Severe Clostridium Difficile-associated Disease Research Articles

Preclinical evaluation of the maximum tolerated dose and toxicokinetics of enteric-coated lantibiotic OG253 capsules

Clostridium difficile associated disease (CDAD) is the leading infectious cause of antibiotic-associated diarrhea and colitis in the United States. Both the incidence and severity of CDAD have been increased over the past two decades. We evaluated the maximum tolerated dose (MTD) and toxicokinetics of OG253, a novel lantibiotic in development for the treatment of CDAD. OG253 was orally administered to Wistar Han rats as enteric-coated capsules in a one-day dose escalation study, followed by a seven-day repeated dose toxicokinetics study. All three doses of OG253 (6.75, 27 and 108 mg/day) were generally well-tolerated with no treatment-related clinical signs, alterations in body weight or food consumption in both one-day acute tolerability and seven-days repeated dose tolerability and toxicokinetics study. OG253 capsule administration neither significantly alter the weight of organs nor affect the hematology, coagulation, clinical biochemistry parameters and urine pH compared to placebo capsule administered rats. LC-MS/MS analysis did not detect OG253 in the plasma, indicating that OG253 is not absorbed into the blood from the rat gastrointestinal tract. Glandular atrophy of the rectal mucosa was noticed in two out of six rats administered with a high dose of OG253. Surprisingly, we found that OG253 treatment significantly lowered both serum cholesterol and triglyceride levels in both sexes of rats. Overall, there was a 29.8 and 61.38% decrease in the serum cholesterol and triglyceride levels, respectively as compared to placebo-treated rats. The well-tolerated high dose of OG253 (425.7 mg/kg/day) is recommended as the MTD for safety and efficacy studies. Further preclinical study is needed to evaluate the safety profile of OG253 under longer exposure.

Immunogenicity of Clostridium difficile DNA-based vaccine in an aging mouse model

Event Abstract Back to Event Immunogenicity of Clostridium difficile DNA-based vaccine in an aging mouse model Mariana E. Bernui1*, Scott Baliban1, Jeffrey Jacobson1 and Michele Kutzler1 1 Drexel University College of Medicine, Department of Medicine; Department of Microbiology and Immunology, United States Clostridium difficile infection (CDI) is a major source of morbidity and mortality in the United States, costing our healthcare system ~ $1.1 billion/year. CDI has led to a doubling of mortality with greater than 90% of these deaths occurring in individuals >85yrs. There is a significant correlation between advanced age and risk of recurrent CDI. Protection against severe Clostridium difficile-associated disease and reduction of recurrent CDI is mediated by host antibody responses against the toxins of C. difficile. The goal of our study is to determine the immunogenicity of a DNA based anti-toxin vaccine in an aging mouse model. Thus, young (4 mo.) and old (>18mo.) mice were immunized with our optimized DNA vaccine encoding toxin A and toxin B receptor-binding domain of Clostridium difficile (A-RBD; B-RBD). Day 12 after the first immunization the younger mice had significantly higher IgG titers against A-RBD than older mice, with 25 ug/ul versus 5 ug/ul anti-toxin serum IgG. However 10 days post second immunization the old and young mice had comparable IgG titers of approximately 500 ug/ul IgG against A-RBD. Interestingly, anti toxin B-RBD IgG responses in older mice remained statistically lower when compared to young following the second immunization (1000 ug/ul vs 2000 ug/ul). We also observe differences in anti-toxin IgG and IgA in fecal extracts post immunization between aged and young mice. These data suggest that our DNA vaccine platform is able to generate an antibody response against C. difficile toxin-based DNA vaccines in older mice but defects in vaccine priming may be occurring leading to lower titers. Two weeks post second immunization, mice were euthanized and their cellular response to the DNA vaccine was analyzed. Using flow and ELISpot assays, higher frequencies of CD4+/CD44+ (activated) T cells were detected in older mice than in the younger cohorts. Finally, we observed a higher frequency of toxin-specific CD4+ T cells that secrete pro-inflammatory cytokines (IFN-g, IL2) and Th2 cytokines (IL4, IL10) in older mice, supporting the notion of a deleterious “inflamm-aging” response. These data warrant further study of the mechanism by which lower vaccine priming or inflammation in aged mice lead to lower titers of anti-toxin vaccine responses. Keywords: Clostridium difficile, immunosenescence, immunization in elderly, aging mouse model, immune response in aging Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Translational immunology and immune intervention Citation: Bernui ME, Baliban S, Jacobson J and Kutzler M (2013). Immunogenicity of Clostridium difficile DNA-based vaccine in an aging mouse model. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00914 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 27 Jun 2013; Published Online: 22 Aug 2013. * Correspondence: Dr. Mariana E Bernui, Drexel University College of Medicine, Department of Medicine; Department of Microbiology and Immunology, Philadelphia, PA, United States, mariana.bernui@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Mariana E Bernui Scott Baliban Jeffrey Jacobson Michele Kutzler Google Mariana E Bernui Scott Baliban Jeffrey Jacobson Michele Kutzler Google Scholar Mariana E Bernui Scott Baliban Jeffrey Jacobson Michele Kutzler PubMed Mariana E Bernui Scott Baliban Jeffrey Jacobson Michele Kutzler Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Drugs and Severity of an Emerging Disease— Clostridium difficile Associated Disease

