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February 2014
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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.

Viral Etiologies of Moderate-to-Severe Influenza-like Illness in the Elderly
Reviewed by Jonathan Li, MD

Influenza-like illnesses (ILI) cause significant morbidity in the elderly, but determining the exact viral etiology can be challenging. In a study mainly performed by GlaxoSmithKline and published in The Journal of Infectious Diseases, investigators evaluated the viral etiology of ILI in patients 65 and older in an international influenza vaccine study.

Study samples were collected through the INFLUENCE65 phase III randomized, controlled influenza vaccine trial. Participants were enrolled from Canada, Mexico, Europe, and Taiwan. An ILI was defined as the combination of at least one respiratory symptom (e.g., nasal congestion, sore throat, cough) and one systemic symptom (e.g., fever, headache, fatigue). Moderate-to-severe ILI was defined as the presence of pneumonia, hospitalization, or an elevated Influenza Symptom Severity score. Nasal and throat swabs were collected, and the presence of 18 viruses and viral subtypes were evaluated by a qualitative multiplex RT-PCR assay. Of 5,389 ILI episodes, 556 episodes of moderate-to-severe ILI from 553 elderly participants met the inclusion criteria and were assessed.

The mean age of participants was 73 years, and 89 percent lived independently. The presence of any virus was found in nearly 58 percent of samples. The most commonly detected virus was influenza A (33 percent), followed by rhinovirus/enterovirus (26 percent), respiratory syncytial virus (RSV) (13 percent), coronavirus (10 percent), and metapneumovirus (10 percent). The median duration of ILI episodes was 15 days. Only a minor subset of participants were hospitalized (12 percent) or were diagnosed with pneumonia (5 percent). While participants with RSV were more likely to be hospitalized, the authors detected no significant differences in the duration of the ILI episodes or pattern of symptoms between viruses. There were no deaths associated with the ILI episodes.

This study opens a window into the underlying viral etiologies of ILI in the elderly, which is a diagnosis that can be difficult to obtain in routine practice. Understanding the relative contribution of each virus to morbidity in this vulnerable population has implications for the targeted development of vaccine and treatment strategies.

(Falsey et al. J Infect Dis. 2014. First published online: Jan 29. doi: 10.1093/infdis/jit839.)

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Trends in Pediatric Antimicrobial Susceptibilities: Which Antibiotic is Best?
Reviewed by Terri Stillwell, MD

It is well known that appropriate empiric antibiotics influence outcomes in patients with infection. Larger health care institutions often benefit from a locally generated antibiogram to help guide these empiric treatment decisions; smaller institutions may not have such readily available resources. A recent article in Infection Control and Hospital Epidemiology attempts to address this issue by creating a national pediatric antibiogram, using existing institution-specific information.

The authors surveyed 233 pediatric institutions, requesting antibiogram data from 2005-2011, and created a national pediatric antibiogram by pooling data from January 2010 to December 2011 submitted by 55 participating institutions. Additionally, region-specific antibiograms were created and resistance trends were assessed over time.

Clinically relevant Gram-negative and Gram-positive organisms were included. The study revealed ampicillin/sulbactam to be inferior to other beta-lactams in its activity against common Gram-negative organisms, whereas carbapenems maintained the highest activity. Cefepime had greater activity than piperacillin/tazobactam for most Gram-negative organisms, except for Pseudomonas, where the reverse was true. (However, the June 2011 Clinical and Laboratory Standards Institute breakpoint changes were not incorporated in this data). In the limited number of institutions reporting extended-spectrum beta-lactamase (ESBL) testing (n=6), 6-8 percent ESBL production was found among Escherichia coli and Klebsiella pneumoniae isolates.

Regarding Gram-positive organisms, 50 percent of Staphylococcus aureus isolates were reported to be methicillin resistant, but maintained a 79 percent susceptibility to clindamycin. Fifty-five percent of Enterococcus faecium were reported to be vancomycin resistant.  

