Update on Clostridium difficile infections

Clostridium difficile infections (CDI) occur primarily in hospitalized patients with risk factors such as concomitant or recent use of antibiotics. CDI related additional costs are important for the global population and health-care facilities. CDI epidemiology has changed since 2003: they became more frequent boosted by large outbreaks, more severe, more resistant to antibiotic treatment, and spread to new groups of population without any risk factor. This is partly due to the emergence and worldwide dissemination of new and more virulent C. difficile strains such as the epidemic clone 027/NAP1/BI. The host immune response plays a central role in the pathogenesis of CDI and could also be involved in the occurrence of recurrent or severe forms. New guidelines including new molecular tests (NAAT) have recently clarified and simplified the diagnostic strategies for the microbiological diagnosis of CDI. The CDI incidence was proven to be related to the level of clinical suspicion and the frequency of microbiological screening for C. difficile. The current recommendations for the treatment of CDI mention oral metronidazole as the first line treatment for mild to moderate diarrhea. Oral vancomycin use should be restricted to severe cases. In the absence of consensus, the treatment of multiple recurrences remains a major concern. New and more targeted antibiotics and innovative therapeutic strategies (fecal transplantation, monoclonal antibodies, and vaccination) have emerged as new therapies for CDI.     

The potential value of Clostridium difficile vaccine: An economic computer simulation model

Efforts are currently underway to develop a vaccine against Clostridium difficile infection (CDI). We developed two decision analytic Monte Carlo computer simulation models: (1) an Initial Prevention Model depicting the decision whether to administer C. difficile vaccine to patients at-risk for CDI and (2) a Recurrence Prevention Model depicting the decision whether to administer C. difficile vaccine to prevent CDI recurrence. Our results suggest that a C. difficile vaccine could be cost-effective over a wide range of C. difficile risk, vaccine costs, and vaccine efficacies especially, when being used post-CDI treatment to prevent recurrent disease.     

Development of a recombinant toxin fragment vaccine for Clostridium difficile infection

Clostridium difficile infection (CDI) is the major cause of antibiotic-associated diarrhea and pseudomembranous colitis, a disease associated with significant morbidity and mortality. The disease is mostly of nosocomial origin, with elderly patients undergoing anti-microbial therapy being particularly at risk. C. difficile produces two large toxins: Toxin A (TcdA) and Toxin B (TcdB). The two toxins act synergistically to damage and impair the colonic epithelium, and are primarily responsible for the pathogenesis associated with CDI. The feasibility of toxin-based vaccination against C. difficile is being vigorously investigated. A vaccine based on formaldehyde-inactivated Toxin A and Toxin B (toxoids) was reported to be safe and immunogenic in healthy volunteers and is now undergoing evaluation in clinical efficacy trials. In order to eliminate cytotoxic effects, a chemical inactivation step must be included in the manufacturing process of this toxin-based vaccine. In addition, the large-scale production of highly toxic antigens could be a challenging and costly process.     

High prevalence of toxinogenic Clostridium difficile in Nigerian adult HIV patients

Clostridium difficile is the most commonly identified bacterial cause of nosocomial and HIV-related diarrhea. In many developing countries, antibiotic access is unregulated. Nigeria has the third highest HIV burden worldwide. Due to perceptions of low prevalence and resource incapacity, patients with diarrhea are not tested for toxinogenic C. difficile infection (CDI). In this pilot study which included 97 HIV-positive patients at two hospitals in Nigeria, the estimated prevalence of CDI was 43% and 14% for in-patients and out-patients respectively. HIV-positive out-patients were more likely to have toxinogenic CDI than non-HIV out-patients (P = 0.007, Fisher's exact test).     

Serum anti-toxin B antibody correlates with protection from recurrent Clostridium difficile infection (CDI)

Background

Previous studies have demonstrated a correlation between Clostridium difficile anti-toxin A serum antibodies and protection against symptomatic disease and recurrence.

Methods

A neutralizing monoclonal antibody to C. difficile toxin A (CDA1) developed by MBL and Medarex, Inc. was studied in a phase II, randomized, double-blind, placebo-controlled trial in patients receiving standard of care treatment for C. difficile infection (CDI). Twenty-nine subjects received a single intravenous infusion of 10 mg/kg CDA1 and 17 subjects received placebo and were evaluated for recurrence of CDI during the 56-day study period. Serum antibodies against C. difficile toxin A and B were measured by ELISA and cytotoxicity assay at various time points before and after infusion.

