Clostridium difficile infection

Clostridium difficile is an anaerobic species consisting of bacilli with large, oval, subterminal spores, normally found in intestines. It uses two toxins, which produce cytopathic changes in the intestinal mucosae, causing diarrhea. Patients can present a spectrum of disease that varies from uncomplicated antibiotic-associated diarrhea to life threatening antibiotic-associated pseudomembranous colitis. C. difficile is the only species. There are no defined sterotypes. Toxigenic and nontoxigenic strains exist. The former produce varying amounts of toxin A (enterotoxin) and toxin B (Cytotoxin). Broad spectrum antiboiotic therapy eliminates much competing normal flora, permitting intestinal overgrowth of toxigenic C. difficile. There are no defined host defenses. Metronidazole and vancomycin should be used therapeutically, however, relapses can occur. Supportive therepy may be needed.     

Clostridium difficile isolates with increased sporulation: emergence of PCR ribotype 002 in Hong Kong

We identified a predominant clone of Clostridium difficile PCR ribotype 002, which was associated with an increased sporulation frequency. In 2009, 3,528 stool samples from 2,440 patients were tested for toxigenic C. difficile in a healthcare region in Hong Kong. A total of 345 toxigenic strains from 307 (13.3%) patients were found. Ribotype 002 was the predominant ribotype, which constituted 35 samples from 29 (9.4%) patients. The mean sporulation frequency of ribotype 002 was 20.2%, which was significantly higher than that of the 56 randomly selected ribotypes other than 002 as concurrent controls (3.7%, p?<?0.001). Patients carrying toxigenic ribotype 002 were more frequently admitted from an elderly home (p?=?0.01) and received more ??-lactam antibiotics in the preceding 3 months compared with the controls (p?=?0.04) . The identification of toxigenic ribotype 002 in 2009 was temporally related to a significant increase in both the incidence of toxigenic C. difficile from 0.53 to 0.95 per 1,000 admissions (p?<?0.001) and the rate of positive detection from 4.17% to 6.28% (p?<?0.001) between period 1 (2004?C2008) and period 2 (2009). This finding should alert both the physician and the infection control team to the establishment of and possible outbreaks by ribotype 002 in our hospitals, as in the case of ribotype 027.     

Genomic investigation of a sequence type 67 Clostridium difficile causing community-acquired fulminant colitis in Hong Kong

In 2017, we identified a Clostridium difficile strain HKCD4 that caused community-acquired fulminant colitis in a previously healthy child. Phylogenetically, it belonged to clade 2, sequence type 67 and was resistant to fluoroquinolone and tetracycline. The strain was pathogenicity locus and binary toxin positive. It has a mutation in the trehalose repressor treR leading to the L172I substitution that was previously reported in the epidemic ribotype 027 lineage. HKCD4 has a tcdB sequence that shared very high identities with 3 highly virulent reference strains. It has a CpG depleted genome that is characteristic of hypervirulent C. difficile. The emergence of ST67 lineage with molecular feature of hypervirulence in the community is concerning and emphasizes the need for full characterization of strains causing severe disease in patients without classical risk factors.     

Mathematical modeling of Clostridium difficile infection

Clostridium difficile diarrhea is a major cause of morbidity and mortality in hospitals. However, the number of cases in an outbreak is usually relatively small. This precludes many traditional statistical methods of modeling epidemics. Stochastic models are designed to deal with small numbers and are promising methods of understanding C. difficile epidemiology. This is illustrated by a reversible jump Markov chain Monte Carlo model based on the herd immunity hypothesis of C. difficile outbreaks.     

Nosocomial acquisition of Clostridium difficile infection

We studied the acquisition and transmission of Clostridium difficile infection prospectively on a general medical ward by serially culturing rectal-swab specimens from 428 patients admitted over an 11-month period. Immunoblot typing was used to differentiate individual strains of C. difficile. Seven percent of the patients (29) had positive cultures at admission. Eighty-three (21 percent) of the 399 patients with negative cultures acquired C. difficile during their hospitalizations. Of these patients, 52 (63 percent) remained asymptomatic and 31 (37 percent) had diarrhea; none had colitis. Patient-to-patient transmission of C. difficile was evidenced by time-space clustering of incident cases with identical immunoblot types and by significantly more frequent and earlier acquisition of C. difficile among patients exposed to roommates with positive cultures. Of the hospital personnel caring for patients with positive cultures, 59 percent (20) had positive cultures for C. difficile from their hands. The hospital rooms occupied by symptomatic patients (49 percent) as well as those occupied by asymptomatic patients (29 percent) were frequently contaminated. Eighty-two percent of the infected cohort still had positive cultures at hospital discharge, and such patients were significantly more likely to be discharged to a long-term care facility. We conclude that nosocomial C. difficile infection, which was associated with diarrhea in about one third of cases, is frequently transmitted among hospitalized patients and that the organism is often present on the hands of hospital personnel caring for such patients. Effective preventive measures are needed to reduce nosocomial acquisition of C. difficile.     

