Antimicrobial drugs and community-acquired Clostridium difficile--associated disease, UK.In a population-based case-control study case-control study, n an investigation employing an epidemiologic approach in which previously existing incidents of a medical condition are used in lieu of gathering new information from a randomized population. of community-acquired Clostridium clostridium Any of the rod-shaped, usually gram-positive bacteria (see gram stain) that make up the genus Clostridium. They are found in soil, water, and the intestinal tracts of humans and other animals. Some species grow only in the complete absence of oxygen. difficile--associated disease (CDAD CDAD Clostridium Difficile-Associated Diarrhea CDAD Component Data Administrator ), we matched 1,233 cases to 12,330 controls. CDAD risk increased 3-fold with use of any antimicrobial antimicrobial /an·ti·mi·cro·bi·al/ (-mi-kro´be-al) 1. killing microorganisms or suppressing their multiplication or growth. 2. an agent with such effects. agent and 6-fold with use of fluoroquinolones. Prior use of antimicrobial agents Antimicrobial agents Chemical compounds biosynthetically or synthetically produced which either destroy or usefully suppress the growth or metabolism of a variety of microscopic or submicroscopic forms of life. did not affect risk for CDAD after 6 months. ********** Recent reports suggest that Clostridium difficile-associated disease (CDAD), including community-acquired CDAD, is increasing in occurrence and severity (1-4). Antimicrobial drug use is widely believed to be a key driver of CDAD infections, with differences in risk depending on class of antimicrobial agent (2). Differences in risk are postulated pos·tu·late tr.v. pos·tu·lat·ed, pos·tu·lat·ing, pos·tu·lates 1. To make claim for; demand. 2. To assume or assert the truth, reality, or necessity of, especially as a basis of an argument. 3. to be caused by differences in properties of the microbial microbial pertaining to or emanating from a microbe. microbial digestion the breakdown of organic material, especially feedstuffs, by microbial organisms. agents, such as the magnitude and the duration of their effects on the fecal flora (5), their activity against C. difficile, and possibly their drug or metabolite metabolite, organic compound that is a starting material in, an intermediate in, or an end product of metabolism. Starting materials are substances, usually small and of simple structure, absorbed by the organism as food. levels in the intestinal lumen (6). However, most studies of CDAD and antimicrobial drugs have been hospital based. Because inpatients are often exposed to multiple antimicrobial drugs, these studies may have limited ability to evaluate agents rarely prescribed or rarely prescribed alone (e.g., macrolides). We expand on previous work by assessing whether and to what extent the risk for community-acquired CDAD varies with the type of antimicrobial drug prescribed. We also evaluate whether and how long this effect takes to dissipate after drug discontinuation dis·con·tin·u·a·tion n. A cessation; a discontinuance. Noun 1. discontinuation - the act of discontinuing or breaking off; an interruption (temporary or permanent) discontinuance , beyond the 90-day period previously explored with this population (3,4). The Study We further analyzed data from a population-based case-control study that was constructed using the United Kingdom's General Practice Research Database (GPRD GPRD General Practice Research Database ). GPRD is a well-validated (7) clinical database that records information taken from general practice records. The cohort used in this study has been extensively described (3). Briefly, we identified all patients who had had CDAD (based on either clinical diagnosis or a positive toxin test result) from 1993 through 2004 and who were registered for [greater than or equal to] 2 years in a general practice anywhere in the United Kingdom. Approximately 90% of tests for C. difficile toxin had neither a positive nor negative result in the GPRD (the result was not recorded as a variable but may be included