Treatment failure and recurrence of Clostridium difficile infection following treatment with vancomycin or metronidazole: a systematic review of the evidence

Vardakas, Konstantinos Z.; Polyzos, Konstantinos A.; Patouni, Konstantina; Rafailidis, Petros I.; Samonis, George; Falagas, Matthew E.

doi:10.1016/j.ijantimicag.2012.01.004

Cited by 224 publications

(181 citation statements)

References 53 publications

(352 reference statements)

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“…Metronidazole and vancomycin are recommended for treatment of CDI (9,10), but neither drug is sporocidal, and treatment failures and recurrences are an increasing clinical challenge (11,12). Both of these antibiotics also disrupt the normal colonic microbiota, resulting in increased risk of reinfection (11); furthermore, C. difficile strains that are resistant to both drugs are emerging at an alarming rate (13).…”

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confidence: 99%

“…Both of these antibiotics also disrupt the normal colonic microbiota, resulting in increased risk of reinfection (11); furthermore, C. difficile strains that are resistant to both drugs are emerging at an alarming rate (13). A relatively new antibiotic, fidaxomicin, has a somewhat narrower spectrum of activity and lower recurrence rates, but only for non-BI/NAP1/027 strains (14); it has not been widely used due to cost (15,16).…”

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confidence: 99%

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Safety, Tolerability, Systemic Exposure, and Metabolism of CRS3123, a Methionyl-tRNA Synthetase Inhibitor Developed for Treatment of Clostridium difficile, in a Phase 1 Study

Nayak

Griffiss

Blumer

et al. 2017

Antimicrob Agents Chemother

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Clostridium difficile causes antibiotic-associated diarrhea and is a major public health concern. Current therapies disrupt the protective intestinal flora, do not reliably prevent recurrent infections, and will be decreasingly effective should less susceptible strains emerge. CRS3123 is an oral agent that inhibits bacterial methionyl-tRNA synthetase and has potent activity against C. difficile and aerobic Gram-positive bacteria but little activity against Gram-negative bacteria, including anaerobes. This first-in-human, double-blind, placebo-controlled, dose escalation study evaluated the safety and systemic exposure of CRS3123 after a single oral dose in healthy adults. Five cohorts of eight subjects each received CRS3123 or placebo in a 3:1 ratio. Doses for the respective active arms were 100 mg, 200 mg, 400 mg, 800 mg, and 1,200 mg. Blood and urine were collected for pharmacokinetic analysis. CRS3123 concentrations were measured with validated LC-MS/MS techniques. There were no serious adverse events or immediate allergic reactions during administration of CRS3123. In the CRS3123-treated groups, the most frequent adverse events were decreased hemoglobin, headache, and abnormal urine analysis; all adverse events in the active-treatment groups were mild to moderate, and their frequency did not increase with dose. Although CRS3123 systemic exposure increased at higher doses, the increase was less than dose proportional. The absorbed drug was glucuronidated at reactive amino groups on the molecule, which precluded accurate pharmacokinetic analysis of the parent drug. Overall, CRS3123 was well tolerated over this wide range of doses. This safety profile supports further investigation of CRS3123 as a treatment for C. difficile infections. (This study has been registered at ClinicalTrials.gov under identifier NCT01551004.)

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confidence: 99%

Safety, Tolerability, Systemic Exposure, and Metabolism of CRS3123, a Methionyl-tRNA Synthetase Inhibitor Developed for Treatment of Clostridium difficile, in a Phase 1 Study

Nayak

Griffiss

Blumer

et al. 2017

Antimicrob Agents Chemother

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“…Various treatment options for CDAD include antibiotics, fecal transplantation therapy, and, potentially, toxin-specific antibodies, vaccines, and replenishment of the patient microflora with oral probiotic therapy (3,4). However, the emergence of strains with reduced susceptibility to antibiotics such as metronidazole and vancomycin and high rates of recurrent infection have limited the treatment options, necessitating more effective therapeutics that target the pathogenic mechanism of C. difficile (5)(6)(7).…”

