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We have previously reported on the susceptibility and epidemiology of Clostridioides difficile isolates from six geographically dispersed medical centers in the United States. This current survey was conducted with isolates collected in 2020-2021 from six geographically dispersed medical centers in the United States, with specific attention to susceptibility to ridinilazole as well as nine comparators. C. difficile isolates or stools from patients with C. difficile antibiotic-associated diarrhea were collected and referred to a central laboratory. After species confirmation of 300 isolates at the central laboratory, antibiotic susceptibilities were determined by the agar dilution method [M11-A9, Clinical and Laboratory Standards Institute (CLSI)] against the 10 agents. Ribotyping was performed by PCR capillary gel electrophoresis on all isolates. Ridinilazole had a minimum inhibitory concentration (MIC) 90 of 0.25 mcg/mL, and no isolate had an MIC greater than 0.5 mcg/mL. In comparison, fidaxomicin had an MIC 90 of 0.5 mcg/mL. The vancomycin MIC 90 was 2 mcg/mL with a 0.7% resistance rate [both CLSI and European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria]. The metronidazole MIC 90 was 1 mcg/mL, with none resistant by CLSI criteria, and a 0.3% resistance rate by EUCAST criteria. Among the 50 different ribotypes isolated in the survey, the most common ribotype was 014-020 (14.0%) followed by 106 (10.3%), 027 (10%), 002 (8%), and 078-126 (4.3%). Ridinilazole maintained activity against all ribotypes and all strains resistant to any other agent tested. Ridinilazole showed excellent in vitro activity against C. difficile isolates collected between 2020 and 2021 in the United States, independent of ribotype., Competing Interests: D.S. had research contracts with Tufts Medical Center from Prolacta, Summit Therapeutics, Seres Health, and Merck. Consultant to Prolacta and Merck. E.D. is an employee of Summit (Oxford) Ltd. at the time of manuscript submission, and owns stock options in Summit Therapeutics (parent company). K.G. had research funding paid to the University of Houston from Summit Therapeutics, Seres Health, Paratek, and Acuryx Pharmaceuticals. K.C. has research funds paid to her institution from Meridian, BioRad, Qiagen, and Great Basin as well as a consultant fee from B.D. Diagnostics. She serves on the Scientific Advisory Boards of Co-Diagnostics, Inc., Cytovale, Inc., and Pattern Diagnostics, Inc. E.G. is a consultant for Accurx Pharmaceuticals, L.L.C., Merck, Summit Pharmaceuticals P.L.C., Shionogi, Kindred Hospital system, BioK+, and speakers bureaus for Merck and Shionogi. S.J. is a consultant for Accurx, BioK+, Ferring Pharmaceuticals, and Summit Therapeutics. D.G. is a consultant for Destiny Pharma, Plc., and holds a patent for treatment of CDI with a non-toxigenic C. difficile licensed to Destiny Pharma. C.T. has received research funding through grants to Tufts Medical Center from Actelion, Merck, and Summit Therapeutics, Plc. She has served as a consultant to Summit Plc and Delnove. S.W., Q.W., A.S., D.B., L.G., L.M., and C.L. have no conflicts to disclose.

Background: Clostridioides difficile infection (CDI) causes significant morbidity in nursing home residents. Our aim was to describe adherence to a bundled CDI prevention initiative, which had previously been deployed nationwide in Veterans Health Administration (VA) long-term care facilities (LTCFs), and to improve compliance with reinforcement., Methods: A multicenter pre- and post-reinforcement of the VA bundle consisting of environmental management, hand hygiene, and contact precautions was conducted in 6 VA LTCFs. A campaign to reinforce VA bundle components, as well as to promote select antimicrobial stewardship recommendations and contact precautions for 30 days, was employed. Hand hygiene, antimicrobial usage, and environmental contamination, before and after bundle reinforcement, were assessed., Results: All LTCFs reported following the guidelines for cleaning and contact precautions until diarrhea resolution pre-reinforcement. Environmental specimens rarely yielded C difficile pre- or post-reinforcement. Proper hand hygiene across all facilities did not change with reinforcement (pre 52.51%, post 52.18%), nor did antimicrobial use (pre 87-197 vs. post 84-245 antibiotic days per 1,000 resident-days). LTCFs found it challenging to maintain prolonged contact precautions., Discussion: Variation in infection prevention and antimicrobial prescribing practices across LTCFs were identified and lessons learned., Conclusions: Introducing bundled interventions in LTCFs is challenging, given the available resources, and may be more successful with fewer components and more intensive execution with feedback., (Published by Elsevier Inc.)