as case notes that we were unable to review), and so a clinical diagnosis often indicates a test result that was not available to the investigators. Case-patients were defined as patients with community-acquired CDAD, that is, patients who had not been not hospitalized during the year before their CDAD diagnosis. Each case-patient was matched by practice and age ([+ or -] 2 years) to 10 control-patients who also had not been hospitalized during the prior year. Control-patients were also registered in the GPRD for at least 2 years. By matching these control-patients to specific case-patients, we could assess the antimicrobial use in the source population from which the case-patients arose. Control-patients had the same index date as the case-patient to which they were individually matched, which enabled us to account for changing drug patterns and disease rates over time in this database. We used the British National Formulary The British National Formulary (BNF) contains a wide spectrum of information on prescribing and pharmacology, among others indications, side effects and costs of the prescription of all medications available on the National Health Service. to define the following anti-microbial drug classes: penicillins, cephalosporins Cephalosporins Definition Cephalosporins are medicines that kill bacteria or prevent their growth. Purpose Cephalosporins are used to treat infections in different parts of the body—the ears, nose, throat, lungs, sinuses, and and other [beta]-lactams, tetracyclines Tetracyclines Definition Tetracyclines are medicines that kill certain infection-causing microorganisms. Purpose Tetracyclines are called "broad-spectrum" antibiotics, because they can be used to treat a wide variety of , macrolides, sulfonamides Sulfonamides Definition Sulfonamides are medicines that prevent the growth of bacteria in the body. Purpose Sulfonamides are used to treat many kinds of infections caused by bacteria and certain other microorganisms. and trimethoprim trimethoprim /tri·meth·o·prim/ (-meth´o-prim) an antibacterial closely related to pyrimethamine; almost always used in combination with a sulfonamide, primarily for the treatment of urinary tract infections. , fluoroquinolones, and all others. A total of 1,233 case-patients were matched to 12,330 control-patients. The results of antimicrobial exposure, by drug class, are presented in Table 1. The adjusted odds ratio (OR) for CDAD with use of any antimicrobial drug in the 90 days before the index date was 3.1 (95% confidence interval confidence interval, n a statistical device used to determine the range within which an acceptable datum would fall. Confidence intervals are usually expressed in percentages, typically 95% or 99%. [CI]: 2.7-3.6). Adjusted ORs for different classes of antimicrobial drugs were as follows: tetracyclines 0.85, sulfonamides 1.88, penicillins 1.89, macrolides 2.15, cephalosporins 2.21, and fluoroquinolones 6.20. The mean number of antimicrobial classes for those who received the drugs was 1.4 for case-patients and 1.2 for control-patients. With respect to patients who received at least 1 antimicrobial drug, 67% of case-patients and 82% of control-patients received only 1 class of antimicrobial drug (compared with 50% of case-patients and 59% of control-patients among fluoroquinolone fluoroquinolone /flu·o·ro·quin·o·lone/ (-kwin´o-lon) any of a subgroup of fluorine-substituted quinolones, having a broader spectrum of activity than nalidixic acid. fluor·o·quin·o·lone n. users who received only a single class of antimicrobial drug). Table 2 describes the residual effects after discontinuation of antimicrobial agents, fluoroquinolones in particular, as a function of the time since the last prescription. The risk (OR 3.1, CI 2.7-3.6) with current antimicrobial drug use diminished after 3 months, dropped to OR 1.8 (95% CI 1.4-2.3), and essentially disappeared after 6 months (OR 1.3, 95% CI 1.0-1.6). A similar pattern was observed after discontinuation of fluoroquinolone use. This is much lower than the effect in the 90-day window before diagnosis with CDAD. To reduce the risk for protopathic protopathic /pro·to·path·ic/ (-path´ik) affected first; pertaining to sensing of stimuli in a nonspecific, usually nonlocalized, manner. pro·to·path·ic adj. bias (8), we did a sensitivity analysis in which we considered any patient /// who had a recent (90-day) diagnosis of infectious diarrhea
