Clostridium difficile infection
Monash Infectious Diseases participates in research studies and clinical trials of new agents for the management and prevention of C. difficile infection.
Investigators and Collaborators
Investigators
Collaborators
- Prof Dena Lyras (Monash University)
- Prof Tom Riley (The University of Western Australia)
Research studies
Clostridium difficile Ribotype 244
Emergence and spread of predominantly community-onset Clostridium difficile PCR ribotype 244 infection in Australia, 2010 to 2012.
Eyre DW, Tracey L, Elliott B, Slimings C, Huntington PG, Stuart RL, Korman TM, Kotsiou G, McCann R, Griffiths D, Fawley WN, Armstrong P, Dingle KE, Walker AS, Peto TE, Crook DW, Wilcox MH, Riley TV.
Euro Surveill. 2015 Mar 12;20(10). pii: 21059.
Abstract
We describe an Australia-wide Clostridium difficile outbreak in 2011 and 2012 involving the previously uncommon ribotype 244. In Western Australia, 14 of 25 cases were community-associated, 11 were detected in patients younger than 65 years, 14 presented to emergency/outpatient departments, and 14 to non-tertiary/community hospitals. Using whole genome sequencing, we confirm ribotype 244 is from the same C. difficile clade as the epidemic ribotype 027. Like ribotype 027, it produces toxins A, B, and binary toxin, however it is fluoroquinolone-susceptible and thousands of single nucleotide variants distinct from ribotype 027. Fifteen outbreak isolates from across Australia were sequenced. Despite their geographic separation, all were genetically highly related without evidence of geographic clustering, consistent with a point source, for example affecting the national food chain. Comparison with reference laboratory strains revealed the outbreak clone shared a common ancestor with isolates from the United States and United Kingdom (UK). A strain obtained in the UK was phylogenetically related to our outbreak. Follow-up of that case revealed the patient had recently returned from Australia. Our data demonstrate new C. difficile strains are an on-going threat, with potential for rapid spread. Active surveillance is needed to identify and control emerging lineages.
Emergence of a ribotype 244 strain of Clostridium difficile associated with severe disease and related to the epidemic ribotype 027 strain.
Lim SK, Stuart RL, Mackin K, Carter G, Kotsanas D, Francis M, Easton M, Dimovski K, Elliot B, Riley TV, Hogg G, Paul E, Korman TM, Seemann T, Stinear TP, Lyras D, Jenkin GA.
Clin Infect Dis. 2014 Jun;58(12):1723-30. doi: 10.1093/cid/ciu203. Epub 2014 Apr 4.
Abstract
BACKGROUND: We identified 12 patients with Clostridium difficile infection between July 2011 and March 2012 from whom an unusual C. difficile strain was isolated. This strain had a single-nucleotide deletion of the tcdC gene at position 117 and binary toxin genes, which are characteristic of the hypervirulent ribotype (RT) 027 strain.
METHODS: A retrospective cohort study of 12 patients infected with C. difficile RT244 and 24 patients infected with non-RT244/non-RT027 strains matched for place of diagnosis and time of collection of specimen was performed. We performed whole-genome sequencing to understand the relationship of the RT244 strain to other C. difficile strains and further understand its virulence potential.
RESULTS: Clostridium difficile RT244 was associated with more severe disease and a higher mortality rate. Phylogenomic analysis using core genome single-nucleotide polymorphisms showed that RT244 is in the same genetic clade (clade 2) as RT027 but is distinct from all RT027 strains. The pathogenicity locus of the RT244 strain encodes a variant toxin B, and this was confirmed by demonstration of Clostridium sordellii-like cytopathic effect on Vero cells. Toxin B production in culture supernatants was lower than that seen with a RT027 strain.
CONCLUSIONS: Our findings demonstrate the pathogenic potential of this RT244 C. difficile strain and emphasize the importance of ongoing surveillance for emergent strains.
Comment in
Editorial commentary: Changing epidemiology of Clostridium difficile and emergence of new virulent strains. [Clin Infect Dis. 2014]
Clinical trials
Current studies
Clostridium difficile Toxoid Vaccine in Subjects at Risk for C. difficile Infection (Cdiffense)
ClinicalTrials.gov Identifier: NCT01887912
Study website: Cdiffense.org
Summary: The aim of this Phase 3 study is to evaluate the efficacy of the candidate Clostridium difficile vaccine to prevent primary symptomatic C. difficile infection (CDI) in subjects a risk for CDI where there is a substantial unmet medical need.
Site Principal Investigator: Dr Grant Jenkin
Completed studies
Human Monoclonal Antibodies to Clostridium Difficile Toxin A and Toxin B in Participants Receiving Antibiotic Therapy for Clostridium Difficile Infection (MODIFY I).
