C. difficile infection – Can we do better?

Abstract

The anaerobic bacterium Clostridium difficile, which has recently been reclassified as Clostridioides difficile, is the aetiological agent of pseudomembranous colitis and a leading cause of antibiotic-associated diarrhoea. It is a major nosocomial pathogen, but is also increasingly recognized as an important diarrhoeal pathogen in the community, not invariably associated with antibiotic therapy. The 2011/12 European Centre for Disease Prevention and Control (ECDC) point prevalence survey of healthcare-associated infections and antimicrobial use in European acute care hospitals estimated that 123 997 patients develop C. difficile infection (CDI) each year and that this was the microorganism responsible for 48% of healthcare-associated gastrointestinal infections [[1]ECDC Point prevalence survey of healthcare-associated infections and antimicrobial use in European acute care hospitals. ECDC, Stockholm2013Google Scholar]. Although the aetiological role of CDI in pseudomembranous colitis has been known for 40 years [[2]Larson H.E. Price A.B. Honour P. Borriello S.P. Clostridium difficile and the aetiology of pseudomembranous colitis.Lancet. 1978; 1: 1063-1066Abstract PubMed Google Scholar], since 2000 there has been an exponential rise in reports of CDI reflecting large increases in CDI cases and reported outbreaks, occurrence of severe disease, and descriptions of novel risk factors [[3]Freeman J. Bauer M.P. Baines S.D. Corver J. Fawley W.N. Goorhuis B. et al.The changing epidemiology of Clostridium difficile infections.Clin Microbiol Rev. 2010; 23: 529-549Crossref PubMed Scopus (654) Google Scholar]. Much of this change has been attributed to the emergence and rapid spread in North America and Europe of the hypervirulent PCR ribotype 027 strain [[4]Warny M. Pepin J. Fang A. Killgore G. Thompson A. Brazier J. 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: 1079-1084Abstract Full Text Full Text PDF PubMed Scopus (1197) Google Scholar] at the start of the current millennium [[5]Honda H. Dubberke E.R. The changing epidemiology of Clostridium difficile infection.Curr Opin Gastroenterol. 2014; 30: 54-62Crossref PubMed Scopus (45) Google Scholar]. However, other PCR ribotypes of C. difficile have also caused outbreaks and contributed to the spread of CDI in Europe and worldwide [[6]Bauer M.P. Notermans D.W. van Benthem B.H. Brazier J.S. Wilcox M.H. Rupnik M. et al.Clostridium difficile infection in Europe: a hospital-based survey.Lancet. 2011; 377: 63-73Abstract Full Text Full Text PDF PubMed Scopus (866) Google Scholar]. As a result of these changes in the epidemiology and clinical features of CDI, there has been a great deal of effort and activity aimed at developing and implementing comprehensive guidance for the surveillance, diagnosis, prevention, control and management of this major pathogen. In Europe, the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Clostridium difficile (ESGCD) has played a leading role in these activities. It is apparent that the systematic application of such measures, coupled with developments and improvements in the clinical management of CDI are capable of reducing the associated morbidity and mortality. For example, in the UK, significant decreases in CDI have been attributed to a multi-disciplinary approach, including establishment of mandatory surveillance, application of evidence-based guidance for treatment and management of CDI patients, and restrictive antimicrobial stewardship policies, with an overall organizational driver of government targets for CDI reduction [7Duerden B.I. Contribution of a government target to controlling Clostridium difficile in the NHS in England.Anaerobe. 2011; 17: 175-179Crossref PubMed Scopus (27) Google Scholar, 8Nathwani D. Sneddon J. Malcolm W. Wiuff C. Patton A. Hurding S. et al.Scottish Antimicrobial Prescribing Group (SAPG): development and impact of the Scottish National Antimicrobial Stewardship Programme.Int J Antimicrob Agents. 2011; 38: 16-26Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar, 9Lawes T. Lopez-Lozano J.M. Nebot C.A. Macartney G. Subbarao-Sharma R. Wares K.D. et al.Effect of a national 4C antibiotic stewardship intervention on the clinical and molecular epidemiology of Clostridium difficile infections in a region of Scotland: a non-linear time-series analysis.Lancet Infect Dis. 2017; 17: 194-206Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar]. However, despite these successes CDI remains a very significant infection challenge in many parts of Europe and beyond. In this theme section, we provide a series of short reviews that address some of these current issues. Surveillance is fundamental to our understanding of the epidemiology of CDI in Europe. The first pan-European surveillance study, the ‘European Clostridium Infection Survey’ (ECDIS), supported by ECDC, was performed in 2008/09 [[6]Bauer M.P. Notermans D.W. van Benthem B.H. Brazier J.S. Wilcox M.H. Rupnik M. et al.Clostridium difficile infection in Europe: a hospital-based survey.Lancet. 