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February 2017
Journal Club

In this feature, a panel of IDSA members identifies and critiques important new studies in the current literature that have a significant impact on the practice of infectious diseases medicine.

Click here for the previous edition of Journal Club. For a review of other recent research in the infectious diseases literature, see "In the Literature," by Stanley Deresinski, MD, in each issue of Clinical Infectious Diseases.

Nephrotoxicity of Vancomycin/Piperacillin-Tazobactam Combination Therapy: Enough Smoke to Be Fire?

Reviewed by Christopher J. Graber, MD, MPH, FIDSA

The combination of vancomycin and piperacillin-tazobactam (V/PT) is one of the most commonly prescribed empiric antibiotic regimens in the inpatient setting. Several retrospective studies have demonstrated increased rates of nephrotoxicity with this combination, but they have been limited by small sample size and residual confounding (particularly when comparing nephrotoxicity among patients receiving V/PT to vancomycin alone). However, two recently published studies, one from Detroit Medical Center in Clinical Infectious Diseases, and one from the University of Kentucky HealthCare system in Antimicrobial Agents and Chemotherapy, while still retrospective, addressed some of these issues, primarily by matching patients receiving V/PT to those receiving a vancomycin/cefepime (V/C) combination.

In the Detroit study, 279 patients from 2011-13 who received at least 48 hours of V/PT were matched 1:1 to patients receiving V/C, based on severity of sepsis, ICU status, duration of therapy, daily dose of vancomycin, and number of concomitant nephrotoxins. Patients with baseline creatinine > 1.2 mg/dL were excluded, and nephrotoxicity was assessed by three different criteria (with similar findings for each). In Cox proportional hazards multivariable analysis controlling for race, gender, admission from home, comorbid conditions, presence of septic shock, baseline WBC, and source of infection, V/PT was independently associated with acute kidney injury (AKI) by RIFLE (Risk, Injury, Failure, Loss, End Stage Renal Disease) criteria: hazard ratio 4.3; 95 percent confidence interval (CI) 2.7-6.7, p<0.0001. Onset of AKI was faster in V/PT patients (median 3 vs. 5 days) and independent of vancomycin trough, while trough-dependent in V/C patients.

In the Kentucky study, 1,633 patients from 2010-14 who received at least 48 hours of V/PT were matched 3:1 to 578 patients receiving V/C according to a nearest neighbor propensity scoring algorithm that included age, gender, comorbidity index, hypotension exposure, number of nephrotoxic exposures, baseline creatinine clearance, and receipt of IV contrast. Patients with baseline creatinine clearance < 30 ml/min or who had AKI before 48 hours were excluded from study. AKI by RIFLE criteria was significantly higher in the V/PT group (21.4 percent vs. 12.5 percent, p<0.0001) and significantly higher according to multivariate logistic regression controlling for vancomycin dose/duration of therapy and specific nephrotoxins (odds ratio 2.18, 95 percent CI 1.64-2.94). Time to AKI was shorter in the V/PT group (median 5 vs. 8 days).

Neither study demonstrated increased mortality in patients receiving V/PT or specifically addressed the causal pathway for increased nephrotoxicity (though the Detroit study’s demonstration of nephrotoxicity of V/PT independent of vancomycin trough deserves further study). However, their similar findings can serve as arrows in the quiver of antimicrobial stewards who work to convince their providers against the routine use of V/PT in patients that do not need it. Whether V/C is an overall preferable alternative to V/PT in patients who need broad coverage remains to be seen.

( Navalkele et al. Clin. Infect. Dis. >2017:64(2):116-123. )

Rutter et al. Antimicrob Agents Chemother. 2017:61(2). pii. e02089-16. )

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Valganciclovir for Cytomegalovirus Prevention in Renal Transplant Patients: Low Dose vs. High Dose

Reviewed by Erica Kaufman West, MD

Current recommendations for cytomegalovirus (CMV) prophylaxis in renal transplant patients reflect the degree of concern for reactivation. Given the high seroprevalence of CMV in the U.S., the majority of patients fall into an “intermediate-risk” group, being donor and recipient positive (D+/R+). For this group, international consensus guidelines recommend high-dose valganciclovir (VGCV) 900 mg by mouth daily for three months after transplant, despite VGCV having no Food and Drug Administration approval for this indication. Some centers are offering low-dose VGCV prophylaxis at 450 mg by mouth daily for three months based on pharmacokinetic data and experience.

