocerciasis, also known as river blindness. The drug defeats the parasitic worm by binding to glutamate-gated chloride ion channels; it is licensed by the nonprofit Medicines Development for Global Health.

Another antiparasitic drug, benznidazole, was approved to treat children aged 2-12 years with Chagas disease in 2017, Dr. Finch said.



Also in 2017, a topical quinolone, ozenoxacin (Xepi) was approved to treat impetigo in adults and children aged at least 2 months. Formulated as a 1% cream, ozenoxacin is applied twice daily for 5 days. In clinical trials, ozenoxacin was shown to be noninferior to retapamulin, he said.

A new topical choice is important as mupirocin resistance climbs, Dr. Finch added. A recent Greek study showed that 20% (437) of 2,137 staph infections studied were mupirocin resistant. Of the 20%, all but one were skin and skin structure infections (SSSIs), with 88% of these being impetigo.

In the United States, mupirocin resistance has been seen in one in three outpatients in a Florida study and in 31% of patients in a New York City sample. Other studies have shown mupirocin resistance in Staphylococcus aureus isolates with resistance in the 10%-15% range among children with SSSIs, Dr. Finch said.

Two other new antibiotics to fight SSSIs can each be administered orally or intravenously. One, omadacycline (Nuzyra), is a novel tetracycline that maintains efficacy against bacteria that express tetracycline resistance through efflux and ribosomal protection. Approved in late 2018 for acute bacterial SSSIs, omadacycline treats not just methicillin-sensitive and methicillin-resistant S. aureus, but also Streptococcus species and gram-negative rods such as Enterobacter and Klebsiella pneumoniae, Dr. Finch noted.

Another new fluorinated quinolone, approved in 2017, delafloxacin (Baxdela) has broad spectrum activity against gram-negative and gram-positive bacteria.

Dr. Finch reported that he has no relevant conflicts of interest.

 

ORLANDO – What’s new in infectious disease therapeutics for dermatologists? More topical choices, antiparasitics, and some “big guns” to target skin and skin structure infections, according to Justin Finch, MD. He ran through an array of updates at the Orlando Dermatology Aesthetic and Clinical Conference.

Kari Oakes/MDedge News
Dr. Justin Finch

While naturally occurring smallpox was globally eradicated in 1980, small research stores are held in the United States and Russia, and effective antivirals are part of a strategy to combat bioweapons. Tecovirimat (TPOXX) is an antiviral that inhibits a major envelope protein that poxviruses need to produce extracellular virus. Approved by the Food and Drug Administration in mid-2018, it is currently the only antiviral for treating variola virus infection approved in the United States, noted Dr. Finch of the University of Connecticut, Farmington. He added that 2 million doses are currently held in the U.S. Strategic National Stockpile.

Another anti-infective agent that won’t be used by those practicing in the United States, but which promises to alleviate a significant source of suffering in the developing world, is moxidectin. The anthelmintic had previously been approved for veterinary uses, but in June 2018, the FDA approved moxidectin to treat onchocerciasis, also known as river blindness. The drug defeats the parasitic worm by binding to glutamate-gated chloride ion channels; it is licensed by the nonprofit Medicines Development for Global Health.

Another antiparasitic drug, benznidazole, was approved to treat children aged 2-12 years with Chagas disease in 2017, Dr. Finch said.



Also in 2017, a topical quinolone, ozenoxacin (Xepi) was approved to treat impetigo in adults and children aged at least 2 months. Formulated as a 1% cream, ozenoxacin is applied twice daily for 5 days. In clinical trials, ozenoxacin was shown to be noninferior to retapamulin, he said.

A new topical choice is important as mupirocin resistance climbs, Dr. Finch added. A recent Greek study showed that 20% (437) of 2,137 staph infections studied were mupirocin resistant. Of the 20%, all but one were skin and skin structure infections (SSSIs), with 88% of these being impetigo.

In the United States, mupirocin resistance has been seen in one in three outpatients in a Florida study and in 31% of patients in a New York City sample. Other studies have shown mupirocin resistance in Staphylococcus aureus isolates with resistance in the 10%-15% range among children with SSSIs, Dr. Finch said.

Two other new antibiotics to fight SSSIs can each be administered orally or intravenously. One, omadacycline (Nuzyra), is a novel tetracycline that maintains efficacy against bacteria that express tetracycline resistance through efflux and ribosomal protection. Approved in late 2018 for acute bacterial SSSIs, omadacycline treats not just methicillin-sensitive and methicillin-resistant S. aureus, but also Streptococcus species and gram-negative rods such as Enterobacter and Klebsiella pneumoniae, Dr. Finch noted.

Another new fluorinated quinolone, approved in 2017, delafloxacin (Baxdela) has broad spectrum activity against gram-negative and gram-positive bacteria.

Dr. Finch reported that he has no relevant conflicts of interest.

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Earlier diagnosis, treatment needed to curb dramatic rise in neonatal HSV

Diagnostic conundrum persists despite new data
Article Type
News
Changed
Tue, 04/09/2019 - 17:34
Author(s)
Jill D. Pivovarov

A 56% increase in neonatal herpes simplex virus (HSV) infection over 7 years was determined as part of a retrospective, multistate, longitudinal cohort study using information collected from the MarketScan Medicaid Database, reported Sanjay Mahant, MD, of the University of Toronto, and his associates.

Comprehensive coordinated care – as well as public health strategies targeting disease prevention, early diagnosis, and treatment – are needed to manage the growing number of neonates diagnosed with HSV, Dr. Mahant and his colleagues said.

A total of 900 newborn Medicaid enrollees aged 0-28 days were chosen from 2,107,124 births for inclusion in the study. All patients, who were diagnosed with HSV infection during hospital admission, were born during Jan. 1, 2009–Dec. 31, 2015.