2011; 377: 63-73Abstract Full Text Full Text PDF PubMed Scopus (866) Google Scholar]. Based on the results of the ECDIS study, it was decided to provide support for further capacity building for surveillance of CDI across Europe. This resulted in the ECDIS-net project [[10]ECDIS-net. ECDIS-Net Home Page. 2017. Available at: http://www.ecdisnet.eu/. [Accessed 4 August 2017].Google Scholar], in which ESGCD and its members played a key role. Following the development of the surveillance protocol, a pilot study of standardized surveillance of C. difficile infection in European acute care hospitals was undertaken [[11]van Dorp S.M. Kinross P. Gastmeier P. Behnke M. Kola A. Delmee M. et al.Standardised surveillance of Clostridium difficile infection in European acute care hospitals: a pilot study, 2013.Euro Surveill. 2016; 21Crossref Scopus (48) Google Scholar]. The protocol developed now forms the basis of the ECDC protocol for surveillance of CDI in Europe [[12]ECDC. ECDC Surveillance Protocol for CDI. 2017. Available at: https://ecdc.europa.eu/en/clostridium-difficile-infections/surveillance-and-disease-data. [Accessed 4 August 2017].Google Scholar]. However, the implementation of national CDI surveillance programmes can be challenging, particularly in resource-poor settings. In their review, Krutova and colleagues (review article in the current issue) describe, based upon the existing ECDC protocol, how to undertake surveillance for CDI. In addition, they present the results of a survey that they have performed, which describes the current state of CDI surveillance across Europe. Accurate diagnosis is a cornerstone of any laboratory-based surveillance system, and is essential to inform rational clinical management of CDI. Moreover, even where there is the laboratory capability to undertake accurate diagnostic testing, the comparability of resulting surveillance data is crucially dependent upon the criteria employed for sampling and testing. The provision of such specific guidance in Europe was addressed by the publication in 2009 of ESCMID recommendations for the diagnosis of CDI developed by ESGCD [[13]Crobach M.J. Dekkers O.M. Wilcox M.H. Kuijper E.J. European society of clinical Microbiology and infectious diseases (ESCMID): data review and recommendations for diagnosing Clostridium difficile-infection (CDI).Clin Microbiol Infect. 2009; 15: 1053-1066Abstract Full Text Full Text PDF PubMed Scopus (369) Google Scholar]. A recent review of this guidance, with evaluation of the current evidence, led to the publication of updated ESGCD guidelines in 2016 [[14]Crobach M.J. Planche T. Eckert C. Barbut F. Terveer E.M. Dekkers O.M. et al.European society of clinical Microbiology and infectious diseases: update of the diagnostic guidance document for Clostridium difficile infection.Clin Microbiol Infect. 2016; 4: S63-S81Abstract Full Text Full Text PDF Scopus (364) Google Scholar]. In the current issue Barbut and colleagues review the state-of-the-art in CDI diagnostic testing (review article in the current issue). Another outstanding issue is the propensity for patients to develop recurrent C. difficile infection (rCDI), which occurs in 20%–30% of patients [[15]Louie T.J. Miller M.A. Mullane K.M. Weiss K. Lentnek A. Golan Y. et al.Fidaxomicin versus vancomycin for Clostridium difficile infection.N Engl J Med. 2011; 364: 422-431Crossref PubMed Scopus (1210) Google Scholar]. In hospital inpatients it has been shown that rCDI is associated with increased mortality and decreased quality of life [[16]Johnson S. Recurrent Clostridium difficile infection: a review of risk factors, treatments, and outcomes.J Infect. 2009; 58: 403-410Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar]. Moreover, those who suffer a first episode of rCDI are at greatly increased risk of developing further recurrent episodes [[17]Kelly C.P. Can we identify patients at high risk of recurrent Clostridium difficile infection?.Clin Microbiol Infect. 2012; 18: 21-27Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar]. Recurrent CDI has a significant additional impact on patient morbidity and infection control resources. Although it has been shown that the clinical risk factors for rCDI are similar to those for an initial episode of CDI [18Deshpande A. Pasupuleti V. Thota P. Pant C. Rolston D.D.K. Hernandez A.V. et al.Risk factors for recurrent Clostridium difficile infection: a systematic review and meta-analysis.Infect Control Hosp Epidemiol. 