ClinicalTrials.gov Identifier: NCT01241552
Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection.
Wilcox MH, Gerding DN, Poxton IR, Kelly C, Nathan R, Birch T, Cornely OA, Rahav G, Bouza E, Lee C, Jenkin G, Jensen W, Kim YS, Yoshida J, Gabryelski L, Pedley A, Eves K, Tipping R, Guris D, Kartsonis N, Dorr MB; MODIFY I and MODIFY II Investigators.
N Engl J Med. 2017 Jan 26;376(4):305-317. doi: 10.1056/NEJMoa1602615.
Abstract
BACKGROUND: Clostridium difficile is the most common cause of infectious diarrhea in hospitalized patients. Recurrences are common after antibiotic therapy. Actoxumab and bezlotoxumab are human monoclonal antibodies against C. difficile toxins A and B, respectively.
METHODS: We conducted two double-blind, randomized, placebo-controlled, phase 3 trials, MODIFY I and MODIFY II, involving 2655 adults receiving oral standard-of-care antibiotics for primary or recurrent C. difficile infection. Participants received an infusion of bezlotoxumab (10 mg per kilogram of body weight), actoxumab plus bezlotoxumab (10 mg per kilogram each), or placebo; actoxumab alone (10 mg per kilogram) was given in MODIFY I but discontinued after a planned interim analysis. The primary end point was recurrent infection (new episode after initial clinical cure) within 12 weeks after infusion in the modified intention-to-treat population.
RESULTS: In both trials, the rate of recurrent C. difficile infection was significantly lower with bezlotoxumab alone than with placebo (MODIFY I: 17% [67 of 386] vs. 28% [109 of 395]; adjusted difference, -10.1 percentage points; 95% confidence interval [CI], -15.9 to -4.3; P<0.001; MODIFY II: 16% [62 of 395] vs. 26% [97 of 378]; adjusted difference, -9.9 percentage points; 95% CI, -15.5 to -4.3; P<0.001) and was significantly lower with actoxumab plus bezlotoxumab than with placebo (MODIFY I: 16% [61 of 383] vs. 28% [109 of 395]; adjusted difference, -11.6 percentage points; 95% CI, -17.4 to -5.9; P<0.001; MODIFY II: 15% [58 of 390] vs. 26% [97 of 378]; adjusted difference, -10.7 percentage points; 95% CI, -16.4 to -5.1; P<0.001). In prespecified subgroup analyses (combined data set), rates of recurrent infection were lower in both groups that received bezlotoxumab than in the placebo group in subpopulations at high risk for recurrent infection or for an adverse outcome. The rates of initial clinical cure were 80% with bezlotoxumab alone, 73% with actoxumab plus bezlotoxumab, and 80% with placebo; the rates of sustained cure (initial clinical cure without recurrent infection in 12 weeks) were 64%, 58%, and 54%, respectively. The rates of adverse events were similar among these groups; the most common events were diarrhea and nausea.
CONCLUSIONS: Among participants receiving antibiotic treatment for primary or recurrent C. difficile infection, bezlotoxumab was associated with a substantially lower rate of recurrent infection than placebo and had a safety profile similar to that of placebo. The addition of actoxumab did not improve efficacy. (Funded by Merck; MODIFY I and MODIFY II ClinicalTrials.gov numbers, NCT01241552 and NCT01513239 ).
Efficacy and Safety of Cadazolid Versus Vancomycin in Subjects With Clostridium difficile infection
ClinicalTrials.gov Identifier: NCT01987895
Summary: This Phase 3 study is conducted to assess the efficacy of cadazolid compared to vancomycin in subjects with Clostridium difficile-associated diarrhea (CDAD). Subjects selected to participate in the study are treated either with cadazolid or vancomycin for 10 days. At the end of treatment, clinical cure is assessed; subjects are then followed-up to assess any disease recurrence.
CB-183,315 (Surotomycin) in Patients With Clostridium difficile infection
ClinicalTrials.gov Identifier: NCT01598311
Summary: 608 patients with Clostridium Difficile Associated Diarrhea (CDAD) will participate in this Phase 3 study and receive either oral vancomycin or CB-183,315 in a blinded fashion. Treatment will last for 10 days and participants will be followed up for at least 40 days and a maximum of 100 days. The purpose of this study is to evaluate how well CB-183,315 treats CDAD as compared to vancomycin.
Publications
Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection.
Wilcox MH, Gerding DN, Poxton IR, Kelly C, Nathan R, Birch T, Cornely OA, Rahav G, Bouza E, Lee C, Jenkin G, Jensen W, Kim YS, Yoshida J, Gabryelski L, Pedley A, Eves K, Tipping R, Guris D, Kartsonis N, Dorr MB; MODIFY I and MODIFY II Investigators.