Clostridium difficile mixed infection and reinfection

Isolates from consecutive Clostridium difficile infection (CDI) fecal samples underwent multilocus sequence typing. Potential reinfections with different genotypes were identified in 88/560 (16%) sample pairs taken 1 to 1,414 days (median, 24; interquartile range [IQR], 1 to 52 days) apart; odds of reinfection increased by 58% for every doubling of time between samples. Of 109 sample pairs taken on the same day, 3 (3%) had different genotypes. Considering samples 0 to 7 days apart as the same CDI, 7% of cases had mixed infections with >1 genotype.     

Mouse relapse model of Clostridium difficile infection

Clostridium difficile is the causative agent of primary and recurrent antibiotic-associated diarrhea and colitis in hospitalized patients. The disease is caused mainly by two exotoxins, TcdA and TcdB, produced by the bacteria. Recurrent C. difficile infection (CDI) constitutes one of the most significant clinical issues of this disease, occurs in more than 20% of patients after the first episode, and may be increasing in frequency. However, there is no well-established animal model of CDI relapse currently available for studying disease pathogenesis, prevention, and therapy. Here we report the establishment of a conventional mouse model of recurrence/relapse CDI. We found that the primary episode of CDI induced little or no protective antibody response against C. difficile toxins and mice continued shedding C. difficile spores. Antibiotic treatment of surviving mice induced a second episode of diarrhea, while a simultaneous reexposure of animals to C. difficile bacteria or spores elicited a full spectrum of CDI similar to that of the primary infection. Moreover, mice treated with immunosuppressive agents were prone to more severe and fulminant recurrent disease. Finally, utilizing this model, we demonstrated that vancomycin only delayed disease recurrence, whereas neutralizing polysera against both TcdA and TcdB completely protected mice against CDI relapse. In conclusion, we have established a mouse relapse CDI model that allows for future investigations of the role of the host immune response in the disease's pathogenesis and permits critical testing of new therapeutics targeting recurrent disease.     

Clostridium difficile infection: a comprehensive review

Clostridium difficile is one of the most important causes of healthcare acquired diarrhea. The disease spectrum caused by C. difficile infection ranges from mild, self-limited, illness to a severe, life-threatening colitis. The incidence of C. difficile associated disease has risen dramatically over the last decade, leading to increased research interest aiming at the discovery of new virulence factors and the development of new treatment and prevention regimens. This review summarizes the pathogenesis and changing epidemiology of C. difficile associated disease, the clinical spectrum and laboratory methods to diagnose C. difficile infection, and current treatment strategies.     

Update of treatment algorithms for Clostridium difficile infection

BackgroundClostridium difficile is the leading cause of antibiotic-associated diarrhoea, both in healthcare facilities and in the community. The recurrence rate of C. difficile infection (CDI) remains high, up to 20%. Since the publication of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidance document on CDI treatment in 2014, new therapeutic approaches have been developed and tested to achieve higher sustained clinical cure in CDI.AimTo review novel treatments and approaches for CDI, except probiotics and vaccines. We focused on new antibiotics, antibiotic inactivators, monoclonal antibodies and gut microbiota modulating therapies.SourcesA literature review was performed for clinical trials published in PubMed, Embase or Cochrane Library between January 2013 and November 2017.ContentWe analysed 28 clinical trials and identified 14 novel agents. Completed phase 2 studies were found for cadazolid, LFF571, ridinilazole and nontoxigenic C. difficile strains. Four phase 3 active comparator studies comparing vancomycin with bezlotoxumab, surotomycin (n = 2) and rifaximin have been published. Seven clinical trials for treatment of multiple recurrent CDI with faecal microbiota transplantation were analysed, describing faecal microbiota transplantation by upper or lower gastrointestinal route (n = 5) or by capsules (n = 2).ImplicationsMetronidazole is mentioned in the ESCMID guideline as first-line therapy, but we propose that oral vancomycin will become the first choice when antibiotic treatment for CDI is necessary. Fidaxomicin is a good alternative, especially in patients at risk of relapse. Vancomycin combined with faecal microbiota transplantation remains the primary therapy for multiple recurrent CDI. We anticipate that new medication that protects the gut microbiota will be further developed and tested to prevent CDI during antibiotic therapy.     