We also conducted sensitivity analyses based on the source of the CDAD diagnosis (test-based or clinical only). These analyses showed a similar effect for exposure to any antimicrobial agents for clinical and test-based diagnoses. Among antimicrobial classes, although fluoroquinolones appear to have higher ORs in the test-based group (OR 6.7; 95% CI 4.5-10.0) than in the group with clinically based diagnoses (OR 5.2; 95% CI 2.6-10.6), this difference is not statistically different. All other antimicrobial agents were stronger risk factors for development of CDAD when the definition of CDAD was determined by clinical diagnosis alone, without a toxin-positive test result. Conclusions Almost all antimicrobial drugs were associated with increased risk for community-acquired CDAD. The risk associated with fluoroquinolones was particularly elevated, as has been found in other recent studies on CDAD in hospital settings (2,9-11). Because broad-spectrum antimicrobial drugs are more commonly prescribed for patients with more severe infections, the underlying indications for fluoroquinolone prescription could also be contributing to the increased risk for CDAD. That is, channeling of antimicrobial drugs toward such patients may result in confounding confounding when the effects of two, or more, processes on results cannot be separated, the results are said to be confounded, a cause of bias in disease studies. confounding factor by indication (12). The sharp reduction in residual risk Residual risk Related: Unsystematic risk among fluoroquinolone users suggests that chronic health status confounding is likely to be minor. Although the residual effects of antimicrobial prescriptions never drop to zero (which may indicate a minor effect of confounding), they drop significantly and quickly. This does not exclude the possibility of confounding by indication due to the infection for which the fluoroquinolone was prescribed. In addition, our sensitivity analysis suggested some degree of robustness of this result because of misclassification, from either misdiagnosis mis·di·ag·no·sis n. pl. mis·di·ag·no·ses An incorrect diagnosis. mis·di ag·nose of CDAD as another form of diarrhea or from the source of
the diagnosis. However, despite the high sensitivity and specificity
seen in studies that use database codes to identify CDAD cases (13) and
the successful use of this approach in other studies (14,15), more
validation work on this endpoint remains to be done to completely
describe the process of recording community-based CDAD diagnoses.
Our results suggest that antimicrobial drugs are a risk factor for CDAD, including community-acquired CDAD. Despite the high risk that appears to be associated with fluoroquinolone use, only 7% of the case-patients in this sample were exposed to a fluoroquinolone, and only 37% were exposed to any class of antimicrobial drug. Therefore, while good prescribing practices for antimicrobial drugs should continue to be encouraged, these drugs are unlikely to be the primary driver of community-acquired CDAD infections in this population. A.B. is a consultant for AstraZeneca Inc and Altana Pharma Inc. This study was funded by the Canadian Institutes of Health Research Canadian Institutes of Health Research (CIHR) is the major federal agency responsible for funding health research in Canada. It is the successor to the Medical Research Council of Canada. (CIHR CIHR Canadian Institutes of Health Research CIHR Cambodian Institute of Human Rights ) and the Canadian Foundation for Innovation. S.D. is a Chercheur-Boursier Clinicien and A.B. a Chercheur National awardee, both from the Fonds de la Recherche La Recherche is a monthly French language popular science magazine covering recent scientific news. It is published by the Société d'éditions