N Engl J Med. 2017 Jan 26;376(4):305-317. doi: 10.1056/NEJMoa1602615.
Australasian Society of Infectious Diseases updated guidelines for the management of Clostridium difficile infection in adults and children in Australia and New Zealand.
Trubiano JA, Cheng AC, Korman TM, Roder C, Campbell A, May ML, Blyth CC, Ferguson JK, Blackmore T, Riley TV, Athan E.
Intern Med J. 2016 Apr;46(4):479-93. doi:10.1111/imj.13027.
Antimicrobial surveillance of C. difficile in Australia.
Knight DR, Giglio S, Huntington PG, Korman TM, Kotsanas D, Moore CV, Paterson D, Prendergast L, Huber CA, Robson J, Waring L, Wehrhahn MC, Weldhagen GF, Wilson RM, Riley TV.
J Antimicrob Chemother. 2015 Nov;70(11):2992-9. doi: 10.1093/jac/dkv220. Epub 2015 Jul 28.
Molecular characterization and antimicrobial susceptibilities of Clostridium difficile clinical isolates from Victoria, Australia.
Mackin KE, Elliott B, Kotsanas D, Howden BP, Carter GP, Korman TM, Riley TV, Rood JI, Jenkin GA, Lyras D.
Anaerobe. 2015 Aug;34:80-3. doi: 10.1016/j.anaerobe.2015.05.001. Epub 2015 May 2.
Emergence and spread of predominantly community-onset Clostridium difficile PCR ribotype 244 infection in Australia, 2010 to 2012.
Eyre DW, Tracey L, Elliott B, Slimings C, Huntington PG, Stuart RL, Korman TM, Kotsiou G, McCann R, Griffiths D, Fawley WN, Armstrong P, Dingle KE, Walker AS, Peto TE, Crook DW, Wilcox MH, Riley TV
Euro Surveill. 2015 Mar 12;20(10). pii: 21059.
Diagnosis and Management of Clostridium difficile infection.
Korman TM.
Semin Respir Crit Care Med. 2015 Feb;36(1):31-43. doi: 10.1055/s-0034-1398741. Epub 2015 Feb 2.
Clostridium difficile infection: an Australian clinical perspective.
Jenkin GA.
Microbiology Australia 2015;36(3):106-108.
Emergence of a ribotype 244 strain of Clostridium difficile associated with severe disease and related to the epidemic ribotype 027 strain.
Lim SK, Stuart RL, Mackin K, Carter G, Kotsanas D, Francis M, Easton M, Dimovski K, Elliot B, Riley TV, Hogg G, Paul E, Korman TM, Seemann T, Stinear TP, Lyras D, Jenkin GA.
Clin Infect Dis. 2014 Jun;58(12):1723-30. doi: 10.1093/cid/ciu203. Epub 2014 Apr 4.
Clostridium difficile - what is the Australian story?
Johnson PD, Stuart RL.
Med J Aust. 2014 Mar 17;200(5):242-3. No abstract available.
The Anti-Sigma Factor TcdC Modulates Hypervirulence in an Epidemic BI/NAP1/027 Clinical Isolate of Clostridium difficile.
Carter GP, Douce GR, Govind R, Howarth PM, Mackin KE, Spencer J, Buckley AM, Antunes A, Kotsanas D, Jenkin GA, Dupuy B, Rood JI, Lyras D.
PLoS Pathog. 2011 Oct;7(10):e1002317. Epub 2011 Oct 13.
Clostridium difficile laboratory testing in Australia and New Zealand: national survey results and Australasian Society for Infectious Diseases recommendations for best practice.
Ferguson JK, Cheng AC, Gilbert GL, Gottlieb T, Korman T, McGregor A, Richards M, Roberts S, Robson J, Van Gessel H, Riley TV.
Pathology. 2011 Aug;43(5):482-7. doi: 10.1097/PAT.0b013e328348c9b4.
Australasian Society for Infectious Diseases guidelines for the diagnosis and treatment of Clostridium difficile infection.
Cheng AC, Ferguson JK, Richards MJ, Robson JM, Gilbert GL, McGregor A, Roberts S, Korman TM, Riley TV.
Med J Aust. 2011 Apr 4;194(7):353-8.
Clostridium difficile infection: a new threat on our doorstep.
Stuart RL, Marshall C.
Med J Aust. 2011 Apr 4;194(7):331-2.
ASID/AICA position statement – Infection control guidelines for patients with Clostridium difficile infection in healthcare settings.
Stuart RL, Marshall C, McLaws M, Boardman C, Russo PL, Harrington G, Ferguson JK.
Healthcare Infect 2011;16(1):33-39.