2015; 36: 452-460Crossref PubMed Scopus (154) Google Scholar, 19Garey K.W. Sethi S. Yadav Y. DuPont H.L. Meta-analysis to assess risk factors for recurrent Clostridium difficile infection.J Hosp Infect. 2008; 70: 298-304Abstract Full Text Full Text PDF PubMed Scopus (303) Google Scholar, 20Abou Chakra C.N. Pepin J. Sirard S. Valiquette L. Risk factors for recurrence, complications and mortality in Clostridium difficile infection: a systematic review.Plos One. 2014; 9Crossref Scopus (167) Google Scholar], microbiological factors associated with recurrence are less well described. In their article Chilton and colleagues highlight that a range of factors, including the host gut microbiota, spore persistence, viability and germination efficiency, may influence recurrence (review article in the current issue). The management of patients with rCDI remains a significant challenge for clinicians. Since the publication of the updated ESCMID guidance document on CDI treatment in 2014, new therapeutic approaches have been developed and tested to achieve a sustained clinical cure [[21]Debast S.B. Bauer M.P. Kuijper E.J. European society of clinical Microbiology and infectious diseases: update of the treatment guidance document for Clostridium difficile infection.Clin Microbiol Infect. 2014; 20: 1-26Abstract Full Text Full Text PDF PubMed Scopus (915) Google Scholar]. There is also considerably more experience of the use of faecal microbial transplantation, and of the antibiotic fidaxomicin, which appears to be less disruptive of the gut microbiota. In addition, a number of novel agents for the treatment of CDI that may be more protective of the gut microbiota have entered development and testing. Ooijevaar et al. (review article in the current issue) have reviewed the literature on treatment of CDI published since the last ESCMID guidance was produced and suggest that withdrawal of the initiating antibiotic should still be the first approach for the treatment of the individual patient with mild CDI. However, in the light of pooled results of two large multicentre randomized controlled trials, they propose that oral vancomycin should be the first choice when antibiotic treatment for CDI is necessary. They also anticipate that novel medications that protect the microbiota will be further developed and tested to prevent CDI development during antibiotic therapy. Finally, although there is much current interest in the contribution of community-acquired cases to the total burden of CDI, prevention in the healthcare setting remains a key focus of activity. Recent advances in the application of whole genome sequencing for the analysis of the molecular epidemiology of CDI has yielded important new insights into the transmission and spread of CDI [[22]He M. Miyajima F. Roberts P. Ellison L. Pickard D.J. Martin M.J. et al.Emergence and global spread of epidemic healthcare-associated Clostridium difficile.Nat Genet. 2013; 45: 109-113Crossref PubMed Scopus (525) Google Scholar]. With particular reference to healthcare-associated cases, such studies have demonstrated that a significant proportion of such infections cannot be accounted for by direct transmission from other symptomatic cases [[23]Eyre D.W. Cule M.L. Wilson D.J. Griffiths D. Vaughan A. O'Connor L. et al.Diverse sources of C. difficile infection identified on whole-genome sequencing.N Engl J Med. 2013; 369: 1195-1205Crossref PubMed Scopus (470) Google Scholar], raising questions around the role of asymptomatic carriers and other reservoirs of infection as potential sources. In the remaining article of this themed-review section Tschudin-Sutter, who led the recent revision of the ESCMID guidance on prevention and control of CDI, and colleagues provide a further update on novel insights into the transmission of CDI (review article in the current issue), and how these may help to inform our current and future strategies for control of CDI. It should be apparent that the answer to the question posed in the title of this editorial is yes, we can do better in tackling the ongoing challenge of CDI. This goal will be achieved by a combination of using interventions that are already successfully applied in some healthcare systems to achieve dramatic reductions in CDI, together with the continued development and implementation of novel measures. As the articles presented here exemplify, this combined approach will generate new insights and novel technologies, together with adopting a pragmatic approach to their implementation based upon targeted application in resource-limited settings, and underpinned by a foundation of high-quality evidence-based guidance. The author reports personal fees from MSD, outside the submitted work.