Background: Geographic and temporal trends in the distribution of PCR ribotypes for Clostridioides difficile associated diarrheal isolates obtained in the United States (US) are changing. As part of a US national surveillance program of C. difficile susceptibility to fidaxomicin, we quantified the distribution of PCR ribotypes of stool isolates collected from 2011 to 2016., Methods: C. difficile isolates or C. difficile toxin + stools from patients with C. difficile infection (CDI) were submitted for testing to Tufts Medical Center from 6 geographically distinct medical centers. Following isolation and confirmation as C. difficile, approximately 35% of the isolates were randomly sampled, stratified by center, for PCR ribotyping by capillary gel electrophoresis. Toxin gene profiling was performed on all isolates., Results: 939 isolates from a total of 2814 (33.4%) isolated over the 6 years were analyzed. Seventy unique ribotypes were observed, including 19 ribotypes observed 10 or more times. Sixteen ribotypes were not previously observed in our data base. Ribotype 027 declined by more than 60% over the 6 years of the survey from 35.3% to 13.1% (p < 0.001). Ribotype 106 was the most common in 2016, followed by 027 and 014-020. There were strong correlations between 027 and binary toxin with the 18 base pair deletion of tcdC and ribotype 078-126 had 100% concordance with the previously described tcdC 39 base pair deletion., Conclusions: The frequency of ribotypes in the US has changed with a marked decline in 027. Each of the geographical areas had variations which differed from each other, but collectively, these results suggest that the changing epidemiology of C. difficile in the US is consistent with what is being seen in Europe. Continued surveillance and monitoring of changes in ribotype distributions of C. difficile are warranted., Competing Interests: Declaration of competing interest Dr. Dale N Gerding is a member of the Advisory Board for Merck. Dr. Ellie Goldstein has been on advisory boards for Merck, Summit Therapeutics, LLC. He has been on a speaker bureau for Merck. Dr. Stephen G. Jenkins has no conflicts of interest as they relate to this project. Dr. Stuart Johnson has no conflicts of interest related to this project. Ms. Laura McDermott has no conflicts of interest as they relate to this project. Dr. Robin Patel reports grants from CD Diagnostics, Merck, Hutchison Biofilm Medical Solutions, Accelerate Diagnostics, ContraFect, TenNor Therapeutics Limited and Shionogi. Dr. Patel is a consultant to Curetis, Specific Technologies, NextGen Diagnostics, PathoQuest, Selux Diagnostics and Qvella; monies are paid to Mayo Clinic. In addition, Dr. Patel has a patent on Bordetella pertussis/parapertussis PCR issued, a patent on a device/method for sonication with royalties paid by Samsung to Mayo Clinic, and a patent on an anti-biofilm substance issued. Dr. Patel receives travel reimbursement from ASM and IDSA, an editor's stipend from IDSA, and honoraria from the NBME, Up-to-Date and the Infectious Diseases Board Review Course. Dr. David R. Snydman has current research funds from Merck, Pfizer and Summit Therapeutics, LLC. Dr. Snydman has been an advisor to Merck, and Summit Therapeutics, LLC. Dr. Cheleste M. Thorpe has received research funds from Merck (formerly Cubist/Optimer), Actelion, and Summit Therapeutics, LLC. She has also been on a Summit Advisory Board and received a travel grant from Summit Therapeutics, LLC. Dr. Seth T. Walk has no conflicts of interest to report., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In 2011, we initiated a sentinel surveillance network to assess changes in Clostridioides (formerly Clostridium ) difficile antimicrobial susceptibility to fidaxomicin from 6 geographically dispersed medical centers in the United States. This report summarizes data from 2013 to 2016. C. difficile isolates or toxin-positive stools from patients were referred to a central laboratory. Antimicrobial susceptibility was determined by agar dilution. CLSI, EUCAST, or FDA breakpoints were used, where applicable. Toxin gene profiles were characterized by multiplex PCR on each isolate. A random sample of approximately 40% of isolates, stratified by institution and year, was typed by restriction endonuclease analysis (REA). Among 1,889 isolates from 2013 to 2016, the fidaxomicin MIC 90 was 0.5 μg/ml; all isolates were inhibited at ≤1 μg/ml. There were decreases in metronidazole and vancomycin MICs over time. Clindamycin resistance remained unchanged (27.3%). An increase in imipenem resistance was observed. By 2015 to 2016, moxifloxacin resistance decreased in all centers. The proportion of BI isolates decreased from 25.5% in 2011 to 2012 to 12.8% in 2015 to 2016 ( P < 0.001). The BI REA group correlated with moxifloxacin resistance (BI 84% resistant versus non-BI 12.5% resistant). Fidaxomicin MICs have not changed among C. difficile isolates of U.S. origin over 5 years post licensure. There has been an overall decrease in MICs for vancomycin, metronidazole, moxifloxacin, and rifampin and an increase in isolates resistant to imipenem. Moxifloxacin resistance remained high among the BI REA group, but the proportion of BI isolates has decreased. Continued geographic variations in REA groups and antimicrobial resistance persist., (Copyright © 2019 American Society for Microbiology.)

