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Clostridium difficile Research

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Publications

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 M, Blyth C, Ferguson J, Blackmore T, Riley TV, Athan E.
Int Med J 2016 [in press]

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 Jul 28. pii: dkv220. [Epub ahead of print]

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 May 2. pii: S1075-9964(15)30017-2. doi: 10.1016/j.anaerobe.2015.05.001. [Epub ahead of print]
PMID:25944720

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.

PMID: 25643269 [PubMed – in process]

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 Apr 4. [Epub ahead of print]
PMID: 24704722 [PubMed – as supplied by publisher]

Clostridium difficile – what is the Australian story?

Johnson PD, Stuart RL.
Med J Aust. 2014 Mar 17;200(5):242-3. No abstract available.
PMID: 24641129 [PubMed – in process]

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.
PMID: 22022270 [PubMed – in process] Free PMC Article

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.
PMID: 21716158 [PubMed – indexed for MEDLINE]

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.
PMID: 21470086 [PubMed – in process]

Clostridium difficile infection: a new threat on our doorstep.
Stuart RL, Marshall C.
Med J Aust. 2011 Apr 4;194(7):331-2.
PMID: 21470079 [PubMed – in process]

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.

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MODIFY (C. difficile therapy)

A Study of MK-3415, MK-6072, and MK-3415A in Participants Receiving Antibiotic Therapy for Clostridium Difficile Infection (MK-3415A-001 AM2) (MODIFY I)

clinicaltrials.gov

C. difficile infection (CDI) is the most common cause of infectious diarrhoea in hospitalised patients in the developed world with increased incidence of recurrent infection.  Antibiotic therapy is usually successful in treating the initial episode of CDI; however, approximately 15-30% of these patients will have a recurrent episode. Patients who have experienced at least one episode of recurrent CDI have a 33-60% chance of experiencing additional episodes.

Treatment with monoclonal antibodies against Clostridium difficile toxins (Lowy et al. N Eng J Med 2010 Jan 21;362(3):197-205)
A new adjunctive approach to the treatment of CDI is the use of monoclonal antibodies directed against the toxins. Results from the Phase II clinical study of a single infusion of the combination of monoclonal antibodies directed against toxins A and B (MK-3415A) demonstrated a significant difference (p = 0.001) in CDI recurrence between recipients of the monoclonal antibodies (7% [7/101]) and those who received placebo (25% [25/99]). The safety of MK-3415A was comparable to placebo.

Summary

This is a randomized, double-blind, placebo-controlled, multicentre, Phase III study evaluating the efficacy, safety, and tolerability of monoclonal antibodies to C. difficile exotoxins. Participants receiving standard of care (SOC) therapy will be randomised equally into 1 of 4 treatment groups. On Day 1 participants will receive MK-3415 (toxin A only), MK-6072 (toxin B only), MK-3415A or placebo.

This study will investigate whether:

  • treatment with MK-3415A (Human Monoclonal Antibodies to Clostridium Difficile Toxin A and Toxin B) in addition to standard of care (SOC) antibiotic therapy will decrease Clostridium difficile infection (CDI) recurrence as compared to treatment with MK-6072 or MK-3415,
  • treatment with MK-3415A, MK-6072  (Human Monoclonal Antibody to Clostridium Difficile Toxin B), or MK-3415 (Human Monoclonal Antibody to Clostridium Difficile Toxin A), in addition to SOC antibiotic therapy will decrease CDI recurrence as compared to placebo, and
  • MK-3415A, MK-6072, and MK-3415 will be generally well tolerated in participants receiving SOC therapy for CDI as compared to placebo.

