Update on Clostridium difficile Infection

[David in Seattle]

Update on Clostridium difficile Infection

Caoilfhionn O'Donoghue; Lorraine Kyne

Curr Opin Gastroenterol. 2011;27(1):38-47. © 2011 Lippincott Williams & Wilkins

Abstract

Purpose of review This review summarizes the most recent epidemiological data and advances in research into the pathogenesis, diagnosis and treatment of Clostridium difficile infection (CDI).
Recent findings The epidemiology of CDI has changed with the emergence of hypervirulent strains. CDI rates have increased in the community, in children and in patients with inflammatory bowel disease. Although the North American pulsed-field gel electrophoresis type 1, restriction endonuclease analysis group BI, PCR ribotype 027 (NAP1/BI/027) strain remains prevalent in North America, surveillance suggests that it is decreasing in Europe. A similar strain, PCR ribotype 078, is emerging which is associated with community-associated CDI and has been isolated in animals and food products. The Society for Healthcare Epidemiology of America and the Infectious Diseases Society of America have published new guidelines on the epidemiology, diagnosis, treatment, infection control and environmental management of C. difficile. Several novel therapies for CDI are at different stages of development. There have been promising trial results with fidaxomicin, a novel antibiotic for the treatment of CDI and monoclonal antibodies against toxins A and B, which have been shown to significantly reduce CDI recurrence rates.
Summary Major advances have been made in our understanding of the spread and pathogenesis of C. difficile and new treatment options are becoming available.

Introduction

During the past decade, rates of Clostridium difficile infection (CDI) increased worldwide. Morbidity and mortality rates increased associated with the emergence of hypervirulent strains such as North American pulsed-field gel electrophoresis type 1, restriction endonuclease analysis group BI, PCR ribotype 027 (NAP1/BI/027), also synonymous with toxinotype III. In this article we review the latest information on epidemiological trends, recent advances in diagnostics and the progress of effective treatment of this ubiquitous pathogen.

Healthcare Facility-associated Clostridium difficile Infection

CDI is the most common cause of infectious diarrhea in healthcare settings.[1–4] Although there is no mandatory reporting of CDI in the United States, it is estimated that there are at least 500 000 cases in US hospitals and nursing homes per year.[5••] Data from Canadian surveillance studies estimate their incidence to be approximately 4.6 cases per 10 000 patient admissions.[6,7•] A recently completed pan-European hospital-based survey shows a similar European incidence of 4.1 cases per 10 000 patient days.[8••]

The latest data from the United Kingdom, where reporting of CDI is mandatory since 2007, shows a 54% reduction in CDI between 2007 and 2010; from 8.8 to 3.8 cases per 10 000 bed days (http://www.hpa.org.uk/web/HPAwebfile/HPAweb_C/1274091661838; Accessed 13 September 2010). This reduction has mirrored a reduction in methicillin-resistant Staphylococcus aureus rates and has been largely attributed to enhanced infection prevention and control strategies and targets set by government bodies for reduction in healthcare-associated infections.

Community-associated Clostridium difficile Infection

Rates of CDI in the community are difficult to assess, partly due to lower rates of testing and differences in the definitions of community-associated CDI (CA-CDI). In May 2010, the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA) published new clinical practice guidelines for CDI.[9••] These include definitions for CDI origin and onset, which aim to standardize surveillance and simplify comparisons across facilities and regions. They are in line with definitions recommended by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID).[10]

Incidence rates of CA-CDI in US population studies range from 6.9 to 46 cases per 100 000 person years.[11•,12–14] A retrospective survey of CDI cases in North Carolina in 2005 estimated that 20% of CDI cases were community-associated.[11•] This is similar to published rates from Canada and Europe.[15•,16–18]

In the Netherlands, Bauer et al. [19••] found that the prevalence of C. difficile in the stools of patients with community-onset diarrhea was 1.5%. Similarly, a prospective case–control study of CA-CDI in the United Kingdom found a prevalence of 2.1% and an annual incidence of 20–30 per 100 000 population.[20] Rates of CA-CDI not associated with recent antibiotic use remain high at 40–60%.[11•,19••,20]

Risk Factors

Risk factors for CDI include antimicrobial use, advanced age, number of comorbidities, underlying disease severity, duration of hospitalization and exposure to other patients with CDI.[4,21,22•,23,24,25•] The role of acid-suppressing medications as a risk for CDI remains unclear.[26,27•] Recent studies suggest that they are markers for other risk factors such as underlying disease severity.[1,25•,28•,29•,30]

Rates of CDI in populations previously considered low risk are increasing. Cases in peripartum women have been documented[13,31,32] with 40% requiring hospitalization in one series.[13]

 

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Clostridium difficile Infection in Children

The annual rate of pediatric hospitalization with CDI in the United States rose from 7.24 per 10 000 hospitalizations in 1997 to 12.8 in 2006.[33•] Although C. difficile has been implicated as a pathogen in high-risk neonatal patients, CDI in children under the age of 1 year remains rare.[34•]

Patients with cystic fibrosis (CF) also appear to be at lower risk of CDI despite receiving multiple antimicrobials and having high carriage rates of C. difficile. However, when CDI occurs in these patients, they often have a more fulminant course.[35••] A recent case series of CDI among CF pediatric lung transplant recipients suggests a higher rate in CF patients following lung transplantation compared to the CF population as a whole.[36•] Children with inflammatory bowel disease (IBD) have been shown to have higher rates of C. difficile carriage, CDI and recurrence.[37•,38•]

Inflammatory Bowel Disease as a Risk Factor for Clostridium difficile Infection

IBD in adults is emerging as an important risk factor for CDI.[39•,40] Ananthakrishnan et al. [41•] recently reported that there has been a temporal increase in CDI complicating IBD hospitalizations between 1998 and 2007. It appears that this increase is disproportionate to the increase in the general population.[41•] Colonic involvement appears to confer a greater risk, with left-sided or pancolonic disease more frequently complicated by CDI than disease with limited colonic involvement.[40,42]