The diarrheal pathogen Clostridium difficile consists of at least six distinct evolutionary lineages. The RT017 lineage is anomalous, as strains only express toxin B, compared to strains from other lineages that produce toxins A and B and, occasionally, binary toxin. Historically, RT017 initially was reported in Asia but now has been reported worldwide. We used whole-genome sequencing and phylogenetic analysis to investigate the patterns of global spread and population structure of 277 RT017 isolates from animal and human origins from six continents, isolated between 1990 and 2013. We reveal two distinct evenly split sublineages (SL1 and SL2) of C. difficile RT017 that contain multiple independent clonal expansions. All 24 animal isolates were contained within SL1 along with human isolates, suggesting potential transmission between animals and humans. Genetic analyses revealed an overrepresentation of antibiotic resistance genes. Phylogeographic analyses show a North American origin for RT017, as has been found for the recently emerged epidemic RT027 lineage. Despite having only one toxin, RT017 strains have evolved in parallel from at least two independent sources and can readily transmit between continents., (Copyright © 2017 Cairns et al.)

Objectives: The aim of this study was to evaluate the susceptibilities of Clostridium difficile isolates to cadazolid, a novel antibiotic for the treatment of C. difficile infection., Methods: Ribotyping and susceptibilities were determined for C. difficile isolates from a multicentre, double-blind, Phase 2 study of oral cadazolid in patients with C. difficile infection (NCT01222702, ClinicalTrials.gov; EudraCT 2010-020941-29, European Clinical Trials Database). Patients were randomized to receive 250, 500 or 1000 mg of cadazolid twice daily or 125 mg of vancomycin four times daily, for 10 days. MICs of cadazolid, vancomycin, fidaxomicin, linezolid and moxifloxacin were determined at baseline for all patients and post-baseline for patients with clinical failure or recurrence, using the agar dilution method., Results: Seventy-eight of 84 patients had an evaluable toxigenic C. difficile isolate at baseline. The most frequent PCR ribotype was 027 (15.4%). Cadazolid MICs for baseline isolates (including epidemic strain 027) ranged from 0.06 to 0.25 mg/L. Baseline cadazolid MICs were similar to those of fidaxomicin and lower than those of vancomycin, linezolid and moxifloxacin. For each clinical outcome group (clinical cure, clinical failure, sustained clinical response and clinical failure or recurrence), the baseline cadazolid MIC range was 0.06-0.25 mg/L. Mean (min-max) cadazolid faecal concentration (μg/g) on day 5 was 884 (101-2710), 1706 (204-4230) and 3226 (1481-12 600) for the doses 250, 500 and 1000 mg, respectively., Conclusions: For all cadazolid doses, the faecal concentration was in excess of several thousand-fold the MIC90 for C. difficile. The MIC of cadazolid for all C. difficile isolates, including epidemic strains, was low and in the same narrow range regardless of treatment outcome., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.)

Unlabelled: Clostridium difficile is a leading cause of antibiotic-associated diarrhea, a significant animal pathogen, and a worldwide public health burden. Most disease-causing strains secrete two exotoxins, TcdA and TcdB, which are considered to be the primary virulence factors. Understanding the role that these toxins play in disease is essential for the rational design of urgently needed new therapeutics. However, their relative contributions to disease remain contentious. Using three different animal models, we show that TcdA(+) TcdB(-) mutants are attenuated in virulence in comparison to the wild-type (TcdA(+) TcdB(+)) strain, whereas TcdA(-) TcdB(+) mutants are fully virulent. We also show for the first time that TcdB alone is associated with both severe localized intestinal damage and systemic organ damage, suggesting that this toxin might be responsible for the onset of multiple organ dysfunction syndrome (MODS), a poorly characterized but often fatal complication of C. difficile infection (CDI). Finally, we show that TcdB is the primary factor responsible for inducing the in vivo host innate immune and inflammatory responses. Surprisingly, the animal infection model used was found to profoundly influence disease outcomes, a finding which has important ramifications for the validation of new therapeutics and future disease pathogenesis studies. Overall, our results show unequivocally that TcdB is the major virulence factor of C. difficile and provide new insights into the host response to C. difficile during infection. The results also highlight the critical nature of using appropriate and, when possible, multiple animal infection models when studying bacterial virulence mechanisms., Importance: Clostridium difficile is a leading cause of antibiotic-associated diarrhea and an important hospital pathogen. TcdA and TcdB are thought to be the primary virulence factors responsible for disease symptoms of C. difficile infections (CDI). However, the individual contributions of these toxins to disease remain contentious. Using three different animal models of infection, we show for the first time that TcdB alone causes severe damage to the gut, as well as systemic organ damage, suggesting that this toxin might be responsible for MODS, a serious but poorly understood complication of CDI. These findings provide important new insights into the host response to C. difficile during infection and should guide the rational development of urgently required nonantibiotic therapeutics for the treatment of CDI., (Copyright © 2015 Carter et al.)

