McDonald LC, Killgore GE, Thompson A, Owens RC, Kazakova SV, Sambol SP, Johnson S, Gerding DN (Epidemiology and Laboratory Branch, Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia; Departments of Pharmacy and Infectious Diseases, Maine Medical Center, Portland, Maine; College of Medicine, University of Vermont, Burlington, Vermont; and Infectious Disease Section and Research Service, Department of Medicine, Hines Veterans Affairs Hospital, and Loyola University Stritch School of Medicine, Hines, Illinois). An epidemic, toxin gene-variant strain of Clostridium difficile. N Engl J Med 2005;353:2433–2440. Loo VG, Poirier L, Miller MA, Oughton M, Libman MD, Michaud S, Bourgault AM, Nguyen T, Frenette C, Kelly M, Vibien A, Brassard P, Fenn S, Dewar K, Hudson TJ, Horn R, Rene P, Monszak Y, Dascal A (Department of Microbiology, McGill University Health Center, Montreal, Quebec, Canada; Hôpital Maisonneuve-Rosemont; Université de Montréal; Sir Mortimer B. Davis–Jewish General Hospital; St. Mary’s Hospital; Centre Hospitalier Univrsitaire de Montréal Hôpital St. Luc; Hôpital Jean Talon; McGill University and Genome Québec Innovation Center, Montreal; Cité de la Santé de la Laval, Laval, Quebec, Canada; Centre Hospitalier Universitaire de Sherbrooke and Université de Sherbrooke, Sherbrooke, Quebec, Canada; Hôpital Charles LeMoyne, Longueuil, Quebec, Canada; and Réseau Santé Richelieu-Yamaska, St. Hyacinthe, Quebec, Canada). A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality. N Engl J Med 2005; 353:2442–2449.Several reports have highlighted an increased number and severity of Clostridium difficile-associated diarrhea (CDAD) cases over the past several years. A University of Pittsburgh teaching hospital reported a doubling in incident cases from June 1990 through 1999 to 2000 to 2001, with an associated marked increase in severity. Twenty-six patients with severe disease required a colectomy and 18 died. The Centers for Disease Control and Prevention (CDC) has received increased reports of severe CDAD, and collected isolates from 8 health care facilities that had reported outbreaks from 2001 through 2003. Isolates were analyzed either at the CDC or the Hines Veterans Administration Hospital in Chicago, by restriction endonuclease analysis (REA) typing and pulsed-field gel electrophoresis (PFGE) to identify strains and toxinotyping. They also analyzed 2 markers of potentially increased virulence, which were a binary toxin (similar to the iota toxin of C perfringens) produced by some strains and gene deletions in the tcdC gene that could interfere with normal negative feedback of toxin production with subsequent increased toxin production.Antibiotic sensitivity was also tested. In the first article, McDonald et al report that 187 C difficile isolates were collected from 8 health care facilities in which outbreaks of C difficile-associated disease had occurred between 2000 and 2003. The investigators found 96 (51%) were a unique group, REA group BI and PFGE type 1 (NAP1). Thus named BI/NAP1, all isolates were further analyzed and found to have partial deletions in the tcdC gene (the pathogenicity locus gene), that might result in increased production of toxin A and B. They also were found to be >80% related (and most were >90% related), and to be similar to strains in the Hines historical data base. One difference was that resistance to moxifloxacin and gatifloxacin was more common in the BI/NAP1 strains. This previously uncommon strain has been a cause of geographically dispersed outbreaks of CDAD.Since March 2003, many hospitals in Quebec noted an increased incidence of CDAD with an increase in disease severity. In the second article, a prospective study of nosocomial CDAD was conducted in 12 Quebec hospitals to determine the incidence of nosocomial CDAD and its complications. A case-control study was performed to identify patient risk factors for the development of CDAD. Over a 5-month period in 2004, 12 hospitals implemented surveillance programs. Information assessed included patient demographics, 30-day attributable mortality, rates of colectomy, and intensive care unit (ICU) stay. The case-control study used a random sample of 15% of cases in the prospective study, with controls matched for time and site of hospitalization. Ten consecutive stool samples from each hospital were analyzed by PFGE, binary toxin, partial tcdC gene deletion, and antibiotic sensitivity. A total of 1,703 patients were analyzed—30-day mortality was 422 (24.8%), of which C difficile was the attributable cause of death in 117 (6.9 %). One hundred ten required ICU care (5.5%); 33 required colectomy (1.9%).The case-control study group patients were matched for age, gender, ward, and independent risk factors. Case patients were more likely than matched controls to have received fluoroquinolones, cephalosporins, or multiple