Cutting edges in Clostridioides difficile infections
Clostridioides difficile is the most common cause of hospital-acquired diarrhoea and one of the most important causes of hospital-acquired infections. It results in significant morbidity, mortality and economic burden - especially in the context of recurrent infections. After initial antibiotic therapy of a C. difficile infection, recurrence occurs in about 20% of all patients, which increases the risk of further recurrence to about 45%.
Traditional therapeutic options for treatment of C. difficile infection include metronidazole or vancomycin. Newer therapy options such as fidaxomicin, the administration of monoclonal antibodies or faecal microbiota transplantation demonstrate significant advantages over traditional therapies, particularly regarding the reduction of the recurrence rate.
This article highlights the main differences between the recommendations of the Swiss Society for Infectious Diseases on the management of “Clostridioides difficile infection” and the IDSA/SHEA reference guideline “Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA)” and discusses some important challenges in -treatment of C. difficile.
- Bauer MP, Notermans DW, van Benthem BH, Brazier JS, Wilcox MH, Rupnik M, et al.; ECDIS Study Group. Clostridium difficile infection in Europe: a hospital-based survey. Lancet. 2011 Jan;377(9759):63–73. https://doi.org/10.1016/S0140-6736(10)61266-4
- Davies KA, Longshaw CM, Davis GL, Bouza E, Barbut F, Barna Z, et al. Underdiagnosis of Clostridium difficile across Europe: the European, multicentre, prospective, biannual, point-prevalence study of Clostridium difficile infection in hospitalised patients with diarrhoea (EUCLID). Lancet Infect Dis. 2014 Dec;14(12):1208–19. https://doi.org/10.1016/S1473-3099(14)70991-0
- Fenner L, Frei R, Gregory M, Dangel M, Stranden A, Widmer AF. Epidemiology of Clostridium difficile-associated disease at University Hospital Basel including molecular characterisation of the isolates 2006-2007. Eur J Clin Microbiol Infect Dis. 2008 Dec;27(12):1201–7. https://doi.org/10.1007/s10096-008-0564-9
- Kohler P, Bregenzer-Witteck A, Rafeiner P, Schlegel M. Presumably hospital-transmitted Clostridium difficile infections based on epidemiological linkage. Swiss Med Wkly. 2013 Jul;143:w13824. https://doi.org/10.4414/smw.2013.13824
- Vernaz N, Sax H, Pittet D, Bonnabry P, Schrenzel J, Harbarth S. Temporal effects of antibiotic use and hand rub consumption on the incidence of MRSA and Clostridium difficile. J Antimicrob Chemother. 2008 Sep;62(3):601–7. https://doi.org/10.1093/jac/dkn199
- Widmer AF, Frei R, Kuijper EJ, Wilcox MH, Schindler R, Spaniol V, et al. Multicenter Prevalence Study Comparing Molecular and Toxin Assays for Clostridioides difficile Surveillance, Switzerland. Emerg Infect Dis. 2020 Oct;26(10):2370–7. https://doi.org/10.3201/eid2610.190804
- McDonald LC, Gerding DN, Johnson S, Bakken JS, Carroll KC, Coffin SE, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018 Mar;66(7):e1–48. https://doi.org/10.1093/cid/cix1085
- Teasley DG, Gerding DN, Olson MM, Peterson LR, Gebhard RL, Schwartz MJ, et al. Prospective randomised trial of metronidazole versus vancomycin for Clostridium-difficile-associated diarrhoea and colitis. Lancet. 1983 Nov;2(8358):1043–6. https://doi.org/10.1016/S0140-6736(83)91036-X
- Wenisch C, Parschalk B, Hasenhündl M, Hirschl AM, Graninger W. Comparison of vancomycin, teicoplanin, metronidazole, and fusidic acid for the treatment of Clostridium difficile-associated diarrhea. Clin Infect Dis. 1996 May;22(5):813–8. https://doi.org/10.1093/clinids/22.5.813
- Cohen SH, Gerding DN, Johnson S, Kelly CP, Loo VG, McDonald LC, et al.; Society for Healthcare Epidemiology of America; Infectious Diseases Society of America. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA). Infect Control Hosp Epidemiol. 2010 May;31(5):431–55. https://doi.org/10.1086/651706
- Johnson S, Louie TJ, Gerding DN, Cornely OA, Chasan-Taber S, Fitts D, et al.; Polymer Alternative for CDI Treatment (PACT) investigators. Vancomycin, metronidazole, or tolevamer for Clostridium difficile infection: results from two multinational, randomized, controlled trials. Clin Infect Dis. 2014 Aug;59(3):345–54. https://doi.org/10.1093/cid/ciu313
- Zar FA, Bakkanagari SR, Moorthi KM, Davis MB. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis. 2007 Aug;45(3):302–7. https://doi.org/10.1086/519265
- Nelson RL, Suda KJ, Evans CT. Antibiotic treatment for Clostridium difficile-associated diarrhoea in adults. Cochrane Database Syst Rev. 2017 Mar;3:CD004610.