Inclusion Criteria

  • participant must be 18 years of age or older.
  • participant has a diagnosis of CDI as defined by: a. Presence of diarrhea, as defined by passage of 3 or more loose stools in 24 or fewer hours, AND b. A positive stool test for toxigenic C. difficile.
  • participant must be receiving SOC therapy for CDI. SOC therapy is defined as the receipt of oral metronidazole, oral vancomycin, IV metronidazole concurrent with oral vancomycin, oral fidaxomicin, or oral fidaxomicin concurrent with IV metronidazole.
  • participant is highly unlikely to become pregnant or to impregnate a partner since they meet at least one of the following criteria: a. A female participant who is not of reproductive potential is eligible without requiring the use of contraception. A female participant who is not of reproductive potential is defined as: one who has either (1) reached natural menopause (defined as 6 months of spontaneous amenorrhea with serum follicle stimulating hormone (FSH) levels in the postmenopausal range as determined by the local laboratory, or 12 months of spontaneous amenorrhea); (2) 6 weeks post surgical bilateral oophorectomy with or without hysterectomy; or (3) bilateral tubal ligation. Spontaneous amenorrhea does not include cases for which there is an underlying disease that causes amenorrhea (e.g. anorexia nervosa). b. A participant who is of reproductive potential agrees to remain abstinent or use (or have their partner use) 2 acceptable methods of birth control starting at enrollment and through the 12 Week study period. Acceptable methods of birth control are: intrauterine device (IUD), diaphragm with spermicide, contraceptive sponge, condom, vasectomy and any registered and marketed hormonal contraceptives that contain an estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or intramuscular agents)
  • participant or legal representative must have voluntarily agreed to participate by providing written informed consent after the nature of the study has been fully explained.

Exclusion Criteria

  • participant with an active chronic diarrheal illness such as, but not limited to, ulcerative colitis or Crohn’s disease or with a condition that causes routine passage of loose stool (e.g., an ostomy).
  • participant with a planned surgery for CDI within 24 hours.
  • participant has a positive pregnancy test in the 48 hours before the infusion or is unwilling to undergo pregnancy testing if a pre-menopausal female who is not sterilized and therefore has the potential to bear a child.
  • participant is breast-feeding or plans to breast-feed prior to the completion of the 12-week study period.
  • A female participant who plans to donate ova prior to the completion of the 12-week study period, or a male participant who is planning to impregnate or provide sperm donation prior to the completion of the 12-week study period.
  • participant has previously participated in this study or has previously received MK-3415 or MK- 6072 (either alone or in combination).
  • participant plans to donate blood and/or blood products within 6 months following the infusion.
  • participant has received immune globulin within 6 months prior to receipt of the infusion or is planning to receive immune globulin prior to the completion of the 12-week study period.
  • Treatment with SOC therapy is planned for longer than 14 days
  • participant has received cholestyramine, rifaximin, or nitazoxanide within 14 days prior to receipt of the infusion or is planning to receive these medications prior to the completion of the 12-week study period.
  • participant plans to take antiperistaltic agents, such as loperamide (Imodiumâ„¢) or diphenoxylate hydrochloride/atropine sulfate (LOMOTILâ„¢), at any time during the 14 days following infusion. Participants receiving opioid medications at the onset of diarrhea may be included if they are on a stable dose or if there is anticipation of a dose decrease or cessation of use.
  • participant plans to take the probiotic Saccharomyces boulardii at any time following infusion (Day 1) and through the completion of the 12-week study period.
  • participant has received another investigational study agent within the previous 30 days, or is currently participating in or scheduled to participate in any other clinical trial during the 12-week study period.
  • participant is not expected to survive for 72 hours.
  • participant has any other condition that, in the opinion of the investigator, would jeopardize the safety or rights of the participant participating in the study, would make it unlikely for the participant to complete the study, or would confound the results of the study.

Primary Outcome Measures

Proportion of participants with Clostridium difficile infection (CDI) recurrence [ Time Frame: 12 weeks ]

Secondary Outcome Measures

  • Proportion of participants with Global Cure [ Time Frame: 12 weeks ]
  • Proportion of participants with CDI recurrence in those with clinical cure of the initial CDI episode [ Time Frame: 12 weeks ]

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Cdiffense (C. difficile vaccine)

Study of a Candidate Clostridium difficile Toxoid Vaccine in Subjects at Risk for C. difficile Infection

The aim of this study is to evaluate the efficacy of the candidate Clostridium difficile (C. difficile) vaccine to prevent primary symptomatic C. difficile infection (CDI) in subjects a risk for CDI where there is a substantial unmet medical need.

The study is designed as an event-driven group sequential protocol with 2 stages of enrollment, 3 interim analyses at defined clinical endpoints and a final analysis when number of clinical endpoints are reached.

In both Stage 1 and Stage 2, subjects will be randomly assigned to receive either the candidate vaccine or a placebo that will be administered in a 3-dose schedule. Stage 2 will be initiated after completing the second interim analysis of the Stage 1 cohort.

