Multi-Faceted Approach to Hypervirulent C. difficile Control

Abstract & Commentary

By Robert Muder, MD Hospital Epidemiologist, Pittsburgh VA Medical Center Dr. Muder does research for Aventis and Pharmacia This article originally appeared in the December 2007 issue of Infectious Disease Alert. It was edited by Stan Deresinski, MD, FACP, and peer reviewed by Connie Price, MD. Dr. Deresinski is Clinical Professor of Medicine, Stanford University; Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, and Dr. Price is Assistant Professor, University of Colorado School of Medicine. Dr. Deresinski is on the speaker's bureau for Merck, Pharmacia, GlaxoSmithKline, Pfizer, Bayer, and Wyeth, and does research for Merck. Dr. Price reports no financial relationships relevant to this field of study.

Synopsis: Early identification, coupled with appropriate control measures, reduces the rate of C. difficile infection and the frequency of adverse events.

Source: Muto CA et al. Control of an outbreak of infection with the hypervirulent Clostridium difficile BI strain in a university hospital using a comprehensive "bundle" approach. Clin Infect Dis. 2007;45:1266-1273.

Beginning in 2000, the University of Pittsburgh Medical Center (UPMC) Presbyterian experienced a marked increase in hospital-acquired C. difficile infection, from 2.7 infections per 1000 discharges (0.46 per 1000 patient days) in the two preceding years to 7.2 per 1000 discharges (1.17 per 1000 patients days). Concurrently, there was an increase of severe C. difficile-associated disease, defined as that resulting in colectomy or death from 0.15 cases per 1000 discharges to 0.60 per 100 discharges. REA typing of C. difficile isolates collected in 2001 showed that 51% were of two highly related types. Further testing of these isolates by the CDC showed that they were the hypervirulent BI strain.

Beginning in June 2000, the Infection Control Team, in cooperation with other relevant hospital departments, initiated a series of interventions aimed at reducing C. difficile transmission and use of antimicrobials associated with an increased risk of C. difficile disease. Interventions included institution of a standardized education module, increased case surveillance, and a C. difficile management team that evaluated patients for illness severity and appropriate treatment. Specific infection control measures included environmental cleaning with dilute bleach, electronic alerts, hand hygiene with soap and water, and infection control audits of isolation practices. In addition, the duration of patient isolation was extended from the previous end point of cessation of diarrhea to the duration of hospitalization.

A targeted antimicrobial restriction initiative began in October 2002. The targeted antimicrobials were those that a previous investigation had shown to be associated with increased risk of C. difficile infection in that facility.1 These included fluoroquinolones, ceftriaxone, and clindamycin.

There was a gradual decrease in hospital-acquired C. difficile infection. By 2006, the rate had declined to 3.0 per 1000 hospital discharges (0.46 per 1000 patient days). The rate of severe disease declined dramatically to 0.03 per 1000 hospital discharges. Use of targeted antimicrobials decreased by 54%. In a second survey of C. difficile conducted in 2005, 13.5% contained BI strain.


C. difficile is a common hospital-acquired pathogen that leads to significant morbidity and occasional mortality. There is mounting evidence that the severity of C. difficile disease is increasing, most likely due to an increasing prevalence of a particularly virulent strain, identified as BI. This strain has a gene deletion, leading to hyperproduction of C. difficile toxins A and B. In addition, it produces a novel binary toxin;2 the majority of reported isolates have been resistant to fluoroquinolones. It is likely that both the increasing frequency and severity of C. difficile infection at UPMC-Presbyterian was associated with the introduction of this strain into the medical center, since the majority of stains analyzed in 2001 were of this type. Dissemination of BI strains has been associated with widespread outbreaks of severe C. difficile disease in both the United States2 and Canada3.

The multi-faceted assault on C. difficile reported by Muto and colleagues was followed by both a significant reduction in disease incidence and disease severity. It's likely that control was the result of both the efforts to reduce transmission, such as case identification, isolation, and environmental cleaning, and the control of antimicrobial use.

As with many reports of successful programs directed against hospital-acquired infection, one is not able to assess the relative importance of individual interventions. They were introduced step-wise, and the decrease in C. difficile disease was gradual. However, insistence on purity of study design, during an epidemic in which major surgical procedures or death are potential outcomes, is a luxury that Infection Control programs don't have in the real world.


1. Muto CA, et al. A large outbreak of Clostridium difficile-associated disease with an unexpected proportion of deaths and colectomies at a teaching hospital following increased fluoroquinolone use. Infect Control Hosp Epidemiol. 2005;26:273-280.

2. McDonald LC, et al. An epidemic, toxin gene-variant strain of Clostridium difficile. N Engl J Med. 2005; 353:2433-2441.

3. Loo VG, et al. A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality. N Engl J Med. 2005;353:2442-2449.