The potential for emerging therapeutic options for Clostridium difficile infection

Abstract

Clostridium difficile is mainly a nosocomial pathogen and is a significant cause of antibiotic-associated diarrhea. It is also implicated in the majority of cases of pseudomembranous colitis. Recently, advancements in next generation sequencing technology (NGS) have highlighted the extent of damage to the gut microbiota caused by broad-spectrum antibiotics, often resulting in C. difficile infection (CDI). Currently the treatment of choice for CDI involves the use of metronidazole and vancomycin. However, recurrence and relapse of CDI, even after rounds of metronidazole/vancomycin administration is a problem that must be addressed. The efficacy of alternative antibiotics such as fidaxomicin, rifaximin, nitazoxanide, ramoplanin and tigecycline, as well as faecal microbiota transplantation has been assessed and some have yielded positive outcomes against C. difficile. Some bacteriocins have also shown promising effects against C. difficile in recent years. In light of this, the potential for emerging treatment options and efficacy of anti-C. difficile vaccines are discussed in this review.

Keywords: ATCC, American Type Culture Collection; CDI, Clostridium difficile infection; CdtLoc, binary toxin locus; Clostridium difficile; DNA, deoxyribonucleic acid; DPC, Dairy Products Collection; ESCMID, European Society of Clinical Microbiology and Infectious Diseases; ETEC, enterotoxigenic E. coli; FDA, Food and Drug Administration; FMT, faecal microbiota transplantation; GIT, gastrointestinal tract; HIV, human immunodeficiency virus; IDSA, Infectious Diseases Society of America; IgG, immunoglobulin G; LTA, lipoteichoic acid; M21V, methionine to valine substitution at residue 21; MIC, minimum inhibitory concentration; NGS, next generation sequencing; NVB, Novacta Biosystems Ltd; PMC, pseudomembranous colitis; PaLoc, pathogenicity locus; R027, ribotype 027; RBD; RBS, ribosome binding site; RNA, ribonucleic acid; SHEA, Society for Healthcare Epidemiology of America; V15F, valine to phenylalanine substitution at residue 15; antibiotics; faecal microbiota transplantation; receptor binding domain; toxins; vaccines.

Figure 1.

(A) Clostridium difficile pathogenicity locus (PaLoc). Schematic organization of the C. difficile PaLoc, which is 19.6 kb in length. tcdA and tcdB (shaded in gray) are the 2 genes encoding the 2 large C. difficile toxins, TcdA and TcdB respectively. tcdR (shaded in black) encodes a positive regulator of transcription, whereas tcdC (shaded in black) encodes a putative negative regulator/modulatory protein. tcdE (shaded in white) encodes a holin protein. Adapted from J Dupuy et al. J Med Microbiol 2008; 57: 685–90 and Carter et al. J Bacteriol 2007; 189: 7290–7301. (B) Binary toxin locus (CdtLoc) from C. difficile 630. Schematic organization of the binary toxin locus (4.2 kb in length) from the binary toxin-negative C. difficile 630 strain. The CDT binary toxin-encoding pseudogenes, cdtAB, are shaded in gray. The response regulator gene, cdtR is shaded in black. The highly conserved 5′ and 3′ boundaries are also indicated. Adapted from Carter et al. J Bacteriol 2007; 189: 7290–7301. (C) Binary toxin locus (CdtLoc) from C. difficile QCD-32g58. Schematic organization of the binary toxin locus (6.2 kb in length) from the binary toxin-positive C. difficile QCD-32g58 strain. The CDT binary toxin-encoding genes cdtA and cdtB, are shaded in gray. The response regulator gene, cdtR, is shaded in black. The highly conserved 5′ and 3′ boundaries are also indicated. Adapted from Carter et al. J Bacteriol 2007; 189: 7290–7301. © American Society for Microbiology. Reproduced by permission of Becky Zwadyk. Permission to reuse must be obtained from the rightsholder.

Figure 2.

Narrow spectrum antimicrobial effects of thuricin CD. The effect of thuricin CD (90 μM) on family-level taxonomic distribution of the microbial communities present in model of the distal colon, expressed as percentage of total assignable sequences. Redrawn from Rea et al. Proc Natl Acad Sci U S A 2011; 108: 4639–44. © Proceedings of the National Academy of Sciences of the United States of America. Reproduced by permission of Kay McLaughlin. Permission to reuse must be obtained from the rightsholder.

Figure 3.

Broad spectrum antimicrobial effects of vancomycin, metronidazole and the bacteriocin lacticin 3147. The effects of the broad spectrum antimicrobials vancomycin, metronidazole and lacticin 3147 on phylum level diversity of gut communities in a model of the distal colon, expressed as percentage of total population of assignable tags. Other phyla: Actinobacteria, Spirochaetes, Lentisphaerae, and Tenericutes. Redrawn from Rea et al. Proc Natl Acad Sci U S A 2011; 108: 4639–44. © Proceedings of the National Academy of Sciences of the United States of America. Reproduced by permission of Kay McLaughlin. Permission to reuse must be obtained from the rightsholder.