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May 2009
Vol. 19 No. 5
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IDSA Journal Club
May 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.

The Killer B?  Role of Toxin B in Clostridium difficile Virulence
Reviewed by Christopher J. Graber, MD

In contrast to previous studies, toxin B, rather than toxin A, is essential for the virulence of C. difficile, a finding that has implications for diagnosis, according to a study published in the April 30 issue of Nature.  The investigators constructed isogenic mutant strains of C. difficile with interruptions in the genes for toxins A and B and used a hamster model of colitis to compare the virulence of each mutant strain to wild type.

Western blots demonstrated that no toxin was produced when its gene was interrupted; of note, toxin B mutants produced more toxin A than wild type.  Cytotoxicity assays demonstrated the functionality of either toxin when the other one was mutated.  In the hamster model, the hamsters inoculated and colonized with toxin A mutants had similar outcomes with regard to mortality compared to wild type (94 percent vs. 90 percent), while the hamsters colonized with toxin B mutants had markedly decreased mortality (21 percent).  Fecal pellets from three of the hamsters that died after being colonized with toxin B mutants were analyzed to show that toxin B activity had been restored in all three, likely from the mutant strain at least partially reverting to wild type.  This phenomenon was not seen in the toxin A mutants.

This study contrasts with prior animal studies showing that purified toxin A alone induces pathology and that toxin B is not toxic unless combined with toxin A. This demonstrates the importance of using natural infection models to study the relative impact of toxins on virulence. From a clinical standpoint, this study calls into question diagnostic strategies that rely on detection of toxin A (and not toxin B) activity, as it seems clear that C. difficile strains that only produce toxin B are capable of causing disease.

(Lyras D, et al. Nature 2009; 458:1176-81.)

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Is it Safe to Use Alcohol-based Hand Gel in a Day-care Setting?
Reviewed by Paul Pottinger, MD

Children in day-care centers are at high risk of transmitting and acquiring communicable infections, and alcohol-based hand disinfectants are proven to reduce the risk of many of these infections. However, many child-care centers have not adopted the use of these products because of concerns over ethanol toxicity to children.  It is true that ethanol can be absorbed transcutaneously or via mucous membranes, and this has been described at least twice in exotic circumstances.  But does this happen in common practice? A Finnish study published in the May issue of American Journal of Infection Control suggests that this is unlikely.

In the study, 82 children aged 3-7 years rubbed their hands with either 1.5 ml or 3 ml of 70 percent ethanol gel.  Three independent observers recorded the number of times that children put their fingers into contact with their mouths, noses, or eyes within 15 minutes of applying the gel (average: 2.4 times, peak number: 30).  Each child’s alcohol level was measured using a standard police-issue breath analyzer pre-application and again at 15 and 60 minutes post-application.  All breath alcohol levels were undetectable. 

This study’s major limitations are its relatively small size and its reliance on breath alcohol levels rather than blood levels.  Nevertheless, it demonstrates the likely safety of this technology when applied in a very common setting.  Skeptical parents and day-care workers may still raise concern regarding the toxicity of hand rub when swallowed in significant quantities, but the risk of this happening among average children seems remote.  The implications of this elegant study have the potential to augment hand hygiene practices in a very high-yield setting.

(Kinnula, et al.  Am J Infect Control 2009;37:318-21.)

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A Comprehensive Look at Native Valve Endocarditis: Health Care Contact is a Major Risk Factor
Reviewed by Nina Kim, MD

Nearly half of all health care-associated cases of native valve endocarditis are acquired outside of the hospital, according to a large international cohort study from the May 5 issue of the Annals of Internal Medicine.

This is the largest prospective study on native valve endocarditis (NVE) and emerges from data collected by the International Collaboration on Endocarditis Prospective Cohort Study (ICE-PCS), a global registry of endocarditis from 61 centers in 28 countries. Investigators included only those cases that met definite criteria for NVE according to the modified Duke criteria, with an identified place of acquisition and no history of injected drug use. Cases were considered nosocomial if signs and symptoms of endocarditis developed more than 48 hours after the patient was hospitalized.  Cases were considered health care-associated (HCA) but non-nosocomial if signs and symptoms were present on admission or within the first 48 hours of hospitalization but the patient had extensive out-of-hospital contact with health care interventions (recent hospitalization in past 90 days, residence in nursing home, receipt of hemodialysis, chemotherapy, wound care or intravenous therapy).  The remainder cases were considered community-acquired.

Of the total 1,622 patients who met criteria for definite NVE, 557 (34 percent) were health care-associated NVE and of those, a sizable minority, 254 (46 percent), were thought to have acquired their infection outside of the hospital. Like their nosocomial counterparts, non-nosocomial patients tended to be older and have comorbid conditions such as diabetes or cancer and were more likely to have persistent bacteremia and die than patients with community-acquired NVE. Many of the non-nosocomial HCA cases received hemodialysis (54 percent vs. 9 percent). A substantial proportion – 48 percent of nosocomial and 35 percent of non-nosocomial – of patients had undergone invasive medical procedures such as endoscopy or urologic or vascular manipulations within a few months of symptom onset. Staphylococcus aureus comprised the bulk of HCA cases (45 percent MSSA, 47 percent MRSA). Enterococci were responsible for 15 percent of cases.

