Antibiotics are a risk factor for Clostridium difficile infection (CDI) because of the consequent perturbations of the normal intestinal microbiota, permitting C difficile colonization, overgrowth, and expression of toxins. Standard antibiotic therapy in CDI with vancomycin or metronidazole is limited by their broad antimicrobial spectrum and additional perturbation of the intestinal microbiota, with resulting high recurrence rates.
In addition, antibiotics are often a non-modifiable risk factor in certain patients because of immunodeficiency and/or the need for antibiotics for their underlying condition. A humoral immune response against toxins A and B provides additional protection against CDI and recurrences.1 We review novel antibiotic therapies that may limit the impact on the gut microbiome, as well as passive immunization products that may bolster the immune response to C difficile toxins and possibly reduce the frequency of toxigenic strains. While some therapies are currently approved by the US Food and Drug Administration (FDA), others are in various stages of clinical and pre-clinical investigation.
Fidaxomicin (OPT-80), a novel oral macrocyclic inhibitor of bacterial nucleic acid synthesis, was FDA-approved for CDI in adults in 2011.2 It is bactericidal for C difficile with little activity against enteric commensals like Bacteroides species that confer resistance against C difficile colonization.2 Pooled clinical trial data show that fidaxomicin (200 mg twice a day [BID] for 10 days in adults) significantly reduced CDI recurrences compared with oral vancomycin (125 mg 4 times a day [QID] for 10 days) (17% vs 29%; P =.048).3,4 Widespread use of fidaxomicin is currently limited by its high cost. Phase 2 clinical trial data in children suggest it is safe,5 and a phase 3 clinical trial is in progress.
Surotomycin, a novel cyclic lipopeptide similar to daptomycin, disrupts bacterial cell membranes including C difficile with relatively little activity against most gut organisms.2 It has recently been studied in a phase 3 randomized double blind trial of subjects with CDI in comparison with oral vancomycin. In this international trial, 290 subjects received oral surotomycin 250 mg BID and 280 received oral vancomycin 125 mg QID. Surotomycin failed to meet noninferiority or superiority criteria for sustained clinical response and may not be developed further.6
Cadazolid is a novel oxazolidinone antibiotic structurally similar to linezolid with potent activity against C difficile. It inhibits C difficile sporulation and protein synthesis, including toxins A and B. It also has fluoroquinolone-like activity with some inhibition of DNA synthesis.2 Cross-resistance appears to be rare because cadazolid is active in vitro against linezolid and/or moxifloxacin-resistant C difficile. In a phase 2 randomized clinical trial, 84 adults with first CDI or first recurrence of CDI received oral vancomycin 125 mg QID or cadazolid 250 mg, 500 mg, or 1000 mg BID for 10 days.7 All groups had similar clinical cure rates, and the cadazolid subjects at all dosages had lower recurrence rates than the vancomycin recipients (18% to 25% vs 50%). No evidence of cadazolid resistance was observed, and fecal concentrations were more than several thousand-fold above the MIC for C difficile. A phase 3 clinical trial is ongoing.
Ridinilazole (SMT19969) is a novel antibiotic with potent activity against C difficile with limited activity against B fragilis and most Gram-positive intestinal flora.2 Results of a recent phase 2 randomized double blind comparison with oral vancomycin in 100 adults with CDI are promising.8 In the trial, 50 patients were randomly assigned to receive oral ridinilazole 200 mg every 12 hours and 50 patients to receive oral vancomycin 125 mg every 6 hours for 10 days. The efficacy analysis included 69 patients (36 ridinilazole, 33 vancomycin). Sustained clinical response was noted in 67% of patients in the ridinilazole group and 42% of patients in the vancomycin group (P =.0004). Ridinilazole was well tolerated and had a similar rate of adverse events to vancomycin; no adverse events led to its discontinuation. Although this was a small study with a number of subjects who did not complete the protocol, it is likely that ridinilazole will be studied further.
LIMITING THE IMPACT OF ANTIBIOTIC THERAPY
Although avoiding broad-spectrum antibiotics is an excellent strategy to prevent CDI and recurrences, antibiotics remain a necessary medical intervention for many patients. Ribaxamase (SYN-004) is an experimental β-lactamase designed to be used orally concomitantly with intravenous β-lactam antibiotics. This agent is intended to degrade excess β-lactams that reach the small intestine with the goal of protecting the gut microbiome from disruption, thus potentially preventing CDI. In pigs given IV ceftriaxone, the pigs also receiving oral ribaxamase had the same serum ceftriaxone levels as pigs not receiving ribaxamase, but they were also protected against significant changes to the gut microbiome.9 In a phase 2a human clinical trial, ribaxamase completely degraded ceftriaxone in the gut to below the level of detection.10 The co-administration was well-tolerated, and ceftriaxone plasma pharmacokinetics were unaffected. Co-administration of ribaxamase with a proton pump inhibitor did not affect ribaxamase degradation of ceftriaxone in the intestine. In a recently concluded phase 2b study of 512 patients randomly assigned 1:1 to receive ribaxamase or placebo, oral ribaxamase during and for 72 hours after intravenous (IV) ceftriaxone administration was associated with a 71% reduction in CDI and 49% reduction in new colonization by vancomycin-resistant Enterococcus. There was also less loss of gut microbiome diversity in the ribaxamase group.11 Because of these promising findings, the FDA has given ribaxamase Breakthrough Therapy Designation for CDI prevention.