Upon further analysis, some of these trends varied by region. When assessing resistance trends over time, comparing 2005-2006 data to 2010-2011 data, the majority of organisms tested had stable resistance patterns.

Despite some institutional differences and a tendency to include larger academic institutions, the authors provide the first national pediatric-specific antibiogram to aid empiric treatment choices and provide a foundation for future trending of resistance in this patient population.

(Tamma et al. Infect Control Hosp Epidemiol. 2013;34(12):1244-51.

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Generic Antibiotics: Does Bioequivalence Equal Therapeutic Equivalence to the Branded Original?
Reviewed by Christopher J. Bruno, MD

In the U.S., generic antibiotics must show bioequivalence to the branded original by displaying similar potency and pharmacokinetics. Therapeutic equivalence is assumed, but not required to be directly demonstrated. Recent animal model studies have suggested that bioequivalence does not necessarily predict therapeutic equivalence. Two recent studies further investigated this question.

In the first, in the February issue of Antimicrobial Agents and Chemotherapy, researchers compared three generic formulations of meropenem with the branded agent using in vitro susceptibility testing, liquid chromatography/mass spectrometry, and in vivo efficacy in several animal models of infection. The concentration, potency, in vitro susceptibility, and pharmacokinetics were identical for all four formulations. Despite this, two of the generic products were pharmacodynamically inferior in the suppression of pseudomonas in the neutropenic guinea pig soleus infection model, requiring 91 percent (generic A) and 122 percent (generic C) higher doses to achieve comparable bacteriostatic affect.

A potential mechanism for this was suggested by liquid chromatography/mass spectrometry analysis, which revealed structural differences between some of the generics and the branded antibiotic. These differences in chemical structure made the generics less stable at room temperature and more susceptible to hydrolysis by a mammalian metalloenzyme.

In a related article in the February 15 issue of Clinical Infectious Diseases, researchers performed a systematic review of the literature comparing branded and generic antimicrobials. The studies proved too heterogeneous for a meta-analysis, making generalization difficult. However, of the 37 studies reviewed, 14 (37.8 percent) found significant differences between generic and branded antibiotics, although the nature of the differences studied were highly variable, including in vivo efficacy, in vitro activity, and tolerability. Several studies found that despite comparable in vitro antimicrobial effect (as measured by MIC and MBC) generics demonstrated lower Emax (maximum effect in log10 colony-forming units/g) in animal models than the innovator antibiotic.

The evidence was limited regarding clinical efficacy of generics in humans, totaling six studies, including two that showed inferiority of the generic. One was a quasi-experimental study finding higher rates of wound infection after cardiac surgery with use of generic cefuroxime compared to the innovator. The other was a case report of a liver transplant patient with persistent bacteremia on generic vancomycin, which cleared rapidly after he was switched to the branded agent. Several other large, retrospective studies of carbapenems (meropenem or imipenem) for the treatment of serious infections did not find significant differences.

Taken together these studies demonstrate that there may be plausible mechanisms by which a seemingly pharmaceutically equivalent generic may perform differently than its branded alternative in vivo. However, the lack of clinical trial research and the heterogeneity of existing data preclude any definitive conclusions on how this translates to clinical efficacy in humans and what bearing it may have on clinical practice. Based on the wide usage of generics, it would seem further research is urgently needed.

(Agudelo et al. Antimicrob. Agents Chemother. 2014;58(2):1005-1018 and Tattevin et al. Clin Infect Dis. 2014;58(4):458-469.)

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Treatment of Rectal Chlamydia in MSM: Doxycycline over Azithromycin?
Reviewed by Michael T. Melia, MD

More than 50 percent of chlamydia infections among men who have sex with men (MSM) are rectal infections, and an infection prevalence of approximately 8 percent has been reported. While azithromycin and doxycycline achieve equivalent (97-98 percent) cure rates for genital tract chlamydia infections, no prospective trial comparing these two agents for treatment of rectal chlamydia has been performed.

