Exploring Non-Conventional Antimicrobial, Alternate Therapies in Clostridium difficile Treatment

Complementary and alternative medicine can decrease the rate of antimicrobial resistance and reduce treatment costs.

Niloufar Roshan

A newly published Australian review from Anaerobe suggests that due to the increasing frequency of highly virulent Clostridium difficile strains, coupled with antimicrobial treatment failures, hospital outbreaks and patients with severe complications or recurrent Clostridium difficile infections (CDI), there is an increasing demand for new understandings of CDI treatment options.

The study suggests there is a need to determine how alternative therapeutic agents like complementary and alternative therapies (CAM) primarily used to treat other diarrheal-associated diseases may affect CDI, and whether alternative (or non-conventional) antimicrobial therapies might be effective against recurrence of CDI in patients.

Lead author, microbiology graduate student Niloufar Roshan with the school of Biomedical Sciences at the University of Western Australia, with assistance and direction from Thomas V. Riley, MAppEpid, PhD, Professorial Research Fellow at Edith Cowan University, and Professor of Public Health at Murdoch University, provides a detailed summary of current knowledge on non-conventional antimicrobial and alternative therapies used to treat CDI, and argues that more research is crucial to the development of future therapies.

According to Roshan, Riley and colleagues, conventional treatment options for CDI include treatment with the antimicrobials metronidazole and/or vancomycin, with metronidazole used in mild to moderate cases of CDI and vancomycin used in more severe cases or antimicrobial-resistant/hypervirulent strains of CDI. A third antimicrobial, Fidaxomicin, which carries additional bactericidal properties against CDI, was approved in 2011 by the US Food and Drug Administration (FDA).

In addition to these standard therapies there are several alternative and non-conventional treatments for CDI in various stages of testing for CDI, such as: Teicoplanin, a glycopeptide antimicrobial; Tigecycline, a broad-spectrum antibiotic still in in-vitro testing for its efficacy against CDI; Ramoplanin, a antimicrobial lipoglycopeptide in phase 2 trials for use against CDI; Surotomycin, an lipopeptide antibiotic; Cadazolid, an oxazolidinone-fluoroquinolone that acts by inhibiting protein synthesis in CDI; and Ridnilazole, a narrow spectrum antimicrobial.

Roshan and Riley also discuss the use of fecal microbiota transplantation (FMT) as a conventional non-antimicrobial treatment, used primarily for recurrent CDI. There is also, according to the review article, increased interest in immunotherapy treatment of CDI, including research into recombinant vaccines against CDI.

Thomas V. Riley, MAppEpid, PhD

In an interview with MD Magazine Roshan and Riley stated that research into investigating potential alternative therapies and therapy options is important due to CDI's "growing resistance to antimicrobials as well as the cost associated with this problem." Roshan and Riley continue, stating that "while standard pharmacological antimicrobial treatment is a suitable therapeutic option for most mild to moderate cases of CDI (or just stopping the inciting antimicrobial), approximately 25% of patients experience the return of symptoms or recurrence of disease" making the evaluation of complementary and alternative medicine (CAM) treatments, "including a range of popular and novel compounds that are primarily used for the treatment of other diarrheal diseases, for therapeutic action against CDI" distinctly worthwhile.

The study discusses the importance of investigations looking at CAMs as a response to increasing incidences of difficult to treat strains of CDI due to treatment resistance. Roshan and Riley, in interview, state that "many complementary and alternative therapeutic options such as natural products inhibit pathogens using mechanisms different from those employed by antimicrobials, making it difficult for pathogens to develop resistance."

The review discusses CAMs which may be used as adjuvants to conventional therapies. Some of the therapies mentioned are the use of toxic binding agents (colestipol, cholestyramine, polymers, and oligosaccharides), bacteriophages ("phage therapy") to reduce toxin production of CDI, probiotics which "stimulate the immune response and the production of antimicrobial molecules that degrade bacterial toxins or block their adhesion sites," and bacteriocins of probiotics which could serve as viable alternatives to antimicrobials but require further study.

Roshan and Riley also argue for investigation into CAM connected to traditional medicines, such as plant and herbal extracts, manuka honey, peppermint oil, ginger, and Chinese herbal formulas to determine their efficacy against CDI.

When asked in interview if they anticipated any resistance to their proposal that CAM therapies should be investigated for their scientific merit, Roshan and Riley stated that it was "definitely a possibility."

"Some believe that we need to stop testing alternative therapies and they argue that testing them is like justifying whether magic works," the researchers said. "Unfortunately the alternative therapy industry does not help itself by making outrageous statements about benefits that have not been proven. What’s required is randomized clinical trials but that will require government funding."

The researchers suggest that clinical trials based on scientifically well-supported preclinical observations are needed in order to determine the effect of CAM in treatment of CDI in patients. Further investigation is also necessary, in regards to the mechanisms of action, toxicological profiles, drug-drug interaction and effects of CAM therapies on commensal flora in order to determine their clinical usefulness. Investigations into potential alternative therapies could lead to a new range of therapeutic options for treating CDI, which is particularly important, according to Roshan and Riley, given the fact that standard therapies for CDI could become "obsolete over time due to overuse" or in the face of resistant strains.

"Non-conventional antimicrobial and alternative therapies for the treatment of Clostridium difficile infection" appears in the February 2018 issue of Anaerobe.

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