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August 2008
Vol. 18 No. 8
IDSA Journal Club, August 2008

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.

For more from Clinical Infectious Diseases and The Journal of Infectious Diseases, see the "In the IDSA Journals" section of IDSA News.

Plenty of Downsides, Little Upside to Adding Rifampin for Staph Endocarditis
Sara E. Cosgrove, MD, MS

The use of rifampin as adjunctive therapy in the treatment of native valve endocarditis due to Staphylococcus aureus is associated with drug-drug interactions, transaminase elevations, and emergence of rifampin resistance during therapy while not offering clear benefit, according to a study in the July edition of Antimicrobial Agents and Chemotherapy

The authors compared 42 case patients with S. aureus native valve endocarditis who were treated with adjunctive rifampin to 42 control patients who did not receive rifampin.  Three quarters of patients in both groups had methicillin-resistant S. aureus.  The median duration of rifampin therapy was 20 days. Emergence of resistance to rifampin occurred in nine (21 percent) of cases; all were bacteremic when rifampin was initiated.  Elevation of transaminases to five or more times baseline was more common in cases than controls (21 percent vs. 2 percent, p = 0.014); all patients who experienced this side effect had infection with hepatitis C virus.  Fifty-two percent of patients had drug interactions while on rifampin; the implicated agents were methadone, warfarin, protease inhibitors, azole antifungal agents, and phenytoin. 

Cases were more likely to have left-sided endocarditis, had a longer median duration of bacteremia, were more likely to require valve surgery, and had higher mortality, suggesting that they may have had more complicated disease than controls.  Consequently, it is difficult to derive conclusions regarding the efficacy of the addition of rifampin to standard therapy from this study.  Nonetheless, this study demonstrates the important and likely underestimated potential adverse effects of adjunctive rifampin, reminding clinicians of the importance of monitoring hepatic function and assessing for drug interaction when using the agent.  In addition, it suggests that if rifampin is used, it may be optimal to wait until blood cultures have cleared before adding the agent to avoid emergence of resistance. (Riedel et al., Antimicrob Agents Chemother. 2008;52:2463-7.)

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Empirical Fluconazole Not Beneficial in Critically Ill Adults at Risk for Candida
Khalil G. Ghanem, MD

In the intensive care unit (ICU), it is not uncommon for clinicians to consider adding empiric antifungal coverage in patients who are persistently febrile despite being on broad spectrum antibiotics.

In the July 15 issue of Annals of Internal Medicine, Schuster et al. randomized 270 such patients to receive either 800 mg daily of fluconazole or placebo for two weeks. They followed these patients for an additional month after therapy.  A successful outcome was defined as resolution of fever, absence of invasive fungal infection, no discontinuation because of toxicity, and no need for other systemic antifungal medication.

Only about a third of either group had a successful outcome, mainly because fevers did not resolve (51 percent fluconazole vs. 57 percent placebo). Documented invasive candidiasis occurred in 5 percent of fluconazole recipients and 9 percent of placebo recipients (relative risk [RR], 0.57 [95 percent CI, 0.22 to 1.49]). Fifteen percent of patients colonized with Candida species at baseline who received fluconazole developed invasive fungal infection, compared with 25 percent of patients who received placebo (RR, 0.63 [CI, 0.23 to 1.67]).

An important limitation was the relatively small sample size: The rates of invasive fungal infections were lower than what the authors had anticipated. Thus, the authors could not exclude a relative benefit of fluconazole of up to 32 percent, which is clinically significant.

This study suggests that, in general, the empirical use of fluconazole may not provide additional benefit in febrile ICU patients already receiving broad spectrum antimicrobial therapy. However, this study does not address the potential benefits of fluconazole in other patients who are at high risk of candidal infection, such as those colonized with Candida species, receiving total parenteral nutrition, recovering from recent surgery, etc. (Schuster et al., Ann Intern Med. 2008;149:83-90.)

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Two Nucleic Acid Amplification Tests Detect Pharyngeal and Rectal Gonorrhea, Chlamydia
Khalil G. Ghanem, MD

Persons who engage in unprotected receptive oral and anal sex are at increased risk of Neisseria gonorrhoeae (GC) and Chlamydia trachomatis (CT) infections at these sites, but the nucleic acid amplification tests (NAATs) that have revolutionized testing for GC and CT infections of the lower genital tract are not currently FDA-approved for pharyngeal and rectal samples.