Clostridium difficile is the causative agent of C. difficile-associated diarrhea (CDAD), with increased risk in elderly populations. Kibdelomycin, a novel natural-product inhibitor of type II topoisomerase enzymes, was evaluated for activity against C. difficile and gastrointestinal anaerobic organisms. Toxigenic C. difficile isolates (n=168) from U.S. hospitals and anaerobic Gram-positive and Gram-negative organisms (n=598) from Chicago-area hospitals were tested. Kibdelomycin showed potent activity against toxigenic C. difficile (MIC90=0.25 μg/ml) and most Gram-positive aerobic organisms but had little activity against Bacteroides species (MIC50>32 μg/ml; n=270). Potent anti-C. difficile activity was also observed in the hamster model of C. difficile colitis. Dosing at 1.6 mg/kg (twice-daily oral dose) resulted in protection from a lethal infection and a 2-log reduction in C. difficile cecal counts. A 6.25-mg/kg twice-daily oral dose completely eliminated detectable C. difficile counts in cecal contents. A single 6.25-mg/kg oral dose showed that cecal contents were exposed to the drug at >2 μM (eightfold higher than the MIC), with no significant plasma exposure. These findings support further exploration of kibdelomycin for development of an anti-C. difficile agent.

Objective: Describe the clinical and molecular epidemiology of incident Clostridium difficile infection (CDI) cases in Chicago area acute healthcare facilities (HCFs)., Design and Setting: Laboratory, clinical, and epidemiologic information was collected for patients with incident CDI who were admitted to acute HCFs in February 2009. Stool cultures and restriction endonuclease analysis typing of the recovered C. difficile isolates was performed., Patients: Two hundred sixty-three patients from 25 acute HCFs., Results: Acute HCF rates ranged from 2 to 7 patients with CDI per 10,000 patient-days. The crude mortality rate was 8%, with 20 deaths occurring in patients with CDI. Forty-two (16%) patients had complications from CDI, including 4 patients who required partial, subtotal, or total colectomy, 3 of whom died. C. difficile was isolated and typed from 129 of 178 available stool specimens. The BI strain was identified in 79 (61%) isolates. Of patients discharged to long-term care who had their isolate typed, 36 (67%) had BI-associated CDI., Conclusions: Severe disease was common and crude mortality was substantial among patients with CDI in Chicago area acute HCFs in February 2009. The outbreak-associated BI strain was the predominant endemic strain identified, accounting for nearly two-thirds of cases. Focal HCF outbreaks were not reported, despite the presence of the BI strain. Transfer of patients between acute and long-term HCFs may have contributed to the high incidence of BI cases in this investigation.

Strategies to reduce rates of Clostridium difficile infection (CDI) generally recommend isolation or cohorting of active cases and the reduced use of cephalosporin and quinolone antibiotics. Data supporting these recommendations come predominantly from the setting of epidemic disease caused by ribotype 027 strains. We introduced an initiative involving a restrictive antibiotic policy and a CDI-cohort ward at an acute, 820-bed teaching hospital where ribotype 027 strains account for only one quarter of all CDI cases. Antibiotic use and monthly CDI cases in the 12 months before and the 15 months after the initiative were compared using an interrupted time series analysis and segmented regression analysis. The initiative resulted in a reduced level of cephalosporin and quinolone use (22.0% and 38.7%, respectively, both p <0.001) and changes in the trends of antibiotic use such that cephalosporin use decreased by an additional 62.1 defined daily doses (DDD) per month (p <0.001) and antipseudomonal penicillin use increased by 20.7 DDD per month (p = 0.011). There were no significant changes in doxycycline or carbapenem use. Although the number of CDI cases each month was falling before the intervention, there was a significant increase in the rate of reduction after the intervention from 3% to 8% per month (0.92, 95% CI 0.86-0.99, p = 0.03). During the study period, there was no change in the proportion of cases having their onset in the community, nor in the proportion of ribotype 027 cases. CDI cohorting and restriction of cephalosporin and quinolone use are effective in reducing CDI cases in a setting where ribotype 027 is endemic.