antibiotics when assessed by multivariate logistic regression analysis, thus serving as important independent risk factors. Of 157 isolates, 129 (82%) had an identical PFGE pattern; 132 (84%) had binary toxin genes and partial deletions in the tcdC gene. Quebec had seen a 4-fold increase in incidence of CDAD and these authors conclude that a single predominating strain was circulating among the Quebec institutions. A major risk factor was exposure to antibiotics, especially fluroquinolones or cephalosporins, but not clindamycin.CommentClostridium difficile is a well-known cause of epidemics, and is the most common cause of nosocomial diarrhea. The first reports were multiple cases in the 1970s associated with the new antibiotics, lincomycin and subsequently clindamycin, both antibiotics with broad-spectrum activity against anaerobic gut flora. Clindamycin was used in the hamster model of pseudomembranous colitis, which led to identification of toxins A and B and subsequent identification of C difficile as the pathogen. Later epidemiologic studies identified nosocomial risk factors, including environmental sources of infection (N Engl J Med 1989;320:204–210).Who gets C difficile and why? It may be more complicated than just blaming antibiotics. We have recognized 3 types of risk factors, but now there may be 4. Recognized risk factors include patient risks, treatment risks, and environmental risks. Individual patient risks include older age, severity of illness, and having gastrointestinal tract disease or surgery. Recently, there has been the recognition of the importance of immune response, specifically the failure to mount a sufficient IgG response to toxin A (N Engl J Med 2000 342:390–397). Treatment risk factors are predominantly antibiotics, especially broad-spectrum antibiotics, with activity against anaerobic flora, but also includes cancer chemotherapy. Environmental risk factors also well known—hospitals and chronic care facilities serve as a reservoir for C difficile and spores.Now we need to add a fourth risk factor—the C difficile strain itself. These 2 papers both report isolation of a unique strain of C difficile from multiple hospitals in 2 countries, the United States and Canada (N Engl J Med 2005;353:2433–2449; N Engl J Med 2005;353:2442–2449). Both studies resulted from recognition of an increased incidence and increased severity of CDAD, earlier in the United States than in Canada, with up to a 4-fold increase in cases and an increased number of ICU stays, colectomies, and deaths. Both papers analyzed specific strains of C difficile and found the predominance of a unique but not new strain—one that produces a binary toxin in addition to toxins A and B (although it is not known if it is pathogenic), and has a gene deletion that allows for increased production of toxins A and B, possibly with resulting increased virulence. Finally, the strain is resistant to newer broad-spectrum quinolones—moxifloxacin and gatifloxacin. As mentioned, this strain was previously uncommon, but is similar to some strains in the Hines Veterans Administration data base of 6,000 C difficile strains collected from 1984 through 1990. One interesting and important difference is that sensitivity to clindamycin was similar, but quinolone resistance was seen only in the newer variant.What are the implications for us as clinicians? First, we need to be evermore vigilant in suspecting CDAD in hospitalized patients, especially in the presence of a markedly elevated WBC count, even without diarrhea, but also in healthy out patients; there has been a striking increase in severe community-acquired CDAD. Diagnostic tests are imperfect, and a high clinical suspicion should prompt immediate treatment with metronidazole or vancomycin, even if diagnostic tests are equivocal or negative. Our hospitals need to have accurate surveillance to recognize epidemics early. We need to practice careful hand washing (and model it for our staff, students, and house officers). Note that soap and water is better to prevent C difficile; alcohol hand gels do not inactivate spores. We need to recognize the limitations of diagnostic tests—the prior gold standard toxin B assay have been largely replaced by enzyme immunoassays for toxins A and/or B. Those that test for both are better. If only toxin A is tested, one may miss 3%–5% of strains with a mutant toxin A.We need to be cautious when using antibiotics. Just as earlier epidemics of clindamycin-resistant C difficile were controlled with limiting use of clindamycin (Ann Intern Med 1998;128:989–995), the current epidemics may need restriction of some fluoroquinolone use.Finally, the increase in disease severity underscores the need for better therapies—especially for severe and recurrent disease. Metronidazole and vancomycin remain cornerstones, but recent reports suggest increasing metronidazole