With similar presentations, it can be difficult to distinguish clinically between a flare of IBD and CDI even with endoscopy.[39•] The optimal management of these patients is also unclear. A recent observational study suggested that patients treated with a combination of immunomodulators and antibiotics did worse than patients treated with antibiotics alone.[43•] It is prudent to treat initially for CDI when a stool sample tests positive for toxigenic C. difficile in the setting of diarrhea but treatment of underlying IBD should not be delayed if there is not a rapid improvement in symptoms.[44]

Virulence factors associated with the North American pulsed-field gel electrophoresis type 1, restriction endonuclease analysis group BI, PCR ribotype 027

Multiple synergistic factors have contributed to the emergence of NAP1/BI/027 as a hypervirulent strain. Warny et al. [45] demonstrated that NAP1/BI/027 isolates produced excess toxins in vitro compared to a mixture of nonepidemic strains. More recently, Merrigan et al. [46••] found that although NAP1/BI/027 strains displayed robust toxin production during the stationary phase of growth, the toxin amounts were not significantly different from those produced by nonhypervirulent strains. Like others, they found that NAP1/BI/027 strains had enhanced sporulation activity.[47,48••] Recently, Underwood et al. [49••] demonstrated that inactivation of genes involved in sporulation initiation resulted in an asporogeneous phenotype and a marked defect in C. difficile toxin production. This suggests that there is a regulatory link between sporulation and toxin production.[49••] This may have given an adaptive advantage to the NAP1/BI/027 strain. An additional factor likely to have helped in its dissemination is its acquisition of resistance to antimicrobials frequently used in healthcare settings.[48••,50]

Epidemiology of the North American Pulsed-field Gel Electrophoresis Type 1, Restriction Endonuclease Analysis Group BI, PCR ribotype 027

Since the identification of NAP1/BI/027 as the causative strain in 82% of cases during the CDI outbreaks in Quebec from 2001 to 2003,[50,51] it has been isolated in cases and implicated in outbreaks of CDI worldwide.[52–60,61••] In a study of the distribution of C. difficile strains isolated during a treatment trial in three continents from 2005 to 2007, NAP1/BI/027 was the most frequently isolated strain and accounted for 36% of isolates in North America.[62••]

The recent pan-European CDI survey, however, is encouraging in that the prevalence of the NAP1/BI/027 strain in 34 countries in 2008 was only 5%. A recent survey from the Netherlands[63•] has also demonstrated that the incidence of NAP1/BI/027 has decreased dramatically since the second half of 2006. However, this decrease was mirrored by the emergence of a new hypervirulent strain known as PCR ribotype 078.

PCR ribotype 078

PCR ribotype 078 strains belong to toxinotype V and are associated with CDI in animals and humans. Ribotype 078 isolates contain a 39-base pair deletion in the toxin regulator gene (tcdC).[64–66] Jhung et al. [64] demonstrated that in-vitro toxin production by ribotype 078 isolates is less than that observed in ribotype 027 isolates but significantly greater than that observed in nonepidemic toxinotype 0 isolates. In common with ribotype 027, ribotype 078 causes severe diarrhea in 40% of cases. However in contrast, it appears to be associated with lower levels of complicated disease.[66]

PCR ribotype 078 in the Community, Animals and Food

In the Netherlands, the incidence of ribotype 078 among isolates obtained from patients with CDI increased from 3% in 2005 to 13% in 2008.[66] This strain was found more frequently in the community and tended to affect younger people. There was an overlap in the occurrence of human CDI cases caused by ribotype 078 and the distribution of pig farms in the eastern part of the country.[19••,66] Data from the United States also report that ribotype 078 is the third most frequently isolated strain from CA-CDI cases.[67•] Although there is no direct evidence of interspecies transmission, human, porcine and bovine ribotype 078 strains have been shown to be genetically very similar.[64,68,69•,70•] This suggests that there may be a common environmental source of this strain.[64]

More recently, ribotypes 078 and 027 have been isolated from retail meat products in the United States and Canada but no link between ingested contaminated food products and CDI has been demonstrated.[71••,72•]

 

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Healthcare-associated PCR ribotype 078

In Europe, ribotype 078 was the third most frequently isolated ribotype from hospitalized patients in 2008, and accounted for 8% of typeable isolates.[8••] In a recent national surveillance study in Ireland,[73] ribotype 078 accounted for 13.7% of isolates typed from healthcare-associated CDI cases and 33% of CA-CDI cases. It was also the second most common strain isolated during a recent hospital outbreak of CDI.[74•]

Single Tests for Diagnosing Clostridium difficile Infection

The reference standards for the detection of C. difficile toxins are either the cell culture cytotoxicity assay (CTA) or toxigenic culture.[9••,75••] Most microbiology laboratories use an enzyme immunoassay (EIA) test for toxin A alone or toxin A and toxin B. This provides same day results but with a low sensitivity when compared with reference standard tests (64–94%).[9••,75••] In addition if the prevalence of toxin positive fecal samples is low (i.e. <10%), the positive predictive value (PPV) of these assays may be as low as 50% in some settings.[76,77••] This increases the false-positive rate and may lead to unnecessary treatment and isolation of patients.

Alternatives to EIA detection of C. difficile toxins include EIA kits to detect the presence of glutamate dehydrogenase (GDH) or the use of real-time PCR, which detects the presence of C. difficile toxin genes directly in feces. GDH detection assays are useful as negative screening tools for C. difficile as they have sensitivities of 88–100% and negative predictive values (NPVs) of 98.8–100%.[77••,78,79,80•] However, their low PPV (53–63%) precludes them from being a useful single diagnostic test for C. difficile.