Treatment of C. difficile diarrhea with metronidazole or vancomycin is highly effective at relieving symptoms. The high rate of diarrhea recurrence is concerning, but fortunately most patients respond to a second course of treatment. The problem of vancomycin resistance in hospital organisms has markedly reduced usage of this agent as a first-line treatment for C. difficile diarrhea, leaving metronidazole as the mainstay of treatment in the United States where teicoplanin and fusidic acid are not marketed. It is likely that any new antimicrobial agent used to treat C. difficile will be similarly plagued by a high rate of recurrence, presumably incurred as a result of disruption of normal bowel flora. There is a need for improved treatment and prevention of this increasingly frequent and debilitating nosocomial infection. Treatments that utilize passive antibodies, immunization, nontoxigenic C. difficile, or other forms of biotherapy may hold the key to improved treatment and prevention of C. difficile disease in the future. In the meantime, it behooves all practitioners to use antimicrobials judiciously in order to prevent as many cases of C. difficile diarrhea as possible.

Background: Clostridium difficile is the most common infectious cause of nosocomial diarrhea, but its role in diarrhea associated with tube feeding has not been rigorously investigated., Objective: To determine the incidence of C. difficile acquisition and C. difficile-associated diarrhea in tube-fed and non-tube-fed patients., Design: Prospective cohort study., Setting: A university-affiliated Veterans Affairs Medical Center., Patients: 76 consecutive hospitalized, tube-fed patients and 76 hospitalized, non-tube-fed patients. The two cohorts were matched for age, unit location, duration of hospitalization before surveillance, and severity of illness., Measurements: Incidence of C. difficile acquisition, incidence of C. difficile-associated diarrhea, and C. difficile restriction endonuclease analysis typing results., Results: More tube-fed patients than non-tube-fed patients acquired C. difficile (15 of 76 patients [20%] compared with 6 of 76 patients [8%]; P=0.03) and developed C. difficile-associated diarrhea (7 of 76 patients [9%] compared with 1 of 76 patients [1%]; P=0.03). The mean proportion (+/-SD) of surveillance days with diarrhea was greater for tube-fed patients after the development of C. difficile-associated diarrhea than for tube-fed patients without this diarrhea (0.68+/-0.4 compared with 0.22+/-0.2 [95% CI for the mean difference, 0.08 to 0.84]). Postpyloric tube feeding (odds ratio, 3.14 [CI, 1.008 to 9.77]) and duration of surveillance (odds ratio, 1.08 [CI, 1.0009 to 1.16]) were risk factors for the acquisition of C. difficile. Nineteen restriction endonuclease analysis types of C. difficile were identified from 20 patients., Conclusions: Hospitalized, tube-fed patients, especially those receiving postpyloric tube feeding, are at greater risk for the acquisition of C. difficile and the development of C. difficile-associated diarrhea than are hospitalized, non-tube-fed patients. Clinicians should test for C. difficile in tube-fed patients with diarrhea.

A prospective, case-control study was performed in which enteric protein loss and nutritional status were measured in patients with symptomatic and asymptomatic infections due to Clostridium difficile. Enteric protein loss, measured by elevated levels of fecal alpha1-antitrypsin, was detected in 14 of 20 cases and controls with diarrhea (9 of 10 cases with C. difficile-associated diarrhea and 5 of 10 age-matched control with diarrhea not associated with C. difficile) compared with none of 20 asymptomatic cases and controls (10 colonized cases and 10 noncolonized controls without diarrhea who were matched by age and clinical diagnosis) (P < .0001). Cases and controls with diarrhea had higher prognostic nutritional index values (P = 0.005) and lower levels of serum albumin, transferrin, and cholesterol than did the asymptomatic cases and controls. Decreased nutritional status, measured by increased prognostic nutritional index values, was associated with the presence of diarrhea but not with the presence of C. difficile. Protein-losing enteropathy was associated with C. difficile only in the presence of diarrhea, and we did not detect an increased risk of protein-losing enteropathy or malnutrition as a consequence of asymptomatic colonization with C difficile.