Susceptibility to primary HSV-1 infection among younger women has been attributed to an increase in oral sex practices over the past 2 decades, which is putting adolescents and young adults at greater risk of genital HSV-1 infection (J Infect Dis. 2007;196[12]:1852-9). As a result, more “primary or nonprimary genital HSV-1 infections among childbearing women” are believed to be the likely cause for the increasing numbers of neonatal HSV cases, the authors speculated, citing a recent study (J Infect Dis. 2014 Feb 1;209[3]:315-7).

HSV, a rare infection typically contracted immediately before or after birth, has both high morbidity and mortality rates; transmission rates “after exposure and during delivery increase from 2% in recurrent infection to 25% and 60% in nonprimary and primary infections, respectively,” Dr. Mahant and his colleagues noted.

Over the study period, disease incidence grew from 3.4/10,000 births in 2009 (1/2,941 births) to 5.3/10,000 births in 2015 (1/1,886 births).

Dr. Mahant and his associates noted several limitations in the study that might explain the increase in incidence.

ICD diagnosis codes, which they characterized as imperfect in their ability to correctly identify neonatal HSV infections, may have led researchers to include infants who were not actually infected or (less likely) to have excluded infants who were infected. States participating in the MarketScan Medicaid Database also may have changed over the study period. Incomplete follow-up after hospitalization made it impossible to track infants who had changed insurers, moved to other states, or died during the study. They also cautioned that outcomes may not be transferable to the general population because outcomes were specific to Medicaid enrollees.

The total cost for initial hospitalization and treatments provided during 6 months of follow-up was $60,620,431 ($87,602 median cost per patient) for the cohort of 900 infants. This is significant given that the authors reported a median length of stay of 18 days for initial hospitalization. Of the 846 patients discharged (54, or 6%, died during initial hospitalization), follow-up data was available for 692 (81%). A total of 316 (46%) infants required at least one subsequent visit to the emergency room, and another 112 (16%) experienced at least one hospital readmission.

That Dr. Mahant and his colleagues “observed high health care use and associated payments over the first 6 months, including and after hospitalization for neonatal HSV” suggests that there is a need for comprehensive, coordinated care once neonatal patients receive a diagnosis of HSV.

“Public health strategies that are targeted on disease prevention and early diagnosis and treatment are needed,” they advised.

The authors had no relevant financial disclosures. The study was funded by the National Institutes of Health.

SOURCE: Mahant S et al. Pediatrics. 2019 Mar. doi: 10.1542/peds.2018-3233.

Body

The rise in herpes simplex virus cases among neonates reported by Mahant et al. is significant, but there are other possible explanations that warrant additional research, James Gaensbauer, MD, and Joseph A. Grubenhoff, MD, wrote in an accompanying editorial.

Among those explanations, Dr. Gaensbauer and Dr. Grubenhoff cite recommendations made nationally in 2013 to screen asymptomatic infants who had been exposed to HSV at the time of delivery as one possible factor elevating the number of cases being reported. More widespread use of polymerase chain reaction (PCR)–based diagnostic testing, which is reported to be more sensitive, also could play a role in increasing the number of cases being identified.

As part of a larger diagnostic “conundrum” challenging clinicians, the editorialists noted that, at present, there is no uniform consensus for performing HSV testing and providing empirical treatment. “Current recommendations from the American Academy of Pediatrics identify and emphasize the importance of recognition of the factors associated with increased likelihood of HSV infection but do not specify a more comprehensive (e.g., all febrile infants) strategy.” Stakeholders should build flexibility into their recommended treatment approaches for the benefit of practitioners operating on the front lines, they advised.

Ultimately, if the increase in incidence of neonatal HSV cases proves largely attributable to the changing behaviors of young women, who have been engaging more frequently in oral sex, as Dr. Mahant and his colleagues suggest, further research will be warranted, cautioned Dr. Gaensbauer and Dr. Grubenhoff.

“With their work, the authors contribute further nuance to a complicated and ongoing question: How do we correctly identify all infants with neonatal HSV in a timely manner while avoiding subjecting large numbers of children to unnecessary tests and empirical treatments?” This debate “is likely to be transformed by increasing availability of rapid PCR testing for HSV,” they said.

The “pathway to better clarity will depend on researchers and clinicians such as Mahant et al., who continue to provide important data and ask critical questions,” Dr. Gaensbauer and Dr. Grubenhoff concluded.

Dr. Gaensbauer and Dr. Grubenhoff are affiliated with the Denver Health Medical Center; the Children’s Hospital Colorado, Aurora; and the department of pediatrics at University of Colorado at Denver, Aurora. This is a summarization of their editorial, which accompanied the article by Mahant et al. (Pediatrics. 2019 Mar. doi: 10.1542/peds.2019-0159). They received no external funding and had no relevant financial disclosures.

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Body

The rise in herpes simplex virus cases among neonates reported by Mahant et al. is significant, but there are other possible explanations that warrant additional research, James Gaensbauer, MD, and Joseph A. Grubenhoff, MD, wrote in an accompanying editorial.

Among those explanations, Dr. Gaensbauer and Dr. Grubenhoff cite recommendations made nationally in 2013 to screen asymptomatic infants who had been exposed to HSV at the time of delivery as one possible factor elevating the number of cases being reported. More widespread use of polymerase chain reaction (PCR)–based diagnostic testing, which is reported to be more sensitive, also could play a role in increasing the number of cases being identified.

As part of a larger diagnostic “conundrum” challenging clinicians, the editorialists noted that, at present, there is no uniform consensus for performing HSV testing and providing empirical treatment. “Current recommendations from the American Academy of Pediatrics identify and emphasize the importance of recognition of the factors associated with increased likelihood of HSV infection but do not specify a more comprehensive (e.g., all febrile infants) strategy.” Stakeholders should build flexibility into their recommended treatment approaches for the benefit of practitioners operating on the front lines, they advised.

Ultimately, if the increase in incidence of neonatal HSV cases proves largely attributable to the changing behaviors of young women, who have been engaging more frequently in oral sex, as Dr. Mahant and his colleagues suggest, further research will be warranted, cautioned Dr. Gaensbauer and Dr. Grubenhoff.