Several PCR assays are now commercially available that detect the presence of tcdB (the gene encoding production of toxin B) directly in feces.[77••,81••] Although these assays have good sensitivity (80–94%), specificity (93–97%) and excellent NPV (>98%), their PPV may be less than 68% when the prevalence of CDI is low.[77••,82••] In addition, the presence of the toxin gene may not necessarily correlate with the presence of toxin. Newer multiplex real-time PCR assays detect the presence of genes encoding toxin A, toxin B and binary toxin.[81••,82••,83,84••] Base pair deletions in the tcdC gene may also be detected allowing rapid screening for hypervirulent strains of C. difficile.[81••,82••,83]

Two-step and Three-step Algorithms for Diagnosing Clostridium difficile Infection

Because of the suboptimal performance of single tests, many microbiology laboratories now use a two-step or three-step testing algorithm. Two-step algorithms commonly use an initial screening EIA test for C. difficile toxins or GDH with further testing of positive samples using CTA, toxigenic culture or PCR.[79,85•,86••] Recently, Goldenberg et al. [86••] demonstrated that the sensitivity, specificity, PPV and NPV of a two-step algorithm using EIA–GDH as an initial screen and confirmation of positive tests using a PCR assay for tcdB were 94, 99, 94 and 99%, respectively. Although PCR is expensive, it can be performed quickly thereby minimizing diagnostic delays, which may occur if CTA or toxigenic culture is used as the confirmatory test.[80•,86••] Larson et al. [87••] recently reported on a three-step algorithm in which direct stool PCR was used to evaluate GDH EIA-positive, toxin EIA-negative specimens with a sensitivity of 83.8% and PPV of 99.7%.

Published data on the efficacy of these algorithms is limited.[88•] Both the SHEA–IDSA and ESCMID guidelines advise the use of two-step algorithms for the diagnosis of CDI.[9••,75••] Testing should only be performed on unformed stools and all test results should be interpreted in correlation with the patient's symptoms.

Guidelines for general and specific treatment of initial episodes of CDI stratified by disease severity are outlined in Fig. 1.[9••,89••,90••,91]

Figure 1.

Treatment guidelines for CDI stratified by disease severity
CDI, Clostridium difficile infection; CT, computerized tomography.



Recurrence of CDI occurs in approximately 20% of cases, more commonly in older, sicker patients requiring additional antibiotic therapy.[92,93,94•] First recurrences should be treated with the same regimen as the initial episode stratified for disease severity. Any further recurrence may be treated with vancomycin, using a tapered and/or pulsed regimen.[9••]

 

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Newer and Alternative Antibiotics for Clostridium difficile Infection

Fidaxomicin, or OPT-80, is a poorly absorbed macrocyclic antibiotic with potent in-vitro activity against C. difficile and limited activity against normal fecal flora.[95•] Two phase III trials involving over 1000 patients in more than 100 sites in North America and Europe have demonstrated that fidaxomicin 200 mg twice a day is at least as effective as vancomycin 125 mg four times a day for the treatment of initial or first recurrences of CDI. Recurrence rates with fidaxomicin were significantly lower (13%) compared to vancomycin (25%).[96•] Fidaxomicin is not yet available for patient use anywhere in the world, but it is expected that new drug applications will be submitted to the European Medicines Agency and the US Food and Drug Administration agency this year.

Tigecycline is a structural analogue of minocycline and has been used intravenously (i.v.) off-label as adjunctive therapy for severe and refractory CDI. It was shown to be successful in five cases reported in the literature.[97•,98•] A recent case report,[99•] however, was less optimistic and cautioned against its use.

Rifaximin has been used off-label for the treatment of patients with multiple recurrences of CDI.[100•,101] In uncontrolled studies, Johnson et al. report a success rate of 86% (12 of 14 patients cured) for postvancomycin treatment with rifaximin 400 mg twice a day for 2 weeks. Although promising, there are concerns that C. difficile may develop resistance to rifaximin and this may limit its future utility.[100•,102•]

Nitazoxanide is a thiazolide compound licensed for the treatment of intestinal parasitic infections. A small-scale double-blind clinical trial suggested that it may be as effective as vancomycin for CDI treatment.[103•] Nitazoxanide is expensive, but it may have a role as salvage therapy for refractory or recurrent CDI.[104]

Other established and novel antibiotics under investigation for the treatment of CDI include ramoplanin, rifalazil, REP3123, oritavancin, and NVB302.[105•]

Microbiological Therapy

Numerous recent case series continue to highlight the efficacy of fecal transplantation in restoring the colonic microflora of patients with recurrent CDI.[106•,107•] Acceptability of this treatment modality and the risk of horizontal transmission of pathogens may limit its use. The fecal microorganisms responsible for its success and their development into a more deliverable form warrant further investigation.[108••] The first known randomized controlled study comparing donor feces instillation with antibiotic therapy in recurrent CDI is underway in the Netherlands.[109•]

Merrigan et al. [110••] recently reported that colonization with nontoxigenic strains of C. difficile was protective against toxigenic challenge in hamsters receiving antibiotics. Further studies are required to determine whether this is a viable treatment option in humans.

Probiotics

Evidence supporting the benefit of probiotics in CDI prevention or treatment remains sparse. Two recent reviews describe the lack of large, good quality clinical trials of probiotics, issues concerning their quality control and the potential risks associated with their use.[111•,112•] They also highlight the wide variety of potential benefits and the need for further study.

A recent large trial demonstrated a dose-related reduction in the incidence of antibiotic-associated diarrhea and CDI associated with a proprietary probiotic formula called BIO-K+ CL-1285 compared with placebo. The study was limited by the fact that it was single center and patients under 50 and over 70 years of age were excluded.[113•]

Intravenous Immunoglobulins

Intravenous immunoglobulin (IVIG) is frequently used off-license to treat severe or refractory CDI with mixed results.[114] Recently, Abougergi et al. [115•] reported a high mortality rate (57%) in 21 patients treated with IVIG for severe CDI. The authors found that higher Acute Physiological Assessment and Chronic Health Evaluation II scores on the day of IVIG infusion were significantly associated with higher mortality. They suggest that IVIG may have a role to play in patients with severe CDI that is confined to the colon but that once extracolonic organ dysfunction and systemic inflammatory response syndrome develop it may be less beneficial.[115•]

Monoclonal Antibodies

A recent major advance in immunotherapy for CDI has been the development of human monoclonal antibodies (mAbs) against C. difficile toxins. The results of a large multicenter phase II trial of two fully human neutralizing mAbs against C. difficile toxins A and B were recently published.[116••] They were administered i.v. as an adjuvant to standard antimicrobial therapy in patients with CDI. Treatment was associated with a 72% relative reduction in recurrence rates compared to placebo but did not reduce the severity of infection or the duration of diarrhea or hospitalization.[116••] Future studies are needed to determine which patients will benefit most from this treatment and whether this treatment is cost-effective.

