Posted on 12/02/2005 2:11:12 PM PST by neverdem
Recent experience with influenza, the severe acute respiratory syndrome (also known as SARS), avian influenza, and community-acquired methicillin- resistant Staphylococcus aureus has demonstrated how old pathogens can emerge with increased virulence and challenge scientists to explain their rebirth, clinicians to care for patients, and infection- control personnel to prevent their spread. Clostridium difficile appears to illustrate these challenges. It already has some distinctive features: it causes disease almost exclusively in the presence of exposure to antibiotics, it is the only anaerobe that poses a nosocomial risk, and it produces toxin in vivo only in the colon.
About 3 percent of healthy adults and 20 to 40 percent of hospitalized patients are colonized with C. difficile,1,2 which in healthy persons is metabolically inactive in the spore form. The assumption is that perturbation of the competing flora promotes a conversion to vegetative forms that replicate and produce toxins. The characteristic clinical expression is watery diarrhea and cramps, and the characteristic pathologic finding is pseudomembranous colitis.
The history of antibiotic-associated colitis began with a multitude of reports early in the antibiotic era, most of them involving surgical patients and generally attributing the condition to S. aureus. In 1974, Tedesco et al.3 reported on a prospective study of 200 consecutive patients given clindamycin, of whom 41 had diarrhea and 20 (10 percent of all those receiving clindamycin) had pseudomembranous colitis. C. difficile was reported as the cause of pseudomembranous colitis in 1978,4 and within three years, toxins A and B were described, the cytotoxin assay became the standard diagnostic test, clinical studies showed that nearly any antibiotic with an antibacterial spectrum could cause this complication, and oral vancomycin became the standard treatment. Studies showed that toxins A and B act by disrupting the actin-cytoskeleton of fibroblasts in tissue culture5 and in intestinal epithelial cells by uridine 5 '-diphosphate glucose dependent glucosylation of Rho proteins.6 In the past 20 years, C. difficile has become the most commonly recognized microbial cause of nosocomial diarrhea, ref lecting high rates of colonization in hospitalized patients3 and the frequent use of antimicrobial agents. The most commonly implicated agent in the 1970s was clindamycin, and in the 1980s it was cephalosporins, but the recent surge of cases suggests that fluoroquinolones may now play a prominent role.6
Many previous reports of C. difficile–induced disease concerned epidemics, but the reports were generally restricted to single institutions or wards. Recently, however, there appears to be a wider distribution. An example is a regional outbreak in Sherbrooke, Quebec, in 2002, in which there were reports of more disease and more serious disease. A retrospective chart review of 1721 cases of C. difficile–associated diarrhea occurring over 13 years showed that the rate of this complication increased by a factor of 4 during this period and that the cases were also increasingly severe; major risk factors were age over 65 years and receipt of fluoroquinolones.7 A similar experience was reported in Pittsburgh8 and at other hospitals in the United States.9 The question is whether these were isolated events or whether there was something different about medical practice, the pathogen, or the antibiotic use involved in them.
This issue of the Journal includes two large studies that, taken together, describe a new strain of C. difficile and implicate a possible role of flu- oroquinolone use as driving its emergence. The report by McDonald et al.9 is an extensive microbial analysis of 187 isolates obtained from patients with C. difficile–associated enteric disease from eight outbreaks at U.S. health care facilities occurring between 2000 and 2003. Notable is the quality of the microbial analysis and the availability of 6000 control strains of C. difficile. Recently collected isolates showed that the epidemic strain was BI/NAP1 of toxinotype III, was positive for binary toxin, contained an 18-base pair tcdC deletion, and was universally resistant to fluoroquinolones. The binary toxin is similar to the iota toxin of Clostridium perfringens type E and plays an uncertain role in the pathogenesis of C. difficile– associated enteric disease. Because the tcdC gene is a negative regulator of the production of toxins A and B, this deletion could augment the production of toxins.10 This hypothesis is supported by recent studies showing that this C. difficile strain produces 16 to 23 times more toxins A and B in vitro than do other strains.11 The BI/NAP1 strain accounted for 51 percent of the current cases of infection but only 17 percent of the historic control isolates.11
The other report, by Loo et al.,12 provides a similar microbial analysis that is augmented with important clinical and epidemiologic data. They report on a prospective review of C. difficile–associated enteric disease in 1703 patients at 12 hospitals in Quebec over a period of 5.5 months in 2004. The reported incidence of 22.5 per 1000 admissions and an attributable mortality of 6.9 percent are strikingly high. Of particular concern is the very high incidence and mortality associated with increasing age: the incidence among patients over 90 years of age was 74.4 per 1000 admissions and the mortality was 14 percent. Analysis of the isolates showed that most strains were resistant to fluoroquinolones, and 84 percent of the implicated strains had binary toxin and the tcdC gene deletion. Fluoroquinolones were implicated either alone or with other antibiotics as the inducing agent in 52 percent of cases. These data support the concept that a more virulent strain of C. difficile is causing epidemic disease at selected locations and is associated with more frequent and more severe disease, as indicated by higher rates of toxic megacolon, leukemoid reaction, shock, requirement of colectomy, and death.7,8,12
What should we do? Control hinges on prevention, recognition of cases, and optimal management of disease. Physicians and infection-control personnel need to monitor for an increasing incidence of C. difficile–associated disease on the basis of some classic features: the administration of antibiotics complicated by diarrhea, fever, leukocytosis, sometimes with a leukemoid reaction, and hypoalbuminemia or toxic megacolon, or both. Standard stool assays available in most laboratories will not identify this epidemic strain, but the strain might be suspected on the basis of the number and severity of cases. Treatment consists of the prompt discontinuation of the implicated antimicrobial agent and the administration of oral metronidazole; for severely ill patients and those who do not have a prompt response to metronidazole, oral vancomycin should be considered. Prevention efforts should include fastidious use of barrier precautions, isolation of the patient, careful cleaning of the environment with sporicidal agents active against C. difficile, and fastidious use of hand hygiene. This last requirement should include washing hands with soap and water as a supplement to the use of alcohol-based sanitizers, since such sanitizers do not eradicate C. difficile. Particularly important is antibiotic stewardship with restraint in the use of epidemiologically implicated antimicrobial agents, usually secondand third-generation cephalosporins, clindamycin, or f luoroquinolones, or a combination of the three.