“With their work, the authors contribute further nuance to a complicated and ongoing question: How do we correctly identify all infants with neonatal HSV in a timely manner while avoiding subjecting large numbers of children to unnecessary tests and empirical treatments?” This debate “is likely to be transformed by increasing availability of rapid PCR testing for HSV,” they said.

The “pathway to better clarity will depend on researchers and clinicians such as Mahant et al., who continue to provide important data and ask critical questions,” Dr. Gaensbauer and Dr. Grubenhoff concluded.

Dr. Gaensbauer and Dr. Grubenhoff are affiliated with the Denver Health Medical Center; the Children’s Hospital Colorado, Aurora; and the department of pediatrics at University of Colorado at Denver, Aurora. This is a summarization of their editorial, which accompanied the article by Mahant et al. (Pediatrics. 2019 Mar. doi: 10.1542/peds.2019-0159). They received no external funding and had no relevant financial disclosures.

Body

The rise in herpes simplex virus cases among neonates reported by Mahant et al. is significant, but there are other possible explanations that warrant additional research, James Gaensbauer, MD, and Joseph A. Grubenhoff, MD, wrote in an accompanying editorial.

Among those explanations, Dr. Gaensbauer and Dr. Grubenhoff cite recommendations made nationally in 2013 to screen asymptomatic infants who had been exposed to HSV at the time of delivery as one possible factor elevating the number of cases being reported. More widespread use of polymerase chain reaction (PCR)–based diagnostic testing, which is reported to be more sensitive, also could play a role in increasing the number of cases being identified.

As part of a larger diagnostic “conundrum” challenging clinicians, the editorialists noted that, at present, there is no uniform consensus for performing HSV testing and providing empirical treatment. “Current recommendations from the American Academy of Pediatrics identify and emphasize the importance of recognition of the factors associated with increased likelihood of HSV infection but do not specify a more comprehensive (e.g., all febrile infants) strategy.” Stakeholders should build flexibility into their recommended treatment approaches for the benefit of practitioners operating on the front lines, they advised.

Ultimately, if the increase in incidence of neonatal HSV cases proves largely attributable to the changing behaviors of young women, who have been engaging more frequently in oral sex, as Dr. Mahant and his colleagues suggest, further research will be warranted, cautioned Dr. Gaensbauer and Dr. Grubenhoff.

“With their work, the authors contribute further nuance to a complicated and ongoing question: How do we correctly identify all infants with neonatal HSV in a timely manner while avoiding subjecting large numbers of children to unnecessary tests and empirical treatments?” This debate “is likely to be transformed by increasing availability of rapid PCR testing for HSV,” they said.

The “pathway to better clarity will depend on researchers and clinicians such as Mahant et al., who continue to provide important data and ask critical questions,” Dr. Gaensbauer and Dr. Grubenhoff concluded.

Dr. Gaensbauer and Dr. Grubenhoff are affiliated with the Denver Health Medical Center; the Children’s Hospital Colorado, Aurora; and the department of pediatrics at University of Colorado at Denver, Aurora. This is a summarization of their editorial, which accompanied the article by Mahant et al. (Pediatrics. 2019 Mar. doi: 10.1542/peds.2019-0159). They received no external funding and had no relevant financial disclosures.

Title
Diagnostic conundrum persists despite new data
Diagnostic conundrum persists despite new data

A 56% increase in neonatal herpes simplex virus (HSV) infection over 7 years was determined as part of a retrospective, multistate, longitudinal cohort study using information collected from the MarketScan Medicaid Database, reported Sanjay Mahant, MD, of the University of Toronto, and his associates.

Comprehensive coordinated care – as well as public health strategies targeting disease prevention, early diagnosis, and treatment – are needed to manage the growing number of neonates diagnosed with HSV, Dr. Mahant and his colleagues said.

A total of 900 newborn Medicaid enrollees aged 0-28 days were chosen from 2,107,124 births for inclusion in the study. All patients, who were diagnosed with HSV infection during hospital admission, were born during Jan. 1, 2009–Dec. 31, 2015.

Susceptibility to primary HSV-1 infection among younger women has been attributed to an increase in oral sex practices over the past 2 decades, which is putting adolescents and young adults at greater risk of genital HSV-1 infection (J Infect Dis. 2007;196[12]:1852-9). As a result, more “primary or nonprimary genital HSV-1 infections among childbearing women” are believed to be the likely cause for the increasing numbers of neonatal HSV cases, the authors speculated, citing a recent study (J Infect Dis. 2014 Feb 1;209[3]:315-7).

HSV, a rare infection typically contracted immediately before or after birth, has both high morbidity and mortality rates; transmission rates “after exposure and during delivery increase from 2% in recurrent infection to 25% and 60% in nonprimary and primary infections, respectively,” Dr. Mahant and his colleagues noted.

Over the study period, disease incidence grew from 3.4/10,000 births in 2009 (1/2,941 births) to 5.3/10,000 births in 2015 (1/1,886 births).

Dr. Mahant and his associates noted several limitations in the study that might explain the increase in incidence.

ICD diagnosis codes, which they characterized as imperfect in their ability to correctly identify neonatal HSV infections, may have led researchers to include infants who were not actually infected or (less likely) to have excluded infants who were infected. States participating in the MarketScan Medicaid Database also may have changed over the study period. Incomplete follow-up after hospitalization made it impossible to track infants who had changed insurers, moved to other states, or died during the study. They also cautioned that outcomes may not be transferable to the general population because outcomes were specific to Medicaid enrollees.

The total cost for initial hospitalization and treatments provided during 6 months of follow-up was $60,620,431 ($87,602 median cost per patient) for the cohort of 900 infants. This is significant given that the authors reported a median length of stay of 18 days for initial hospitalization. Of the 846 patients discharged (54, or 6%, died during initial hospitalization), follow-up data was available for 692 (81%). A total of 316 (46%) infants required at least one subsequent visit to the emergency room, and another 112 (16%) experienced at least one hospital readmission.