Drugs and Severity of an Emerging Disease— Clostridium difficile Associated Disease

Clostridium difficile‐associated disease in allogeneic hematopoietic stem‐cell transplant recipients: risk associations, protective associations, and outcomes

The purpose of this study was to evaluate risk factors, protective factors, and outcomes associated with Clostridium difficile-associated disease (CDAD) in allogeneic hematopoietic stem-cell transplant (HSCT) recipients. A case-control study was performed with 37 CDAD cases and 67 controls. In the multivariable logistic regression analysis, receipt of a third or fourth generation cephalosporin was associated with increased risk of CDAD (OR = 4.6, 95% CI 1.6-13.1). Receipt of growth factors was associated with decreased risk of CDAD (OR=0.1, 95% CI 0.02-0.3). Cases were more likely to develop a blood stream infection after CDAD than were controls at any point before discharge (p < 0.001). CDAD cases were more likely than controls to develop new onset graft-vs.-host disease (GVHD) (p < 0.001), new onset severe GVHD (p < 0.001), or new onset gut GVHD (p = 0.007) after CDAD/discharge. Severe CDAD was a risk factor for death at 180 d in multivariable Cox proportional hazards regression (HR=2.6, 95% CI 1.1-6.2). CDAD is a significant cause of morbidity and mortality in allogeneic HSCT patients, but modifiable risk factors exist. Further study is needed to determine the best methods of decreasing patients' risk of CDAD.

Systemic absorption of oral vancomycin in a peripheral blood stem cell transplant patient with severe graft‐versus‐host disease of the gastrointestinal tract

Oral vancomycin is often considered the drug of choice for severe Clostridium difficile-associated disease due to both its efficacy and pharmacokinetics. The potential for absorption is not well described in patients with impaired gastrointestinal (GI) mucosa. We describe a case of significant and potentially toxic absorption of oral vancomycin in a peripheral blood stem cell transplant patient with grade IV graft-versus-host disease (GVHD) of the GI tract. In patients with GI GVHD clinicians need to be aware of the potential for oral absorption and, in select cases, monitoring of levels may be appropriate.

Clinically important interaction between statin drugs and Clostridium difficile toxin?