failures. Newer antibiotics are being tested, and nonantibiotic approaches including probiotics, resins, and vaccines are in development. Improved therapies will be welcome. McDonald LC, Killgore GE, Thompson A, Owens RC, Kazakova SV, Sambol SP, Johnson S, Gerding DN (Epidemiology and Laboratory Branch, Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia; Departments of Pharmacy and Infectious Diseases, Maine Medical Center, Portland, Maine; College of Medicine, University of Vermont, Burlington, Vermont; and Infectious Disease Section and Research Service, Department of Medicine, Hines Veterans Affairs Hospital, and Loyola University Stritch School of Medicine, Hines, Illinois). An epidemic, toxin gene-variant strain of Clostridium difficile. N Engl J Med 2005;353:2433–2440. Loo VG, Poirier L, Miller MA, Oughton M, Libman MD, Michaud S, Bourgault AM, Nguyen T, Frenette C, Kelly M, Vibien A, Brassard P, Fenn S, Dewar K, Hudson TJ, Horn R, Rene P, Monszak Y, Dascal A (Department of Microbiology, McGill University Health Center, Montreal, Quebec, Canada; Hôpital Maisonneuve-Rosemont; Université de Montréal; Sir Mortimer B. Davis–Jewish General Hospital; St. Mary’s Hospital; Centre Hospitalier Univrsitaire de Montréal Hôpital St. Luc; Hôpital Jean Talon; McGill University and Genome Québec Innovation Center, Montreal; Cité de la Santé de la Laval, Laval, Quebec, Canada; Centre Hospitalier Universitaire de Sherbrooke and Université de Sherbrooke, Sherbrooke, Quebec, Canada; Hôpital Charles LeMoyne, Longueuil, Quebec, Canada; and Réseau Santé Richelieu-Yamaska, St. Hyacinthe, Quebec, Canada). A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality. N Engl J Med 2005; 353:2442–2449. Several reports have highlighted an increased number and severity of Clostridium difficile-associated diarrhea (CDAD) cases over the past several years. A University of Pittsburgh teaching hospital reported a doubling in incident cases from June 1990 through 1999 to 2000 to 2001, with an associated marked increase in severity. Twenty-six patients with severe disease required a colectomy and 18 died. The Centers for Disease Control and Prevention (CDC) has received increased reports of severe CDAD, and collected isolates from 8 health care facilities that had reported outbreaks from 2001 through 2003. Isolates were analyzed either at the CDC or the Hines Veterans Administration Hospital in Chicago, by restriction endonuclease analysis (REA) typing and pulsed-field gel electrophoresis (PFGE) to identify strains and toxinotyping. They also analyzed 2 markers of potentially increased virulence, which were a binary toxin (similar to the iota toxin of C perfringens) produced by some strains and gene deletions in the tcdC gene that could interfere with normal negative feedback of toxin production with subsequent increased toxin production. Antibiotic sensitivity was also tested. In the first article, McDonald et al report that 187 C difficile isolates were collected from 8 health care facilities in which outbreaks of C difficile-associated disease had occurred between 2000 and 2003. The investigators found 96 (51%) were a unique group, REA group BI and PFGE type 1 (NAP1). Thus named BI/NAP1, all isolates were further analyzed and found to have partial deletions in the tcdC gene (the pathogenicity locus gene), that might result in increased production of toxin A and B. They also were found to be >80% related (and most were >90% related), and to be similar to strains in the Hines historical data base. One difference was that resistance to moxifloxacin and gatifloxacin was more common in the BI/NAP1 strains. This previously uncommon strain has been a cause of geographically dispersed outbreaks of CDAD. Since March 2003, many hospitals in Quebec noted an increased incidence of CDAD with an increase in disease severity. In the second article, a prospective study of nosocomial CDAD was conducted in 12 Quebec hospitals to determine the incidence of nosocomial CDAD and its complications. A case-control study was performed to identify patient risk factors for the development of CDAD. Over a 5-month period in 2004, 12 hospitals implemented surveillance programs. Information assessed included patient demographics, 30-day attributable mortality, rates of colectomy, and intensive care unit (ICU) stay. The case-control study used a random sample of 15% of cases in the prospective study, with controls matched for time and site of hospitalization. Ten consecutive stool samples from each hospital were analyzed by PFGE, binary toxin, partial tcdC gene deletion, and antibiotic sensitivity. A total of 1,703 patients were analyzed—30-day mortality was 422 (24.8%), of which C difficile was the attributable cause of death in 117 (6.9 %). One hundred ten required ICU care (5.5%); 33 required colectomy (1.9%). The case-control study group patients were