Findings

CDI recurrence occurred in 5 of 29 (17%) in the CDA1 group and 3 of 17 (18%) (p = NS) in the placebo group with a trend toward delay in time to recurrence in the group treated with CDA1. The geometric mean concentration of antibody to an epitope of the receptor-binding domain of toxin B (0.300 and 1.20 μg/ml, respectively; p = 0.02) and geometric mean titer of neutralizing B antibody (8.00 and 100, respectively; p = 0.02) at study day 28 were lower for those subjects with recurrence compared to those who did not recur. In addition, a significantly greater proportion of subjects who recurred were infected with the epidemic BI/NAP1/027 strain compared with those that did not recur (88% vs. 22%; p = 0.002). Finally, in a multiple logistic regression analysis neutralizing anti-toxin B at day 14 (p < 0.001), anti-toxin A at day 28 (p < 0.001) and infection with the BI/NAP1/027 strain at enrollment (p = 0.002) were all predictive of CDI recurrence.

Interpretation

In this prospective study, lower concentrations of neutralizing anti-toxin B and anti-toxin A antibody and infection with the BI/NAP1/027 strain of C. difficile were significantly associated with recurrence of CDI.     

Quantifying Transmission of Clostridium difficile within and outside Healthcare Settings

To quantify the effect of hospital and community-based transmission and control measures on Clostridium difficile infection (CDI), we constructed a transmission model within and between hospital, community, and long-term care-facility settings. By parameterizing the model from national databases and calibrating it to C. difficile prevalence and CDI incidence, we found that hospitalized patients with CDI transmit C. difficile at a rate 15 (95% CI 7.2–32) times that of asymptomatic patients. Long-term care facility residents transmit at a rate of 27% (95% CI 13%–51%) that of hospitalized patients, and persons in the community at a rate of 0.1% (95% CI 0.062%–0.2%) that of hospitalized patients. Despite lower transmission rates for asymptomatic carriers and community sources, these transmission routes have a substantial effect on hospital-onset CDI because of the larger reservoir of hospitalized carriers and persons in the community. Asymptomatic carriers and community sources should be accounted for when designing and evaluating control interventions.     

Environmental survey to assess viral contamination of air and surfaces in hospital settings

This report describes an outbreak of Clostridium difficile infection (CDI) in a vascular surgery ward in 2009 caused by a high-level clindamycin-resistant ribotype 106. A case of CDI was defined as a patient with diarrhoea, positive for C. difficile toxin and negative for other enteric pathogens. Cultures were sent to the Scottish Salmonella Shigella and Clostridium difficile Reference Laboratory (SSSCDRL) for PCR ribotyping, antibiotic susceptibility testing and PCR detection of ermB. The mean age of the nine patients was 73 years (range: 38–90 years). All had received clindamycin and ciprofloxacin. All cases were typed as PCR ribotype 106 and they showed high-level resistance to clindamycin. Five of these isolates were tested by PCR for the presence of the ermB gene and no amplification was detected. This strain has rarely been isolated from patients on this ward. The outbreak was controlled successfully by closure of the ward with terminal cleaning, reinforcement of infection control precautions and the introduction of a new antibiotic policy. It is notable that this outbreak was caused by a strain with high-level clindamycin resistance not mediated by ermB. It also re-emphasizes that outbreaks of CDI can be caused by C. difficile PCR ribotypes other than 027. The outbreak was most likely associated with the use of clindamycin and ciprofloxacin cross-infection with spores in this environment. Implementation of strict infection control precautions, antimicrobial stewardship and enhanced environmental cleaning are key components in managing such an outbreak successfully. The number of meticillin-resistant Staphylococcus aureus acquisitions also fell substantially after these interventions.     

