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June 2009
Vol. 19 No. 6
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IDSA Journal Club
June 2009

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

Oral Rifampin Plus Trimethoprim-Sulfamethoxazole: A Treatment Option for S. aureus Osteomyelitis?
Reviewed by Sara Cosgrove, MD

Oral rifampin plus trimethoprim-sulfamethoxazole (TMP/SMX) may be an alternative to parenteral anti-staphylococcal penicillins for the treatment of debrided non-axial methicillin susceptible S. aureus osteomyelitis, according to a study published in the June issue of Antimicrobial Agents and Chemotherapy

Fifty patients were enrolled in the study between 1991 and 1996; 22 received cloxacillin parenterally for six weeks followed by oral cloxacillin for two weeks, and 28 received rifampin and TMP/SMX orally for eight weeks. All patients underwent extensive surgical debridement and removal of foreign material when possible (90 percent of the 20 patients with foreign bodies had hardware removed). Patients were followed through April 2007. One patient in each arm of the study was lost to follow up. In the intent to treat analysis, 19 of the 21 evaluable patients who received cloxacillin and 24 of the 27 evaluable patients who received rifampin plus TMP/SMX were cured (90.5 percent and 88.9 percent, respectively). Similar results were noted in the per-protocol analysis. Retained foreign body and incomplete treatment were independent predictors of failure on multivariate analysis.

Because of the small numbers of patients in this single center study, it is difficult to draw definitive conclusions regarding the efficacy of oral rifampin plus TMP/SMX for treatment of osteomyelitis relative to conventional parenteral therapy. Nevertheless, it does provide some evidence that oral therapy with this regimen may be a viable alternative for some patients.  Important caveats are that no patients in the study had methicillin resistant S. aureus, all patients had surgical debridement, and patients with vertebral osteomyelitis were not included.

(Euba et al. Antimicrob Agents Chemother 2009 Jun;53(6):2672-6.)

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Multiple HIV Resistance Mutations Detected in Malawian Patients who Failed First-line Antiretroviral Regimen
Reviewed by Nina Kim, MD

Stavudine, lamivudine and nevirapine (d4T/3TC/NVP) comprise the most widely used first-line antiretroviral therapy (ART) in the developing world today, largely because the generic formulations are among the least expensive. Additionally, many resource-limited settings rely on clinical and immunologic rather than virologic monitoring to assess treatment failure. A study of the Malawian ART program, published in the June issue of AIDS, calls both of these cost-saving practices into question.

More than 150,000 patients have initiated first-line ART through the national ART program in Malawi since 2001. Investigators screened participants from hospitals in Lilongwe and Blantyre over 18 months (2006-2007) and identified 94 patients who experienced ART failure based on clinical (new or progressive stage 4 condition) or immunologic (CD4 cell count decline below baseline or >30 percent decrease from highest value) criteria. These patients had confirmed serum HIV-1 RNA level >1000 copies/mL and samples available for genotyping.

The authors discovered an alarmingly high rate of broad nucleoside reverse transcriptase inhibitor (NRTI) resistance: 81 percent of samples had a 3TC-associated M184V/I mutation, and 56 percent had thymidine-analogue mutations (TAMs), associated with AZT or d4T resistance (72 percent had multiple TAMs). Tenofovir-associated mutations (K65R or K70E) emerged in 24 percent of patients exposed to d4T compared with only 7 percent of those with a history of AZT. Pan-nucleoside resistance mutations occurred in 17 percent of patients. Nearly all (96 percent) patients developed high-grade resistance to non-nucleoside reverse transcriptase inhibitors.

Both the use of d4T in subtype C virus and the delay in detection of virologic failure likely contributed to the accumulation of multiple NRTI mutations. The implications of these data are profound and should inform future World Health Organization guidelines on ART. This study underscores the danger of extrapolating our clinical experience of subtype B HIV-1 to other subtypes.

(Hosseinipour et al. AIDS 2009; 23:1127-1134.)

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Antibiotics for Skin and Soft Tissue Infections in Children in the Age of MRSA: More Questions Than Answers?
Reviewed by Christopher J. Graber, MD, MPH

Trimethoprim-sulfamethoxazole (TMP-SMZ) was associated with a higher rate of treatment failure than either a beta-lactam or clindamycin among pediatric outpatients treated for skin and soft tissue infections (SSTI) that were not drained or cultured, even in a setting where community-associated methicillin-resistant Staphylococcus aureus (MRSA) was endemic, according to a study published in the June issue of Pediatrics. Although the findings may add to concerns that TMP-SMZ does not provide adequate coverage in SSTI caused by group A streptococci, the study should be interpreted with caution.

By using ICD-9 codes for various SSTI, the authors reviewed electronic medical records from January 2004 to March 2007 from the emergency department of a metropolitan children’s hospital and its five affiliated pediatric primary care centers for patients presenting with a new SSTI. The review was limited to those treated with a beta-lactam, clindamycin, or TMP-SMZ, excluding patients who had a drainage procedure, wound culture, or admission on the day of their initial visit.