A recent paper published in Transplant Infectious Disease looked at the safety and efficacy of those two dosing groups. The primary end point for this retrospective study was CMV disease within 12 months of transplant. Secondary end points included breakthrough CMV infection while on VGCV treatment, ganciclovir-resistant CMV, allograft loss, patient death, opportunistic infections, and new-onset diabetes after transplantation. Baseline group characteristics were similar, except for more low-dose patients having a living donor transplant and more rabbit anti-thymocyte globulin induction. Safety was similar with the low-dose group having less leukopenia, fewer VGCV dose reductions or discontinuations, and less use of granulocyte colony-stimulating factor (G-CSF). There was no difference in developing CMV infection or disease and no difference in biopsy-proven rejection. More patients in the high-dose group had opportunistic infections, but BK virus and herpes infections were similar in both groups.

In this study, the most frequently isolated Candida species was C. albicans (50 percent), followed by C. parapsilosis (25 percent), with various other Candida species compromising the remainder of the cohort. Thirty-day all-cause inpatient mortality was 10.5 percent. CVC retention had a statistically significant association with an increased risk of death on any given day (OR: 3.59). This association remained significant even when adjusting for age and clinical complexity (OR: 2.50).

The authors concluded that low-dose VGCV seems both safe and effective in CMV D+/R+ renal transplant patients. The striking difference in the safety parameters, such as bone marrow suppression and use of G-CSF, was impressive. There was also an improvement in estimated glomerular filtration rate at 12 months in the low-dose group. This paper does give confidence in the low-dose option, although a prospective, blinded, randomized clinical trial would be appreciated.

( Heldenbrand et al. J Transplant Infect Dis. 2016;18:904-912. )

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Important New Data on Cardiovascular Risk in HIV-Infected Persons

Reviewed by Brian R. Wood, MD

Infection with HIV increases risk for cardiovascular events, including myocardial infarction (MI) and stroke, but the exact mechanisms remain unclear. Traditional MI risk factors are more prevalent in persons living with HIV (PLWH), HIV infection likely plays a role, antiretroviral therapy (ART) may contribute, and coinfections are frequent. Risk prediction tools have generally underestimated MI risk in this population, and two recent studies advance our understanding of MI and risk calculators in PLWH. Both were published in JAMA Cardiology and were based on data from a large, multicenter U.S. cohort.

First, in a robust analysis of the 2013 American College of Cardiology/American Heart Association pooled cohort equations (PCEs) in PLWH, investigators analyzed data from 11,288 PLWH (82 percent male, 39 percent black, mean age 41.6, 70 percent taking ART). Several results are notable: 1) MIs were more frequent in black men and women, individuals older than 40, and those not virally suppressed; 2) PCEs discriminated MI risk adequately overall but underperformed for women and black individuals; 3) two separate risk prediction tools that incorporated HIV-specific data like CD4 count, viral load, and ART or protease inhibitor use did not improve MI risk prediction; and 4) PCEs underestimated MI probability for individuals with low-to-moderate risk (less than 10 percent predicted 10-year risk), especially for black men and women. Importantly, this low-to-moderate risk group includes decision thresholds for statins. The study authors and editorialists noted that PCE estimations in this range should be considered minimum risk.

Another intriguing finding was a high rate of type 2 MI (oxygen demand-supply mismatch), as opposed to type 1 (plaque rupture), especially in black men and women. Interestingly, the second analysis, which reviewed 571 cases of definite or probable MI in PLWH, revealed that an astounding 50.4 percent of MIs in PLWH are type 2. The most common causes of type 2 MI were sepsis/bacteremia (34.7 percent), vasospasm from cocaine or other illicit drugs (13.5 percent), and hypertensive emergency (9.7 percent).

The implications are striking: A significant proportion of MIs in PLWH may not be triggered by traditional atherosclerotic risk factors. Therefore, prevention strategies may need to be different than in the general population, with more emphasis on interventions that prevent bacteremia (such pneumococcal or meningococcal vaccination) and addiction treatment services. Perhaps the drastically different etiology is one of the reasons that risk calculators, which are calibrated to traditional risk factors and type 1 MI, perform less well for PLWH. As the authors noted, it may be time to rethink some of these risk-assessment tools, because prevention should match risk.

( Feinstein et al. JAMA Cardiol. 2017;2(2): 155-162. )

( Crane et al. JAMA Cardiol. 2017 Jan 4. )

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Azithromycin Provides No Benefit in Acute Asthma Exacerbations

Reviewed by Manie Beheshti, MD

Both U.S.-based and globally focused guidelines discourage the use of antibiotics for treatment of acute asthma exacerbations. Yet, the overuse of antibiotics in this setting remains prevalent. Some macrolide antibiotics have antiviral and anti-inflammatory properties in addition to their antimicrobial effects. Therefore, they could have theoretical clinical benefit in acute asthma exacerbations.