Despite the limitations of hospital-based data entry and the potential for misclassification, this study provides an important contemporary examination of native valve endocarditis and emphasizes the emergence of outpatient health care contact as a major risk factor.

(Benito et al., Annals of Internal Medicine 2009; 150:586-594.)

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Telaprevir Shows Promise as Treatment for Hepatitis C
Reviewed by Ed Dominguez, MD

Hepatitis C virus (HCV) infection affects almost 200 million people worldwide. Although therapy is available by combining pegylated-interferon and ribavirin, HCV genotype 1 – the most prevalent genotype in North America and Europe – is associated with sustained virological response (SVR) rates of less than 50 percent after a standard 48-week course of therapy. Phase 2B results of the Protease Inhibition for Viral Evaluation (PROVE) trial reported in the April 30 issue of The New England Journal of Medicine suggest telaprevir may be a useful addition to the protocol for the treatment of individuals with suboptimal response to the standard therapy.

An inhibitor of the NS3/4A HCV protease, telaprevir exhibited potent antiviral activity in Phase 1B trials; however, breakthrough resistance occurred with monotherapy. The PROVE trial is a multicenter randomized, placebo-controlled trial focusing on treatment-naïve individuals and consists of a U.S. arm (PROVE1) and a European arm (PROVE2). PROVE1 was double-blinded and PROVE2 was partially double-blinded. Participants in PROVE1 were randomized into one of four arms: a telaprevir-peginterferon-ribavirin arm for 12 weeks (T12PR12); a 12-week telaprevir plus 48-week peginterferon-ribavirin arm (T12PR48); and a control group of 48-week peginterferon-ribavirin. Participants in PROVE2 did not have the T12PR48 arm but rather a 12-week telaprevir plus 12-week peinterferon without ribavirin arm (T12P12). The primary endpoint for both trials was SVR defined as undetectable viral load 24 weeks after completion of therapy.

In the PROVE1 trial, the T12PR24 and T12PR48 groups displayed SVRs of 61 percent and 67 percent, respectively, while the control group (PR48) had an SVR of 41 percent. In the PROVE2 trial, the T12PR24 group had an SVR of 60 percent compared with the PR48 group, which had an SVR of 46. In both trials, treatment-limiting side effects were rash and pruritus seen particularly in patients receiving telaprevir. Virological breakthrough occurred in 7 percent of telaprevir patients in PROVE1 and in 10 percent in PROVE2.

These results are cautiously encouraging, particularly in light of the suboptimal response to therapy in patients with HCV genotype 1, although neither study evaluated patients with cirrhosis. The optimal duration of therapy with a three-drug regimen remains uncertain, although it does appear that ribavirin is necessary (partly as it may minimize the breakthrough of telaprevir resistance). Investigators in PROVE1 developed a protocol to deal with the telaprevir rash, but unfortunately it was implemented near the end of the trial. Ameliorating this side effect will be imperative as Phase 3 trials are planned.

(McHutchison, et al. N Engl J Med 2009;360:1827-1838 and Hezode, et al. New Engl J Med 2009;360:1839-1850.)

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Bedroom Bat Exposure: Should We Continue to Recommend Prophylaxis for Rabies? 
Reviewed by Sara E. Cosgrove, MD

Current recommendations for rabies prophylaxis after exposure to bats while sleeping should be reconsidered based on the rarity of acquisition of rabies by this route and the magnitude of resources required to provide prophylaxis to this group, according to a study in the June 1 edition of Clinical Infectious Diseases.

The authors calculated the number needed to treat (NNT) to prevent one case of rabies using the following formula: the percentage of the population exposed annually multiplied by the inverse crude incidence of rabies without intervention. They estimated the percentage of the population exposed annually via a random-digit-dial telephone survey in Quebec, Canada, which assessed bat exposure and uptake of post-exposure prophylaxis.  Among 36,445 persons surveyed, five had direct bat contact without a bite, 34 had exposure to a bat in the room while sleeping (bedroom exposure), 41 had exposure to a bat elsewhere in the house with the bedroom door open while sleeping (bedroom access exposure), and 77 had other exposures without direct bat contact. Only two sought post-exposure prophylaxis; both had bedroom exposures.

The authors calculated the incidence of bat-associated rabies by dividing the number of cases with different types of exposure in the U.S. and Canada between 1990 and 2007 by the sum of the populations from each year.  The NNT to prevent one human case of rabies ranged from ~59,000 (direct bat contact) to ~2.7 million (bedroom exposure) persons.  In a sensitivity analysis, the costs to investigate potential exposures were never below 293 professional FTEs and 228,000,000 Canadian dollars.

This study confirms that the practice of post-exposure prophylaxis following bedroom bat exposure is costly and leads to overtreatment.  However, it would be difficult to recommend a change in practice unless formal guidelines are modified, given the emotionally charged response that might result from the perception that potentially life-saving treatment is being withheld.  The data provide reassuring information to patients regarding the low risk of rabies associated with bat exposure.

(De Serres, et al. CID 2009; 48:11, 1493-1499.)

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