 

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Vaccine

Active vaccination with a C. difficile toxoid vaccine has been successful in treating a small number of patients with recurrent CDI.[117,118] A phase II randomized, dose-ranging trial of a C. difficile toxoid vaccine for the prevention of recurrent CDI is currently underway in centers in the United States and the United Kingdom (clinicaltrials.gov NCT00772343). The estimated study completion date is December 2011.

Lee et al. [119••] recently published an economic computer simulation model of the potential value of a C. difficile vaccine. They found that over a wide range of vaccine costs, vaccine efficacies and C. difficile risks that the vaccine would be cost-effective for the prevention of CDI in high-risk patients and also for the prevention of recurrent CDI.

Gardiner et al. [120••] recently reported that they have developed the first DNA vaccine capable of inducing neutralizing antibodies to C. difficile toxin A in mice. Development of a similar vaccine approach to C. difficile toxin B is underway. DNA vaccination may eventually be more efficacious and less toxic than traditional vaccine methods, but the platform technology for this is only in the early stages of development.

Conclusion

The clinical picture of CDI has changed in the past decade. Hypervirulent strains have emerged which have adapted well to healthcare settings. CDI is becoming problematic in the community, and high-risk groups have emerged in the pediatric population.

Despite this, there are reasons to be optimistic. Surveillance demonstrates a decrease in healthcare-associated CDI rates in the United Kingdom and a reduction in the prevalence of NAP1/BI/027 in Europe. A decade of research triggered by the emergence of epidemic strains has led to the development of novel therapeutic options including newer antibiotics and passive and active immunotherapy agents. This year also saw the publication of new European and American clinical practice guidelines for the diagnosis and management of CDI in adults which will aid healthcare providers in preventing and treating this increasingly prevalent and difficult to manage infectious disease.

Sidebar

Key Points

* Hypervirulent strains of Clostridium difficile such as NAP1/BI/027 and PCR ribotype 078 have emerged in the past decade that have changed the epidemiology of Clostridium difficile infection (CDI).
* Community-associated CDI is more common, as is CDI in children and in patients with inflammatory bowel disease.
* The role of C. difficile as a food-borne pathogen remains unclear.
* New two-step and three-step diagnostic algorithms are being adopted that focus on accurate and rapid diagnosis.
* Novel therapeutic agents, including antimicrobials and antitoxin monoclonal antibodies, have been developed that are associated with lower rates of recurrent CDI.

 

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• The author presents a case vignette of recurrent CDI and a concise review of CDI.
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• Using the 1997–2006 Kids' Inpatient Database and the 2006 National Hospital Discharge Survey, the authors calculate rates of CDI in pediatric patients, and the increasing incidence over a decade. The authors also speculate that the increasing rates may be due to reporting bias for diarrheal illnesses as they also noted a concomitant increase in rotavirus-related hospitalizations.
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[David in Seattle]