scientifiques (the Scientific Publishing Group), a subsidiary of Financière Tallandier. en Sante du Quebec. S.S. is the recipient of a Distinguished Investigator award from CIHR References (1.) McDonald LC, Owings M, Jemigan DB. Clostridium difficile Clostridium difficile A common cause of bacterial colitis; it is the causative agent in 99% of pseudomembranous colitis, and 20-30% of antibiotic-associated diarrhea infection in patients discharged from US short-stay hospitals, 1996-2003. Emerg Infect Dis. 2006; 12:409-15. (2.) McDonald LC, Killgore GE, Thompson A, Owens RC Jr, Kazakova SV, Sambol SP, et al. An epidemic, toxin gene-variant strain of Clostridium difficile. N Engl J Med. 2005;353:2433-41. (3.) Dial S, Delaney JA, Barkun AN, Suissa S. Use of gastric acid-suppressive agents and the risk of community-acquired Clostridium difficile--associated disease. JAMA JAMA abbr. Journal of the American Medical Association . 2005;294:2989-95. (4.) Dial S, Delaney JA, Schneider V, Suissa S. Proton pump inhibitor proton pump inhibitor n. A class of drugs that inhibit gastric acid secretion by interfering with the movement of hydrogen ions across cell membranes and are used mainly to treat peptic ulcers, gastroesophageal reflux disease, and esophagitis. use and risk of community-acquired Clostridium difficile-associated disease defined by prescription for oral vancomycin vancomycin (văn'kōmī`sĭn), antibiotic resembling penicillin in the way it acts. It is derived from the bacterium Streptomyces orientalis, which was isolated from soil of India and Indonesia. therapy. CMAJ CMAJ Canadian Medical Association Journal . 2006;175:745-8. (5.) Spencer RC. The role of antimicrobial agents in the aetiology aetiology see etiology. of Clostridium difficile-associated disease. J Antimicrob Chemother. 1998;41(Suppl C):21-7. (6.) Freeman J, O'Neill F J, Wilcox MH. Effects of cefotaxime and desacetylcefotaxime upon Clostridium difficile proliferation and toxin production in a triple-stage chemostat model of the human gut. J Antimicrob Chemother. 2003;52:96-102. (7.) Lawrenson R, Williams T, Farmer R. Clinical information for research; the use of general practice databases. J Public Health Med. 1999;21:299-304. (8.) Horwitz RI, Feinstein AR. The problem of "protopathic bias" in case-control studies. Am J Med. 1980;68:255-8. (9.) Pepin J, Saheb N, Coulombe MA, Alary a·la·ry adj. Variant of alar. Adj. 1. alary - having or resembling wings aliform, wing-shaped, alar biological science, biology - the science that studies living organisms ME, Corriveau MP, Authier S, et al. Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficile--associated diarrhea: a cohort study A cohort study is a form of longitudinal study used in medicine and social science. It is one type of study design. In medicine, it is usually undertaken to obtain evidence to try to refute the existence of a suspected association between cause and disease; failure to refute during an epidemic in Quebec. Clin Infect Dis. 2005;41:1254-60. (10.) Loo VG, Poirier L, Miller MA, Oughton M, Libman MD, Michaud S, et al. A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality Morbidity and Mortality can refer to:
(11.) McCusker ME, Harris AD, Perencevich E, Roghmann MC. Fluoroquinolone use and Clostridium difficile--associated diarrhea. Emerg Infect Dis. 2003;9:730-3. (12.) Blais L, Ernst P, Suissa S. Confounding by indication and channeling over time: the risks of beta 2-agonists. Am J Epidemiol. 1996;144:1161-9. (13.) Dubberke ER, Reske KA, McDonald LC, Fraser VJ. ICD-9 codes The following is a list of codes for International Statistical Classification of Diseases and Related Health Problems. These codes are in the public domain. (14.) Buchner AM, Sonnenherg A. Epidemiology of Clostridium difficile infection in a large population of hospitalized US military veterans. Dig Dis Sci. 2002;47:201-7. (15.) Dhalla IA, Mamdani MM, Simor AE, Kopp A, Rochon PA, Juurlink DN. Are broad-spectrum fluoroquinolones more likely to cause Clostridium difficile--associated disease? Antimicrob Agents Chemother. 