- Vardakas KZ, Polyzos KA, Patouni K, Rafailidis PI, Samonis G, Falagas ME. Treatment failure and recurrence of Clostridium difficile infection following treatment with vancomycin or metronidazole: a systematic review of the evidence. Int J Antimicrob Agents. 2012 Jul;40(1):1–8. https://doi.org/10.1016/j.ijantimicag.2012.01.004
- Al-Nassir WN, Sethi AK, Nerandzic MM, Bobulsky GS, Jump RL, Donskey CJ. Comparison of clinical and microbiological response to treatment of Clostridium difficile-associated disease with metronidazole and vancomycin. Clin Infect Dis. 2008 Jul;47(1):56–62. https://doi.org/10.1086/588293
- Wilcox MH, Howe R. Diarrhoea caused by Clostridium difficile: response time for treatment with metronidazole and vancomycin. J Antimicrob Chemother. 1995 Oct;36(4):673–9. https://doi.org/10.1093/jac/36.4.673
- Debast SB, Bauer MP, Kuijper EJ ; European Society of Clinical Microbiology and Infectious Diseases. European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection. Clin Microbiol Infect. 2014 Mar;20 Suppl 2:1–26. https://doi.org/10.1111/1469-0691.12418
- Louie T, Miller M, Donskey C, Mullane K, Goldstein EJ. Clinical outcomes, safety, and pharmacokinetics of OPT-80 in a phase 2 trial with patients with Clostridium difficile infection. Antimicrob Agents Chemother. 2009 Jan;53(1):223–8. https://doi.org/10.1128/AAC.01442-07
- Louie TJ, Cannon K, Byrne B, Emery J, Ward L, Eyben M, et al. Fidaxomicin preserves the intestinal microbiome during and after treatment of Clostridium difficile infection (CDI) and reduces both toxin reexpression and recurrence of CDI. Clin Infect Dis. 2012 Aug;55 Suppl 2:S132–42. https://doi.org/10.1093/cid/cis338
- Johnson S, Homann SR, Bettin KM, Quick JN, Clabots CR, Peterson LR, et al. Treatment of asymptomatic Clostridium difficile carriers (fecal excretors) with vancomycin or metronidazole. A randomized, placebo-controlled trial. Ann Intern Med. 1992 Aug;117(4):297–302. https://doi.org/10.7326/0003-4819-117-4-297
- Baines SD, O’Connor R, Saxton K, Freeman J, Wilcox MH. Activity of vancomycin against epidemic Clostridium difficile strains in a human gut model. J Antimicrob Chemother. 2009 Mar;63(3):520–5. https://doi.org/10.1093/jac/dkn502
- Deshpande A, Hurless K, Cadnum JL, Chesnel L, Gao L, Chan L, et al. Effect of Fidaxomicin versus Vancomycin on Susceptibility to Intestinal Colonization with Vancomycin-Resistant Enterococci and Klebsiella pneumoniae in Mice. Antimicrob Agents Chemother. 2016 Jun;60(7):3988–93. https://doi.org/10.1128/AAC.02590-15
- Freeman J, Baines SD, Saxton K, Wilcox MH. Effect of metronidazole on growth and toxin production by epidemic Clostridium difficile PCR ribotypes 001 and 027 in a human gut model. J Antimicrob Chemother. 2007 Jul;60(1):83–91. https://doi.org/10.1093/jac/dkm113