Objectives: To review and summarize the status of diagnosis, epidemiology, infection control, and treatment of Clostridium difficile-associated disease (CDAD)., Diagnosis: A case definition of CDAD should include the presence of symptoms (usually diarrhea) and at least one of the following positive tests: endoscopy revealing pseudomembranes, stool cytotoxicity test for toxin B, stool enzyme immunoassay for toxin A or B, or stool culture for C difficile (preferably with confirmation of organism toxicity if a direct stool toxin test is negative or not done). Testing of asymptomatic patients, including those who are asymptomatic after treatment, is not recommended other than for epidemiologic purposes. Lower gastrointestinal endoscopy is the only diagnostic test for pseudomembranous colitis, but it is expensive, invasive, and insensitive (51% to 55%) for the diagnosis of CDAD. Stool culture is the most sensitive laboratory test currently in clinical use, but it is not as specific as the cell cytotoxicity assay., Epidemiology: C difficile is the most frequently identified cause of nosocomial diarrhea. The majority of C difficile infections are acquired nosocomially, and most patients remain asymptomatic following acquisition. Antimicrobial exposure is the greatest risk factor for patients, especially clindamycin, cephalosporins, and penicillins, although virtually every antimicrobial has been implicated. Cases of CDAD unassociated with prior antimicrobial or antineoplastic use are very rare. Hands of personnel, as well as a variety of environmental sites within institutions, have been found to be contaminated with C difficile, which can persist as spores for many months. Contaminated commodes, bathing tubs, and electronic thermometers have been implicated as sources of C difficile. Symptomatic and asymptomatic infected patients are the major reservoirs and sources for environmental contamination. Both genotypic and phenotypic typing systems for C difficile are available and have enhanced epidemiologic investigation greatly., Infection Control: Successful infection control measures designed to prevent horizontal transmission include the use of gloves in handling body substances and replacement of electronic thermometers with disposable devices. Isolation, cohorting, handwashing, environmental disinfection, and treatment of asymptomatic carriers are recommended practices for which convincing data of efficacy are not available. The most successful control measure directed at reduction in symptomatic disease has been antimicrobial restriction., Treatment: Treatment of symptomatic (but not asymptomatic) patients with metronidazole or vancomycin for 10 days is effective; metronidazole may be preferred to reduce risk of vancomycin resistance among other organisms in hospitals. Recurrence of symptoms occurs in 7% to 20% of patients and is due to both relapse and reinfection. Over 90% of first recurrences can be treated successfully in the same manner as initial cases. Combination treatment with vancomycin plus rifampin or the addition orally of the yeast Saccharomyces boulardii to vancomycin or metronidazole treatment has been shown to prevent subsequent diarrhea in patients with recurrent disease.

The major controversy in the diagnosis of symptomatic gastrointestinal infection due to Clostridium difficile is whether laboratory evidence of the C. difficile organism in culture is sufficient or if evidence of one of the C. difficile toxins in stool should be required. Cultures performed properly on selective media currently are the most sensitive method for detection of C. difficile, whereas the cell cytotoxin assay for detection of toxin B is the most specific. Stool specimens from patients with clinical diarrhea are sometimes found to be culture-positive for C. difficile but assay-negative for cytotoxin. Samples from these patients can be viewed as false-positive by culture or false-negative by cytotoxin test. Evidence from endoscopy indicates that some patients whose stool is culture-positive for the organism but assay-negative for toxin do have pseudomembranous colitis, but its incidence among such patients (11%) is lower than that among patients whose stool is culture- and assay-positive (51%). Response to treatment with vancomycin or metronidazole is similar in the two groups of patients, and withholding treatment from patients whose stool contains C. difficile but not cytotoxin may result in increased morbidity and mortality. Up to one-third of C. difficile organisms from stool specimens that are culture-positive but assay-negative are incapable of producing cytotoxin in vitro, a finding that suggests these organisms may not be the cause of diarrhea.(ABSTRACT TRUNCATED AT 250 WORDS)

The frequency of introduction and spread of specific Clostridium difficile strains among hospitalized patients were assessed by serial cultures of patients admitted to a medical-surgical ward with endemic C. difficile-associated diarrhea. Stool cultures were obtained from 634 (94%) of 678 consecutive admissions to the ward (ward admissions), and all C. difficile isolates were typed by restriction endonuclease analysis. Sixty-five ward admissions introduced C. difficile to the ward, and 54 initially culture-negative admissions acquired C. difficile on the ward. Ward admissions hospitalized within the prior 30 days in the medical center were more likely to be culture-positive for C. difficile at admission to the study ward than those not previously hospitalized at the institution (16% vs. 7%, P less than .001). Nosocomial acquisition of a C. difficile strain was preceded by a documented introduction of that strain to the ward by another asymptomatic ward admission in 16 (84%) of 19 instances, suggesting that C. difficile-colonized new admissions are a major source of nosocomial C. difficile infections.

