The potential for emerging therapeutic options for<i>Clostridium difficile</i>infection

Mathur, Harsh; Rea, Mary C.; Cotter, Paul D.; Ross, R. Paul; Hill, Colin

doi:10.4161/19490976.2014.983768

Cited by 34 publications

(29 citation statements)

References 136 publications

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“…Emerging data indicate that sporulation rates may vary based on ribotype, with a heightened rate of sporulation for C. difficile ribotype 027 (24), which is associated with the higher disease recurrence rate for this particular ribotype (25). Enhancing the therapeutic options to address such disease recurrence is clearly an unmet need that is currently being evaluated with strategies such as fecal microbiota transplantation (FMT) and C. difficile vaccines (26)(27)(28)(29)(30). Should the activity observed in these in vitro experiments mirror activity in the human gut, then the use of ramoplanin as an agent for secondary prophylaxis may be a therapeutic option for clinicians.…”

Section: Discussionmentioning

confidence: 99%

Ambush of Clostridium difficile Spores by Ramoplanin: Activity in an In Vitro Model

Kraus

Lyerly

Carman

2015

Antimicrob Agents Chemother

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bClostridium difficile infection (CDI) is a gastrointestinal disease caused by C. difficile, a spore-forming bacterium that in its spore form is tolerant to standard antimicrobials. Ramoplanin is a glycolipodepsipeptide antibiotic that is active against C. difficile with MICs ranging from 0.25 to 0.50 g/ml. The activity of ramoplanin against the spores of C. difficile has not been well characterized; such activity, however, may hold promise, since posttreatment residual intraluminal spores are likely elements of disease relapse, which can impact more than 20% of patients who are successfully treated. C. difficile spores were found to be stable in deionized water for 6 days. In vitro spore counts were consistently below the level of detection for 28 days after even brief (30-min) exposure to ramoplanin at concentrations found in feces (300 g/ml). In contrast, suppression of spore counts was not observed for metronidazole or vancomycin at human fecal concentrations during treatment (10 g/ml and 500 g/ml, respectively). Removal of the C. difficile exosporium resulted in an increase in spore counts after exposure to 300 g/ml of ramoplanin. Therefore, we propose that rather than being directly sporicidal, ramoplanin adheres to the exosporium for a prolonged period, during which time it is available to attack germinating cells. This action, in conjunction with its already established bactericidal activity against vegetative C. difficile forms, supports further evaluation of ramoplanin for the prevention of relapse after C. difficile infection in patients. Clostridium difficile infection (CDI) remains a clinically important disease, with increasing incidence and mortality rates in the United States; it now surpasses methicillin-resistant Staphylococcus aureus as the most common health care-associated infection (HAI) and results in an annual cost burden to the health care system of $4.8 billion (1-3). A prolonged cure for treated patients remains elusive, as evidenced by the high rates of relapse (same ribotype within 30 days) and reinfection (different ribotype within 30 days). Recurrence rates have ranged from 15% to 40% (4-6) and are most commonly associated with the ribotype 027 epidemic strain (7). One contributing factor for high relapse rates is the presence of spores that persist within the intestinal lumen and evade elimination by standard anti-CDI treatments (8, 9). C. difficile spores are tolerant to standard antimicrobial therapy; hence, antimicrobial interventions targeting vegetative cells alone are unlikely to eradicate this disease reservoir (10).Ramoplanin is a glycolipodepsipeptide antibiotic produced from Actinoplanes, which inhibits peptidoglycan biosynthesis by limiting lipid II availability (11); it is bactericidal to many Grampositive aerobic and anaerobic bacteria, including C. difficile and vancomycin-resistant Enterococcus (11). Ramoplanin has known bactericidal activities against wild-type C. difficile and strains with reduced susceptibilities to vancomycin and has been studied in an open-labe...

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Section: Discussionmentioning

confidence: 99%

Ambush of Clostridium difficile Spores by Ramoplanin: Activity in an In Vitro Model

Kraus

Lyerly

Carman

2015

Antimicrob Agents Chemother

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“…might warrant a more selective approach than is possible with existing antibiotics. Highly specific antimicrobials such as bacteriocins could be useful in such cases (Mathur et al, 2014). The third consideration is that, besides providing a secondary costimulatory signal for T cell priming (or merely igniting innate signaling pathways involving TLR, NLR, or inflammasome platforms), immunogenic bacteria might provide the primary cognate MHC-peptide complex interaction with the TCR and hence elicite cognate immune responses that then crossreact with tumor antigens.…”

Section: Implementation Of Adjunctive Oncomicrobioticsmentioning

confidence: 99%

Resistance Mechanisms to Immune-Checkpoint Blockade in Cancer: Tumor-Intrinsic and -Extrinsic Factors

Pitt¹,

Vétizou²,

Daillère³

et al. 2016

Immunity

844

649

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Inhibition of immune regulatory checkpoints, such as CTLA-4 and the PD-1-PD-L1 axis, is at the forefront of immunotherapy for cancers of various histological types. However, such immunotherapies fail to control neoplasia in a significant proportion of patients. Here, we review how a range of cancer-cell-autonomous cues, tumor-microenvironmental factors, and host-related influences might account for the heterogeneous responses and failures often encountered during therapies using immune-checkpoint blockade. Furthermore, we describe the emerging evidence of how the strong interrelationship between the immune system and the host microbiota can determine responses to cancer therapies, and we introduce a concept by which prior or concomitant modulation of the gut microbiome could optimize therapeutic outcomes upon immune-checkpoint blockade.

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“…[37] Their study also demonstrated that a narrow spectrum bacteriocin such as thuricin CD, was effective at killing Clostridium difficile in the distal colon, but had no significant impact on the other members of the gut microbiota. This highlights the potential benefits of WGS in helping to assess the efficacy of new treatments and vaccines in the management of C. difficile infections; as outlined in the recent review by Mathur et al [38] Recently, WGS helped identify a novel antimicrobially active inhibitor of Vibrio cholera, [39] and also helped identify new drug targets in M. tuberculosis. [40] All indications are that WGS is positioned to play a critical role in the fight against antibiotic resistance.…”

Section: Future Prospectsmentioning

confidence: 95%

Bacterial whole genome sequencing: The future of clinical bacteriology

Aliyu¹

2014

Ann Nigerian Med

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The potential for emerging therapeutic options forClostridium difficileinfection

Cited by 34 publications

References 136 publications

Ambush of Clostridium difficile Spores by Ramoplanin: Activity in an In Vitro Model

Ambush of Clostridium difficile Spores by Ramoplanin: Activity in an In Vitro Model

Resistance Mechanisms to Immune-Checkpoint Blockade in Cancer: Tumor-Intrinsic and -Extrinsic Factors

Bacterial whole genome sequencing: The future of clinical bacteriology

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