In the July issue of Sexually Transmitted Diseases, Schachter et al. evaluated two NAATs, Becton Dickinson's ProbeTec Strand Displacement Assay and Gen-Probe's APTIMA Combo 2 Assay, to detect oral and pharyngeal CT and GC infections in 1,110 men who have sex with men. (Roche's Amplicor CT/NG PCR-based test was abandoned because of poor specificity in detecting oropharyngeal GC infection.) Both tests were superior to culture: Culture was only about 40 percent sensitive to detect rectal and pharyngeal GC, compared to 70-90 percent for the NAATs. Similarly, CT culture was about 30-40 percent sensitive vs. 60-100 percent for NAATs. Specificity of NAATs was greater than 99 percent.

Strikingly, the prevalence of GC and CT infections in the oropharynx and rectum of asymptomatic men was just as high as for symptomatic men. This finding reinforces the importance of testing all persons if exposure has occurred, even those without symptoms.

Despite having a relatively small sample size, this study is important because it highlights the limitation of culture-based methods to detect non-genital GC and CT infections and suggests that some NAATs may be used instead. Since FDA has not yet cleared any of the NAATs for testing on non-genital specimens, laboratories must perform in-house validation studies to use NAATs on rectal and pharyngeal swabs in order to adhere to Clinical Laboratory Improvement Amendments (CLIA) guidelines. (Schachter et al., Sex Transm Dis. 2008;35:637-642.)

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Darunavir as First-line Therapy?
Sabrina Renee Kendrick, MD

Darunavir is generally prescribed for patients with virus resistant to other protease inhibitors. In a study in the July 31 edition of AIDS, darunavir/ritonavir (DRV/r) proved non-inferior to lopinavir/ritonavir (LPV/r) in treatment-naïve HIV-1 infected patients at 48 weeks, with lower incidence of diarrhea and other gastrointestinal side effects,.

Nearly 700 patients with a median CD4 count of 225 cells/ml and mean baseline HIV-1 RNA load of 4.85 log10 copies/ml were randomized in this open-label trial to receive DRV/r 800/100 mg qd or LPV/r 800/200 mg total daily dose (bid or qd) plus fixed-dose tenofovir and emtricitibine.

At 48 weeks, 84 percent of DRV/r and 78 percent of LPV/r patients achieved HIV-1 RNA less than 50 copies/ml (p<0.001), demonstrating non-inferiority between the comparators. Significantly higher response rates were observed with DRV/r in patients with HIV-1 RNA load of at least 100,000 copies/ml (p<0.05).

Gastrointestinal-related adverse events, including moderate-to-severe diarrhea, were less common in the DRV/r group (4 percent vs. 10 percent). Three percent of patients discontinued DRV/r because of adverse events, compared to 7 percent for LPV/r. However, the flexibility in LPV/r dosing across the study sites may limit the findings of gastrointestinal-related adverse events. This potential confounder may need sorting in future analyses.

Although the data offers DRV/r as a safe and effective option, clinicians should note that no changes in the treatment guidelines have been made for treatment-naïve HIV-1 infected patients, and these trials are still ongoing. Stay tuned for further details. (Ortiz et al, AIDS 2008, 22:1389-1397.)

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Risk-Factor Screening Does Not Predict HPV Infection
Jason B. Weinberg, MD

Screening adolescents for risk factors does not predict future infection with human papillomavirus (HPV) and is therefore unlikely to be an adequate strategy for the implementation of catch-up HPV vaccination, according to a study in the July 2008 issue of Pediatrics.

Universal HPV immunization is recommended for all 11- to 12-year old girls. Catch-up vaccination for older adolescents and young adults is also advised, but there are multiple barriers to comprehensive catch-up vaccination. Dempsey and colleagues studied the utility of a risk factor-based approach to HPV catch-up vaccination.

Risk factors were assessed in a large cohort of adolescent females. Sexually active subjects were assessed for previously identified risk factors for HPV infection and HPV-associated disease, while risk factors associated with future sexually transmitted diseases or eventual high-risk sexual behaviors were assessed for subjects who were not sexually active. Several years later, subjects were tested for HPV.

Neither initial adolescent sexual activity status nor assessed risk factors predicted future infection with vaccine-specific HPV types or other HPV types assessed in the study.

These findings suggest that the use of risk factors to identify adolescents and young adults for HPV catch-up vaccination will ultimately not provide adequate protection, because essentially all individuals who become sexually active are at risk. As the authors suggest, comprehensive catch-up vaccination will be more likely to substantially reduce the incidence of HPV infection and HPV-associated cervical carcinoma. Emphasis must therefore be placed on overcoming the logistical and financial barriers to providing universal access to the vaccine. (Dempsey et al., Pediatrics. 2008;122:1-7.)

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