Trends in Incidence and Clinical Outcomes of Clostridioides difficile Infection,Hong Kong

We conducted a territorywide survey to investigate the epidemiology, risk factors, and clinical outcomes of Clostridioides difficile infection (CDI) among hospitalized patients in Hong Kong. A total of 17,105 cases of CDI were identified, of which 15,717 (91.9%) were healthcare-associated and 1,025 (6.0%) were community-associated. Although CDI incidence increased substantially from 2006 to 2017, it plateaued in 2018 and 2019. The 30-day mortality rates decreased from 20.1% in 2015 to 16.8% in 2019, whereas the 60-day recurrence rates remained constant at ≈11% during the study period. Cross-correlation statistic showed significant correlations between incidence trend and overall antimicrobial drug use (r = 0.865, p<0.001), which has decreased as a result of an antibiotic stewardship program initiated in 2017. Our data suggest a turning point in C. difficile epidemiology that could be related to the changing pattern of antimicrobial drug use.     

Clostridium difficile acquisition rate and its role in nosocomial diarrhoea at a university hospital in Turkey

Infection with Clostridium difficile can present with various clinical pictures ranging from an asymptomatic carrier state to pseudomembranous colitis and plays an important part in the etiology of nosocomial diarrhoea. To identify risk factors for C. difficile colonization and diarrhoea in hospitalized subjects, patients admitted to a general medicine ward at Marmara University hospital during a one year period were entered into the study. Of the 202 patients, nosocomial diarrhoea developed in 45 (22.3%). Fourteen patients (6.9%) were colonized with C. difficile during their hospitalization period. Ten of the colonized patients (71.4%) developed diarrhoea and were found to be positive by toxin assay. Pseudomembranous colitis was confirmed endoscopically in 3 of the patients with diarrhoea. Administration of beta lactam agents such as ampicillin and cephalosporins; gastrointestinal manipulations and admission to the intensive care unit were found as major risk factors for C. difficile colonization.     

Tackling the recurrence of Clostridium difficile infection

The pathogenesis of recurrent Clostridium difficile infection (CDI) is still poorly understood. The risk of recurrence is approximately 20% after an initial CDI episode and dramatically increases with subsequent CDI recurrences. Several factors may play a role in recurrent CDI (rCDI), including conditions influencing germination, metabolic pathways that influence toxin production of C. difficile, and the microbiota composition offering protection against colonization and disease caused by C. difficile. Paradoxically, the currently recommended treatment for acute symptomatic CDI, i.e. metronidazole or vancomycin, can cause modification of the intestinal flora. Indeed, administration of anti-CDI antibiotics leads to suppression of C. difficile, along with collateral damage of the protective intestinal microbiota and opening of a “window of vulnerability” for recurrence. Host factors also have a prominent role, including innate and acquired humoral immunity, i.e. passive antibodies administration or active vaccination as a prevention strategy. They play a crucial role in the protection against severe and recurrent CDI. The assessment of risk factors of recurrence and modeling prediction scores could help in preventing the troublesome experience of CDI recurrence. Six studies have methodologically assessed prediction scores for rCDI. However, the definition of recurrence was heterogeneous, external validation was often not performed, and immunological factors were often not considered. There is a need for further studies on the pathophysiology of recurrence to design models for prediction that are sound and applicable in clinical practice.     

Exploring ways to improve CDI outcomes

Clostridium difficile is an anaerobic spore-forming Gram-positive bacillus recognized as an evolving international health problem. Metronidazole and vancomycin were – until recently – the only drugs available to treat C. difficile infection (CDI). Better knowledge of the pathophysiology and the development of new drugs completely modified the management of initial episodes and recurrences of CDI. Fidaxomicin significantly reduced recurrences compared with vancomycin. New drugs are also currently evaluated (cadazolid, surotomycin, ridinilazole, rifaximin). Gut microbiota homeostasis was clearly shown to be a key determinant in recurrences as demonstrated by the development of gut microbiota transplantation and alternative microbiota substitution. Passive immunotherapy and vaccinal approaches are also currently being evaluated. In conclusion, CDI treatment has evolved with the development of new therapeutic pathways which now need to be implemented in international guidelines.     