Clostridium difficile infection in children hospitalized due to diarrhea

The frequency of Clostridium difficile infection (CDI)-related hospitalizations is increasing. The aim of this study was to determine the extent of CDI among children hospitalized with diarrhea, risk factors or predictors for severe CDI, the prevalence of NAP1, and to compare the course of CDI depending on bacteria toxicity profile. A retrospective analysis of case records of 64 children (age range 3 months–16 years, median age 2.12 years) with CDI as defined by diarrheal disease and positive polymerase chain reaction (PCR) test (Xpert C. difficile) was conducted. Modified national adult guidelines were used to assess the severity of CDI. CDIs represented 2.7 % of patients with diarrhea (13.5 cases per 1,000 admissions). Thirty-three CDIs (52 %) were community-associated. Antibacterial use preceded CDI in 61 patients (95 %). Seventeen cases (27 %) were binary toxin-positive (CDT+), 13 of which were NAP1 (20.5 %). Over 75 % of CDIs with NAP1 was hospital-acquired, and more often proceeded with generalized infection (p?<?0.05). Risk factors for severe CDI (34 %) included NAP1 [odds ratio (OR), 4.85; 95 % confidence interval (Cl), 1.23, 21.86) and co-morbidities (OR, 4.25; 95 % Cl, 1.34, 14.38). Diarrhea ≥10 stools daily was associated with severe CDI (p?=?0.01). Recurrence occurred in three patients (4.5 %). There was no mortality. C. difficile is an important factor of antibiotic-associated diarrhea in children. Co-morbidities and NAP1 predispose to severe CDI.     

Prairie dog model for antimicrobial agent-induced Clostridium difficile diarrhea.

We have noted that prairie dogs given cefoxitin develop diarrhea and lose weight yet survive for periods of up to 4 weeks. Therefore, we tested the hypothesis that cefoxitin causes Clostridium difficile cecitis in prairie dogs. Six prairie dogs were given a single intramuscular dose of 100 mg of cefoxitin per kg of body weight, and six control animals received saline; both groups were sacrificed 1 week later. Controls had no diarrhea and lost 2% of their body weight, whereas cefoxitin-treated animals had diarrhea (P less than 0.001) and lost 16% of their body weight (P less than 0.001); one animals died 6 days after cefoxitin challenge. None of the controls yielded C. difficile or had cecal cytotoxin or pseudomembranes detected. Cecal contents from all cefoxitin-treated animals, however, yielded C. difficile (P less than 0.01) and had cecal cytotoxin present (P less than 0.01). Four of five surviving animals also had cecal pseudomembranes present (P less than 0.01). These results demonstrate that in prairie dogs cefoxitin induces C. difficile cecitis. We conclude that the prairie dog is another model for the study of antibiotic-induced diarrhea. The disease in prairie dogs may have a more chronic course than in other animal models of C. difficile-induced diarrhea and may be useful as a model for studying certain aspects of C. difficile-induced diarrhea.     

Clinical characteristics of relapses and re-infections in Clostridium difficile infection

The purpose of this study was to identify factors associated with relapses or re-infections in patients with recurring Clostridium difficile infections (CDIs). From September 2008 to January 2012, cases with two or more isolates from consecutive CDI episodes were included. PCR-ribotyping and multilocus variable-number tandem-repeat analysis were performed using paired isolates. Among 473 patients, 68 (14.4%) experienced one to five recurrences. Fifty-one of these with two or more isolates from consecutive CDI episodes were included in the study; 25 (49%) were classified as relapses and 26 (51%) as re-infections. Recurrence interval was shorter in the relapse group (26.0 versus 67.5 p 0.001), but more patients in the re-infection group were hospitalized during recurrence interval (53.8% versus 8.0%, p <0.001). Relapse rates in infections by ribotype 017, ribotype 018 and other ribotypes were 63.6%, 63.6% and 22.2%, respectively (p 0.274, p 0.069, and p 0.005). In multivariate logistic regression, infections by ribotypes 017 and 018 were associated with CDI relapse (OR 4.77, 95% CI 1.02–22.31, p 0.047; OR 11.49, 95% CI 2.07–63.72, p 0.005). Conversely, admission during recurrence interval lowered the risk of relapse (OR 0.044, 95% CI 0.006–0.344, p 0.003). In conclusion, relapse was more likely when infection was caused by PCR ribotypes 017 and 018.