That Dr. Mahant and his colleagues “observed high health care use and associated payments over the first 6 months, including and after hospitalization for neonatal HSV” suggests that there is a need for comprehensive, coordinated care once neonatal patients receive a diagnosis of HSV.

“Public health strategies that are targeted on disease prevention and early diagnosis and treatment are needed,” they advised.

The authors had no relevant financial disclosures. The study was funded by the National Institutes of Health.

SOURCE: Mahant S et al. Pediatrics. 2019 Mar. doi: 10.1542/peds.2018-3233.

A 56% increase in neonatal herpes simplex virus (HSV) infection over 7 years was determined as part of a retrospective, multistate, longitudinal cohort study using information collected from the MarketScan Medicaid Database, reported Sanjay Mahant, MD, of the University of Toronto, and his associates.

Comprehensive coordinated care – as well as public health strategies targeting disease prevention, early diagnosis, and treatment – are needed to manage the growing number of neonates diagnosed with HSV, Dr. Mahant and his colleagues said.

A total of 900 newborn Medicaid enrollees aged 0-28 days were chosen from 2,107,124 births for inclusion in the study. All patients, who were diagnosed with HSV infection during hospital admission, were born during Jan. 1, 2009–Dec. 31, 2015.

Susceptibility to primary HSV-1 infection among younger women has been attributed to an increase in oral sex practices over the past 2 decades, which is putting adolescents and young adults at greater risk of genital HSV-1 infection (J Infect Dis. 2007;196[12]:1852-9). As a result, more “primary or nonprimary genital HSV-1 infections among childbearing women” are believed to be the likely cause for the increasing numbers of neonatal HSV cases, the authors speculated, citing a recent study (J Infect Dis. 2014 Feb 1;209[3]:315-7).

HSV, a rare infection typically contracted immediately before or after birth, has both high morbidity and mortality rates; transmission rates “after exposure and during delivery increase from 2% in recurrent infection to 25% and 60% in nonprimary and primary infections, respectively,” Dr. Mahant and his colleagues noted.

Over the study period, disease incidence grew from 3.4/10,000 births in 2009 (1/2,941 births) to 5.3/10,000 births in 2015 (1/1,886 births).

Dr. Mahant and his associates noted several limitations in the study that might explain the increase in incidence.

ICD diagnosis codes, which they characterized as imperfect in their ability to correctly identify neonatal HSV infections, may have led researchers to include infants who were not actually infected or (less likely) to have excluded infants who were infected. States participating in the MarketScan Medicaid Database also may have changed over the study period. Incomplete follow-up after hospitalization made it impossible to track infants who had changed insurers, moved to other states, or died during the study. They also cautioned that outcomes may not be transferable to the general population because outcomes were specific to Medicaid enrollees.

The total cost for initial hospitalization and treatments provided during 6 months of follow-up was $60,620,431 ($87,602 median cost per patient) for the cohort of 900 infants. This is significant given that the authors reported a median length of stay of 18 days for initial hospitalization. Of the 846 patients discharged (54, or 6%, died during initial hospitalization), follow-up data was available for 692 (81%). A total of 316 (46%) infants required at least one subsequent visit to the emergency room, and another 112 (16%) experienced at least one hospital readmission.

That Dr. Mahant and his colleagues “observed high health care use and associated payments over the first 6 months, including and after hospitalization for neonatal HSV” suggests that there is a need for comprehensive, coordinated care once neonatal patients receive a diagnosis of HSV.

“Public health strategies that are targeted on disease prevention and early diagnosis and treatment are needed,” they advised.

The authors had no relevant financial disclosures. The study was funded by the National Institutes of Health.

SOURCE: Mahant S et al. Pediatrics. 2019 Mar. doi: 10.1542/peds.2018-3233.

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Cellulitis pearls

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Opinion
Changed
Fri, 03/29/2019 - 08:58
Author(s)
Douglas S. Paauw, MD

A 38-year-old man is admitted to the hospital with a painful, swollen left leg. This was not the first instance of this kind for him. He had been admitted for the same problem 3 months earlier. During the earlier admission, he was diagnosed with cellulitis and treated with intravenous cefazolin for 4 days, then discharged on cephalexin with resolution of his swelling and pain. Today, his blood pressure is 120/70, pulse is 90, temperature is 38.2°C, his left leg is edematous from the mid-calf to the ankle, and he has erythema and warmth over the calf. His white blood cell count is 13,000, and a diagnosis of cellulitis is made. Which of the following treatments is most likely to shorten his hospital stay?

Dr. Paauw


A. Vancomycin therapy instead of cefazolin.

B. Piperacillin/tazobactam therapy instead of cefazolin.

C. Prednisolone therapy in addition to antibiotics.

D. Furosemide therapy in addition to antibiotics.

The correct answer is C, prednisolone therapy in addition to antibiotics. Corticosteroids have been used as therapy for a number of infectious diseases, and steroid use has been shown to improve survival in patients with bacterial meningitis, tuberculous meningitis, tuberculous pericarditis, severe typhoid fever, tetanus, or pneumocystis pneumonia with moderate to severe hypoxemia.1 Corticosteroid use in many other infections has been studied, and for many infections, symptomatic benefit has been shown. Berkvist and Sjobeck studied 112 patients admitted to the hospital with lower-extremity erysipelas/cellulitis and randomized the patients to receive prednisolone or placebo in addition to antibiotic treatment.2 The prednisolone-treated patients had a shorter hospital stay (5 days vs. 6 days; P less than .01), and had a shorter length of intravenous antibiotic treatment ( 3 days vs. 4 days; P less than .05). The same researchers followed up the study cohort a year later to see if there was any difference in relapse between the steroid- and placebo-treated patients.3 There was no statistically significant difference in relapse (six patients treated with prednisolone relapsed, compared with 13 who received placebo). Solomon et al. did a retrospective study of patients admitted with erysipelas/cellulitis over a 7-year period.4 The control group was defined as patients who received antibiotics but did not receive prednisone, while the other patients in the study received both antibiotics and prednisone. The patients who received antibiotics and prednisone had more severe cellulitis (most had bullous cellulitis) than the patients in the control group. Long-term follow-up showed a higher incidence of erythema and recurrence of cellulitis in the control group. The return to full function was faster in the prednisone-treated patients than in the control group.