Clostridium difficile associated disease (CDAD), a common type of antibiotic associated diarrhea, is increasing in frequency and affecting patients outside of traditional populations. At one time CDAD exclusively occurred in hospitalized patients or frail elderly patients receiving antibiotic therapy. It is now occurring more commonly in younger patients who are relatively healthy and may not be receiving antibiotics. Co-factors that might explain this increase incidence and changing demographic are of great public health interest. Recent investigations have identified gastric acid suppression, particularly via proton pump inhibitors, as a risk factor for the development of CDAD by mechanisms which are not entirely clear. C. difficile toxin comes as two major forms that are closely related, toxin A and toxin B and both are able to produce CDAD. These toxins have a glucosyltransferase domain that glucosylates actived Rho, a small GTP binding protein involved in multiple cellular signaling pathways. Glucosylation inactivates Rho and modifies cell cycle, cytoskeletal and inflammatory pathways. The lipid lowering drugs called statins also inhibit Rho but at an earlier step in the Rho pathway. Statins inhibit the isoprenylation of Rho and therefore inhibits membrane anchoring a key step in Rho signaling. We propose that statins potentiate C. difficile toxin effects on colonic epithelium which leads to an increased risk of CDAD. We present preliminary data from a retrospective cohort which demonstrated an increased rate of CDAD in patients receiving statins compared to non-statin controls. The weight of the evidence leads to our hypothesis that statins interact with C difficile toxin A and B causing an increase in the rate and severity of CDAD.

Clinical Risk Factors for SevereClostridium difficile–associated Disease

Identifying patients who are at high risk for severe Clostridium difficile-associated disease (CDAD) early in the course of their infection may help clinicians improve outcomes. Therefore, we compared clinical features associated with severe versus nonsevere CDAD by retrospectively reviewing records of hospitalized patients whose fecal assays were positive for C. difficile toxin. Of 336 patients, 12.2% had severe disease and 10.1% died from all causes. Regression modeling showed the following to be significantly associated with severe CDAD (p< or =0.05): age >70 years (odds ratio [OR] 3.35), maximum leukocyte count >20,000 cells/mL (OR 2.77), minimum albumin level <2.5 g/dL (OR 3.44), maximum creatinine level >2 mg/dL (OR 2.47), small bowel obstruction or ileus (OR 3.06), and computed tomography scan showing colorectal inflammation (OR 13.54). These clinical and laboratory markers for severe disease may be useful for identifying patients at risk for serious outcomes or death.

Clinical Characteristics and Changing Epidemiology of Clostridium difficile-Associated Disease (CDAD)

The spectrum of Clostridium difficile-associated disease (CDAD) ranges from mild diarrhea to life-threatening colitis. Recent studies reported an increase in incidence and severity of CDAD and the presence of severe community-acquired CDAD (CA-CDAD). The aims of this study were to investigate the incidence of CA-CDAD and non-antibiotics-associated CDAD, and to compare the clinical characteristics between hospital-acquired (HA) and CA-CDAD. The medical records of 86 patients who were diagnosed as CDAD in Hanyang University Guri Hospital between January 2005 and October 2007 were retrospectively reviewed. Of the 86 patients (mean age 64 years), 53 patients were women. The most frequently prescribed antibiotics were cephalosporins (67.4%), followed by aminoglycosides (38.4%) and quinolones (14%). Of the 86 patients, the average duration of treatment and recovery time of symptoms were 11.5 days and 4.6 days, respectively. Seven percent of patients experienced relapse treatment. The overall incidence rate of CA-CDAD and non-antibiotics-associated CDAD were 10.5% and 22.1%, respectively. CA-CDAD group had lower rate of antimicrobial exposure whilst showing higher rate of complications compared to HA-CDAD group. Three patients in the CA-CDAD progressed towards a severe complicated clinical course, including septic shock. The incidence rate of CA-CDAD and non-antibiotics-associated CDAD were 10.5% and 22.1%, respectively. CA-CDAD tends to have a higher complication rate compared to HA-CDAD. Community clinicians needs to maintain a high level of suspicion for CDAD, whilst coping with the ever evolving epidemiologic change.

