lff571 and Clostridium-Infections

Clostridium difficile infections (CDI) remain a challenge to treat clinically due primarily to limited number of antibiotics available and unacceptably high recurrence rates. Because of this, there has been significant demand for creating innovative therapeutics, which has resulted in the development of several novel antibiotics.. This review updates seven different antibiotics that are currently in development to treat CDI including fidaxomicin, surotomycin, ridinilazole, ramoplanin, cadazolid, LFF571, and CRS3123. Available preclinical and clinical data are compared between these antibiotics.. Many of these new antibiotics display almost ideal properties for antibiotics directed against CDI. Despite these properties, not all clinical development of these compounds has been successful. These studies have provided key insights into the pathogenesis of CDI and will continue to inform future drug development. Successful phase III clinical trials should result in several new and novel antibiotics to treat CDI.

Topics: Anti-Bacterial Agents; Benzimidazoles; Benzopyrans; Clinical Trials as Topic; Clostridium Infections; Depsipeptides; Humans; Lipopeptides; Oxazolidinones; Peptides, Cyclic; Pyridines; Thiazoles; Thiophenes

Clostridium difficile is the most common cause of antibacterial-associated diarrhea. Clear clinical presentation and rapid diagnostics enable targeted therapy for C. difficile infection (CDI) to start quickly. CDI treatment includes metronidazole and vancomycin (VAN). Despite decades of use for CDI, no clinically meaningful resistance to either agent has emerged. Fidaxomicin (FDX), an RNA polymerase inhibitor, is also approved to treat CDI. Mutants with reduced susceptibility to FDX have been selected in vitro by single and multistep methods. Strains with elevated FDX minimum inhibitory concentrations (MICs) were also identified from FDX-treated patients in clinical trials. LFF571 is an exploratory agent that inhibits EF-Tu. In a proof-of-concept study, LFF571 was safe and effective for treating CDI. Spontaneous mutants with reduced susceptibility to LFF571 were selected in vitro in a single step, but not via serial passage. Although there are several agents in development for treatment of CDI, this review summarizes the frequencies and mechanisms of C. difficile mutants displaying reduced susceptibility to FDX or LFF71.

Topics: Aminoglycosides; Anti-Bacterial Agents; Clinical Trials, Phase III as Topic; Clostridioides difficile; Clostridium Infections; Drug Resistance, Bacterial; Fidaxomicin; Genotype; Humans; Microbial Sensitivity Tests; Mutation; Thiazoles

Clostridium difficile infection causes diarrheal disease with potentially fatal complications. Although treatments are available, including vancomycin, metronidazole, and fidaxomicin, the recurrence of disease after therapy remains a problem. LFF571 is a novel thiopeptide antibacterial that shows in vitro potency against C. difficile that is comparable to or greater than that of other clinically used antibiotics. Here, we compare the pharmacokinetics (PK) of LFF571 and vancomycin in patients with C. difficile infection as part of an early efficacy study. This multicenter, randomized, evaluator-blind, and active-controlled study evaluated the safety, efficacy, and pharmacokinetics of LFF571 in adults with primary episodes or first relapses of moderate C. difficile infections. Patients were randomized to receive 200 mg of LFF571 or 125 mg of vancomycin four times daily for 10 days. The PK parameters were calculated from drug concentrations measured in serum and fecal samples. The systemic exposure following oral administration of 200 mg of LFF571 four times per day for 10 days in patients with C. difficile infection was limited. The highest LFF571 serum concentration observed was 41.7 ng/ml, whereas the levels in feces at the end of treatment were between 107 and 12,900 μg/g. In comparison, the peak vancomycin level observed in serum was considerably higher, at 2.73 μg/ml; the levels of vancomycin in feces were not measured. Similar to healthy volunteers, patients with C. difficile infections exhibited high fecal concentrations and low serum levels of LFF571. These results are consistent with the retention of LFF571 in the lumen of the gastrointestinal tract. (This study has been registered at ClinicalTrials.gov under registration no. NCT01232595.).

