Emerging therapies for Clostridium difficile infection – focus on fidaxomicin

Figures & data

Table 1 Definitions and recommendations for the treatment of Clostridium difficile infection

Clinical definition	Clinical and laboratory data	Recommended therapy
Initial episode, mild or moderate	Leukocytosis with WBC ≤ 15,000 cells/μL, serum creatinine level ≤ 1.5 times the baseline level.	Metronidazole 500 mg PO every 8 hours for 10–14 days.
Initial episode, severe	Leukocytosis with WBC ≥ 15,000 cells/μL, serum creatinine level ≥ 1.5 times the baseline level.	Vancomycin 125 mg PO every 6 hours for 10–14 days.
Initial episode, severe complicated	Hypotension or shock, ileus, megacolon.	Vancomycin 500 mg PO/NG tube every 6 hours, plus metronidazole 500 mg IV every 8 hours. If complete ileus, consider vancomycin rectal enemas.
First recurrence	–	Same as for initial episode.
Second recurrence	–	Vancomycin tapered and/or pulse regimen.

Adapted with permission from Cohen SH, Gerding DN, Johnson S, et al; for Society for Healthcare Epidemiology of America, Infectious Diseases Society of America. Clinical practice guidelines for Clostridium difficile infections 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;31(5):431–455.¹

Abbreviations: WBC, white blood cell; PO, orally; NG, nasogastric; IV, intravenously.

Table 2 Available antibiotics and investigational new agents for the management of CDI

Agent	Dose	Relative efficacy	Recurrence risk	Resistance in clinical isolates	Cost/total treatment costs	Adverse events	Comments
Fidaxomicin	200mg PO BID × 10 days.	+++	+	Not reported.	$$$/$$	Abdominal pain, nausea, vomiting, anemia, neutropenia bowel obstruction, and GI hemorrhage.	FDA approved for CDI. First-in-class oral macrocylic antibiotic with targeted bactericidal activity against C. difficile and minimal impact on normal flora.
Vancomycin	125 mg PO QID × 10–14 days or “taper/pulse” for recurrence: 125 mg PO QID × 10–14 days, then I25 mg PO BID per day × 1 week, then 125 mg PO every 2 or 3 days for 2–8 weeks.	+++	++	Not reported.	$$$$/$$$$	Nausea, not absorbed so systemic symptoms unlikely.	FDA approved for CDI. Potential for resistance induction in other clinically important pathogens.
Metronidazole	500 mg PO TID × 10 days or 250 mg PO QID × 10 days.	++	++	Increased MICs noted in some studies.	$/$	Nausea, neuropathy, abnormal taste in mouth.	Not FDA approved for CDI, increased reports of treatment failures and slow response, less effective in severe CDI.
Nitazoxanide	500 mg PO BID × 10 days.	++	++	Not reported.	$$	Nausea, diarrhea, abdominal pain.	Not FDA approved.
Rifaximin	400 mg PO TID × 10 days or “chaser” regimen 400 mg PO BID × 14 days.	++	+?	Potential for development of high level resistance.	$$$/$$$	Headaches, abdominal pain, nausea, flatulence, not absorbed.	Not FDA approved for CDI, used primarily as post-vancomycin.
Teicoplanin	400 mg PO BID × 10 days.	+++	++	Not reported.	NA in US	Not absorbed so systemic symptoms unlikely.	Not FDA approved for CDI, similar results to vancomycin.
Tigecycline	50 mg IV every 12 hours × 10 days.	++?	?	Not reported.	$$$$	Nausea, vomiting, diarrhea.	Not FDA approved for CDI. Limited case reports of treatment success and failures.
Bacitracin	25,000 units PO QID × 10 days.	+	+++	Increased resistance noted.	$$	Minimal absorbed, poor taste.	Not FDA approved for CDI. Limited efficacy secondary to resistance.
Fusidic acid	250 mg PO TID × 10 days.	++	++	Reported to develop in vivo resistance.	NA in US	Nausea, vomiting, epigastric pain, anorexia.	Not FDA approved for CDI, concern about use as a single agent.
Investigational new agents
Agent	Comments
Ramoplanin	Under investigation (Phase III) for the treatment of CDI. Lipoglycodepsipeptide with spectrum activity similar to vancomycin but consistently more potent.
Cadazolid	Hybrid oxazolidinone–quinolone antibiotic. Currently in Phase II (NCT1222702).
CB-183,315	Narrow spectrum, gram-positive lipopeptide antibiotic in Phase III development status.