An outbreak of Clostridium difficile-associated disease (CDAD) in a German university hospital

We investigated an outbreak of Clostridium difficile (CD)associated disease (CDAD) in a cardiac surgical department that took place between January 25th and April 28th 2007 at Hannover Medical School, Germany. Immediate infection control measures such as changing the surface disinfectant from an alcohol-based glucoprotamine to an oxygen-active disinfectant cleaner and the primary education of staff were proved to be insufficient to control the outbreak. Therefore, a “CD infection control bundle” was created consisting of: (a) implementation of a CDAD outbreak team; (b) education on hand hygiene; (c) the aim of early case finding as soon as clinical symptoms of CDAD were noticed; (d) daily control of microbiological results; (e) suggesting proper antimicrobial therapy of patients on the ward avoiding high-risk substances; (f) reinforcement of currently existing infection control measures, such as including the isolation of CDAD cases in single rooms; (g) and, finally, interim closure of the unit for any new admissions. For the treatment of CDAD, initially, metronidazole and, in the case of failure of initial therapy, oral vancomycin were used. A case–control study was performed. Cases were defined as proposed by the ECDC: (a) onset of diarrhoea ≥48 h after admission or ≥4 weeks after the most recent discharge and (b) positive enzyme-immunoassay (EIA) for CD toxins A or B in stool samples (RIDASCREEN® Clostridium difficile Toxin A/B test, R-Biopharm, Glasgow, United Kingdom) or the culturing of toxin-producing CD (Clostridium difficile-selective media, Oxoid, Hampshire, United Kingdom). The results of Gram strain, colony morphology and biochemical testing with the RapID II ANA System® (Remel, Lenexa, USA) were used for species determination. Cultured strains were examined by pulsed field gel electrophoresis (PFGE) using GelCompar II® software (Applied Maths NV, Sint-Martens-Latern, Belgium) and by polymerase chain reaction (PCR) ribotyping, as described by others [1]. Antimicrobial susceptibility testing was performed by E-test® (AB Biodisk, Solna, Sweden) on agar plates containing vitamin K1, haemin and 5% defibrinated sheep red blood cells (Inverness Medical Deutschland, Cologne, Germany). Breakpoint minimal inhibitory concentrations (MICs) were ≥8 μg/mL for fluoroquinolones (FQ) [2] and ≥4 μg/mL for erythromycin [3]. Severe CDAD was defined as readmission because of relapse, necessity of intensive care because of CDAD, surgical procedure due to CDAD or CDAD contributing to the patient’s death within 30 days after diagnosis [4–6]. Controls were diarrhoeal patients admitted to the same unit during the same time period but were negative for CD toxin EIA, including CD culture (= confirmed CD negative) and negative for other gastrointestinal infectious agents. Age, gender, co-morbidities, underlying diseases, endoscopic procedures, history of antimicrobial exposure, readmission and relapse of CDAD in both groups were Eur J Clin Microbiol Infect Dis (2009) 28:543–545 DOI 10.1007/s10096-008-0655-7

Update in infectious disease treatment

Studies published during the past year on the treatment of several infectious diseases provide valuable information that should enable us to treat our patients more effectively. Among those findings: Oral vancomycin (Vancocin) is superior to oral metronidazole (Flagyl) for treating patients with severe Clostridium difficile-associated disease. The risk of death from any cause may be higher with the use of cefepime (Maxipime) than with other beta-lactam antibiotics. In patients presenting to primary care physicians with symptoms of acute maxillary sinusitis, antibiotics and topical nasal steroids do not seem to be effective, either alone or in combination. For patients with Bell palsy, early treatment with prednisolone improves the chance of complete recovery; antiviral therapy may be indicated for patients with complete facial nerve paralysis. In patients undergoing chemotherapy for acute myelogenous leukemia or myelodysplasia, posaconazole (Noxafil) prevented fungal infections more effectively than fluconazole (Diflucan) or itraconazole (Sporanox) and improved overall survival. Anidulafungin (Eraxis) was not inferior to fluconazole in the treatment of invasive candidiasis.