Back to the case. Which of the following is most important to do for this patient to help prevent future episodes of cellulitis?

A. Daily penicillin.

B. Treatment of tinea pedis.

C. Hydrochlorothiazide treatment for leg edema.

D. Topical triamcinolone treatment of dry skin on legs.



The correct answer here is treatment of concurrent tinea pedis infection. Antibiotic prophylaxis is considered in patients who have multiple recurrent episodes. This patient’s unilateral edema is most likely attributable to the cellulitis and should resolve with therapy, so diuretics would not be indicated. Risk factors for recurrent cellulitis are tinea pedis, obesity, venous insufficiency, and lymphedema.5

 

 

Concheiro and colleagues did a retrospective study of 122 cases of cellulitis and found tinea pedis in 33% of the cases.6 Muller et al. studied the importance of toe web microorganisms and erysipelas and found that the presence of interdigital tinea pedis was correlated with recurrent infection.7 Treatment of tinea pedis is an easily modifiable risk factor in patients with recurrent cellulitis.

Pearls: Consider adding a short course of steroids in patients with more severe erysipelas/cellulitis, as it can decrease hospital stay and IV antibiotics.

Look for tinea pedis and treat if present in patients who have erysipelas/cellulitis.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].

References

1. Arch Intern Med. 2008 May 26;168(10):1034-46.

2. Scand J Infect Dis 1997;29(4):377-82.

3. Scand J Infect Dis. 1998;30(2):206-7.

4. Isr Med Assoc J. 2018 Mar;20(3):137-40.

5. J Dtsch Dermatol Ges. 2004 Feb;2(2):89-95.

6. Actas Dermosifiliogr. 2009 Dec;100(10):888-94.

7. J Dtsch Dermatol Ges. 2014 Aug;12(8):691-5.

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Author(s)
Douglas S. Paauw, MD
Author(s)
Douglas S. Paauw, MD

A 38-year-old man is admitted to the hospital with a painful, swollen left leg. This was not the first instance of this kind for him. He had been admitted for the same problem 3 months earlier. During the earlier admission, he was diagnosed with cellulitis and treated with intravenous cefazolin for 4 days, then discharged on cephalexin with resolution of his swelling and pain. Today, his blood pressure is 120/70, pulse is 90, temperature is 38.2°C, his left leg is edematous from the mid-calf to the ankle, and he has erythema and warmth over the calf. His white blood cell count is 13,000, and a diagnosis of cellulitis is made. Which of the following treatments is most likely to shorten his hospital stay?

Dr. Paauw


A. Vancomycin therapy instead of cefazolin.

B. Piperacillin/tazobactam therapy instead of cefazolin.

C. Prednisolone therapy in addition to antibiotics.

D. Furosemide therapy in addition to antibiotics.

The correct answer is C, prednisolone therapy in addition to antibiotics. Corticosteroids have been used as therapy for a number of infectious diseases, and steroid use has been shown to improve survival in patients with bacterial meningitis, tuberculous meningitis, tuberculous pericarditis, severe typhoid fever, tetanus, or pneumocystis pneumonia with moderate to severe hypoxemia.1 Corticosteroid use in many other infections has been studied, and for many infections, symptomatic benefit has been shown. Berkvist and Sjobeck studied 112 patients admitted to the hospital with lower-extremity erysipelas/cellulitis and randomized the patients to receive prednisolone or placebo in addition to antibiotic treatment.2 The prednisolone-treated patients had a shorter hospital stay (5 days vs. 6 days; P less than .01), and had a shorter length of intravenous antibiotic treatment ( 3 days vs. 4 days; P less than .05). The same researchers followed up the study cohort a year later to see if there was any difference in relapse between the steroid- and placebo-treated patients.3 There was no statistically significant difference in relapse (six patients treated with prednisolone relapsed, compared with 13 who received placebo). Solomon et al. did a retrospective study of patients admitted with erysipelas/cellulitis over a 7-year period.4 The control group was defined as patients who received antibiotics but did not receive prednisone, while the other patients in the study received both antibiotics and prednisone. The patients who received antibiotics and prednisone had more severe cellulitis (most had bullous cellulitis) than the patients in the control group. Long-term follow-up showed a higher incidence of erythema and recurrence of cellulitis in the control group. The return to full function was faster in the prednisone-treated patients than in the control group.



Back to the case. Which of the following is most important to do for this patient to help prevent future episodes of cellulitis?

A. Daily penicillin.

B. Treatment of tinea pedis.

C. Hydrochlorothiazide treatment for leg edema.

D. Topical triamcinolone treatment of dry skin on legs.



The correct answer here is treatment of concurrent tinea pedis infection. Antibiotic prophylaxis is considered in patients who have multiple recurrent episodes. This patient’s unilateral edema is most likely attributable to the cellulitis and should resolve with therapy, so diuretics would not be indicated. Risk factors for recurrent cellulitis are tinea pedis, obesity, venous insufficiency, and lymphedema.5

 

 

Concheiro and colleagues did a retrospective study of 122 cases of cellulitis and found tinea pedis in 33% of the cases.6 Muller et al. studied the importance of toe web microorganisms and erysipelas and found that the presence of interdigital tinea pedis was correlated with recurrent infection.7 Treatment of tinea pedis is an easily modifiable risk factor in patients with recurrent cellulitis.

Pearls: Consider adding a short course of steroids in patients with more severe erysipelas/cellulitis, as it can decrease hospital stay and IV antibiotics.

Look for tinea pedis and treat if present in patients who have erysipelas/cellulitis.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].