- Freeman J, Vernon J, Pilling S, Morris K, Nicolson S, Shearman S, et al.; Pan-European Longitudinal Surveillance of Antibiotic Resistance among Prevalent Clostridium difficile Ribotypes’ Study Group. Five-year Pan-European, longitudinal surveillance of Clostridium difficile ribotype prevalence and antimicrobial resistance: the extended ClosER study. Eur J Clin Microbiol Infect Dis. 2020 Jan;39(1):169–77. https://doi.org/10.1007/s10096-019-03708-7
- Bolton RP, Culshaw MA. Faecal metronidazole concentrations during oral and intravenous therapy for antibiotic associated colitis due to Clostridium difficile. Gut. 1986 Oct;27(10):1169–72. https://doi.org/10.1136/gut.27.10.1169
- Cherian PT, Wu X, Yang L, Scarborough JS, Singh AP, Alam ZA, et al. Gastrointestinal localization of metronidazole by a lactobacilli-inspired tetramic acid motif improves treatment outcomes in the hamster model of Clostridium difficile infection. J Antimicrob Chemother. 2015 Nov;70(11):3061–9. https://doi.org/10.1093/jac/dkv231
- Widmer AF, Frei R, Erb S, Stranden A, Kuijper EJ, Knetsch CW, et al. Transmissibility of Clostridium difficile Without Contact Isolation: Results From a Prospective Observational Study With 451 Patients. Clin Infect Dis. 2017 Feb;64(4):393–400.
- Cusini A, Béguelin C, Stampf S, Boggian K, Garzoni C, Koller M, et al.; Swiss Transplant Cohort Study. Clostridium difficile infection is associated with graft loss in solid organ transplant recipients. Am J Transplant. 2018 Jul;18(7):1745–54. https://doi.org/10.1111/ajt.14640
- Tomas ME, Mana TS, Wilson BM, Nerandzic MM, Joussef-Piña S, Quiñones-Mateu ME, et al. Tapering Courses of Oral Vancomycin Induce Persistent Disruption of the Microbiota That Provide Colonization Resistance to Clostridium difficile and Vancomycin-Resistant Enterococci in Mice. Antimicrob Agents Chemother. 2018 Apr;62(5):e02237-17. https://doi.org/10.1128/AAC.02237-17
- Sethi AK, Al-Nassir WN, Nerandzic MM, Donskey CJ. Skin and environmental contamination with vancomycin-resistant Enterococci in patients receiving oral metronidazole or oral vancomycin treatment for Clostridium difficile-associated disease. Infect Control Hosp Epidemiol. 2009 Jan;30(1):13–7. https://doi.org/10.1086/592710
- Al-Nassir WN, Sethi AK, Li Y, Pultz MJ, Riggs MM, Donskey CJ. Both oral metronidazole and oral vancomycin promote persistent overgrowth of vancomycin-resistant enterococci during treatment of Clostridium difficile-associated disease. Antimicrob Agents Chemother. 2008 Jul;52(7):2403–6. https://doi.org/10.1128/AAC.00090-08
- Miller M, Bernard L, Thompson M, Grima D, Pepin J. Lack of increased colonization with vancomycin-resistant enterococci during preferential use of vancomycin for treatment during an outbreak of healthcare-associated Clostridium difficile infection. Infect Control Hosp Epidemiol. 2010 Jul;31(7):710–5. https://doi.org/10.1086/653613
- Stevens VW, Khader K, Echevarria K, Nelson RE, Zhang Y, Jones M, et al. Use of oral vancomycin for Clostridioides difficile Infection (CDI) and the risk of vancomycin-resistant Enterococci (VRE). Clin Infect Dis. 2020;71(3):645-51.