Adapted with permission from Cornley OA. Current and emerging management options for Clostridium difficile infection: what is the role of fidaxomicin? Clin Microbiol infect. 2012; 18 Suppl 6:28–35⁷² and Venugopal AA, Johnson S. Current state of Clostridium difficile treatment options. Clin Infect Dis. 2012;55 Suppl 2:S71–S76.⁷³

Note: ?not enough data present to give accurate quantitation.

Abbreviations: CDI, Clostridium difficile infection; PO, orally; BID, twice a day; Gl, gastrointestinal; FDA, US Food and Drug Administration; QID, four times a day; VRE, vancomycin-resistant Enterococci; TID, three times a day; MIC, minimal inhibitory concentration; NA, not applicable; IV, intravenous.

Figure 1 Rates of clinical cure at end of treatment (primary efficacy endpoint) in the fidaxomicin Phase III trials (studies 003 and 004).^22,23

Notes: Modified intent-to-treat: patients underwent randomization and received ≥1 dose of study medication. Per protocol: patients in the modified intent-to-treat population who received ≥3 days of study medication (in cases of failure) or ≥8 days (in cases of clinical cure) with documented adherence to study protocol and who underwent end-of-treatment evaluation.Reproduced with permission from Cornley OA. Current and emerging management options for Clostridium difficile infection: what is the role of fidaxomicin? Clin Microbiol Infect. 2012;18 Suppl 6:28–35⁷² and Louie TJ, Miller MA, Mullane KM, et al; for OPT-80-003 Clinical Study Group. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011;364(5):422–431.²²

Abbreviation: ns, not significant.

Figure 2 Rates of sustained clinical cure (clinical cure without recurrence of diarrhoea during the 30-day follow-up period) in the fidaxomicin Phase III trials (studies 003 and 004).^22,23

Notes: Modified intent-to-treat: patients underwent randomization and received ≥1 dose of study medication. Per protocol: patients in the modified intent-to-treat population who received ≥3 days of study medication (in cases of failure) or ≥8 days (in cases of clinical cure) with documented adherence to study protocol and who underwent end-of-treatment evaluation.Reproduced with permission from Cornley OA. Current and emerging management options for Clostridium difficile infection: what is the role of fidaxomicin? Clin Microbiol Infect. 2012;18 Suppl 6:28–35⁷² and Louie TJ, Miller MA, Mullane KM, et al; for OPT-80-003 Clinical Study Group. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011;364(5):422–431.²²

Figure 3 Rates of high-risk patients achieving sustained clinical response (vancomycin versus fidaxomicin).

Table 3 Non-antibiotic alternatives and investigational new agents for the management of CDI

	Comments
Agent
IVIg	Multisystemic side effect profile. Most commonly renal failure. Efficacy for use in adults is inconclusive; in pediatrics, evidence favors efficacy.
Fecal transplantation	Infusion of feces from a healthy donor. Most evidence comes from single center case series and case reports. A recent multicenter, long-term follow-up study has shown positive results.
Probiotics	Multiple studies favor the use of probiotics for the prevention of CDI and antibiotic-associated diarrhea;^Citation90^–^Citation92 however, appropriately powered studies are needed to confirm these findings. Guidelines do not recommend the routine use of probiotics given the lack of definitive evidence of effectiveness and potential risk of blood stream infection.
Investigational new agents
CDAI and CDBI	Human monoclonal antibodies against C. difficile toxins A and B. Phase III trial for prevention of CDI, recurrence (MODIFY I [NCT1241552] and MODIFY II [NCT1513239]).^Citation83,Citation84
ACAM-CDIFF	Active C. difficile toxoid vaccine. Phase II placebo-controlled for primary CDI prevention (NCT0772343).^Citation93^–^Citation95
VP 20621	Nontoxigenic C. difficile. Phase II trial for prevention of CDI recurrence (NCT1259726).^Citation96