References

1. Arch Intern Med. 2008 May 26;168(10):1034-46.

2. Scand J Infect Dis 1997;29(4):377-82.

3. Scand J Infect Dis. 1998;30(2):206-7.

4. Isr Med Assoc J. 2018 Mar;20(3):137-40.

5. J Dtsch Dermatol Ges. 2004 Feb;2(2):89-95.

6. Actas Dermosifiliogr. 2009 Dec;100(10):888-94.

7. J Dtsch Dermatol Ges. 2014 Aug;12(8):691-5.

A 38-year-old man is admitted to the hospital with a painful, swollen left leg. This was not the first instance of this kind for him. He had been admitted for the same problem 3 months earlier. During the earlier admission, he was diagnosed with cellulitis and treated with intravenous cefazolin for 4 days, then discharged on cephalexin with resolution of his swelling and pain. Today, his blood pressure is 120/70, pulse is 90, temperature is 38.2°C, his left leg is edematous from the mid-calf to the ankle, and he has erythema and warmth over the calf. His white blood cell count is 13,000, and a diagnosis of cellulitis is made. Which of the following treatments is most likely to shorten his hospital stay?

Dr. Paauw


A. Vancomycin therapy instead of cefazolin.

B. Piperacillin/tazobactam therapy instead of cefazolin.

C. Prednisolone therapy in addition to antibiotics.

D. Furosemide therapy in addition to antibiotics.

The correct answer is C, prednisolone therapy in addition to antibiotics. Corticosteroids have been used as therapy for a number of infectious diseases, and steroid use has been shown to improve survival in patients with bacterial meningitis, tuberculous meningitis, tuberculous pericarditis, severe typhoid fever, tetanus, or pneumocystis pneumonia with moderate to severe hypoxemia.1 Corticosteroid use in many other infections has been studied, and for many infections, symptomatic benefit has been shown. Berkvist and Sjobeck studied 112 patients admitted to the hospital with lower-extremity erysipelas/cellulitis and randomized the patients to receive prednisolone or placebo in addition to antibiotic treatment.2 The prednisolone-treated patients had a shorter hospital stay (5 days vs. 6 days; P less than .01), and had a shorter length of intravenous antibiotic treatment ( 3 days vs. 4 days; P less than .05). The same researchers followed up the study cohort a year later to see if there was any difference in relapse between the steroid- and placebo-treated patients.3 There was no statistically significant difference in relapse (six patients treated with prednisolone relapsed, compared with 13 who received placebo). Solomon et al. did a retrospective study of patients admitted with erysipelas/cellulitis over a 7-year period.4 The control group was defined as patients who received antibiotics but did not receive prednisone, while the other patients in the study received both antibiotics and prednisone. The patients who received antibiotics and prednisone had more severe cellulitis (most had bullous cellulitis) than the patients in the control group. Long-term follow-up showed a higher incidence of erythema and recurrence of cellulitis in the control group. The return to full function was faster in the prednisone-treated patients than in the control group.



Back to the case. Which of the following is most important to do for this patient to help prevent future episodes of cellulitis?

A. Daily penicillin.

B. Treatment of tinea pedis.

C. Hydrochlorothiazide treatment for leg edema.

D. Topical triamcinolone treatment of dry skin on legs.



The correct answer here is treatment of concurrent tinea pedis infection. Antibiotic prophylaxis is considered in patients who have multiple recurrent episodes. This patient’s unilateral edema is most likely attributable to the cellulitis and should resolve with therapy, so diuretics would not be indicated. Risk factors for recurrent cellulitis are tinea pedis, obesity, venous insufficiency, and lymphedema.5

 

 

Concheiro and colleagues did a retrospective study of 122 cases of cellulitis and found tinea pedis in 33% of the cases.6 Muller et al. studied the importance of toe web microorganisms and erysipelas and found that the presence of interdigital tinea pedis was correlated with recurrent infection.7 Treatment of tinea pedis is an easily modifiable risk factor in patients with recurrent cellulitis.

Pearls: Consider adding a short course of steroids in patients with more severe erysipelas/cellulitis, as it can decrease hospital stay and IV antibiotics.

Look for tinea pedis and treat if present in patients who have erysipelas/cellulitis.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].

References

1. Arch Intern Med. 2008 May 26;168(10):1034-46.

2. Scand J Infect Dis 1997;29(4):377-82.

3. Scand J Infect Dis. 1998;30(2):206-7.

4. Isr Med Assoc J. 2018 Mar;20(3):137-40.

5. J Dtsch Dermatol Ges. 2004 Feb;2(2):89-95.

6. Actas Dermosifiliogr. 2009 Dec;100(10):888-94.

7. J Dtsch Dermatol Ges. 2014 Aug;12(8):691-5.

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Artesunate to become first-line malaria treatment in U.S.

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Changed
Fri, 03/29/2019 - 12:07
Author(s)
Lucas Franki

Starting April 1, 2019, intravenous artesunate will become the first-line treatment for malaria in the United States, following the discontinuation of quinidine, the only Food and Drug Administration–approved intravenous drug for severe malaria treatment.

Although artesunate is not approved or commercially available in the United States, it is recommended by the World Health Organization. The Centers for Disease Control and Prevention have made the drug available through an expanded use investigational new drug protocol, an FDA regulatory mechanism. Clinicians can obtain the medication through the CDC’s Malaria Hotline (770-488-7788); artesunate will be stocked at 10 quarantine stations and will be released to hospitals free of charge, according to a CDC announcement.

Clinical trials have illustrated that intravenous artesunate is safe, well tolerated, and can be administered even to infants, children, and pregnant women in the second and third trimester.

About 1,700 cases of malaria are reported in the United States per year, 300 of which are classified as severe. The CDC believes the supply of artesunate obtained will be sufficient to treat all cases of severe malaria in the country, according to a CDC press release.

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Lucas Franki
Author(s)
Lucas Franki

Starting April 1, 2019, intravenous artesunate will become the first-line treatment for malaria in the United States, following the discontinuation of quinidine, the only Food and Drug Administration–approved intravenous drug for severe malaria treatment.