2006;50:321 6-9. Mr Delaney is completing a doctoral degree in the Department of Epidemiology, Biostatistics, and Occupational Health at McGill University McGill University, at Montreal, Que., Canada; coeducational; chartered 1821, opened 1829. It was named for James McGill, who left a bequest to establish it. Its real development dates from 1855 when John W. Dawson became principal. . His research is focused on methodologic issues in database studies. Address for correspondence: Samy Suissa, Division of Clinical Epidemiology, Royal Victoria Hospital For other places with the same name, see Royal Victoria Hospital (disambiguation). The Royal Victoria Hospital at 687 Pine Avenue West in Montreal, Quebec, Canada was established in 1893, through the financial contributions of two Scottish immigrants, Donald Smith and George , R 4.29 687 Pine Ave West, H3A 1A1, Montreal, Quebec, Canada; email: Samy.suissa@clinepi.mcgill.ca J.A. Chris Delaney, * Sandra Dial, * Alan Barkun, * and Sarny Suissa * * McGill University Health Center, Montreal, Quebec, Canada
Table 1. Antimicrobial drug exposure of patients with and without
Clostridium difficile-associated disease, UK, 1993-2004 *
Antimicrobial drug Case-patients, Control-patients,
received, past 90 d n = 1,233 (%) n = 12,330 (%)
Any 456 (37) 1649 (13)
Tetracyclines 17 (1.4) 106 (0.9)
Penicillins 202 (16.4) 790 (6.4)
Sulfonamides and 71 (5.7) 236 (l.9)
trimethoprim
Macrolides 80 (6.5) 219 (1.7)
Cephalosporins and 76 (6.2) 207 (l.7)
other [beta]-lactams
Fluoroquinolones 70 (5.7) 84 (0.7)
Adjusted OR
Antimicrobial drug ([double dagger])
received, past 90 d Crude OR ([dagger]) (95% CI)
Any 5.0 3.7 (3.1-4.4)
Tetracyclines 1.0 0.9 (0.5-1.5)
Penicillins 2.4 1.9 (1.6- 2.4)
Sulfonamides and 2.3 1.9 (1.5-2.7)
trimethoprim
Macrolides 2.7 2.2 (1.7-3.1)
Cephalosporins and 2.9 2.2 (1.7-3.2)
other [beta]-lactams
Fluoroquinolones 10.9 6.2 (4.4- 8.8)
* OR, odds ratio; CI, confidence interval.
([dagger]) Adjusted for other antimicrobial drugs and prior anti-
microbial drug use to ensure that all comparisons used the same
reference group.
([double dagger]) Adjusted for inflammatory bowel disease,
diverticular disease, peptic ulcer disease and gastroesophageal reflux
disease, Helicobacter pylori-associated disease, pernicious anemia,
cancer including solid tumor and hematologic malignancies, diabetes
mellitus, chronic obstructive pulmonary disease, cirrhosis, non-
steroidal anti-inflammatory agents, aspirin, H2 blockers, proton pump
inhibitors, and antimicrobial drug use in the past 2 years.
Table 2. Most recent prescription for any antimicrobial drug and
effect of proximity on risk of acquiring Clostridium difficile--
associated disease, UK, 1993-2004 *
Case-patients, Control-patients,
Exposure to antimicrobial drug n = 1,233 (%) n = 12,330 (%)
None (reference) 379 (30) 6,449 (52)
Most recent prescription
([double dagger])
1-90 d (current) 456 (37) 1,649 (13)
91-180 d 128 (10) 1067 (9)
181-365d 131 (11) 1,498 (12)
1-2 y 139 (11) 1,674 (13)
Most recent fluoroquinolone
prescription
1-90 d (current) 70 (5.7) 84 (0.7)
91-180 d 12 (1.0) 70 (0.6)
181-365d 27 (2.2) 114 (0.9)
1-2 y 36 (2.9) 198 (1.6)
Adjusted OR
Exposure to antimicrobial drug Crude OR (95% CI) ([dagger])
None (reference) 1.0 1.0 (reference)
Most recent prescription
([double dagger])
1-90 d (current) 5.0 3.7 (3.1-4.4)
91-180 d 2.2 1.8 (1.4-2.3)
181-365d 1.6 1.3 (1.0-1.6)
1-2 y 1.5 1.3 (1.0-1.6)
Most recent fluoroquinolone
prescription
1-90 d (current) 10.9 6.2 (4.4-8.8)
91-180 d 1.7 1.2 (0.6-2.3)
181-365d 5.4 1.7 (1.1-2.7)
1-2 y 1.9 1.3 (0.9-2.0)
* OR, odds ratio; CI, confidence interval.
([dagger]) Adjusted for inflammatory bowel disease, diverticular
disease, peptic ulcer disease gastroesophageal reflux disease,
Helicobacter pylori--associated disease, pemicious anemia, cancer
including solid tumor and hematologic malignancies, diabetes
mellitus, chronic obstructive pulmonary disease, cirrhosis,
nonsteroidal anti-inflammatory agents, aspirin, H2 blockers,
proton pump inhibitors, and antimicrobial use in the past 2 years.
([double dagger]) before the index date.
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