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38. Wultańska D, Banaszkiewicz A, Radikowski A, et al. Clostridium difficile infection in Polish pediatric outpatients with inflammatory bowel disease. Eur J Clin Microbiol Infect Dis 2010; 29:1265–1270.
• In this prospective study the authors tested stool samples for C. difficile from outpatients with IBD and identified isolates by PCR ribotyping to estimate the incidence of CDI and recurrent CDI among this population.
39. Ananthakrishnan AN, Issa M, Binion DG. Clostridium difficile and inflammatory bowel disease. Med Clin North Am 2010; 38:711–728.
40 • This article presents an updated and extensive review of the complex subject of CDI in patients with IBD. 40. Nguyen GC, Kaplan GG, Harris ML, Brant SR. A national survey of the prevalence and impact of Clostridium difficile infection among hospitalized inflammatory bowel disease patients. Am J Gastroenterol 2008; 103:1443–1450.
41. Ananthakrishnan AN, McGinley EL, Saeian K, Binion DG. Temporal trends in disease outcomes related to Clostridium difficile infection in patients with inflammatory bowel disease. Inflamm bowel disease 2010 [Epub ahead of print].
• The authors perform a retrospective study of the incidence of CDI complicating IBD-related hospitalizations in the years 1998, 2004 and 2007. They report an increased excess morbidity related to CDI in hospitalized patients with IBD over this time frame.
42. Powell N, Jung SE, Krishnan B. Clostridium difficile infection and inflammatory bowel disease: a marker for disease extent? Gut 2008; 57:1183–1184.
43. Ben-Horin S, Margalit M, Bossuyt P, et al. Combination immunomodulator and antibiotic treatment in patients with inflammatory bowel disease and Clostridium difficile infection. Clin Gastroenterol Hepatol 2009; 7:981–987.
• In this retrospective review, the authors compare different treatment regimens for patients with flaring IBD and CDI and highlight the need for prospective controlled trials to establish best practice for managing these patients.
44. Stone CD. Prognosis in Clostridium difficile infection complicating inflammatory bowel disease. Gut 2008; 57:150–152.
45. Warny M, Pépin J, Fang A, et al. Toxin production by an emerging strain of Clostridium difficile associated with outbreaks of severe disease in North America and Europe. Lancet 2005; 366:1079–1084.
46. Merrigan M, Venugopal A, Mallozzi M, et al. Human hypervirulent Clostridium difficile strains exhibit increased sporulation as well as robust toxin production. J Bacteriol 2010; 194:4904–4911.
•• The authors examine toxin production and sporulation in hypervirulent C. difficile strains and compare them with nonhypervirulent strains.
47. Akerlund T, Persson I, Unemo M, et al. Increased sporulation rate of epidemic Clostridium difficile type 027/NAP1. J Clin Microbiol 2008; 46:1530–1533.
48. Dawson LF, Valiente E, Wren B. Clostridium difficile– a continually evolving and problematic pathogen. Infect Genet Evol 2009; 9:1410–1417.
# Underwood S, Guan S, Vijayasubhash V, et al. Characterization of the sporulation initiation pathway of Clostridium difficile and its role in toxin production. J Bacteriol 2009; 191:7296–7305.
•• Using ClosTron gene knockout technology the authors demonstrated that inactivation of genes involved in sporulation initiation in C. difficile resulted in an asporogeneous phenotype and also a reduction in toxin production. The authors discuss the implications of these findings for C. difficile sporulation, virulence and transmission.
# Pépin J, Saheb N, Coulombe MA, et al. Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficile-associated diarrhea: a cohort study during an epidemic in Quebec. Clin Infect Dis 2005; 41:1254–1260.
# Loo VG, Poirier L, Miller MA, et al. A predominantly clonal multiinstitutional outbreak of Clostridium difficile–associated diarrhea with high morbidity and mortality. N Engl J Med 2005; 353:2442–2449.
# McDonald LC, Killgore GE, Thompson A, et al. An epidemic, toxin gene-variant strain of Clostridium difficile. N Engl J Med 2005; 353:2433–2441.
# Biller P, Shank B, Lind L, et al. Moxifloxacin therapy as a risk factor for Clostridium difficile-associated disease during an outbreak: attempts to control a new epidemic strain. Infect Control Hosp Epidemiol 2007; 28:198–201.
# Muto CA, Blank MK, Marsh JW, et al. Control of an outbreak of infection with the hypervirulent Clostridium difficile B1 strain in a university hospital using a comprehensive 'bundle' approach. Clin Infect Dis 2007; 45:1266–1273.
# Smith A. Outbreak of Clostridium difficile infection in an English hospital linked to hypertoxin-producing strains in Canada and the US. Euro Surveill 2005; 10:E050630.2.
# Kuijper EJ, Barbut F, Brazier JS, et al. Update of Clostridium difficile infection due to PCR ribotype 027 in Europe, 2008. Euro Surveill 2008; 13ii:18942.
# Riley TV, Thean S, Hool G, Golledge CL. First Australian isolation of epidemic Clostridium difficile PCR ribotype 027. Med J Aust 2009; 190:706–708.
# Tae CH, Jung SA, Song HJ, et al. The first case of antibiotic-associated colitis by Clostridium difficile PCR ribotype 027 in Korea. J Korean Med Sci 2009; 24:520–524.
# Cheng VC, Yam WC, Chan JF, et al. Clostridium difficile ribotype 027 arrives in Hong Kong. Int J Antimicrob Agents 2009; 34:492–493.
# Quesada-Gomez C, Rodriguez C, Gamboa-Coronado Mdel M, et al. Emergence of Clostridium difficile NAP1 in Latin America. J Clin Microbiol 2010; 48:669–670.
# Clements AC, Magalhães RJ, Tatem AJ, et al. Clostridium difficile PCR ribotype 027: assessing the risks of further worldwide spread. Lancet Infect Dis 2010; 10:395–404.
•• The authors present a risk assessment framework for assessing risks of further worldwide spread of epidemic strains of C. difficile with a view to preventing outbreaks in previously unaffected countries. They raise the issue of the role of international trade and travel in disease dissemination.
# Cheknis AK, Sambol SP, Davidson DM, et al. Distribution of Clostridium difficile strains from a North American, European and Australian trial of treatment for C. difficile infections: 2005–2007. Anaerobe 2009; 15:230–233.
•• In this study the authors present the results of C. difficile strain typing of stool samples collected from patients enrolled in two large phase III trials of Tolevamer in North America, Europe and Australia involving over 1000 patients. The authors highlight the importance of coordinating international surveillance to monitor the changing epidemiology of CDI.
# Hensgens MP, Goorhuis A, Notermans DW, et al. Decrease of hypervirulent Clostridium difficile PCR ribotype 027 in the Netherlands. Euro Surveill 2009; 14ii: 19402.
• Following the establishment of a national surveillance program for C. difficile in the Netherlands, Hensgens et al. report a reduction in the prevalence of PCR ribotype 027 to only 3% of all CDI cases, highlighting the role of surveillance and disease control and prevention measures.
# Jhung MA, Thompson AD, Killgore GE, et al. Toxinotype V Clostridium difficile in humans and food animals. Emerg Infect Dis 2008; 14:1039–1045.
# Rupnik M, Widmer A, Zimmermann O, et al. Clostridium difficile toxinotype V, ribotype 078, in animals and humans. J Clin Microbiol 2008; 46:2146.
# Goorhuis A, Bakker D, Corver J, et al. Emergence of Clostridium difficile infection due to a new hypervirulent strain, polymerase chain reaction ribotype 078. Clin Infect Dis 2008; 47:1162–1170.
# Limbago BM, Long CM, Thompson AD, et al. Clostridium difficile strains from community-associated infections. J Clin Microbiol 2009; 47:3004–3007.
• The authors collected stool samples from CA-CDI cases over a 3-month period in 2006 in nine states in the United States. They examined strain types and antimicrobial susceptibility profiles.
# Keel K, Brazier JS, Post KW, et al. Prevalence of PCR ribotypes among Clostridium difficile isolates from pigs, calves, and other species. J Clin Microbiol 2007; 45:1963–1964.
# Bakker D, Corver J, Harmanus C, et al. Relatedness of human and animal Clostridium difficile PCR ribotype 078 isolates based on multi locus variable number of tandem repeat analysis and tetracycline resistance. J Clin Microbiol 2010; 48:3744–3749.
• In this European study of 102 human and 56 porcine C. difficile PCR ribotype 078 strains, the investigators find high degrees of genetic relatedness.
# Debast SB, van Leengoed LA, Goorhuis A, et al. Clostridium difficile PCR ribotype 078 toxinotype V found in diarrhoeal pigs identical to isolates from affected humans. Environ Microbiol 2009; 11:505–511.
• Debast et al. examined C. difficile PCR ribotype 078 strains from both diarrheal piglets and humans and found them indistinguishable in terms of genetic identity, toxin production and antimicrobial sensitivity.