Although artesunate is not approved or commercially available in the United States, it is recommended by the World Health Organization. The Centers for Disease Control and Prevention have made the drug available through an expanded use investigational new drug protocol, an FDA regulatory mechanism. Clinicians can obtain the medication through the CDC’s Malaria Hotline (770-488-7788); artesunate will be stocked at 10 quarantine stations and will be released to hospitals free of charge, according to a CDC announcement.

Clinical trials have illustrated that intravenous artesunate is safe, well tolerated, and can be administered even to infants, children, and pregnant women in the second and third trimester.

About 1,700 cases of malaria are reported in the United States per year, 300 of which are classified as severe. The CDC believes the supply of artesunate obtained will be sufficient to treat all cases of severe malaria in the country, according to a CDC press release.

Starting April 1, 2019, intravenous artesunate will become the first-line treatment for malaria in the United States, following the discontinuation of quinidine, the only Food and Drug Administration–approved intravenous drug for severe malaria treatment.

Although artesunate is not approved or commercially available in the United States, it is recommended by the World Health Organization. The Centers for Disease Control and Prevention have made the drug available through an expanded use investigational new drug protocol, an FDA regulatory mechanism. Clinicians can obtain the medication through the CDC’s Malaria Hotline (770-488-7788); artesunate will be stocked at 10 quarantine stations and will be released to hospitals free of charge, according to a CDC announcement.

Clinical trials have illustrated that intravenous artesunate is safe, well tolerated, and can be administered even to infants, children, and pregnant women in the second and third trimester.

About 1,700 cases of malaria are reported in the United States per year, 300 of which are classified as severe. The CDC believes the supply of artesunate obtained will be sufficient to treat all cases of severe malaria in the country, according to a CDC press release.

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One HCV infection leads to another in HIV+ MSM

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Changed
Fri, 03/29/2019 - 17:00
Author(s)
M. Alexander Otto

 

SEATTLE – Once HIV positive men who have sex with men contract the hepatitis C virus, they are more likely to get it again, according a study of 305 men in New York.

Wikimedia Commons/BruceBlaus
A hepatitis C virus is shown.

Overall, 38 men (12%) picked up another HCV infection a median of 1.9 years after clearance of their first, yielding a reinfection rate was 4.4/100 person-years, “a solid seven times higher than the primary infection rate” among HIV-positive men who have sex with men (MSM), said senior investigator Daniel Fierer, MD, an associate professor of infectious diseases at Mount Sinai Hospital, New York.

Thirty-three men cleared their second infection. Of those, six picked up a third infection at a median of 1.1 years, yielding an overall third infection incidence of 8.7/100 person-years.

The results held no matter how the men cleared HCV, whether spontaneously, as in about 10%, or by interferon before 2013, and direct-acting antivirals (DAAs) after.

Most reinfections occurred within 2 years of initial clearance, but some occurred more than a decade later.

The results suggest that there’s a particular need for HCV prevention efforts among men who have previously cleared the infection. For those patients, testing for HCV at an annual HIV checkup might not be frequent enough, Dr. Fierer said at the Conference on Retroviruses and Opportunistic Infections.

“Long-term surveillance is warranted for all HIV-infected MSM after clearance of HCV infection. Further, strategies to reduce HCV reinfections are needed to meet the goal of eliminating HCV in these men,” he said.

Also, “the large difference between primary” and secondary infection “rates suggests HCV risk is not distributed evenly between HIV-infected MSM, but concentrated among a small subpopulation. By definition, this subpopulation would have a higher prevalence” of risky behavior, such as condomless receptive anal sex and sexualized injection methamphetamine use, he said.

The high reinfection rate “tells us basically that we have not done a good job of” preventing infection and reinfection among at risk, HIV-positive men. There’s an “inadequate level of HCV treatment ... we need to eliminate restrictions on DAA” access, Dr. Fierer said.

As far as prevention goes, “I believe we just don’t know what to do. I tell all of my patients about the body fluids that have HCV in them,” which is a good start, he said.

The median age at first clearance was about 45 years, 82% of the men were white, and there was about a 50-50 split between people with private and public insurance.

The work was funded by Gilead. Dr. Fierer did not mention any disclosures.

SOURCE: Carollo JR et al. CROI 2019, Abstract 86

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M. Alexander Otto
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M. Alexander Otto
Meeting/Event
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Meeting/Event
TBD Meeting (2893-19)

 

SEATTLE – Once HIV positive men who have sex with men contract the hepatitis C virus, they are more likely to get it again, according a study of 305 men in New York.

Wikimedia Commons/BruceBlaus
A hepatitis C virus is shown.

Overall, 38 men (12%) picked up another HCV infection a median of 1.9 years after clearance of their first, yielding a reinfection rate was 4.4/100 person-years, “a solid seven times higher than the primary infection rate” among HIV-positive men who have sex with men (MSM), said senior investigator Daniel Fierer, MD, an associate professor of infectious diseases at Mount Sinai Hospital, New York.

Thirty-three men cleared their second infection. Of those, six picked up a third infection at a median of 1.1 years, yielding an overall third infection incidence of 8.7/100 person-years.

The results held no matter how the men cleared HCV, whether spontaneously, as in about 10%, or by interferon before 2013, and direct-acting antivirals (DAAs) after.

Most reinfections occurred within 2 years of initial clearance, but some occurred more than a decade later.

The results suggest that there’s a particular need for HCV prevention efforts among men who have previously cleared the infection. For those patients, testing for HCV at an annual HIV checkup might not be frequent enough, Dr. Fierer said at the Conference on Retroviruses and Opportunistic Infections.

“Long-term surveillance is warranted for all HIV-infected MSM after clearance of HCV infection. Further, strategies to reduce HCV reinfections are needed to meet the goal of eliminating HCV in these men,” he said.

Also, “the large difference between primary” and secondary infection “rates suggests HCV risk is not distributed evenly between HIV-infected MSM, but concentrated among a small subpopulation. By definition, this subpopulation would have a higher prevalence” of risky behavior, such as condomless receptive anal sex and sexualized injection methamphetamine use, he said.