From the Department of Medicine, Johns Hopkins University School of Medicine, Baltimore.
1. Viscidi R, Willey S, Bartlett JG. Isolation rates and toxigenic potential of Clostridium difficile isolates from various patient populations. Gastroenterology 1981;81:5-9.
2. McFarland LV, Mulligan ME, Kwok RY, Stamm WE. Nosocomial acquisition of Clostridium difficile infection. N Engl J Med 1989;320:204-10.
3. Tedesco FJ, Barton RW, Alpers DH. Clindamycin-associated colitis: a prospective study. Ann Intern Med 1974;81:429-33.
4. Bartlett JG, Chang TW, Gurwith M, Gorbach SL, Onderdonk AB. Antibiotic-associated pseudomembranous colitis due to toxin-producing clostridia. N Engl J Med 1978;298:531-4.
5. Chang TW, Laurermann M, Bartlett JG. Cytotoxicity assay in antibiotic-associated colitis. J Infect Dis 1979;140:765-70.
6. Pepin J, Saheb N, Coulombe MA, et al. Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficileassociated diarrhea: a cohort study during an epidemic in Quebec. Clin Infect Dis 2005;41:1254-60.
7. Pepin J, Valiquette L, Alary ME, et al. Clostridium difficileassociated diarrhea in a region of Quebec from 1991 to 2003: a changing pattern of disease severity. CMAJ 2004;171:466-72.
8. Muto CA, Pokrywka M, Shutt K, 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;26:273-80.
9. McDonald LC, Killgore GE, Thompson A, et al. An epidemic, toxin gene–variant strain of Clostridium difficile. N Engl J Med 2005;353:2433-41.
10. Spigaglia P, Mastrantonio P. Molecular analysis of the pathogenicity locus and polymorphism in the putative negative regulator of toxin production (TcdC) among Clostridium difficile clinical isolates. J Clin Microbiol 2002;40:3470-5.
11. Warny M, Pepin J, Fang A, et al. Toxin production by an emerging strain of Clostridium difficile associated with outbreaks of severe disease in North America and Europe. Lancet 2005; 366:1079-84.
12. Loo VG, Poirier L, Miller MA, et al. A predominantly clonal multi-institutional outbreak of Clostridium difficile–associated diarrhea with high morbidity and mortality. N Engl J Med 2005; 353:2442-9. Copyright © 2005 Massachusetts Medical Society.
What a crappy topic.
This hypothesis is supported by recent studies showing that this C. difficile strain produces 16 to 23 times more toxins A and B in vitro than do other strains.11
Fill in the blank. I *** this **** up.
C. diff is becoming a serious problem, especially among the nursing home communities. My grandmother died this past summer from C.diff related complications. Before that, I've never heard of C.diff. Thanks for posting this article.
Just because you get hit on the head with a wiffle ball,it's unlikely that you need a Neurosurgeon.
Just because you have an earache at 2AM,it doesn't mean that you should call 911 to take you to an Emergency Room.
Just because you have the sniffles,it doesn't mean that you need an antibiotic.
Spineless physicians and selfish patientsare largely responsible for drug resistant bacteria in this country.
Many people don't know that antibiotics aren't effective against viruses, and some doctors are still willing to dispense unnecessary antibiotics just to keep a patient happy. Two people who I worked with in FL in the 1970s would run to a nearby walk-in clinic to get a penicillin shot whenever they got a sore throat or the sniffles. Their mild cold would run it's normal course in a few days and they were then OK. Then they would swear that the shot had kept them from coming down with the flu. Of course the doctor at the clinic knew that antibiotics don't cure a cold or flu, but he gave the shots anyway just to placate the patients I suppose.
It seems to me that the responsible thing for that physician to have done would have been to tell the patient that he had a cold which no antibiotic would cure, so just go home and take aspirin or an over the counter remedy to relieve the symptoms.
I tried to tell those guys that the shots they got were simply acting as a placebo and they were paying for a useless shot, but they wouldn't believe it. Multiply those cases by a factor of countless millions of unnecessary antibiotic pills and shots over the course of 5 or 6 decades and you end up with lots of drug-resistant strains of bacteria.
ping
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