 

[David in Seattle]

# Weese JS. Clostridium difficile in food-innocent bystander or serious threat? Clin Microbiol Infect 2010; 16:3–10.
•• Weese reviews the literature to-date on C. difficile in food products and examines its possible role as a food-borne pathogen.
# Gould LH, Limbago B. Clostridium difficile in food and domestic animals: a new foodborne pathogen? Clin Infect Dis 2010; 51:577–582.
• Gould presents a summary of the data on C. difficile in food and animals, contributing to the discussion on C. difficile as a potential food-borne pathogen.
# Burns K, Skally M, Solomon K, et al. Clostridium difficile infection in the Republic of Ireland: results of a 1-month national surveillance and ribotyping project, March 2009. Infect Control Hosp Epidemiol 2010; 31:1085–1087.
# Burns K, Morris-Downes M, Fawley WN, et al. Infection due to C. difficile ribotype 078: first report of cases in the Republic of Ireland. J Hosp Infect 2010; 75:287–291.
• This report documents an outbreak of CDI in an Irish hospital associated with PCR ribotypes 027 and 078 affecting older patients.
# Crobach MJ, Dekkers OM, Wilcox M, Kuijper EJ. European society of clinical microbiology and infectious diseases (ESCMID): data review and recommendations for diagnosing Clostridium difficile-infection (CDI). Clin Microbiol Infect 2009; 15:1053–1066.
•• An excellent review of current diagnostic tests for CDI and presentation of evidence-based guidelines for the diagnosis of CDI.
# Planche T, Aghaizu A, Holliman R, et al. Diagnosis of Clostridium difficile infection by toxin detection kits: a systematic review. Lancet Infect Dis 2008; 8:777–784.
# Eastwood K, Else P, Charlett A, Wilcox M. Comparison of nine commercially available Clostridium difficile toxin detection assays, a real-time PCR assay for C. difficile tcdB, and a glutamate dehydrogenase detection assay to cytotoxin testing and cytotoxigenic culture methods. J Clin Microbiol 2009; 47:3211–3217.
•• Eastwood et al. compile a comprehensive review of various testing methods for C. difficile, in particular, comparing performances to both cytotoxin testing and cytotoxigenic culture at low (2%) and high (10%) prevalence of C. difficile. They found that PCR for the toxin B gene was the optimal rapid single test for the diagnosis of CDI because it had the highest NPV.
# Gilligan PH. Is a two-step glutamate dehydrogenase antigen-cytotoxicity neutralization assay algorithm superior to the premier toxin A and B enzyme immunoassay for laboratory detection of Clostridium difficile? J Clin Microbiol 2008; 46:1523–1525.
# Ticehurst JR, Aird DZ, Dam LM, et al. Effective detection of toxigenic Clostridium difficile by a two-step algorithm including tests for antigen and cytotoxin. J Clin Microbiol 2006; 44:1145–1149.
# Schmidt ML, Gilligan PH. Clostridium difficile testing algorithms: what is practical and feasible? Anaerobe 2009; 15:270–273.
• A good mini-review and discussion of the strengths and weaknesses of the current reference standards for the diagnosis of CDI and a review of testing algorithms used in their institution.
# Goldenberg SD, Dieringer T, French GL. Detection of toxigenic Clostridium difficile in diarrheal stools by rapid real-time polymerase chain reaction. Diagn Microbiol Infect Dis 2010; 67:304–307.
•• The investigators found that the Cepheid Xpert PCR assay (Sunnyvale, CA) had a sensitivity of 100%, specificity of 96.7%, PPV of 90.5% and NPV of 100% compared to toxigenic culture for the diagnosis of CDI. This multiplex system could detect the tcdB gene, binary toxin gene and a deletion in the tcdC gene, making it useful for predicting the presence of PCR ribotype 027.
# de Boer RF, Wijma JJ, Schuurman T, et al. Evaluation of a rapid molecular screening approach for the detection of toxigenic Clostridium difficile in general and subsequent identification of the tcdC delta117 mutation in human stools. J Microbiol Methods 2010; 83:59–65.
•• In this article the authors evaluate a screening multiplex real-time PCR assay which detects the presence of tcdA and tcdB directly in feces and a separate multiplex real-time PCR typing assay targeting the tcdC gene.
# Persson S, Torpdahl M, Olsen KEP. New multiplex PCR method for the detection of Clostridium difficile toxin A (tcdA) and toxin B (tcdB) and the binary toxin (cdtA/cdtB) genes applied to a Danish strain collection. Clin Microbiol Infect 2008; 14:1057–1064.
# Doing KM, Hintz MS, Keefe C, et al. Reevaluation of the Premier Clostridium difficile toxin A and B immunoassay with comparison to glutamate dehydrogenase common antigen testing evaluating Bartels cytotoxin and Prodesse ProGastro Cd polymerase chain reaction as confirmatory procedures. Diagn Microbiol Infect Dis 2010; 66:129–134.
•• In a large prospective study, the authors compared the performance of a commercial toxinA/B assay to a two-step algorithm that evaluated cytotoxin and PCR as confirmatory methods. The toxin A/B test missed 25% of truepositives. Once again, PCR for the toxin B gene was the most sensitive test. They concluded that molecular techniques, used either as a confirmatory or primary testing strategy, allowed same day reporting and had the highest correlation with toxigenic culture.
# Arnold A, Pope C, Bray S, et al. Prospective assessment of two-stage testing for Clostridium difficile. J Hosp Infect 2010; 76:18–22.
• The authors report the results of the introduction of a two-step diagnostic algorithm for C. difficile using an EIA for toxin A and B followed by cell CTA and toxigenic culture as confirmatory techniques.
# Goldenberg SD, Cliff PR, Smith S, et al. Two-step glutamate dehydrogenase antigen real-time polymerase chain reaction assay for detection of toxigenic Clostridium difficile. J Hosp Infect 2010; 74:48–54.
•• Using culture cytotoxin neutralization as the reference standard, the authors compare EIA for toxin A and B with a two-step algorithm using a GDH screening test and confirmatory PCR assay. They conclude that screening for GDH before confirmation of positives by PCR is cheaper than screening all specimens by PCR. The discussion includes an interesting cost–benefit analysis of two-step testing based on UK costings.
# Larson AM, Fung AM, Fang FC. Evaluation of tcdB real-time polymerase chain reaction in a three-step diagnostic algorithm for detection of toxigenic Clostridium difficile. J Clin Microbiol 2010; 48:124–130.
•• Larson et al. found that a three-step algorithm in which direct stool PCR is used to analyze GDH-positive, toxin EIA negative specimens provided rapid results for 87.7% of specimens. They explore US costs and conclude that the additional annual costs associated with direct stool PCR or three-step algorithms are justified by the earlier detection of CDI.
# Planche TD, Wilcox MH. Two-step testing for C. difficile: no answers yet. J Hosp Infect 2010; 75:325–326.
• In response to the article by Goldenberg et al. [86••], Planche and Wilcox highlight the difficulties associated with the performance characteristics of the two-step algorithm and call for a large well designed prospective study to clarify optimal testing strategies for CDI.
# Bauer MP, Kuijper EJ, van Dissel JT. European society of clinical microbiology and infectious diseases (ESCMID): treatment guidance document for Clostridium difficile infection (CDI). Clin Microbiol Infect 2009; 15:1067–1079.
•• An excellent review of the literature and presentation of treatment guidelines for CDI based on evidence and expert opinion.
# Cloud J, Noddin L, Pressman A, et al. Clostridium difficile strain NAP-1 is not associated with severe disease in a non epidemic setting. Clin Gastroenterol Hepatol 2009; 7:868–873.
•• Examining strain types and outcomes in CDI cases over a 13-month period, the authors identify risk factors for severe CDI and worse outcomes. They highlight the clinical significance of having a leukocyte count more than 20 000 cells/μl and a peak creatinine more than 2.3 mg/dl in predicting severe CDI and CDI-related deaths.