Bezlotoxumab is a recently FDA-approved monoclonal antibody that neutralizes C difficile toxin B.12 In an analysis of pooled data from 2 phase 3 clinical trials, a single dose of IV 10mg/kg bezlotoxumab given to adult patients with primary or recurrent CDI and receiving oral standard-of-care with vancomycin, metronidazole, or fidaxomycin was associated with 17% recurrent CDI compared with 28% with placebo (P <.001).13 The addition of actoxumab, a monoclonal antibody against toxin A, did not provide additional efficacy compared with bezlotoxumab alone. Bezlotoxumab had a favorable safety profile without serious adverse reactions. Compared with antibiotic administration, an advantage of this form of passive immunity is the lack of risk for developing antibiotic resistance. The cost-effectiveness of this passive immunization strategy and potential targeting to individuals with higher risk for relapse require further investigation.
Hyperimmune Bovine Colostrum
Non-antibiotic means of treating CDI, especially CDI with minimal impact on the gut microbiome, would be desirable. Oral administration of a protein concentrate of hyperimmune bovine colostrum (HBC) collected from cows that were vaccinated against C difficile toxins A and B has been studied for almost 2 decades. It has been shown that anti-C difficile toxin antibodies resist degradation while passing through the gastrointestinal (GI) tract. A recent report demonstrated that HBC prevented C difficile-associated diarrhea and colitis in gnotobiotic piglets. HBC did not have an impact on the normal human gut microbiota that had been administered to the piglets. Investigation of HBC for CDI prevention in humans appears warranted.
Larry K. Kociolek, MD, is the associate medical director of Infection Prevention and Control at The Ann & Robert H. Lurie Children’s Hospital of Chicago and assistant professor of Pediatrics at the Northwestern University Feinberg School of Medicine in Illinois.
Stanford T. Shulman, MD, is the medical director of Infection Prevention and Control at The Ann & Robert H. Lurie Children’s Hospital of Chicago and Virginia H. Rogers Professor of Pediatric Infectious Disease is the Northwestern University Feinberg School of Medicine in Illinois.
- Kelly CP, Kyne L. The host immune response to Clostridium difficile. J Med Microbiol. 2011;60:1070-1079. doi:10.1099/jmm.0.030015-0
- Kociolek LK, Gerding DN. Breakthroughs in the treatment and prevention of Clostridium difficile infections. Nat Rev Gastroenterol Hepatol. 2016;13:150-160. doi:10.1038/nrgastro.2015.220
- Cornely OA, Crook DW, Esposito R, 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;12:281-289. doi:10.1016/S1473-3099(11)70374-7
- Mullane KM, Miller MA, Weiss K, et al. Efficacy of fidaxomicin versus vancomycin as therapy for Clostridium difficile infection in individuals taking concomitant antibiotics for other concurrent infections. Clin infect Dis. 2011;53:440-447. doi: 10.1093/cid/cir404
- O’Gorman MA, Michaels MG, Kaplan SL, et al. A safety and pharmacokinetic study of fidaxomicin in children with Clostridium difficile-associated diarrhea: A phase 2a multicenter clinical trial [published online May 31, 2017]. J Pediatric Infect Dis Soc. doi:10.1093/jpids/pix037
- Boix V, Fedorak RN, Mullane KM, et al. Primary outcomes from a phase 3, randomized, double-blind, active-controlled trial of surotomycin in subjects with Clostridium difficile infection. Open Forum Infect Dis. 2017;4:ofw275. doi:10.1093/ofid/ofw275
- Louie TJ, Nord CE, Talbot GH, et al. A multicenter, double-blind, randomized, phase 2 study evaluating the novel antibiotic, cadazolid, in patients with Clostridium difficile infection. Antimicrob Agents Chemother. 2015;59:6266-6273. doi:10.1128/AAC.00504-15
- Vickers RJ, Tillotson GS, Nathan R, et al; CoDIFy study group. Efficacy and safety of ridinilazole compared with vancomycin for the treatment of Clostridium difficile infection: a phase 2, randomised, double-blind, active-controlled, non-inferiority study [published online April 28, 2017]. Lancet Infect Dis. doi:10.1016/S1473-3099(17)30235-9
- Connelly S, Bristol JA, Hubert S, et al. SYN-004 (ribaxamase), an oral beta-lactamase, mitigates antibiotic-mediated dysbiosis in a porcine gut microbiome model [published online February 28, 2017]. J Appl Microbiol. doi:10.1111/jam.13432
- Kokai-Kun JF, Roberts T, Coughlin O, et al. The oral beta-lactamase SYN-004 (Ribaxamase) degrades ceftriaxone excreted into the intestine in phase 2a clinical studies. Antimicrob Agents Chemother. 2017;61: e02197-16. doi:10.1128/AAC.02197-16
- Kokai-Kun JF, Roberts T, Coughlin O, et al. SYN-004 (ribaxamase), an oral beta-lactamase, prevented Clostridium difficile infection and protected patients from colonization by antimicrobial resistant pathogens by preserving gut microbiome diversity in a phase 2b clinical trial. Presented at: Digestive Disease Week; Chicago, Illinois; May 6-9, 2017.
- Bartlett JG. Bezlotoxumab – A new agent for Clostridium difficile infection. N Engl J Med. 2017;376:381-382. doi:10.1056/NEJMe1614726
- Wilcox MH, Gerding DN, Poxton IR, et al; MODIFY I and MODIFY II Investigators. Bezlotoxumab for prevention of recurrent Clostridium difficile infection. N Engl J Med. 2017;376:305-317. doi:10.1056/NEJMoa1602615