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Recombinant Mucin-Type Fusion Proteins with a Galα1,3Gal Substitution as Clostridium difficile Toxin A Inhibitors

et al. 2016

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The capability of a recombinant mucin-like fusion protein, P-selectin glycoprotein ligand-1/mouse IgG2b (PSGL-1/mIgG2b), carrying Gal␣1,3Gal␤1,4GlcNAc determinants to bind and inhibit Clostridium difficile toxin A (TcdA) was investigated. The fusion protein, produced by a glyco-engineered stable CHO-K1 cell line and designated C-PGC2, was purified by affinity and gel filtration chromatography from large-scale cultures. Liquid chromatography-mass spectrometry was used to characterize Oglycans released by reductive ␤-elimination, and new diagnostic ions to distinguish Gal␣1,3Gal-from Gal␣1,4Gal-terminated O-glycans were identified. The C-PGC2 cell line, which was 20-fold more sensitive to TcdA than the wild-type CHO-K1, is proposed as a novel cell-based model for TcdA cytotoxicity and neutralization assays. The C-PGC2-produced fusion protein could competitively inhibit TcdA binding to rabbit erythrocytes, making it a high-efficiency inhibitor of the hemagglutination property of TcdA. The fusion protein also exhibited a moderate capability for neutralization of TcdA cytotoxicity in both C-PGC2 and CHO-K1 cells, the former with and the latter without cell surface Gal␣1,3Gal␤1,4GlcNAc sequences. Future studies in animal models of C. difficile infection will reveal its TcdA-inhibitory effect and therapeutic potential in C. difficile-associated diseases.C lostridium difficile is an opportunistic Gram-positive pathogenic bacterium responsible for antibiotic-associated diarrhea and other gastrointestinal diseases. C. difficile infections, collectively known as C. difficile-associated disease (CDAD), range from mild cases of diarrhea to fatal pseudomembranous colitis (1, 2). Various treatment options for CDAD include antibiotics, fecal transplantation therapy, and, potentially, toxin-specific antibodies, vaccines, and replenishment of the patient microflora with oral probiotic therapy (3, 4). However, the emergence of strains with reduced susceptibility to antibiotics such as metronidazole and vancomycin and high rates of recurrent infection have limited the treatment options, necessitating more effective therapeutics that target the pathogenic mechanism of C. difficile (5-7).Toxin A (TcdA) and toxin B (TcdB), with molecular masses of 308 kDa and 270 kDa, respectively, are the two primary virulence factors secreted by C. difficile, and can inactivate the Rho/Ras superfamily of GTPases by glucosylation (8-10). As Rho GTPases regulate a number of vital cellular processes, their functional inactivation results in the inhibition of cell migration, morphogenesis, division, and membrane trafficking. Glucosylation of Rho family GTPases causes breakdown of the actin cytoskeleton and activation of caspase-3, leading to apoptosis of intoxicated cells. Diarrhea and inflammation ensue, and ultimately, the control of intestinal epithelial barrier function is lost (11-15). Much of the pathology seen during a C. difficile infection is believed to be due to toxin effects. TcdA exhibits many pathobiological functions, such as cell roundin...

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“…Treatment with oral vancomycin or metronidazole, the current standard practice, leads to recurrence of CDI in up to 30% of patients treated for an initial episode. For patients who have already suffered multiple recurrences, the future recurrence rate can be as high as 60% (3,(5)(6)(7). In addition, many cases of CDI in the United States are now linked to a family of more-virulent strains (NAP1/ BI/027) that emerged first in the United Kingdom and then in Canada (8,9).…”

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Effects of Surotomycin on Clostridium difficile Viability and Toxin Production In Vitro

Bouillaut

McBride

Sorg

et al. 2015

Antimicrob Agents Chemother

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Treatment failure and recurrence of Clostridium difficile infection following treatment with vancomycin or metronidazole: a systematic review of the evidence

Cited by 224 publications

References 53 publications

Safety, Tolerability, Systemic Exposure, and Metabolism of CRS3123, a Methionyl-tRNA Synthetase Inhibitor Developed for Treatment of Clostridium difficile, in a Phase 1 Study

Safety, Tolerability, Systemic Exposure, and Metabolism of CRS3123, a Methionyl-tRNA Synthetase Inhibitor Developed for Treatment of Clostridium difficile, in a Phase 1 Study

Recombinant Mucin-Type Fusion Proteins with a Galα1,3Gal Substitution as Clostridium difficile Toxin A Inhibitors

Effects of Surotomycin on Clostridium difficile Viability and Toxin Production In Vitro

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