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The Changing Epidemiology of Clostridium difficile Infection: An Expert Interview With Gonzalo M. Bearman, MD, MPH

Authors: Gonzalo M. Bearman, MD, MPHFaculty and Disclosures

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Editor's Note:

Clostridium difficile infection (CDI) can cause symptoms ranging from diarrhea to life-threatening inflammations of the colon. According to the US Centers for Disease Control and Prevention, C difficile is responsible for tens of thousands of diarrhea cases and at least 5000 deaths each year in the United States.

The bacterium C difficile causes one of the most widespread and serious healthcare-associated infections acquired in a hospital or long-term care facility. Now considered an epidemic, CDI is known to affect approximately 500,000 people in the United States and is responsible for 1 in every 1000 hospital admissions in Europe.

With increases in incidence and severity documented worldwide and the emergence of antimicrobial-resistant and hypervirulent strains, C difficile challenges epidemiologists and clinicans to adhere to prevention, diagnosis, and treatment guidelines. Diagnosis and treatment of C difficile-associated disease, including use of existing and new antibiotic and nonantibiotic agents, are reviewed in the February 5 online first issue of Gut.

Michelle Manzo, MPH, Group Editorial Director for Medscape Infectious Diseases interviewed Gonzalo Bearman, MD, MPH, Assistant Professor of Internal Medicine and Associate Hospital Epidemiologist at Virginia Commonwealth University, Richmond, Virginia, about the evolving epidemiology of CDI and its treatment and control.

Medscape: Why is the severity of CDI increasing?

Dr. Bearman: The severity of C difficile-associated diarrhea (CDAD) is likely increasing due to the appearance of a new hypervirulent strain across Europe and North America. Investigations of hospital outbreaks in Canada, Great Britain, The Netherlands, and the United States have revealed the emergence of a previously uncommon, highly toxigenic strain of C difficile.

The current B1/NAP1 strain is implicated in much of the rising incidence of C difficile. With it is an associated mutation in a critical suppressor gene that downregulates the production of toxins A and B. In the absence of a functional suppressor gene, the organism will hyperproduce toxins A and B, leading to colonic mucosal inflammation and diarrhea.

For example, in a recent outbreak involving multiple hospitals in the province of Quebec, Canada, the incidence of C difficile was 22.5 per 1000 hospital admissions. The attributable mortality was between 6.9% to as high 16.7%. On pulsed-field gel electrophoresis analysis of the isolates, a predominantly clonal, fluoroquinolone-resistant, hypervirulent strain (B1/NAP1) was implicated in the outbreak.

Medscape: How is the epidemiology of CDI shifting?

Dr. Bearman: In addition to the appearance of a hypervirulent strain, many isolates are now showing resistance to fluoroquinolones. This is of epidemiologic importance, especially because quinolone antibiotics are used extensively in both inpatient and ambulatory settings. With broad-spectrum coverage, quinolones are effective in altering the normal colonic flora, paving the way for either colonization with C difficile spores or providing an environment for the germination of already existing spores. The end result is a colonic environment apt for colonization and for the potential germination of C difficile spores. With extensive ongoing use of fluoroquinolones, this selective pressure will likely continue to exist.

Another epidemiologic twist is the appearance of community-onset or community-associated C difficile. Historically, C difficile has been a healthcare system-associated infection, and although this is still largely the case, reports of community-associated C difficile exist. However, there is now an increasing incidence of C difficile-associated diarrhea emerging in an unlikely patient population, that is, young people living in a community setting with few or no comorbidities.

There have been a handful of case reports of severe CDAD in otherwise healthy patients with no significant prior exposure to the healthcare system. Recent studies have suggested that gastric acid suppression may be implicated in community-associated C difficile. Both proton-pump inhibitors and H2-blocker use have been associated with C difficile. The absence of significant acid suppression putatively allows C difficile spores to transform into the vegetative state.

Medscape: What are the current recommendations for hospitals to control infection?

Dr. Bearman: Hand hygiene is the single, most important intervention for the control of C difficile in the hospital. Hand hygiene limits the cross-transmission of C difficile from patient to patient or from the inanimate environment to the patient via the hands of the healthcare worker. There is now evidence to suggest that popularly used alcohol-based sanitizers may be insufficient to halt the cross-transmission of C difficile spores. Although these agents are germicidal, they are ineffective in killing C difficile spores. For patients with known or suspected C difficile, handwashing with antimicrobial soap and water is the preferred method of hand hygiene.

