Investigations of the Mode of Action and Resistance Development of Cadazolid, a New Antibiotic for Treatment of Clostridium difficile Infections

Locher, Hans H.; Caspers, Patrick; Bruyère, Thierry; Schroeder, Susanne; Pfaff, Philippe; Knezevic, Andreja; Keck, Wolfgang; Ritz, Daniel

doi:10.1128/aac.01831-13

Cited by 69 publications

(56 citation statements)

References 21 publications

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“…In contrast, vancomycin (acting on cell wall synthesis) and metronidazole (interacting with DNA metabolism) were weak inhibitors of C. difficile toxin formation in in vitro assays (21,23). Studies addressing the mode of action of cadazolid revealed that it primarily acts as an inhibitor of protein synthesis, while inhibition of DNA synthesis was observed as a weaker additional mode of action as reported in a companion article by Locher et al (30). These findings are in agreement with the inhibitory effect of cadazolid on de novo C. difficile toxin formation as well as the potent activity against linezolid-and fluoroquinolone-resistant strains reported here.…”

Section: Discussionmentioning

confidence: 73%

In VitroandIn VivoAntibacterial Evaluation of Cadazolid, a New Antibiotic for Treatment of Clostridium difficile Infections

Locher

Seiler

Chen

et al. 2014

Antimicrob Agents Chemother

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bClostridium difficile is a leading cause of health care-associated diarrhea with significant morbidity and mortality, and new options for the treatment of C. difficile-associated diarrhea (CDAD) are needed. Cadazolid is a new oxazolidinone-type antibiotic that is currently in clinical development for treatment of CDAD. Here, we report the in vitro and in vivo antibacterial evaluation of cadazolid against C. difficile. Cadazolid showed potent in vitro activity against C. difficile with a MIC range of 0.125 to 0.5 g/ml, including strains resistant to linezolid and fluoroquinolones. In time-kill kinetics experiments, cadazolid showed a bactericidal effect against C. difficile isolates, with >99.9% killing in 24 h, and was more bactericidal than vancomycin. In contrast to metronidazole and vancomycin, cadazolid strongly inhibited de novo toxin A and B formation in stationary-phase cultures of toxigenic C. difficile. Cadazolid also inhibited C. difficile spore formation substantially at growth-inhibitory concentrations. In the hamster and mouse models for CDAD, cadazolid was active, conferring full protection from diarrhea and death with a potency similar to that of vancomycin. These findings support further investigations of cadazolid for the treatment of CDAD.C lostridium difficile infection (CDI), or CDAD for C. difficileassociated diarrhea, is a major health care problem and a leading cause of morbidity and mortality in elderly hospitalized patients (1, 2). During the past decade, there has been a renewed interest in CDAD triggered by an increase in both frequency and severity of the disease in the Western world and the discovery of new hypervirulent strains (3-6), as well as an increased incidence of CDAD in the community (7). CDAD results from overgrowth of toxin-producing strains in the colon, typically following disturbances of the normal protective enteric flora. Clinical symptoms range from asymptomatic colonization to diarrhea, severe pseudomembranous colitis, sepsis, and death. The main virulence factors of C. difficile are two high-molecular-weight toxins, the enterotoxin toxin A (TcdA) and the cytotoxin toxin B (TcdB), while the contribution of the binary toxin remains unclear (8). Toxin A and toxin B cause damage to the intestinal epithelial barrier and promote mucosal inflammation. In fact, the main clinical symptoms of CDAD (secretory diarrhea and inflammation of the colonic mucosa) can be explained by the action of toxins A and B (8). Moreover, C. difficile produces endospores that are resistant to antibiotic treatment and routine disinfection (9). Spores surviving in the gut of patients and in the hospital environment may play a major role in reinfection and relapse of CDAD. Current antibiotic therapy for CDAD includes vancomycin and metronidazole, which have limited treatment success in severe disease, and high recurrence rates of up to 30% have been observed with these treatments (10). Only one new antibiotic, fidaxomicin (11, 12), has been approved in the last 30 years for this indication. In c...

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Section: Discussionmentioning

confidence: 73%

In VitroandIn VivoAntibacterial Evaluation of Cadazolid, a New Antibiotic for Treatment of Clostridium difficile Infections

Locher

Seiler

Chen

et al. 2014

Antimicrob Agents Chemother

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“…In previous studies, we had been unable to generate C. difficile strains with elevated CDZ MICs in vitro by single-step procedures and even in limited-passage experiments (up to 13 serial passages), demonstrating that the strains had a low propensity for resistance development (1). To obtain clones with elevated CDZ MICs for mechanistic analyses, up to 46 alternating passages on agar and in liquid medium were carried out in the presence of gradually increasing CDZ or LZD concentrations.…”