The projected effectiveness of Clostridium difficile vaccination as part of an integrated infection control strategy

BackgroundEarly clinical trials of a Clostridium difficile toxoid vaccine show efficacy in preventing C. difficile infection (CDI). The optimal patient group to target for vaccination programmes remains unexplored. This study performed a model-based evaluation of the effectiveness of different CDI vaccination strategies, within the context of existing infection prevention and control strategies such as antimicrobial stewardship.MethodsAn individual-based transmission model of CDI in a high-risk hospital setting was developed. The model incorporated data on patient movements between the hospital, and catchment populations from the community and long-term care facilities (LTCF), using English national and local level data for model-parameterisation. We evaluated vaccination of: (1) discharged patients who had an CDI-occurrence in the ward; (2) LTCF-residents; (3) Planned elective surgical admissions and (4) All three strategies combined.ResultsWithout vaccination, 10.9 [Interquartile range: 10.0–11.8] patients per 1000 ward admissions developed CDI, of which 31% were ward-acquired. Immunising all three patient groups resulted in a 43% [42–44], reduction of ward-onset CDI on average. Among the strategies restricting vaccination to one target group, vaccinating elective surgical patients proved most effective (35% [34–36] reduction), but least efficient, requiring 146 [133–162] courses to prevent one ICU-onset case. Immunising LTCF residents was most efficient, requiring just 13 [11–16] courses to prevent one case, but considering this only comprised a small group of our hospital population, it only reduced ICU-onset CDI by 9% [8–11]. Vaccination proved most efficient when ward-based transmission rates and antimicrobial consumption were high.ConclusionsStrategy success depends on the interaction between hospital and catchment populations, and importantly, consideration of importations of CDI from outside the hospital which we found to substantially impact hospital dynamics. Vaccination may be most desirable in settings or patient groups where levels of broad-spectrum antimicrobial use are high and difficult to reduce.     

Nosocomial diarrhea and Clostridium Difficile associated diarrhea in a Turkish University Hospital

Background

Clostridium difficile (C. difficile) is a well-established cause of nosocomial diarrhea. The aim of our study was to define the incidence of nosocomial diarrhea in our hospital and to determine the role of C. difficile. Additionally, the risk factors for nosocomial diarrhea and Clostridium difficile associated diarrhea (CDAD) were investigated.

Methods

We included all patients, 18 years of age or more, who were admitted to the Uludag Teaching Hospital between October 1, 2004 and February 1, 2005, and developed diarrhea at least three days after hospital admission. A case-control study was performed.

Results

The total incidence of nosocomial diarrhea was 0.6 per 1,000 hospitalization-days and 5 per 1,000 patients’ admissions. Previous use of chemotherapy was found to be an important predisposing factor for nosocomial diarrhea. The incidence of CDAD was 0.26 per 1,000 hospitalization-days and 2.1 per 1,000 admissions, comparable with incidence rates in Europe.CDAD was diagnosed in 43% of patients with nosocomial diarrhea. No severe cases of CDAD were diagnosed. A correlation was found between CDAD and antibiotic use before admission and during admission in univariate analysis. PCR ribotyping revealed four strains of PCR ribotype 002 and 1 strain of ribotype 012 out of 5 C. difficile strains available for extensive identification.

Conclusion

The incidence rates of nosocomial diarrhea and CDAD are not different than the usual incidence rates in Europe. C. difficile was the causative agent in 43% of patients with nosocomial diarrhea.     

Clostridium difficile in Retail Meat Products, USA, 2007

To determine the presence of Clostridium difficile, we sampled cooked and uncooked meat products sold in Tucson, Arizona. Forty-two percent contained toxigenic C. difficile strains (either ribotype 078/toxinotype V [73%] or 027/toxinotype III [NAP1 or NAP1-related; 27%]). These findings indicate that food products may play a role in interspecies C. difficile transmission.     

Automated system to identify Clostridium difficile infection among hospitalised patients

The purpose of this study was to assess whether data on stool frequency collected electronically could identify patients at high risk for Clostridium difficile infection (CDI). All patients with reports of diarrhoea were assessed prospectively for number of stools per day and number of diarrhoea days. C. difficile testing was requested independently from study investigators. Number of days with diarrhoea and maximum number of unformed stools was assessed as a CDI predictor. A total of 605 patients were identified with active diarrhoea of whom 64 (10.6%) were diagnosed with CDI. In univariate analysis, the maximum number of stools and number of diarrhoea days was associated with increased risk of CDI. Compared to patients with three diarrhoea stools per day (CDI incidence: 6.3%), CDI increased to 13.4% in patients with four or more diarrhoea stools per day [odds ratio (OR): 2.3; 95% confidence interval (CI): 1.3–4.2; P = 0.0054]. Compared to patients with one day of diarrhoea (CDI incidence: 6.3%), CDI increased to 17.4% in patients with two diarrhoea days (OR: 3.1; 95% CI: 1.7–5.6) and to 27.1% in patients with three or more diarrhoea days (OR: 5.5; 95% CI: 2.6–11.7). These results were validated using logistic regression with number of days with diarrhoea identified as the most important predictor. Using an electronic data capture technique, number of days of diarrhoea and maximum number of diarrhoea stools in a 24 h time period were able to identify a patient population at high risk for CDI.     