Topics: Anti-Bacterial Agents; Clostridioides difficile; Clostridium Infections; Feces; Female; Humans; Male; Middle Aged; Thiazoles; Vancomycin

Clostridium difficile infection causes serious diarrheal disease. Although several drugs are available for treatment, including vancomycin, recurrences remain a problem. LFF571 is a semisynthetic thiopeptide with potency against C. difficile in vitro. In this phase 2 exploratory study, we compared the safety and efficacy (based on a noninferiority analysis) of LFF571 to those of vancomycin used in adults with primary episodes or first recurrences of moderate C. difficile infection. Patients were randomized to receive 200 mg of LFF571 or 125 mg of vancomycin four times daily for 10 days. The primary endpoint was the proportion of clinical cures at the end of therapy in the per-protocol population. Secondary endpoints included clinical cures at the end of therapy in the modified intent-to-treat (mITT) population, the time to diarrhea resolution, and the recurrence rate. Seventy-two patients were randomized, with 46 assigned to receive LFF571. Based on the protocol-specified definition, the rate of clinical cure for LFF571 (90.6%) was noninferior to that of vancomycin (78.3%). The 30-day sustained cure rates for LFF571 and vancomycin were 56.7% and 65.0%, respectively, in the per-protocol population and 58.7% and 60.0%, respectively, in the modified intent-to-treat population. Using toxin-confirmed cases only, the recurrence rates were lower for LFF571 (19% versus 25% for vancomycin in the per-protocol population). LFF571 was generally safe and well tolerated. The incidence of adverse events (AEs) was higher for LFF571 (76.1% versus 69.2% for vancomycin), although more AEs in the vancomycin group were suspected to be related to the study drug (38.5% versus 32.6% for LFF571). One patient receiving LFF571 discontinued the study due to an AE. (This study has been registered at ClinicalTrials.gov under registration no. NCT01232595.).

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Clostridioides difficile; Clostridium Infections; Female; Humans; Male; Middle Aged; Thiazoles; Vancomycin

In November 2008, a study was performed with support from the European Centre for Disease Prevention and Control (ECDC) to obtain an overview of Clostridium difficile infections (CDIs) in European hospitals. A collection of 398 C. difficile isolates obtained from this hospital-based survey was utilized to identify antimicrobial susceptibility patterns of common C. difficile PCR ribotypes across Europe.. The MICs of three approved therapeutic agents (vancomycin, metronidazole and fidaxomicin) and LFF571 (a novel semi-synthetic thiopeptide antibiotic) were determined by the agar dilution method.. MICs of fidaxomicin and LFF571 were in general 2-4-fold lower than those of vancomycin and metronidazole. Isolates belonging to clade 2, including the hypervirulent ribotype 027, had one-dilution higher MIC50 and MIC90 values for fidaxomicin and metronidazole, whereas similar MIC values were observed for vancomycin and LFF571. Isolates belonging to C. difficile PCR ribotype 001 were more susceptible to fidaxomicin than other frequently found PCR ribotypes 014/020 and 078. Six isolates from three different countries had a metronidazole MIC of 2 mg/L. Four of the six isolates were characterized as PCR ribotype 001.. There was no evidence of in vitro resistance of C. difficile to any of the four agents tested. However, the results suggest type-specific differences in susceptibility for the treatment agents we investigated. Continuous surveillance of C. difficile isolates in Europe is needed to determine the possible clinical implications of ribotype-specific changes in susceptibility to therapeutic agents.

Topics: Aminoglycosides; Anti-Bacterial Agents; Clostridioides difficile; Clostridium Infections; Cross Infection; Enterocolitis, Pseudomembranous; Europe; Fidaxomicin; Humans; Metronidazole; Microbial Sensitivity Tests; Multilocus Sequence Typing; Polymerase Chain Reaction; Ribotyping; Thiazoles; Treatment Outcome; Vancomycin