With these data in mind, researchers performed a retrospective analysis of 1,480 men diagnosed with rectal chlamydia at a single STD clinic between 1993 and 2012, the results of which appear in the February issue of Sexually Transmitted Diseases. Subjects were treated within 60 days of diagnosis with either azithromycin 1,000 mg once or doxycycline 100 mg twice daily for seven days; men treated with a second drug active against C. trachomatis were excluded. While tests-of-cure were not specifically recommended, men who returned underwent repeat testing per clinic protocol. More than 70 percent of the men were HIV-negative.

Thirty-four percent of the men underwent repeat testing 14-180 days post-treatment, including 407 (33 percent) of 1,231 azithromycin-treated men and 95 (38 percent) of 249 doxycycline-treated men. Eighty-eight (22 percent) of these azithromycin-treated men and eight (8 percent) of the doxycycline-treated men had persistent or recurrent infection (P = 0.002). In multivariate analysis, azithromycin-treated men had a >5-fold higher risk of persistent or recurrent infection 14-90 days post-treatment and a >2-fold higher risk at 14-180 days.

Several limitations germane to observational, retrospective analyses apply, including possible confounding by indication and incomplete measurement of confounders. Further, not all men underwent repeat testing, some repeat testing was performed soon after completion of therapy (when false-positive results are possible owing to residual, non-viable organisms), and the authors were unable to exclude possible reinfection. With those caveats, these findings are consistent with those from a prior observational study, as well as other observational cohorts.

Bottom line: While available data suggest reasons to prefer doxycycline to azithromycin for rectal chlamydia, a prospective trial is needed.

(Khosropour et al. Sex Transm Dis. 2014;41:79-85.)

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Bleach Baths and Prevention of Recurrent Pediatric SSTI
Reviewed by Ed Dominguez, MD, FIDSA

Staphylococcus aureus is the most common pathogen recovered from patients with recurrent skin and soft tissue infection (SSTI). However, there is no consensus on how best to prevent recurrence. One popular option in children is the “bleach bath”—bathing for 15 minutes in a solution of 5 mL of household bleach per gallon of bath water. Pediatricians evaluated this approach in a prospective, randomized, single-blinded, controlled trial and reported their findings in the March 1 issue of Clinical Infectious Diseases.

Children with suspected S. aureus SSTI presenting to Texas Children’s Hospital between the ages of 3 months and 18 years were screened. Those enrolled were assigned to one of two groups: routine hygienic measures (outlined in a handout given to the caretaker) or twice-weekly bleach baths plus routine hygienic measures for 3 months. Clinical and surveillance cultures were obtained at baseline. Children were followed for 12 months or until the first medically attended SSTI. The median age of the 987 children enrolled was just under 2 years old. Methicillin-resistant S. aureus (MRSA) was isolated from clinical cultures of 67 percent of these children.

Nineteen percent of all children experienced a medically attended SSTI within 12 months: 17 percent (84/495) in the bleach bath group and 21 percent (103/492) in the control group (P = 0.15). The recurrence rate for children initially infected with MRSA did not significantly differ from those with methicillin-susceptible S. aureus (MSSA) (21 percent versus 19 percent). However, recurrence was more likely with multiple sites of colonization (16 percent with no sites versus 30 percent with three sites; P = 0.018) in white compared to African American children (19.6 percent versus 23.9 percent, P = 0.04), and in children ≤1.86 years old (2.1 times greater than that for patients >1.86 years old; P < .0001). No adverse effects of the bath were reported.

Despite a modest 20 percent reduction in recurrence using bleach baths compared to routine hygiene alone, the study’s findings suggest that such baths may provide a safe and inexpensive option for prevention of S. aureus SSTI.

(Kaplan et al. Clin Infect Dis. 2014;58(5):679-682.)

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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

  • Management of Acute Hepatitis C Virus Infection
  • Serotonin Syndrome: Linezolid vs Vancomycin

February 1

  • Encephalitis and Bocavirus?
  • HIV Controllers: Not in Total Control

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