Clostridium difficile–associated diarrhea: an emerging threat to pregnant women

To estimate if Clostridium difficile-associated disease (CDAD) is increasing in peripartum women. Peripartum CDAD was assessed through 1) passive surveillance collecting clinical and pathology data on severe cases and 2) survey among infectious disease consultants (ICDs) in the Emerging Infections Network. Ten severe cases were collected; most had associated antibiotic use. Seven women were either admitted to the ICU or underwent colectomy. Three infants were stillborn, and 3 women died. The epidemic Clostridium difficile strain was found in 2 cases. Among 798 ICDs, 419 (52%) participated in the survey. Thirty-seven respondents (9%) recalled 55 cases, mostly in the postpartum period with 21 complications, mainly due to relapse. Severe CDAD may be increasing in peripartum women. Clinicians should have a low threshold for testing, be aware of the potential for severe outcomes, and take steps to reduce both the risk of disease and resultant complications.

Update on the changing epidemiology of Clostridium difficile-associated disease

In the past, Clostridium difficile-associated disease (CDAD) was thought of mainly as a nosocomial disease associated with the use of broad-spectrum antibiotics, but its epidemiology seems to be changing. Since 2002, outbreaks of severe CDAD associated with increased mortality and reduced effectiveness of treatment with metronidazole have focused attention on this challenging pathogen. A fluoroquinolone-resistant strain of C. difficile (BI/NAP1/027) has been predominantly associated with these outbreaks. Changes in the epidemiology of CDAD include the emergence of new at-risk populations and the increased incidence of the disease. Infection control programs and more effective treatments offer hope that future outbreaks of CDAD can be controlled.

Characteristics and incidence of Clostridium difficile-associated disease in The Netherlands, 2005

During a 2-month period in 2005, 13 laboratories participated in a surveillance study of Clostridium difficile-associated disease (CDAD) in 17 hospitals in The Netherlands. The median incidence rate of CDAD was 16/10 000 patient admissions (2.2/10 000 patient-days) and varied from 1 to 46/10 000 patient admissions according to hospital. In total, 81 patients with CDAD were reported; 49 (61%) patients had nosocomial CDAD, and 29 (36%) patients were admitted to hospital when already suffering from diarrhoea. Two (2%) deaths were attributable to CDAD; both of these patients were admitted with severe community-onset CDAD and were aged >80 years. Among 64 toxinogenic isolates, ten (16%) belonged to PCR ribotype 027 and ten (16%) to PCR ribotype 014. Type 027 was identified in ten patients from one hospital during an unrecognised outbreak. Toxinotyping of the 64 isolates revealed the presence of six different toxinogenic types, with 41 (64%) isolates of toxinotype 0, ten (16%) isolates of toxinotype III, and nine (14%) isolates of toxinotype V. Of the 64 toxinogenic isolates, seven (11%) had a 39-bp deletion in the tcdC gene, 11 (17%) had an 18-bp deletion, and one (1%) had a deletion of c. 44 bp. Genes for binary toxin were present in 21 (33%) of the 64 toxinogenic isolates, mainly associated with toxinotypes III and V. It was concluded that the median CDAD incidence rate of 16/10 000 patient admissions in The Netherlands is considerably lower than that in Canada and the USA, and that the emerging type 027 can spread unnoticed. The high proportion (36%) of CDAD cases with a community onset has important implications for future studies of the epidemiology of CDAD.

The Challenges Posed by Reemerging Clostridium difficile Infection

There have been recent, marked increases in the incidence and severity of Clostridium difficile-associated disease (CDAD). These may be attributable to the emergence of a hypervirulent strain of C. difficile that produces increased levels of toxins A and B, as well as an extra toxin known as "binary toxin." This previously uncommon strain has become epidemic, coincident with its development of increased resistance to fluoroquinolones, the use of which is increasingly associated with CDAD outbreaks. Although not necessarily related to this epidemic strain, unusually severe CDAD has been reported in populations that had previously been thought to be at low risk, including peripartum women and healthy persons living in the community. Challenges posed by the changing epidemiology of CDAD are compounded by current limitations in diagnostic testing, treatment, and infection control. Overcoming these challenges and limitations will require a concerted effort from a variety of sources, including an ongoing partnership between infectious disease clinicians and public health professionals.