Among the 2,096 patients that met the criteria, the authors identified 104 cases of treatment failure, defined as eventual hospitalization, drainage procedure, or change of or extension of antibiotic course. Four hundred and eighty treatment successes, roughly matched to the same time period, were randomly selected for comparison. In multivariate models that attempted to adjust for confounding by indication, receipt of TMP-SMZ was associated with an approximately two-fold greater probability of treatment failure as compared to receipt of beta-lactams or clindamycin. Even among patients presenting with induration or abscess, which was also consistently associated with treatment failure, the study found a higher rate of failure with TMP-SMZ.

This study suffers from a number of important limitations, most notably that the retrospective case ascertainment and analysis may not adequately differentiate the broad spectrum of type and severity of outpatient SSTI in the pediatric population. Minor, localized skin infections, such as impetigo, may not require oral antibiotics, and uncomplicated abscesses may only require drainage without antibiotics.

MRSA SSTI are clearly becoming much more common in the pediatric population, as evidenced by a recent study of more than 40 children’s hospitals published in the July 1 issue of Clinical Infectious Diseases. The study showed a steady increase in children hospitalized with MRSA SSTI from 2002 to 2007. Thus, if antibiotics are deemed necessary in the empiric treatment of SSTI in children where S. aureus is a suspected etiologic agent and a culture cannot be performed, anti-MRSA coverage remains warranted pending further studies.    

(Elliott et al. Pediatrics 2009; 123(6):e959-e966 and Gerber et al. CID 2009; 49:65-71.)

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The Use of Intravenous Tigecycline for Severe Refractory C. difficile
Reviewed by Khalil Ghanem, MD, PhD

Intravenous tigecycline may be useful as an alternative or adjunctive therapy for severe refractory Clostridium difficile infection, according to a report published in the June 15 issue of Clinical Infectious Diseases. This conclusion is based on preliminary data from four patients.

C. difficile is a common and potentially life-threatening infection. There are two frequently prescribed antibiotics: Oral or intravenous metronidazole for mild to moderate infections, and oral vancomycin for moderate to severe infections. Most patients respond well to these agents, although relapse is not infrequent. Recently, tigecycline was found to have good in vitro activity against strains of C. difficile, and fecal concentrations of tigecycline were noted to be high.

The authors describe four cases of refractory, not recurrent, C. difficile colitis that did not appear to respond to metronidazole, vancomycin, or both. All cases had four or more clinical severity markers: leukocytosis, renal insufficiency, high lactate levels, hypoalbuminemia, fever, and/or signs of severe colitis. Tigecycline was added as an adjunctive agent in three cases or as an alternate agent (i.e., single agent) in one case. All four patients showed clinical improvement within one week, with no short-term relapses. Stool tigecycline levels were not measured in this study, and given the small sample size, no data on side effects or antibiotic resistance were reported.

Although intriguing, these findings are far from definitive. As such, tigecycline should not be routinely recommended for C. difficile colitis and should not delay other appropriate adjunctive measures, such as surgery, when appropriate. However, given the limited number of alternate agents that are available for severe refractory C. difficile, and given the increasing incidence and severity of this infection, it’s worth keeping tigecycline in mind as an option when other measures have failed.

(Herpers et al. CID 2009;48:1732-35.)

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Vaccine Refusal Associated With Increased Risk for Pertussis Infection
Reviewed by Jason Weinberg, MD

A new report in the May issue of Pediatrics should give pediatricians more data to help counter the increase in parental refusal of childhood vaccinations. Children whose parents refused pertussis immunizations are at increased risk for pertussis infection, according to the study, the first of its kind to identify such a direct link using patient data about vaccination and disease status.

The authors conducted a case-control study of children ages 2 months to 18 years who were enrolled in a Colorado health plan over a 12-year period. Confirmed pertussis cases were selected based on positive PCR or culture results for Bordetella pertussis in conjunction with the presence of ICD-9 codes for B. pertussis. Vaccination status was determined by medical chart review. Children were classified as “vaccine refusers” if it could be determined that their parents had refused one or more pertussis immunizations.

The investigators found that vaccine refusal was strongly associated with pertussis infection, leading to a 23-fold increased risk for pertussis compared to children of parents who accepted pertussis vaccination. The investigators determined that 11 percent of pertussis cases in the study population were attributed to vaccine refusal. Similar findings emerged in a secondary analysis of an additional cohort of patients who were continuously enrolled in the medical plan from ages 2 months to 20 months, reducing the potential for misclassification due to unavailable vaccine records.

The results of this study seem straightforward and intuitive: Unvaccinated children are at increased risk for B. pertussis infection. As the authors point out, however, the study is the first to directly link individual patients’ data on vaccination and disease status in a non-outbreak setting rather than rely on less accurate sources such as school records and census data.

Some important data was potentially missed in the analysis. For instance, unvaccinated children who remained uninfected were not included in the study. However, the results of this study should provide pediatricians with useful data to support their continued efforts to encourage childhood vaccinations, particularly when parental refusal of vaccinations has increased in recent years, and pertussis cases have become more frequent.

(Glanz et al. Pediatrics 2009; 123:1446-51.)

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