Unlike multidrug-resistant pathogens, such as MRSA [methicillin-resistant Staphylococcus aureus] or VRE [vancomycin-resistant Enterococcus], active surveillance cultures or screening of patients for C difficile is not routinely done. C difficile is cultured in the stools of 3% of healthy adults and up to 80% of babies. Additionally, only a minority of colonized patients ever develop diarrhea or colitis. Eradication of the carrier state with antibiotics is not generally effective.

Other strategies for controlling C difficile include antibiotic restriction. There are multiple studies supporting the restriction of clindamycin and third-generation cephalosporins for the control of C difficile in the hospital. As newer strains appear to be resistant to fluoroquinolones, class restriction of this antibiotic would be necessary for adequate control. Lastly, the importance of environmental contamination with C difficile spores cannot be overlooked. All touchable surfaces and all equipment in the room should be cleaned thoroughly at the time of patient discharge using a hospital-approved disinfectant. Sodium hypochlorite (bleach) is preferred over quaternary ammonium products. The goal is decontamination of the inanimate environment.

The triple threat to control C difficile is hand hygiene, antibiotic restriction, and environmental decontamination. With these interventions there is a resultant decrease in colonization pressure, environmental contamination, and cross-transmission.

Medscape: What is known about the burden of disease of CDI in the intensive care unit (ICU) setting?

Dr. Bearman: Although C difficile is not exclusively limited to the ICU setting, critically ill patients suffer greater morbidity and mortality when they develop CDAD and colitis. Due likely to comorbidities and to the receipt of broad-spectrum antibiotics, as many as 10% of ICU patients can manifest CDAD. Complications, such as pseudomembranous colitis and toxic megacolon, although uncommon, appear to occur in the ICU populations. We recently published a historical cohort study on 58 adults with C difficile occurring in ICUs of our hospital. In this cohort of ICU patients with C difficile, advanced age and increased severity of illness at the onset of infection were independent predictors of death. The inpatient crude mortality was 27%.

Medscape: What are current options and considerations for the treatment of CDI?

Dr. Bearman: For many years, it was believed that metronidazole and vancomycin were essentially equivalent, with respect to efficacy, for the treatment of CDAD. Because metronidazole is cheaper than vancomycin and because it exerts less of a selective pressure for vancomycin-restrictive enterococci, metronidazole has been considered the treatment of choice. A recent head-to-head, prospective, double-blind, placebo-controlled trial compared these 2 agents for the management of CDAD. The outcome of clinical cure was further stratified by disease severity. For mild disease, there was no difference in outcomes between the vancomycin and the metronidazole treatment arms. For severe disease, defined by a point score system based on age, temperature, serum albumin, peripheral white blood cell count within 48 hours of enrollment, and endoscopic evidence of pseudomembranous colitis or treatment in the ICU, the vancomycin treatment group fared significantly better. On the basis of this recent quality study, it is believed that for severe CDAD, vancomycin has become the drug of choice.

Newer agents, such as nitazoxanide and rifaximin, also exist for the treatment of C difficle. Nitazoxanide, an oral antiprotozoal agent, is at least as effective as metronidazole for treating C difficle colitis. Rifaximin is a semisynthetic, rifamycin-based, nonsystemic, poorly absorbed antibiotic. Rifaximin has been shown to cause minimal changes in fecal flora, possibly suppressing the recrudescence of vegetative C difficile growth. Recent data from small studies have suggested that when administered following a course of vancomycin therapy, for patients with recurrent C difficile, rifaximin may be an efficacious treatment option.

The Infectious Diseases Society of America (IDSA) is expected to publish an updated guideline in 2008 for the treatment and management of CDAD.

Medscape: What are some of the risk factors and treatment options for recurrent CDI?

Dr. Bearman: Recurrence of C difficile has become increasingly problematic. Relapse of C difficile occurs in 10% to 50% of patients. This is likely due to the persistence and germination of C difficile spores following antibiotic treatment. However, up to 50% of relapses may be due to reinfection with a new strain of C difficile.

Risk factors appear to be advanced age and prior episodes of C difficile. At the present time, there are no evidence-based guidelines for the treatment of recurrent C difficile. For the first recurrence, a repeat of the initial course of therapy is recommended, either with vancomycin or metroniazole. Another alternative, newer agent is nitazoxanide, an oral antiprotozoal agent with noninferiority status when compared with metronidazole. For subsequent and multiple recurrences, no one therapy has been proven superior. Therapeutic options include dose titration and pulse dosing of vancomycin; vancomycin or metronidazole with a probiotic agent, such as Saccharomyces boulardii; vancomycin plus colestipol, a toxin-binding anion resin; vancomycin and rifaximin; and fecal transplantation. Fecal transplantation, although uncommonly done, is supported by a few case series.

This activity is supported by an independent educational grant from ViroPharma.

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