 

[David in Seattle]

# Lamontagne F, Labbé AC, Haeck O, et al. Impact of emergency colectomy on survival of patients with fulminant Clostridium difficile colitis during an epidemic caused by a hypervirulent strain. Ann Surg 2007; 245:267–272.
# Aslam S, Hamill RJ, Musher DM. Treatment of Clostridium difficile-associated disease: old therapies and new strategies. Lancet Infect Dis 2005; 5:549–557.
# Kyne L, Warny M, Qamar A, Kelly CP. Association between antibody response to toxin A and protection against recurrent Clostridium difficile diarrhea. Lancet 2001; 357:189–193.
# Hu MY, Katchar K, Kyne L, et al. Prospective derivation and validation of a clinical prediction rule for recurrent Clostridium difficile infection. Gastroenterology 2009; 136:1206–1214.
• Hu et al. prospectively derive and validate a clinical prediction rule for recurrent CDI incorporating age, Horns index of disease severity and additional antibiotic use after diagnosis of CDI.
# Tannock G, Munro K, Taylor C, et al. A new macrocyclic antibiotic, Fidaxomicin (OPT-80), causes less alteration to the bowel microbiota of Clostridium difficile-infected patients than does vancomycin. Microbiol 2010; 156:3354–3359.
• The investigators compare the effects on the fecal microbiota of fidaxomicin with those of vancomycin.
# Poxton IR. Fidaxomicin: a new macrocyclic, RNA polymerase-inhibiting antibiotic for the treatment of Clostridium difficile infection. Future Microbiol 2010; 5:539–548.
• This review covers the performance to-date of fidaxomicin in clinical trials.
# Lu CL, Liu CY, Liao CH, et al. Severe and refractory Clostridium difficile infection successfully treated with tigecycline and metronidazole. Int J Antimicrob Agents 2010; 35:311–312.
• The authors report a case of successful treatment of severe and recurrent CDI with tigecycline.
# Herpers BL, Vlaminckx B, Burkhardt O, et al. Intravenous tigecycline as adjunctive or alternative therapy for severe refractory Clostridium difficile infection. Clin Infect Dis 2009; 48:1732–1735.
• This series documents four cases of patients successfully treated with tigecycline.
# Kopterides P, Papageorgiou C, Antoniadou A, et al. Failure of tigecycline to treat severe Clostridium difficile infection. Anaesth Intensive Care 2010; 38:755–758.
• In this case report, treatment of severe CDI with tigecycline is unsuccessful and complications of treatment, including the acquisition of other antimicrobial resistant organisms, are discussed.
# Johnson S, Schriever C, Patel U, et al. Rifaximin Redux: treatment of recurrent Clostridium difficile infections with rifaximin immediately postvancomycin treatment. Anaerobe 2009; 15:290–291.
• This article describes a case series of six patients treated for recurrent CDI with rifaximin.
# Garey KW, Jiang ZD, Bellard A, Dupont HL. Rifaximin in treatment of recurrent Clostridium difficile-associated diarrhea: an uncontrolled pilot study. J Clin Gastroenterol 2009; 43:91–93.
# Koo HL, Garey KW, DuPont HL. Future novel therapeutic agents for Clostridium difficile infection. Expert Opin Investig Drugs 2010; 19:825–836.
• The authors perform a thorough review of novel therapies for CDI, including the clinical evidence to support their efficacy.
# Musher DM, Logan N, Bressler Am, et al. Nitazoxanide versus vancomycin in Clostridium difficile infection: a randomized, double blind study. Clin Infect Dis 2009; 48:e41–46.
• A randomized controlled trial of 50 participants comparing the efficacy of nitazoxanide with vancomycin in patients with CDI.
# Musher DM, Logan N, Mehendiratta V, et al. Clostridium difficile colitis that fails conventional metronidazole therapy: response to nitazoxanide. J Antimicrob Chemother 2007; 59:705–710.
# Johnson AP. New antibiotics for selective treatment of gastrointestinal infection caused by Clostridium difficile. Expert Opin Ther Patents 2010; 20:1389–1399.
• This review discusses the use of fidaxomicin, REP3123, oritavancin, NVB302 and nitazoxanide for the treatment of CDI.
# Rohlke F, Surawicz CM, Stollman N. Fecal flora reconstitution for recurrent Clostridium difficile infection: results and methodology. J Clin Gastroenterol 2010; 44:567–570.
• Here the authors describe successful treatment of 19 patients with multiple episodes of recurrent CDI by infusing donor stool through a colonoscope.
# Yoon SS, Brandt LJ. Treatment of refractory/recurrent Clostridium difficile-associated disease by donated stool transplanted via colonoscopy: a case series of 12 patients. J Clin Gastroenterol 2010; 44:562–566.
• Describtion of successful treatment of 12 patients with recurrent CDI by infusing donor stool through a colonoscope.
# Bakken JS. Fecal bacteriotherapy for recurrent Clostridium difficile infection. Anaerobe 2009; 15:285–289.
•• A thorough review of the topic of fecal transplantation for recurrent CDI. The authors describe selection of patients and donors, routes of instillation and success rates. They conclude that this low-tech procedure is easy to perform and is successful in approximately 90% of cases. They speculate on the future development of "synthetic stool" products.
# van Nood E, Speelman P, Kuijper EJ, Keller JJ. Struggling with recurrent Clostridium difficile infections: is donor faeces the solution? Euro Surveill 2009; 14:1–6.
• Another concise review of fecal transplant for recurrent CDI, with details of recruitment for the first randomized controlled study of donor feces instillation for recurrent CDI.
# Merrigan MM, Sambol SP, Johnson S, Gerding D. New approach to the management of Clostridium difficile infection: colonisation with nontoxigenic Clostridium difficile during daily ampicillin or ceftriaxone administration. Int J Antimicrob Agents 2009; 33:S46–S50.
•• Merrigan et al. detail their study on the role of colonization with nontoxigenic C. difficile strains in hamsters receiving antibiotics. They discuss scenarios of colonization and prevention success in hospitalized patients that are likely to occur depending on the susceptibility of the C. difficile strains to the antibiotic the patient is receiving.
# McFarland LV. Evidence-based review of probiotics for antibiotic-associated diarrhea and Clostridium difficile infections. Anaerobe 2009; 15:274–280.
• This article provides a positive review of the role of probiotics, highlighting areas for further research and development.
# Miller M. The fascination with probiotics for Clostridium difficile infection: lack of evidence for prophylactic or therapeutic efficacy. Anaerobe 2009; 15:281–284.
• In contrast, this review of the literature on probiotics for the treatment of CDI finds that they have little role to play in the prevention or therapy of CDI.
# Gao XW, Mubasher M, Fang CY, et al. Dose-response efficacy of proprietary probiotic formula of Lactobacillus acidophilus CL1285 and Lactobacillus casei LBC80R for antibiotic-associated diarrhea and Clostridium difficile-associated diarrhea prophylaxis in adult patients. Am J Gastroenterol 2010; 105:1636–1641.
• The investigators report the results of a double blind, randomized, placebo controlled study of BIO-K+ CL-1285 in an Asian population for the prophylaxis of antibiotic-associated diarrhea.
# Juang P, Skledar SJ, Zgheib NK, et al. Clinical outcomes of intravenous immune globulin in severe Clostridium difficile-associated diarrhea. Am J Infect Control 2007; 35:131–137.
# Abougergi MS, Broor A, Cui W, Jaar BG. Intravenous immunoglobulin for the treatment of severe Clostridium difficile colitis: an observational study and review of the literature. J Hosp Med 2010; 5:e1–e9.
• In this observational study the authors found that IVIG was not beneficial in the treatment of all patients with severe CDI. However, they did observe that benefit appeared to depend on the extent of systemic involvement, prompting a discussion on the optimal timing of IVIG.
# Lowy I, Molrine DC, Leav BA, et al. Treatment with monoclonal antibodies against Clostridium difficile toxins. N Engl J Med 2010; 362:197–205.
•• Lowy et al. report promising results of a phase II clinical trial of two fully human, neutralizing mAbs against C. difficile toxins A and B for the treatment of recurrent CDI.
# Giannasca PJ, Warny M. Active and passive immunization against Clostridium difficile diarrhea and colitis. Vaccine 2004; 22:848–856.
# Sougioultzis S, Kyne L, Drudy D, et al. Clostridium difficile toxoid vaccine in recurrent C. difficile-associated diarrhea. Gastroenterology 2005; 128:764–770.
# Lee BY, Popovich MJ, Tian Y, et al. The potential value of Clostridium difficile vaccine: an economic computer simulation model. Vaccine 2010; 28:5245–5253.
•• Lee et al. have developed an economic model evaluating the cost-effectiveness of a C. difficile vaccine for primary and secondary prevention of CDI.
# Gardiner DF, Rosenberg T, Zaharatos J, et al. A DNA vaccine targeting the receptor-binding domain of Clostridium difficile toxin A. Vaccine 2009; 27:3598–3604.
•• The authors describe the development of a DNA vaccine capable of inducing neutralizing antibodies to C. difficile toxin A, with evidence of protection in mice from death.

Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 88–90).

 

[bobtheman]

i got c.diff about a year ago and im almost positive thats what started this whole vicious cycle

 

[David in Seattle]

i got c.diff about a year ago and im almost positive thats what started this whole vicious cycle

I know what you mean. I was in Santa Fe in spring of 2008 & got a very nasty case of salmonella in an outbreak which the CDC later determined was the result of contaminated peppers. Sickest I've ever been in my life, at least in terms of the gut. I seemed to recover, then a few months later, BAM! I'm undiagnosed, but my current GI is leaning towards post infectious IBS. I think they're only just beginning to understand the complex relationship of the gut and the billions of organisms of thousands of species it contains, the relationship of these bugs and the immune system, etc.

Sure wish I had gone somewhere else that spring...

 

[MADiMarc]

Thanks, David. I treat pedi & several have CDiff. Nasty business.

 

[Keona]

The hospital where I am being treated has just had a C. Diff. breakout... it has been several months since the first. If it weren't for having an overactive immune system (isnt being suppressed yet) I wouldn't go there. Elderly I work with will not go there...smart...

 

[AZMOM]

Yes, interesting. Claire had c. diff about 2 months prior to diagnosis as well.........

 

[Connie]

Hi : )
My daugher was getting ready for sinus surgery. She had to go on a 21day antiobotic before surgery. 4 days prior, she got very sick she lost 6 pounds in 5 days. She tested postive for C-Diff. After treatment, she went for about 1 month and had the same stomach problems. Her test for C-Diff this time, was negative. She had to be scoped, and the biospy came back indetermint colitis. Makes you wonder about that c-diff bateria. Just thought I would add our connection to c-diff.

 

[Trysha]

Thank you David for locating and sharing an excellent review.
Probably only a matter of time before a vaccine is produced.
Trysha