Objective: To compare the efficacy of vancomycin and metronidazole for eradication of asymptomatic Clostridium difficile fecal excretion as a means of controlling nosocomial outbreaks of C. difficile diarrhea., Design: Randomized, placebo-controlled, non-blinded trial., Setting: Six hundred-bed regional referral Veterans Affairs Medical Center., Patients: Thirty patients excreting C. difficile without diarrhea or abdominal symptoms., Interventions: All patients were randomized to receive 10 days of oral vancomycin, 125 mg four times daily; metronidazole, 500 mg twice daily; or placebo, three times daily., Measurements: Stool cultures were obtained during treatment and for 2 months after treatment. All C. difficile isolates were typed by restriction endonuclease analysis (REA)., Results: Clostridium difficile organisms were not detected during and immediately after treatment in 9 of 10 patients treated with vancomycin compared with 3 of 10 patients treated with metronidazole (P = 0.02) and 2 of 10 patients in the placebo group (P = 0.005). The fecal vancomycin concentration was 1406 +/- 1164 micrograms/g feces, but metronidazole was not detectable in 9 of 10 patients. Eight of the nine evaluable patients who had negative stool cultures after treatment with vancomycin began to excrete C. difficile again 20 +/- 8 days after completing treatment. Three of these patients received additional antibiotics before C. difficile excretion recurred, and five acquired new C. difficile REA strains. Four of six patients who received only vancomycin before C. difficile excretion recurred were culture-positive at the end of the study compared with one of nine patients who received only placebo (P = 0.047)., Conclusions: Asymptomatic fecal excretion of C. difficile is transient in most patients, and treatment with metronidazole is not effective. Although treatment with vancomycin is temporarily effective, it is associated with a significantly higher rate of C. difficile carriage 2 months after treatment and is not recommended.

To assess the risk of acquiring Clostridium difficile diarrhoea or colitis in patients colonised with C difficile, rectal swabs taken weekly for 9 weeks from patients with long-term (at least 7 days) hospital stays on three wards were cultured for C difficile. 60 (21%) of 282 patients were culture-positive for C difficile during their hospital stay, of whom 51 were symptom-free faecal excretors. C difficile diarrhoea developed in the other 9 patients; 2 were culture-positive for C difficile and had diarrhoea at the time of first culture, and 7 had diarrhoea or pseudomembranous colitis after 1-6 previously negative weekly rectal cultures. All patients with diarrhoea were on one ward, but symptom-free, excretors were found on all wards. HindIII chromosomal restriction endonuclease analysis (REA) of the C difficile isolates revealed 18 distinct types. All isolates from the patients with diarrhoea were one of two nearly identical REA types, B or B2. 26 of the 29 total B/B2 isolates were from patients on the same ward, which points to a nosocomial outbreak. The symptom-free excretors were not at increased risk of subsequent clinical illness.

One hundred fifty-six patients with presumed or documented abdominal infections were treated with amikacin/metronidazole/placebo (Group 1, 56 patients), amikacin/clindamycin/placebo (Group 2, 57 patients), or amikacin/clindamycin/ampicillin (Group 3, 43 patients) to determine both the therapeutic efficacy of the various regimens and the type of complications due to Clostridium difficile. C. difficile diarrhea occurred in 15 of 156 patients (9.6%), and C. difficile colonization occurred in 14 of 156 patients (9%) during treatment and 30 days of follow-up. The number of C. difficile diarrhea cases in Group 1 (3 of 56) was significantly lower than in Group 2 (9 of 57, p less than 0.05), but not in Group 3 (3 of 43). Exclusion of all patients who received other antibiotics in the 30-day poststudy period revealed no C. difficile diarrhea or colonization in Group 1 (0 of 13) and an acquisition rate of 31% (14 of 45) with the regimens containing clindamycin (p less than 0.02). Successful treatment outcomes (106 evaluable patients) were not statistically different among the three groups (Group 1, 64%; Group 2, 76%; and Group 3, 88%), but these data were difficult to interpret because, by chance, significantly more patients in Group 1 had bacteremia at entry (p less than 0.01), and patients in Group 3 had significantly more biliary tract infections (p less than 0.02) and significantly more favorable acute physiology scores (p less than 0.05). Use of metronidazole can reduce complications related to C. difficile, particularly if additional antimicrobials other than aminoglycosides are avoided.

Endoscopic and clinical features are reported for 39 patients detected early in the course of pseudomembranous colitis. Disease was detected early by virtue of careful surveillance in patients in whom diarrhea developed. Early proctosigmoidoscopic findings in pseudomembranous colitis are illustrated. Clinical presentation includes development of fever, leukocytosis, abdominal pain, and even an ileus picture on radiography in addition to diarrhea.

Direct inoculation to cefoxitin-cycloserine-fructose agar and broth was compared with alcohol shock-chopped meat broth inoculation for optimal detection of Clostridium difficile in fecal samples. Alcohol shock is significantly more sensitive than cefoxitin-cycloserine-fructose agar or broth and may be the method of choice to detect C. difficile in asymptomatic carriers.