Section: Resultsmentioning

confidence: 99%

“…Determination of the MIC. The MICs of C. difficile isolates were determined using the Clinical and Laboratory Standards Institute (CLSI)-recommended reference agar dilution method for anaerobes (29) as described previously (1). For the inoculum, single bacterial colonies or cells collected from colonies exhibiting confluent growth (total culture from passage 46 [CDZ45 and LZD46]) were suspended in supplemented brucella broth and approximately 10 4 to 10 5 CFU were spotted.…”

Section: Discussionmentioning

confidence: 99%

“…It represents a new antibacterial class combining elements of an oxazolidinone moiety with a fluoroquinolone moiety, resulting in unique properties. In C. difficile, CDZ predominantly acts by inhibition of protein synthesis (via its oxazolidinone pharmacophore) rather than by inhibition of DNA synthesis (1). Previous studies indicated that CDZ has a very low propensity of spontaneous resistance development and retains potent activity against C. difficile strains with elevated linezolid (LZD) MICs as well as against fluoroquinolone-resistant strains (1,2,3).…”

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confidence: 99%

“…Additionally, a comparison of mutations selected in vitro with mutations found in clinical isolates was attempted. Resistant clones were analyzed by whole-genome sequencing (WGS) and then further characterized in C. difficile cell-free in vitro transcription/translation (IVTT) assays (1,3) to correlate MIC shifts in resistant clones with mutations detected in ribosomal genes.…”

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confidence: 99%

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Different Resistance Mechanisms for Cadazolid and Linezolid in Clostridium difficile Found by Whole-Genome Sequencing Analysis

Caspers

Locher

Pfaff

et al. 2017

Antimicrob Agents Chemother

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Cadazolid (CDZ) is a new antibiotic currently in clinical development for the treatment of Clostridium difficile infections. CDZ interferes with the bacterial protein synthesis machinery. The aim of the present study was to identify resistance mechanisms for CDZ and compare the results to those obtained for linezolid (LZD) in C. difficile by whole-genome sequencing (WGS) of strains generated by in vitro passages and to those obtained for LZD-resistant clinical isolates. Clones of C. difficile 630 selected with CDZ during 46 passages had a maximally 4-fold increase in CDZ MIC, while the LZD MIC for clones selected with LZD increased up to 16-fold. CDZ cross-resistance with LZD was maximally 4-fold, and no cross-resistance with other antibiotics tested was observed. Our data suggest that there are different resistance mechanisms for CDZ and LZD in C. difficile. Mutations after passages with CDZ were found in rplD (ribosomal protein L4) as well as in tra and rmt, whereas similar experiments with LZD showed mutations in rplC (ribosomal protein L3), reg, and tpr, indicating different resistance mechanisms. Although high degrees of variation between the sequenced genomes of the clinical isolates were observed, the same mutation in rplC was found in two clinical isolates with high LZD MICs. No mutations were found in the 23S rRNA genes, and attempts to isolate the cfr gene from resistant clinical isolates were unsuccessful. Analysis of 50% inhibitory concentrations (IC 50 s) determined in in vitro transcription/translation assays performed with C. difficile cell extracts from passaged clones correlated well with the MIC values for all antibiotics tested, indicating that the ribosomal mutations are causing the resistant phenotype.

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Antibiotic treatment for Clostridium difficile -associated diarrhoea in adults

Nelson

Suda

Evans

2017

Cochrane Database of Systematic Reviews

199

118

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No firm conclusions can be drawn regarding the efficacy of antibiotic treatment in severe CDI as most studies excluded patients with severe disease. The lack of any 'no treatment' control studies does not allow for any conclusions regarding the need for antibiotic treatment in patients with mild CDI beyond withdrawal of the initiating antibiotic. Nonetheless, moderate quality evidence suggests that vancomycin is superior to metronidazole and fidaxomicin is superior to vancomycin. The differences in effectiveness between these antibiotics were not too large and the advantage of metronidazole is its far lower cost compared to the other two antibiotics. The quality of evidence for teicoplanin is very low. Adequately powered studies are needed to determine if teicoplanin performs as well as the other antibiotics. A trial comparing the two cheapest antibiotics, metronidazole and teicoplanin, would be of interest.

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Investigations of the Mode of Action and Resistance Development of Cadazolid, a New Antibiotic for Treatment of Clostridium difficile Infections

Cited by 69 publications

References 21 publications

In VitroandIn VivoAntibacterial Evaluation of Cadazolid, a New Antibiotic for Treatment of Clostridium difficile Infections

In VitroandIn VivoAntibacterial Evaluation of Cadazolid, a New Antibiotic for Treatment of Clostridium difficile Infections

Different Resistance Mechanisms for Cadazolid and Linezolid in Clostridium difficile Found by Whole-Genome Sequencing Analysis

Antibiotic treatment for Clostridium difficile -associated diarrhoea in adults

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