The AZALEA trial (a randomized, double-blind, placebo-controlled clinical trial) recently published in JAMA Internal Medicine investigated the benefit of adding azithromycin to standard care in adults with acute asthma exacerbations. This multi-center study conducted in the United Kingdom recruited 199 adult patients within 48 hours of an acute asthma exacerbation and randomized them to receive azithromycin 500 mg daily or placebo for three days. All randomized patients had depressed lung function (forced expiratory volume in 1 second less than 80 percent predicted or patient’s best at recruitment) and necessitated oral and/or systemic corticosteroids

The primary outcome was symptom score assessed 10 days after randomization. Secondary outcomes included quality-of-life questionnaires, time to improvement, and lung function. After use of multilevel modeling, analysis showed no statistical or clinical benefit to azithromycin compared to placebo in either primary or secondary outcomes. An astounding finding during patient recruitment in this study was the frequency of antibiotic use: 44.6 percent (2,044) of the over 4,500 screened patients had to be excluded from the study because they had already received antibiotics.

This study adds evidence supporting the lack of benefit in using antibiotics for acute asthma exacerbations, but it perhaps raises the greater issue of antibiotic overuse. In contrast to guideline recommendations, a staggering number of patients with acute asthma exacerbation receive unnecessary antibiotics, further highlighting the global problem of antibiotic misuse. As an excellent accompanying editorial suggests, “the overuse of antibiotics is not a knowledge problem or a diagnostic problem; it is largely a psychological problem.”

( Johnston et al. JAMA Intern Med. 2016;176(11):1630-1637. )

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Reducing Blood Culture Contamination Rates: Chlorhexidine vs. Iodine

Reviewed by Zeina Kanafani, MD, MS

Blood cultures remain the standard of care for the diagnosis of bloodstream infections. However, their specificity has been limited by false positive results due to contamination rates reaching up to 4.8 percent in some studies. Iodine solutions have been traditionally used for local antisepsis to prevent contamination at the site of puncture. Whether chlorhexidine antisepsis would offer any advantage over iodine has not been fully elucidated.

In the Journal of Clinical Microbiology, researchers recently reported the results of a prospective randomized crossover study to evaluate the benefit of skin antisepsis using chlorhexidine compared to tincture of iodine in eight nursing units. Over a one-year period, five nursing units used chlorhexidine and the remaining three used iodine. At the end of each three-month block and for four blocks, each unit switched to the other antiseptic agent. Nursing and clinical care technicians underwent in-service training in aseptic technique, and the venipuncture technique was standardized.

A total of 6,095 blood cultures were obtained, 2,965 using chlorhexidine, and 3,130 using iodine tincture. Of the 667 positive cultures, 238 were considered contaminated (115 with chlorhexidine [3.88 percent] and 123 with iodine tincture [3.93 percent]; p = 1.0). There was also no difference among the two study arms in the distribution of isolated contaminant organisms, with coagulase-negative staphylococci being the most common (77.7 percent). The highest contamination rates were reported from the respiratory care unit (6.6 percent), medical inpatient unit (6.5 percent), and medical intensive care unit (5.2 percent), with no significant differences between the two antisepsis techniques.

Although the study is limited by the lack of periodic direct observation of the phlebotomies and the wide variety of patients, it highlights the fact that chlorhexidine use in skin antisepsis does not offer any advantage over tincture of iodine in preventing the contamination of blood cultures. In most settings, chlorhexidine is more expensive than iodine and is therefore less likely to be cost-effective for this indication.

( Story-Roller and Weinstein. J. Clin. Microbiol. 2016;54(12):3007-3009. )

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For a review of other recent research in the infectious diseases literature, see "In the Literature," by Stanley Deresinski, MD, in each issue of Clinical Infectious Diseases:

February 15

  • Choosing a Hospital Bed—If You Do Not Wish to Develop Clostridium difficile Infection, Be Certain the Prior Occupant Did Not Receive Antibiotics
  • Cryptosporidiosis in Solid Organ Transplant Recipients
  • Cerebrospinal Fluid Lactate and Postneurosurgical Meningitis

February 1

  • Febrile Neutropenia in the Emergency Department: “Guideline? We Don’t Need No Stinkin’ Guideline”
  • The Mycobiome of Nonhealing Diabetic Foot Ulcers
  • Case Vignette: Hemorrhagic nephritis post renal transplantation due to herpes simplex virus


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