Adapted with permission from Cornley OA. Current and emerging management options for Clostridium difficile infection: what is the role of fidaxomicin? Clin Microbiol Infect. 2012;18 Suppl 6:28–35⁷² and Venugopal AA, Johnson S. Current state of Clostridium difficile treatment options. Clin Infect Dis. 2012;55(S2):S71–S76.⁷³

Abbreviations: CDI, Clostridium difficile infection; IVIg, intravenous immunoglobulin; CDAI, Clostridium difficile toxin A; CDBI, Clostridium difficile toxin B; VP, ViroPharma.

CohenSHGerdingDNJohnsonSSociety for Healthcare Epidemiology of America, Infectious Diseases Society of AmericaClinical 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 Epidemiol201031543145520307191

 PubMed Web of Science ®Google Scholar

CornelyOACurrent and emerging management options for Clostridium difficile infection: what is the role of fidaxomicin?Clin Microbiol Infect201218Suppl 6283523121552

 PubMed Web of Science ®Google Scholar

VenugopalAAJohnsonSCurrent state of Clostridium difficile treatment optionsClin Infect Dis201255Suppl 2S71S7622752868

 PubMed Web of Science ®Google Scholar

LouieTJMillerMAMullaneKMOPT-80-003 Clinical Study GroupFidaxomicin versus vancomycin for Clostridium difficile infectionN Engl J Med2011364542243121288078

 PubMed Web of Science ®Google Scholar

CornelyOACrookDWEspositoROPT-80-004 Clinical Study GroupFidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trialLancet Infect Dis201212428128922321770

 PubMed Web of Science ®Google Scholar

VidelockEJCremoniniFMeta-analysis: probiotics in antibiotic-associated diarrhoeaAliment Pharmacol Ther201235121355136922531096

 PubMed Web of Science ®Google Scholar

JohnstonBCMaSSGoldenbergJZProbiotics for the prevention of Clostridium difficile-associated diarrhea: a systematic review and meta-analysisAnn Intern Med20121571287888823362517

 PubMed Web of Science ®Google Scholar

ClinicalTrials.govA study of MK-6072 and MK-3415A in participants receiving antibiotic therapy for Clostridium difficile infection (MK-3415A-002) (MODIFY II)ClinicalTrials.gov2013 Available from: http://www.clinicaltrials.gov/ct2/show/NCT1513239Accessed April 29, 2013

 Google Scholar

HussackGArbabi-GhahroudiMvan FaassenHNeutralization of Clostridium difficile toxin A with single-domain antibodies targeting the cell receptor binding domainJ Biol Chem2011286118961897621216961

 PubMed Web of Science ®Google Scholar

HempelSNewberrySJMaherARProbiotics for the prevention and treatment of antibiotic-associated diarrhea: a systematic review and meta-analysisJAMA2012307181959196922570464

 PubMed Web of Science ®Google Scholar

FolgiaGACAM-CDIFF: An active vaccine against Clostridium difficile infectionProceedings of the 10th Anaerobe Society of the AmericasJuly 7–10, 2010

 Google Scholar

ClinicalTrials.govStudy of a Clostridium difficile toxoid vaccine (ACAM-CDIFF™) in subjects with Clostridium difficile infection [webpage on the Internet]ClinicalTrials.gov2012 Available from: http://www.clinicaltrials.gov/ct2/show/NCT0772343Accessed April 29, 2013

 Google Scholar