Gram stains of stools from patients with diarrhea and control patients with no diarrhea were examined for a predominance of gram-positive rods and the presence of polymorphonuclear leukocytes. Results were compared with those from lower gastrointestinal endoscopy for pseudomembranes. Clostridium difficile culturing, and C. difficile toxin assay. The Gram stain was moderately difficult to interpret and was not useful in diagnosing diarrheal disease associated with C. difficile.

In a one-year period, 149 adult cases of Clostridium difficile-associated diarrhea and colitis were compared with 148 diarrhea-free controls. Eighty-seven percent were nosocomial and 75% were on surgical services. Endoscopy revealed pseudomembranes in 51% of the 109 cases in which stool cytotoxin was present, compared with 11% of the 40 cases that were culture-positive but cytotoxin-negative. Cases diagnosed only by stool culture showed essentially no differences from controls, 21% of whom had asymptomatic stool colonization. We estimate that only 20% of these cases had diarrhea due to C difficile. Compared with controls, cases diagnosed by the presence of cytotoxin or pseudomembranes were found to have been hospitalized longer at diarrhea onset, to have had more antecedent infections, and to have received clindamycin, multiple antimicrobials, and therapeutic antimicrobials more often than controls, but controls received prophylactic antimicrobials more frequently than cases. Cultures of the environment, patients, and personnel failed to detect a mechanism of acquisition.

101 patients with Clostridium-difficile-associated diarrhoea or colitis were prospectively randomised to 10-day oral courses of metronidazole, 250 mg four times a day, or vancomycin, 500 mg four times a day. 7 did not complete the protocol and were dropped from analysis. Pseudomembranous colitis (PMC) was diagnosed after endoscopy in 33 patients. Of the remaining patients without PMC, 38 had both C difficile culture and cytotoxin and 23 had only culture evidence of C difficile. 52 evaluable patients received vancomycin and 42 received metronidazole. There were two treatment failures with metronidazole and none with vancomycin (p = 0.20); and two relapses with metronidazole versus six with vancomycin (p = 0.17). Treatment in 1 patient in each group was discontinued because of drug intolerance. Response and relapse rates of the 33 patients with PMC were no different from those of the remaining patients. Pharmacy cost for the dosage used was $387.48 to $520.00 for vancomycin and $11.84 for metronidazole. Metronidazole and vancomycin have equivalent efficacy and relapse rates and are tolerated to a similar extent by patients with C-difficile-related diarrhoea and colitis, but metronidazole is considerably more economical.

A new latex test, Culturette Brand Rapid Latex Test for detection of Clostridium difficile toxin A, was tested on 408 stool samples. In 247 frozen tissue culture supernate specimens previously obtained from patients with C. difficile-associated diarrhea (CAD), the latex test (enterotoxin) was positive in 182 (74%) as compared with 194 (79%) for the repeat tissue culture (P greater than 0.1) cytotoxin (toxin B) test. Testing of 161 fresh stool samples found the latex test superior to tissue culture (P less than 0.05) in cases of CAD (90% positivity vs. 70%), with the two tests being equal in both non-CAD diarrheal and non-diarrheal control groups. In vitro evaluation of 61 C. difficile isolates found all (100%) to be producers of enterotoxin A, while only 53 (87%) produced toxin B. The latex test for C. difficile toxin detection is a rapid, simple test for use in the diagnosis in CAD.

An 18-mo evaluation of culture, cytotoxin, and latex testing for Clostridium difficile was performed between July 1, 1985, and December 31, 1986, on 1,536 specimens from 1,406 patients during evaluation of diarrhea. All cases with at least one test positive were investigated for clinical status. There were 144 Clostridium difficile-associated diarrhea (CAD) patients; 139 (97%) were positive by culture, 96 (67%) by cytotoxin, and 98 (68%) by latex testing. In the 1,262 non-CAD patients with diarrheal stool, 89 (7.1%) were positive by culture, 18 (1.4%) by cytotoxin, and 68 (5.4%) by the latex test. No CAD patient was positive by cytotoxin testing only, and two were positive by latex testing only. The culture and cytotoxin positivity were similar to our previous reports of 90-97% and 70-73%, respectively. Latex sensitivity (68%) was comparable to that of cytotoxin testing in this large group of patients (p greater than 0.5). Overall, in the 1,262 patients without clinical evidence of Clostridium difficile disease, positive tests by latex testing (5.4%) were intermediate between those of culture (7.1%, p less than 0.1) and cytotoxin (1.4%, p less than 0.001).