What’s New with Clostridium difficile?
Most physicians are familiar with this organism as a cause of antibiotic associated colitis (AAC). Historically, the disease has occurred after the use of antibiotics (usually broad-spectrum) and it usually responded to appropriate treatment, though occasionally it could result in colectomy or death and relapses could be problematic.
More recently, however, both the frequency and the severity of AAC due to Clostridium difficile have increased in North America. The National Nosocomial Infections Surveillance System identified an upward slope in cases from the late 1980s through 2001, with a 26% increase between 2000 and 2001. In a nationwide survey of infectious disease physicians conducted last year, 39% reported seeing patients with an increased severity of AAC.
Two sentinel papers, both published in the December 8, 2005 edition of The New England Journal of Medicine, delineated the increased incidence and severity of the disease and the fundamental changes in the organism that are felt to be responsible. The first paper reported a prospective study in twelve hospitals in Quebec in 2004 and a case control study to identify risk factors for the disease. The authors identified 1703 patients with 1719 episodes of AAC for an incidence of 22.5 per 1000 hospital admissions. The comparison rate was 5.8/1000 admissions in 1997. The mean age of patients with this diagnosis was 73 years. The overall attributable 30-day mortality rate of 6.9% was also higher than previously reported, and this rate was strikingly higher in the elderly (2.6% age<40; 6.2% age 81-90, and 14% age>90). In the case control portion of the report any quinolone and any cephalosporin was associated with a statistically significant risk or acquiring the infection. The authors note, “Use of the newer fluoroquinolones among our patients may have promoted the outbreak of this fluoroquinolone-resistant strain, similar to the epidemic of a clindamycin resistant strain among patients who received clindamycin.”
The second paper reported an analysis of 187 isolates of Clostridium difficile collected from eight healthcare facilities in the United States that were experiencing outbreaks of severe AAC. These isolates were characterized by restriction-endonuclease analysis, pulsed-field-gel electropheresis, and toxinotyping and compared with more than 6000 isolates that had been obtained before 2001. The newer strain has been given various designations based upon the analytical method, but the term “epidemic strain” is used most often. This strain is characterized by a mutation resulting in the deletion of a gene responsible for down regulation of toxin production, resulting in a 16-fold increase in the production of toxin A and a 23-fold increase in the production of toxin B. Additionally, this more virulent strain produces a binary toxin which is similar to a toxin produced by Clostridium perfringens. These changes in the organism are felt to be responsible for its increased virulence. Quinolone resistance was rare in historic strains, but the epidemic strain is universally resistant. This observation led the authors to note that “. . . the increasing use of fluoroquinolones in U.S. health care facilities may have provided a selective advantage for this epidemic strain and promoted its widespread emergence.”
Clostridium difficile associated colitis requires both a “seed” and a “growth facilitator”. The organism is the seed and is transferred from patient to patient on the hands of healthcare workers in hospitals, skilled nursing facilities, dialysis units, etc. Any antibiotic that kills bacteria which would normally actively exert competitive inhibition in the colon is a growth facilitator. Therefore, to prevent AAC, all healthcare workers must be conscientious regarding hand hygiene and isolation precautions, and physicians are urged to consider carefully their antibiotic prescribing habits, especially avoiding the unnecessary use of quinolones. Additionally, timely diagnosis and treatment are important to a good outcome. Physicians should have a low threshold for entertaining the diagnosis in a patient with watery diarrhea, order the appropriate diagnostic test, avoid antimotility agents, discontinue the offending antibiotic, and begin treatment with either metronidazole or oral vancomycin. In severe cases, a multidisciplinary approach may be necessary to determine if a colectomy is necessary as a drastic but potentially life-saving intervention. All cases should be reported to the hospital’s infection control department.