Primary objective

To assess the efficacy of the C. difficile vaccine in preventing the onset of symptomatic primary CDI confirmed by polymerase chain reaction (PCR) in adult subjects aged ≥ 50 years who are at risk for CDI and have received at least 1 injection.

Secondary Objectives

Efficacy:

  • To assess prevention of symptomatic PCR-confirmed primary CDI cases after 3 injections administered at 0, 7, and 30 days
  • To assess prevention of symptomatic PCR-confirmed primary CDI cases after completion of at least 2 injections.

Immunogenicity:
To describe the immunogenicity to toxin A and toxin B in the subset of subjects at specific time points.

Safety:
To describe the safety profile of all subjects who receive at least 1 injection.

Inclusion Criteria

  • Aged ≥ 50 years on the day of inclusion
  • Informed consent form has been signed and dated
  • Able to attend all scheduled visits and to comply with all trial procedures
  • Covered by health insurance (if required)
  • Must fulfill at least 1 of the following criteria

Risk Stratum 1:

  • Has had at least 2 hospital stays, each lasting at least ≥ 72 hours, in the 12 months before enrollment, and
  • Has received systemic (not topical) antibiotics in the 12 months before enrollment, or

Risk Stratum 2:

  • Is anticipated to have an in-patient hospitalization for a planned surgical procedure within 60 days of enrollment. The impending hospital stay is planned to be ≥ 72 hours for a surgery involving 1 of the following:
  • Kidney/bladder/urinary system
  • Musculoskeletal system
  • Respiratory system
  • Circulatory system
  • Central nervous system.

Exclusion Criteria

  • Subject is pregnant, or lactating, or of childbearing potential (to be considered of non-childbearing potential, a female must be post-menopausal for at least 1 year, surgically sterile, or using an effective method of contraception or abstinence from at least 4 weeks prior to the first vaccination and until at least 4 weeks after the last vaccination)
  • Participation in the 4 weeks preceding the first trial vaccination or participation during the present trial period in another clinical trial investigating a vaccine, drug, medical device, or medical procedure
  • Receipt of any vaccine in the 4 weeks preceding the first trial vaccination except for influenza (seasonal or pandemic) and pneumococcal vaccines. This exception includes monovalent pandemic influenza vaccines and multivalent influenza vaccines
  • Previous vaccination against C. difficile with either the trial vaccine, another vaccine, or monoclonal antibodies
  • Diarrhea on day of enrollment
  • Self-reported current or prior CDI episode
  • Anticipated or current receipt of kidney dialysis treatment
  • History of gastrointestinal surgery for gastrointestinal malignancy (Note: Colonoscopy, polypectomy, and appendectomy are not exclusion criteria.)
  • History of inflammatory bowel disease, irritable bowel syndrome, colostomy, or small or large intestine bowel surgery where resection was performed
  • Receiving enteral feeding (e.g., nasogastric, gastrostomy, and jejunostomy tube feeding)
  • Known or suspected congenital or acquired immunodeficiency; or receipt of immunosuppressive therapy, such as anti-cancer chemotherapy or radiation therapy, within the preceding 6 months; or long-term systemic corticosteroid therapy (prednisone or equivalent for more than 2 consecutive weeks within the past 3 months)
  • Known systemic hypersensitivity to any of the vaccine components, or history of a life-threatening reaction to the vaccine used in the trial or to a vaccine containing any of the same substances
  • Self-reported thrombocytopenia, contraindicating intramuscular vaccination
  • Deprived of freedom by an administrative or court order, or in an emergency setting, or hospitalized involuntarily
  • Current alcohol abuse or drug addiction that might interfere with the ability to comply with trial procedures in the opinion of the Investigator
  • Chronic illness that, in the opinion of the investigator, is at a stage where it might interfere with trial conduct or completion
  • Moderate or severe acute illness/infection (according to investigator judgment) on the day of vaccination or febrile illness (temperature ≥ 38.0°C [≥ 100.4°F]). A prospective subject should not be included in the study until the condition has resolved or the febrile event has subsided
  • Identified as an Investigator or employee of the Investigator or study center with direct involvement in the proposed study, or identified as an immediate family member (i.e., parent, spouse, natural or adopted child) of the Investigator or employee with direct involvement in the proposed study.

clinicaltrials.gov
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