- Johnson SW, Brown SV, Priest DH. Effectiveness of Oral Vancomycin for Prevention of Healthcare Facility-Onset Clostridioides difficile Infection in Targeted Patients During Systemic Antibiotic Exposure. Clin Infect Dis. 2019. https://doi.org/10.1093/cid/ciz966
- Morrisette T, Van Matre AG, Miller MA, Mueller SW, Bajrovic V, Abidi MZ, et al. Oral Vancomycin Prophylaxis as Secondary Prevention Against Clostridioides difficile Infection in the Hematopoietic Stem Cell Transplantation and Hematologic Malignancy Population. Biol Blood Marrow Transplant. 2019 Oct;25(10):2091–7. https://doi.org/10.1016/j.bbmt.2019.06.021
- Nerandzic MM, Mullane K, Miller MA, Babakhani F, Donskey CJ. Reduced acquisition and overgrowth of vancomycin-resistant enterococci and Candida species in patients treated with fidaxomicin versus vancomycin for Clostridium difficile infection. Clin Infect Dis. 2012 Aug;55 Suppl 2:S121–6. https://doi.org/10.1093/cid/cis440
- Deshpande A, Hurless K, Cadnum JL, Chesnel L, Gao L, Chan L, et al. Effect of Surotomycin, a Novel Cyclic Lipopeptide Antibiotic, on Intestinal Colonization with Vancomycin-Resistant Enterococci and Klebsiella pneumoniae in Mice. Antimicrob Agents Chemother. 2016 May;60(6):3333–9. https://doi.org/10.1128/AAC.02904-15
- Cornely OA, Crook DW, Esposito R, Poirier A, Somero MS, Weiss K, et al.; OPT-80-004 Clinical Study Group. Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trial. Lancet Infect Dis. 2012 Apr;12(4):281–9. https://doi.org/10.1016/S1473-3099(11)70374-7
- Cornely OA, Miller MA, Louie TJ, Crook DW, Gorbach SL. Treatment of first recurrence of Clostridium difficile infection: fidaxomicin versus vancomycin. Clin Infect Dis. 2012 Aug;55 Suppl 2:S154–61. https://doi.org/10.1093/cid/cis462
- Louie TJ, Emery J, Krulicki W, Byrne B, Mah M. OPT-80 eliminates Clostridium difficile and is sparing of bacteroides species during treatment of C. difficile infection. Antimicrob Agents Chemother. 2009 Jan;53(1):261–3. https://doi.org/10.1128/AAC.01443-07
- van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013 Jan;368(5):407–15. https://doi.org/10.1056/NEJMoa1205037
- Morrison C. Antibacterial antibodies gain traction. Nat Rev Drug Discov. 2015 Nov;14(11):737–8. https://doi.org/10.1038/nrd4770
- Wilcox MH, Gerding DN, Poxton IR, Kelly C, Nathan R, Birch T, et al.; MODIFY I and MODIFY II Investigators. Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection. N Engl J Med. 2017 Jan;376(4):305–17. https://doi.org/10.1056/NEJMoa1602615
- Dieterle MG, Young VB. Reducing Recurrence of C. difficile Infection. Cell. 2017 Apr;169(3):375. https://doi.org/10.1016/j.cell.2017.03.039
- Gerding DN, Kelly CP, Rahav G, Lee C, Dubberke ER, Kumar PN, et al. Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection in Patients at Increased Risk for Recurrence. Clin Infect Dis. 2018 Aug;67(5):649–56. https://doi.org/10.1093/cid/ciy171