In vitro activities of 15 antimicrobial agents against 110 toxigenic clostridium difficile clinical isolates collected from 1983 to 2004.

The incidence and severity of Clostridium difficile-associated disease (CDAD) is increasing, and standard treatment is not always effective. Therefore, more-effective antimicrobial agents and treatment strategies are needed. We used the agar dilution method to determine the in vitro susceptibility of the following antimicrobials against 110 toxigenic clinical isolates of C. difficile from 1983 to 2004, primarily from the United States: doripenem, meropenem, gatifloxacin, levofloxacin, moxifloxacin, OPT-80, ramoplanin, rifalazil, rifaximin, nitazoxanide, tizoxanide, tigecycline, vancomycin, tinidazole, and metronidazole. Included among the isolates tested were six strains of the toxinotype III, NAP1/BI/027 group implicated in recent U.S., Canadian, and European outbreaks. The most active agents in vitro were rifaximin, rifalazil, tizoxanide, nitazoxanide, and OPT-80 with MICs at which 50% of the isolates are inhibited (MIC(50)) and MIC(90) values of 0.0075 and 0.015 microg/ml, 0.0075 and 0.03 microg/ml, 0.06 and 0.125 microg/ml, 0.06 and 0.125 microg/ml, 0.125 and 0.125 microg/ml, respectively. However, for three isolates the rifalazil and rifaximin MICs were very high (MIC of >256 microg/ml). Ramoplanin, vancomycin, doripenem, and meropenem were also very active in vitro with narrow MIC(50) and MIC(90) ranges. None of the isolates were resistant to metronidazole, the only agent for which there are breakpoints, with tinidazole showing nearly identical results. These in vitro susceptibility results are encouraging and support continued evaluation of selected antimicrobials in clinical trials of treatment for CDAD.

Recommendations for Surveillance of Clostridium difficile–Associated Disease

The epidemiology of Clostridium difficile-associated disease (CDAD) is changing, with evidence of increased incidence and severity. However, the understanding of the magnitude of and reasons for this change is currently hampered by the lack of standardized surveillance methods. An ad hoc C. difficile surveillance working group was formed to develop interim surveillance definitions and recommendations based on existing literature and expert opinion that can help to improve CDAD surveillance and prevention efforts. A CDAD case patient was defined as a patient with symptoms of diarrhea or toxic megacolon combined with a positive result of a laboratory assay and/or endoscopic or histopathologic evidence of pseudomembranous colitis. Recurrent CDAD was defined as repeated episodes within 8 weeks of each other. Severe CDAD was defined by CDAD-associated admission to an intensive care unit, colectomy, or death within 30 days after onset. Case patients were categorized by the setting in which C. difficile was likely acquired, to account for recent evidence that suggests that healthcare facility-associated CDAD may have its onset in the community up to 4 weeks after discharge. Tracking of healthcare facility-onset, healthcare facility-associated CDAD is the minimum surveillance required for healthcare settings; tracking of community-onset, healthcare facility-associated CDAD should be performed only in conjunction with tracking of healthcare facility-onset, healthcare facility-associated CDAD. Community-associated CDAD was defined by symptom onset more than 12 weeks after the last discharge from a healthcare facility. Rates of both healthcare facility-onset, healthcare facility-associated CDAD and community-onset, healthcare facility-associated CDAD should be expressed as case patients per 10,000 patient-days; rates of community-associated CDAD should be expressed as case patients per 100,000 person-years.