matched for age, gender, ward, and independent risk factors. Case patients were more likely than matched controls to have received fluoroquinolones, cephalosporins, or multiple antibiotics when assessed by multivariate logistic regression analysis, thus serving as important independent risk factors. Of 157 isolates, 129 (82%) had an identical PFGE pattern; 132 (84%) had binary toxin genes and partial deletions in the tcdC gene. Quebec had seen a 4-fold increase in incidence of CDAD and these authors conclude that a single predominating strain was circulating among the Quebec institutions. A major risk factor was exposure to antibiotics, especially fluroquinolones or cephalosporins, but not clindamycin. CommentClostridium difficile is a well-known cause of epidemics, and is the most common cause of nosocomial diarrhea. The first reports were multiple cases in the 1970s associated with the new antibiotics, lincomycin and subsequently clindamycin, both antibiotics with broad-spectrum activity against anaerobic gut flora. Clindamycin was used in the hamster model of pseudomembranous colitis, which led to identification of toxins A and B and subsequent identification of C difficile as the pathogen. Later epidemiologic studies identified nosocomial risk factors, including environmental sources of infection (N Engl J Med 1989;320:204–210).Who gets C difficile and why? It may be more complicated than just blaming antibiotics. We have recognized 3 types of risk factors, but now there may be 4. Recognized risk factors include patient risks, treatment risks, and environmental risks. Individual patient risks include older age, severity of illness, and having gastrointestinal tract disease or surgery. Recently, there has been the recognition of the importance of immune response, specifically the failure to mount a sufficient IgG response to toxin A (N Engl J Med 2000 342:390–397). Treatment risk factors are predominantly antibiotics, especially broad-spectrum antibiotics, with activity against anaerobic flora, but also includes cancer chemotherapy. Environmental risk factors also well known—hospitals and chronic care facilities serve as a reservoir for C difficile and spores.Now we need to add a fourth risk factor—the C difficile strain itself. These 2 papers both report isolation of a unique strain of C difficile from multiple hospitals in 2 countries, the United States and Canada (N Engl J Med 2005;353:2433–2449; N Engl J Med 2005;353:2442–2449). Both studies resulted from recognition of an increased incidence and increased severity of CDAD, earlier in the United States than in Canada, with up to a 4-fold increase in cases and an increased number of ICU stays, colectomies, and deaths. Both papers analyzed specific strains of C difficile and found the predominance of a unique but not new strain—one that produces a binary toxin in addition to toxins A and B (although it is not known if it is pathogenic), and has a gene deletion that allows for increased production of toxins A and B, possibly with resulting increased virulence. Finally, the strain is resistant to newer broad-spectrum quinolones—moxifloxacin and gatifloxacin. As mentioned, this strain was previously uncommon, but is similar to some strains in the Hines Veterans Administration data base of 6,000 C difficile strains collected from 1984 through 1990. One interesting and important difference is that sensitivity to clindamycin was similar, but quinolone resistance was seen only in the newer variant.What are the implications for us as clinicians? First, we need to be evermore vigilant in suspecting CDAD in hospitalized patients, especially in the presence of a markedly elevated WBC count, even without diarrhea, but also in healthy out patients; there has been a striking increase in severe community-acquired CDAD. Diagnostic tests are imperfect, and a high clinical suspicion should prompt immediate treatment with metronidazole or vancomycin, even if diagnostic tests are equivocal or negative. Our hospitals need to have accurate surveillance to recognize epidemics early. We need to practice careful hand washing (and model it for our staff, students, and house officers). Note that soap and water is better to prevent C difficile; alcohol hand gels do not inactivate spores. We need to recognize the limitations of diagnostic tests—the prior gold standard toxin B assay have been largely replaced by enzyme immunoassays for toxins A and/or B. Those that test for both are better. If only toxin A is tested, one may miss 3%–5% of strains with a mutant toxin A.We need to be cautious when using antibiotics. Just as earlier epidemics of clindamycin-resistant C difficile were controlled with limiting use of clindamycin (Ann Intern Med 1998;128:989–995), the current epidemics may need restriction of some fluoroquinolone use.Finally, the increase in disease severity