Treatment of recurrent Clostridium difficile infection: a systematic review

O’Horo, John C.; Jindai, Kazuaki; Kunzer, Bethaney; Safdar, Nasia

doi:10.1007/s15010-013-0496-x

Cited by 69 publications

(61 citation statements)

References 88 publications

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“…Further, the act of transferring the fecal contents from one person to the next often dissuades some from this procedure. Results of probiotic therapy and monoclonal antibody treatment are either inconclusive or still in clinical trials, respectively (19,20). Therefore, there is a need for new treatments which better target C. difficile without collateral damage to the protective commensal species.…”

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Using a Novel Lysin To Help Control Clostridium difficile Infections

Wang

Euler

Delaune

et al. 2015

Antimicrob Agents Chemother

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c As a consequence of excessive antibiotic therapies in hospitalized patients, Clostridium difficile, a Gram-positive anaerobic spore-forming intestinal pathogen, is the leading cause of hospital-acquired diarrhea and colitis. Drug treatments for these diseases are often complicated by antibiotic-resistant strains and a high frequency of treatment failures and relapse; therefore, novel nonantibiotic approaches may prove to be more effective. In this study, we recombinantly expressed a prophage lysin identified from a C. difficile strain, CD630, which we named PlyCD. PlyCD was found to have lytic activity against specific C. difficile strains. However, the recombinantly expressed catalytic domain of this protein, PlyCD 1-174 , displayed significantly greater lytic activity (>4-log kill) and a broader lytic spectrum against C. difficile strains while still retaining a high degree of specificity toward C. difficile versus commensal clostridia and other bacterial species. Our data also indicated that noneffective doses of vancomycin and PlyCD 1-174 when combined in vitro could be significantly more bactericidal against C. difficile. In an ex vivo treatment model of mouse colon infection, we found that PlyCD 1-174 functioned in the presence of intestinal contents, significantly decreasing colonizing C. difficile compared to controls. Together, these data suggest that PlyCD 1-174 has potential as a novel therapeutic for clinical application against C. difficile infection, either alone or in combination with other preexisting treatments to improve their efficacy.

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Using a Novel Lysin To Help Control Clostridium difficile Infections

Wang

Euler

Delaune

et al. 2015

Antimicrob Agents Chemother

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“…Although C. difficile is resistant to many antibiotics, the infection usually resolves upon treatment with metronidazole or oral vancomycin (5). Unfortunately, disease recurs in ϳ20% of patients, and the prognosis for this cohort is poor (4,6,7). The high rate of recurrence has been attributed to germination of C. difficile spores after antibiotic therapy is ended but before restoration of the normal flora (2,8).…”

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“…The high rate of recurrence has been attributed to germination of C. difficile spores after antibiotic therapy is ended but before restoration of the normal flora (2,8). For this reason, there is interest in developing antibiotics that target C. difficile selectively and in treatments such as fecal transplants which work by restoring a healthy microbiome (4,7,9,10).…”

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Identification and Characterization of a Gene Cluster Required for Proper Rod Shape, Cell Division, and Pathogenesis in Clostridium difficile

et al. 2014

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Little is known about cell division in Clostridium difficile, a strict anaerobe that causes serious diarrheal diseases in people whose normal intestinal microbiome has been perturbed by treatment with broad-spectrum antibiotics. Here we identify and characterize a gene cluster encoding three cell division proteins found only in C. difficile and a small number of closely related bacteria. These proteins were named MldA, MldB, and MldC, for midcell localizing division proteins. MldA is predicted to be a membrane protein with coiled-coil domains and a peptidoglycan-binding SPOR domain. MldB and MldC are predicted to be cytoplasmic proteins; MldB has two predicted coiled-coil domains, but MldC lacks obvious conserved domains or sequence motifs. Mutants of mldA or mldB had morphological defects, including loss of rod shape (a curved cell phenotype) and inefficient separation of daughter cells (a chaining phenotype). Fusions of cyan fluorescent protein (CFP) to MldA, MldB, and MldC revealed that all three proteins localize sharply to the division site. This application of CFP was possible because we discovered that O 2 -dependent fluorescent proteins produced anaerobically can acquire fluorescence after cells are fixed with cross-linkers to preserve native patterns of protein localization. Mutants lacking the Mld proteins are severely attenuated for pathogenesis in a hamster model of C. difficile infection. Because all three Mld proteins are essentially unique to C. difficile, they might be exploited as targets for antibiotics that combat C. difficile without disrupting the intestinal microbiome.C lostridium difficile is a strictly anaerobic, Gram-positive, spore-forming bacterium that has become the leading cause of hospital-acquired diarrhea in developed countries. The annual impact of C. difficile infections in the United States has been estimated at 14,000 deaths and over $1 billion in excess medical costs (1). Both the severity and the frequency of C. difficile infections are increasing (2), and a recent report on the impact of antibiotic resistance classified the organism as an "urgent threat," the highest threat level (1).C. difficile infections typically occur in people who have been treated with antibiotics that disrupt the flora of the gastrointestinal tract (3, 4). Although C. difficile is resistant to many antibiotics, the infection usually resolves upon treatment with metronidazole or oral vancomycin (5). Unfortunately, disease recurs in ϳ20% of patients, and the prognosis for this cohort is poor (4, 6, 7). The high rate of recurrence has been attributed to germination of C. difficile spores after antibiotic therapy is ended but before restoration of the normal flora (2, 8). For this reason, there is interest in developing antibiotics that target C. difficile selectively and in treatments such as fecal transplants which work by restoring a healthy microbiome (4, 7, 9, 10).Here we describe a cluster of three genes found in C. difficile that is important for morphogenesis, cell division, and pathogenesis. W...

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“…También se ha descrito el uso de rifaximina 10 y fidaxomicina. Esta última ha mostrado una leve superioridad al compararla con vancomicina 11 , pero su elevado costo ha limitado su uso. En nuestro caso, la ICD se consideró como severa por la presencia de leucocitosis, fiebre y dolor abdominal, y fue tratada como tal acorde a las guías 4 .…”

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“…En nuestro caso, la ICD se consideró como severa por la presencia de leucocitosis, fiebre y dolor abdominal, y fue tratada como tal acorde a las guías 4 . Así también el manejo de las recurrencias se ajustó a lo recomendado, a excepción del uso de rifaximina, que si bien es usada en la práctica clínica ante la escasez de alternativas antimicrobianas, no está avalada por evidencia sólida 10,11 . Los antimicrobianos para el tratamiento de ICD per se pueden disminuir la diversidad de la microbiota intestinal (disbiosis); esto explica la alta tasa de recurrencia post-antibiótico.…”

Section: Discussionunclassified