The high reinfection rate “tells us basically that we have not done a good job of” preventing infection and reinfection among at risk, HIV-positive men. There’s an “inadequate level of HCV treatment ... we need to eliminate restrictions on DAA” access, Dr. Fierer said.

As far as prevention goes, “I believe we just don’t know what to do. I tell all of my patients about the body fluids that have HCV in them,” which is a good start, he said.

The median age at first clearance was about 45 years, 82% of the men were white, and there was about a 50-50 split between people with private and public insurance.

The work was funded by Gilead. Dr. Fierer did not mention any disclosures.

SOURCE: Carollo JR et al. CROI 2019, Abstract 86

 

SEATTLE – Once HIV positive men who have sex with men contract the hepatitis C virus, they are more likely to get it again, according a study of 305 men in New York.

Wikimedia Commons/BruceBlaus
A hepatitis C virus is shown.

Overall, 38 men (12%) picked up another HCV infection a median of 1.9 years after clearance of their first, yielding a reinfection rate was 4.4/100 person-years, “a solid seven times higher than the primary infection rate” among HIV-positive men who have sex with men (MSM), said senior investigator Daniel Fierer, MD, an associate professor of infectious diseases at Mount Sinai Hospital, New York.

Thirty-three men cleared their second infection. Of those, six picked up a third infection at a median of 1.1 years, yielding an overall third infection incidence of 8.7/100 person-years.

The results held no matter how the men cleared HCV, whether spontaneously, as in about 10%, or by interferon before 2013, and direct-acting antivirals (DAAs) after.

Most reinfections occurred within 2 years of initial clearance, but some occurred more than a decade later.

The results suggest that there’s a particular need for HCV prevention efforts among men who have previously cleared the infection. For those patients, testing for HCV at an annual HIV checkup might not be frequent enough, Dr. Fierer said at the Conference on Retroviruses and Opportunistic Infections.

“Long-term surveillance is warranted for all HIV-infected MSM after clearance of HCV infection. Further, strategies to reduce HCV reinfections are needed to meet the goal of eliminating HCV in these men,” he said.

Also, “the large difference between primary” and secondary infection “rates suggests HCV risk is not distributed evenly between HIV-infected MSM, but concentrated among a small subpopulation. By definition, this subpopulation would have a higher prevalence” of risky behavior, such as condomless receptive anal sex and sexualized injection methamphetamine use, he said.

The high reinfection rate “tells us basically that we have not done a good job of” preventing infection and reinfection among at risk, HIV-positive men. There’s an “inadequate level of HCV treatment ... we need to eliminate restrictions on DAA” access, Dr. Fierer said.

As far as prevention goes, “I believe we just don’t know what to do. I tell all of my patients about the body fluids that have HCV in them,” which is a good start, he said.

The median age at first clearance was about 45 years, 82% of the men were white, and there was about a 50-50 split between people with private and public insurance.

The work was funded by Gilead. Dr. Fierer did not mention any disclosures.

SOURCE: Carollo JR et al. CROI 2019, Abstract 86

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AAP updates 2019-2020 flu vaccine recommendations to include nasal spray

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Changed
Thu, 03/28/2019 - 13:07
Author(s)
Christopher Palmer

Although the American Academy of Pediatrics had cited a preference for injected flu vaccines for children during the 2018-2019 flu season, this year’s recommendations say either that or the nasal spray formulation are acceptable, according to a press release. The Centers for Disease Control and Prevention has given similar guidance.

Louise A. Koenig/MDedge News

Because the spray did not work as well against A/H1N1 as the injected vaccine had during the 2013-2014 and 2014-2015 seasons, the AAP did not recommend the spray during the 2015-2016 and 2016-2017 seasons. However, in 2017 the spray’s manufacturer included a new strain of A/H1N1, and new data has supported the spray’s effectiveness against some strains.

The AAP recommends all children aged 6 months and older should be vaccinated, but the flu nasal spray is approved only for nonpregnant patients aged 2-49 years, according to the CDC. That said, the spray is especially appropriate for patients who refuse to receive the injected form, so the choice of formulation is at the pediatrician’s discretion, according to the AAP release.

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Christopher Palmer
Author(s)
Christopher Palmer

Although the American Academy of Pediatrics had cited a preference for injected flu vaccines for children during the 2018-2019 flu season, this year’s recommendations say either that or the nasal spray formulation are acceptable, according to a press release. The Centers for Disease Control and Prevention has given similar guidance.

Louise A. Koenig/MDedge News

Because the spray did not work as well against A/H1N1 as the injected vaccine had during the 2013-2014 and 2014-2015 seasons, the AAP did not recommend the spray during the 2015-2016 and 2016-2017 seasons. However, in 2017 the spray’s manufacturer included a new strain of A/H1N1, and new data has supported the spray’s effectiveness against some strains.

The AAP recommends all children aged 6 months and older should be vaccinated, but the flu nasal spray is approved only for nonpregnant patients aged 2-49 years, according to the CDC. That said, the spray is especially appropriate for patients who refuse to receive the injected form, so the choice of formulation is at the pediatrician’s discretion, according to the AAP release.

Although the American Academy of Pediatrics had cited a preference for injected flu vaccines for children during the 2018-2019 flu season, this year’s recommendations say either that or the nasal spray formulation are acceptable, according to a press release. The Centers for Disease Control and Prevention has given similar guidance.

Louise A. Koenig/MDedge News

Because the spray did not work as well against A/H1N1 as the injected vaccine had during the 2013-2014 and 2014-2015 seasons, the AAP did not recommend the spray during the 2015-2016 and 2016-2017 seasons. However, in 2017 the spray’s manufacturer included a new strain of A/H1N1, and new data has supported the spray’s effectiveness against some strains.

The AAP recommends all children aged 6 months and older should be vaccinated, but the flu nasal spray is approved only for nonpregnant patients aged 2-49 years, according to the CDC. That said, the spray is especially appropriate for patients who refuse to receive the injected form, so the choice of formulation is at the pediatrician’s discretion, according to the AAP release.

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