Bench-to-bedside review: Clostridium difficile colitis

In recent years, the incidence and severity of Clostridium difficile-associated disease (CDAD) have increased dramatically. Beginning in 2000, widespread regional outbreaks associated with a previously uncommon hypervirulent strain of C. difficile have occurred in North America and Europe. Most likely because of increased toxin production as well as other virulence factors, this epidemic strain has caused more severe and refractory disease leading to complications, including intensive care unit admission, colectomies, and death. Worldwide increasing use of fluoroquinolones and cephalosporins has likely contributed to the proliferation of this epidemic strain, which is highly resistant to both. The elderly have been disproportionately affected by CDAD, but C. difficile has also recently emerged in populations previously considered to be at low risk, including healthy outpatients and peripartum women, although it is unknown if these cases are related to the epidemic strain. Nevertheless, transmission within hospitals is the major source of C. difficile acquisition, and previous or concurrent antimicrobial use is almost universal among cases. Applying current evidence-based strategies for management and prevention is critically important, and clinicians should maintain an awareness of the changing epidemiology of CDAD and take measures to reduce the risk of disease in patients.

A Portrait of the Geographic Dissemination of the Clostridium difficile North American Pulsed-Field Type 1 Strain and the Epidemiology of C. difficile-Associated Disease in Quebec

An increase in the incidence and severity of Clostridium difficile-associated disease in Québec and the United States has been associated with a hypervirulent strain referred to as North American pulsed-field type 1 (NAP1)/027. In 2005, a prospective study was conducted in 88 Québec hospitals, and 478 consecutive nosocomial isolates of C. difficile were obtained. The isolates were subjected to pulsed-field gel electrophoresis (PFGE) typing, antimicrobial susceptibility testing, and detection of binary toxin genes and tcdC gene deletion. Data on patient age and occurrence of complications were collected. PFGE typing of 478 isolates of C. difficile yielded 61 PFGE profiles. Pulsovars A (57%), B (10%), and B1 (8%) were predominant. The PFGE profile of pulsovar A was identical to that of strain NAP1. It showed 67% relatedness with 15 other PFGE patterns, among which 11 had both binary toxin genes and a partial tcdC deletion but different antibiotic susceptibility profiles. Pulsovars B and B1 were identical to strain NAP2/ribotype 001. In hospitals showing a predominant clonal A or B-B1 PFGE pattern, incidence of C. difficile-associated disease was 2 and 1.3 times higher, respectively, than in hospitals without any predominant clonal PFGE pattern. Severe disease was twice as frequent among patients with strains possessing binary toxin genes and tcdC deletion than among patients with strains lacking these virulence factors. This study helped to quantify the impact of strain NAP1 on the incidence and severity of C. difficile-associated disease in Québec in 2005. The identification of the geographic dissemination of this predominant strain may help to focus regional infection-control efforts.

Changing Epidemiology of Clostridium difficile-Associated Disease

Recent reports suggest that the frequency and severity of Clostridium difficile-associated disease (CDAD) may be increasing. In March and November 2004, the Infectious Diseases Society of America Emerging Infections Network surveyed 841 infectious diseases consultants about their experiences with CDAD. Of 447 US respondents reporting cases on the first survey, 29% perceived an increase in CDAD frequency; 29%, increased severity; 34%, increased recurrences; and 31%, increased refractoriness to therapy. On the second survey, 221 infectious diseases consultants reported "no change" in their experience during the prior 6 months. Of the remainder, including 76 new respondents and 90 respondents whose experience had changed, 41% perceived an increase in CDAD frequency; 46%, increased severity; 64%, increased recurrences; and 48%, increased disease refractory to therapy. In summary, 29% or more of infectious disease consultants practicing in the United States reported increased caseloads and more severe, recalcitrant, or recurrent CDAD during 2003 to 2004.

Severe Clostridium difficile-Associated Disease in Populations Previously at Low Risk: Four States, 2005

Severe Clostridium difficile-Associated Disease in Populations Previously at Low Risk: Four States, 2005