underscores the need for better therapies—especially for severe and recurrent disease. Metronidazole and vancomycin remain cornerstones, but recent reports suggest increasing metronidazole failures. Newer antibiotics are being tested, and nonantibiotic approaches including probiotics, resins, and vaccines are in development. Improved therapies will be welcome. Clostridium difficile is a well-known cause of epidemics, and is the most common cause of nosocomial diarrhea. The first reports were multiple cases in the 1970s associated with the new antibiotics, lincomycin and subsequently clindamycin, both antibiotics with broad-spectrum activity against anaerobic gut flora. Clindamycin was used in the hamster model of pseudomembranous colitis, which led to identification of toxins A and B and subsequent identification of C difficile as the pathogen. Later epidemiologic studies identified nosocomial risk factors, including environmental sources of infection (N Engl J Med 1989;320:204–210). Who gets C difficile and why? It may be more complicated than just blaming antibiotics. We have recognized 3 types of risk factors, but now there may be 4. Recognized risk factors include patient risks, treatment risks, and environmental risks. Individual patient risks include older age, severity of illness, and having gastrointestinal tract disease or surgery. Recently, there has been the recognition of the importance of immune response, specifically the failure to mount a sufficient IgG response to toxin A (N Engl J Med 2000 342:390–397). Treatment risk factors are predominantly antibiotics, especially broad-spectrum antibiotics, with activity against anaerobic flora, but also includes cancer chemotherapy. Environmental risk factors also well known—hospitals and chronic care facilities serve as a reservoir for C difficile and spores. Now we need to add a fourth risk factor—the C difficile strain itself. These 2 papers both report isolation of a unique strain of C difficile from multiple hospitals in 2 countries, the United States and Canada (N Engl J Med 2005;353:2433–2449; N Engl J Med 2005;353:2442–2449). Both studies resulted from recognition of an increased incidence and increased severity of CDAD, earlier in the United States than in Canada, with up to a 4-fold increase in cases and an increased number of ICU stays, colectomies, and deaths. Both papers analyzed specific strains of C difficile and found the predominance of a unique but not new strain—one that produces a binary toxin in addition to toxins A and B (although it is not known if it is pathogenic), and has a gene deletion that allows for increased production of toxins A and B, possibly with resulting increased virulence. Finally, the strain is resistant to newer broad-spectrum quinolones—moxifloxacin and gatifloxacin. As mentioned, this strain was previously uncommon, but is similar to some strains in the Hines Veterans Administration data base of 6,000 C difficile strains collected from 1984 through 1990. One interesting and important difference is that sensitivity to clindamycin was similar, but quinolone resistance was seen only in the newer variant. What are the implications for us as clinicians? First, we need to be evermore vigilant in suspecting CDAD in hospitalized patients, especially in the presence of a markedly elevated WBC count, even without diarrhea, but also in healthy out patients; there has been a striking increase in severe community-acquired CDAD. Diagnostic tests are imperfect, and a high clinical suspicion should prompt immediate treatment with metronidazole or vancomycin, even if diagnostic tests are equivocal or negative. Our hospitals need to have accurate surveillance to recognize epidemics early. We need to practice careful hand washing (and model it for our staff, students, and house officers). Note that soap and water is better to prevent C difficile; alcohol hand gels do not inactivate spores. We need to recognize the limitations of diagnostic tests—the prior gold standard toxin B assay have been largely replaced by enzyme immunoassays for toxins A and/or B. Those that test for both are better. If only toxin A is tested, one may miss 3%–5% of strains with a mutant toxin A. We need to be cautious when using antibiotics. Just as earlier epidemics of clindamycin-resistant C difficile were controlled with limiting use of clindamycin (Ann Intern Med 1998;128:989–995), the current epidemics may need restriction of some fluoroquinolone use. Finally, the increase in disease severity underscores the need for better therapies—especially for severe and recurrent disease. Metronidazole and vancomycin remain cornerstones, but recent reports suggest increasing metronidazole failures. Newer antibiotics are being tested, and nonantibiotic approaches including probiotics, resins, and vaccines are in development. Improved therapies will be welcome.