器官移植术后并发耐碳青霉烯类肺炎克雷伯菌医院感染的危险因素

 目的 探讨器官移植术后并发耐碳青霉烯类肺炎克雷伯菌（CRKP）医院感染的危险因素,为CRKP的防控提供依据。方法 选取某院器官移植病房2014年1月1日—2018年7月31日确诊为CRKP医院感染的54例住院患者为病例组,选择同期该科室确诊为碳青霉烯类敏感肺炎克雷伯菌（CSKP）医院感染的27例住院患者为对照组,采取回顾性病例对照研究方式进行研究。结果 两组患者医院感染部位均以下呼吸道（42.59%和48.15%）和手术部位（44.44%和25.93%）为主;除头孢唑林外,两组器官移植术后患者分离肺炎克雷伯菌对其他20种抗菌药物的耐药率比较,差异均有统计学意义（均P<0.05）。单因素分析显示,年龄、送检前抗菌药物使用种类≥3种、送检前有碳青霉烯类使用史、送检前有抗真菌药物使用史均与器官移植术后患者发生CRKP医院感染相关（均P<0.05）;多因素分析显示,年龄、送检前抗菌药物使用种类≥3种、送检前有碳青霉烯类使用史是器官移植术后患者发生CRKP医院感染的独立危险因素。结论 应针对危险因素加强器官移植术后患者的医院感染防控措施,尤其是碳青霉烯类抗生素的合理使用。     

Risks and Preventive Strategies for Clostridioides difficile Transmission to Household or Community Contacts during Transition in Healthcare Settings

The burden of Clostridioides difficile infection (CDI) has greatly increased. We evaluated the risks for CDI transmission to community members after hospitalized patients are discharged. We conducted a systematic literature review in MEDLINE/PubMed, EMBASE, CINAHL plus EBSCO, Web of Science, Cochrane Library, and gray literature during January 2000‒February 2019 and identified 4,798 citations were identified. We eliminated 4,554 citations through title and abstract screening; 217 additional citations did not meet full criteria. We reviewed texts for the 27 remaining articles qualitatively for internal/external validity. A few identified studies describing risks to community members lacked accurate risk measurement or preventative strategies. Primary data are needed to assess efficacy of and inform current expertise-driven CDI prevention practices. Raising awareness among providers and researchers, conducting clinical and health services research, linking up integrated monitoring and evaluation processes at hospitals and outpatient settings, and developing and integrating CDI surveillance systems are warranted.     

Prevalence of Antibiotic Resistance in Escherichia coli Fecal Isolates From Healthy Persons and Patients With Diarrhea

Objectives

This study aimed to investigate the prevalence of antibiotic resistance in fecal Escherichia coli isolates from healthy persons and patients with diarrhea.

Methods

E. coli isolates (n = 428) were obtained from fecal samples of apparently healthy volunteers and hospitalized patients with diarrhea. Susceptibility patterns of isolates to 16 antimicrobial agents were determined by agar disc diffusion.

Results

Most E. coli isolates exhibited less than 10% resistance against imipenem, cefotetan, aztreonam, cefepime, cefoxitin, amikacin and netilamicin, although greater than 65% were resistant to ampicillin and tetracycline. No significant difference in resistance rates for all tested antibiotics was found between isolates from the healthy-and diarrheal-patient groups, including for multi-drug resistance (p = 0.22). The highest number of resistant antibiotics was 12 antibiotics. No significant differences in antibiotic resistance were found among the sex and age strata for isolates from healthy individuals. However, antibiotic resistance rates to cefoxitin, cefotaxime, amikacin, and netilamicin were significantly higher in the isolates of men than those of women (p < 0.05) in isolates from patients with diarrhea. Furthermore, isolates from patients with diarrhea older than 40-years of age showed higher resistance to cefepime and aztreonam (p < 0.05).

Conclusion

High resistance to the antibiotics most frequently prescribed for diarrhea was found in isolates from patients with diarrhea and apparently healthy individuals without any significant difference.