cadazolid (ACT-179811) / J&J - LARVOL DELTA

How to spare gut microbiota from antibiotic effects? PK-PD based innovative strategies, target specificity, and molecule-to-medicinal properties. (PubMed, RSC Med Chem) - "Additionally, the discovery of antibacterial clinical candidates, such as afabicin, lolamicin, hygromycin A, cadazolid, and ribaxamase, that exhibit pathogen-specific efficacy with limited gut exposure, has been discussed with an in-depth analysis of their mechanism of actions (MoAs) and specific bacterial targets, molecular structure-to-medicinal insights, and strategic innovations. Collectively, this article provides a perspective for next generation antibacterial drug design and discovery, focusing on innovative strategies, specific biological pathways, and key molecular features that spare gut microbiota while maximizing antibacterial treatment efficacy."

Journal • PK/PD data • Review • Alzheimer's Disease • Cognitive Disorders • Colorectal Cancer • Diabetes • Gastroenterology • Gastrointestinal Disorder • Genetic Disorders • Hepatology • Immunology • Infectious Disease • Inflammatory Bowel Disease • Metabolic Disorders • Obesity • Oncology • Solid Tumor

Fighting against Clostridioides difficile infection: Current medications. (PubMed, Int J Antimicrob Agents) - "Recent guidelines recommend fidaxomicin and vancomycin as first-line drugs to treat CDI, bezlotoxumab to prevent recurrence, and fecal microbiota transplantation (FMT) for rescue treatment. Currently, researchers are investigating therapeutic antibacterial drugs (e.g., teicoplanin, ridinilazole, ibezapolstat, surotomycin, cadazolid, and LFF571), preventive medications against recurrence (e.g., Rebyota, Vowst, VP20621, VE303, RBX7455, and MET-2), primary prevention strategies (e.g., vaccine, ribaxamase, and DAV132) and other anti-CDI medications in the preclinical stage (e.g., Raja 42, Myxopyronin B, and bacteriophage). This narrative review summarizes current medications, including newly marketed drugs and products in development against CDI, to help clinicians treat CDI appropriately and to call for more research on innovation."

Journal • Review • Infectious Disease • Transplantation

Discovery and Structure-Activity Relationship of Cadazolid: A First-In-Class Quinoxolidinone Antibiotic for the Treatment of Clostridioides difficile Infection. (PubMed, J Med Chem) - "In an effort to optimize this class of compounds for the treatment of C. difficile infection (CDI), we have identified cadazolid (9), a first-in-class quinoxolidinone antibiotic, which is a potent inhibitor of C. difficile protein synthesis. In order to achieve narrow-spectrum coverage of clinically most relevant strains without affecting the gut microbiota, an emphasis was placed on abolishing activity against commensals of the intestinal microbiome while retaining good coverage of pathogenic C. difficile, including hypervirulent and epidemic strains."

Journal • Infectious Disease

Microbiome-preserving antibiotics for the treatment of Clostridioides difficile infection: a systematic review and meta-analysis. (PubMed, Tech Coloproctol) - "Fidaxomicin (in seven studies) demonstrated significant improvement in achieving sustained clinical cure. A limitation of this study may that more studies are needed to compare fidaxomicin with other antibiotics."

Clinical • Journal • Retrospective data • Review • Infectious Disease

The Urgent Threat of Clostridioides difficile Infection: A Glimpse of the Drugs of the Future, with Related Patents and Prospects. (PubMed, Biomedicines) - "Many possible drugs of the future for CDI, with diverse mechanisms of action, are in development in the form of microbiota-modulating agents (e.g., ADS024, CP101, RBX2660, RBX7455, SYN-004, SER-109, VE303, DAV132, MET-2, and BB128), small molecules (e.g., ridinilazole, ibezapolstat, CRS3123, DNV3837, MGB-BP-3, alanyl-L-glutamine, and TNP-2198), antibodies (e.g., IM-01 and LMN-201), and non-toxic strains of CD (e.g., NTCD-M3). The development of some therapeutic agents (e.g., DS-2969b, OPS-2071, cadazolid, misoprostol, ramoplanin, KB109, LFF571, and Ramizol) stopped due to failed clinical trials or unknown reasons...The current pipeline of anti-CDI medications appears promising. However, it will be fascinating to see how many of the cited are successful in gaining approval from drug regulators such as the US FDA and becoming medicines for CDI and r-CDI."

Journal • Review • Developmental Disorders • Infectious Disease

Discovery and Development of Antibacterial Agents: Fortuitous and Designed. (PubMed, Mini Rev Med Chem) - "These include solithromycin, plazomicin, lefamulin, omadacycline, eravacycline, delafloxacin, zabofloxacin, finafloxacin, nemonoxacin, gepotidacin, zoliflodacin, cefiderocol, BAL30072, avycaz, zerbaxa, vabomere, relebactam, tedizolid, cadazolid, sutezolid, triclosan and afabiacin. This article aims to review the investigational and recently approved antibacterials with a focus on their structure, mechanisms of action/resistance, and spectrum of activity. Delving deep, their success or otherwise in various phases of clinical trials is also discussed while attributing the same to various causal factors."

Journal

Inhibition of spores to prevent the recurrence of Clostridioides difficile infection - A possibility or an improbability? (PubMed, J Microbiol Immunol Infect) - "Clostridioides difficile is one of the most common nosocomial gastrointestinal pathogens, and recurrence is a problematic issue because approximately 20-30% of patients experience at least one episode of recurrence, even after treatment with a therapeutic drug of choice for C. difficile infection (CDI), such as vancomycin...However, an antimicrobial agent, such as fidaxomicin, which has a good inhibitory effect on both C. difficile vegetative cells and spores is assumed to not only treat CDI but also prevent its recurrence...Some new antimicrobial agents in phase II clinical trials, including cadazolid and ridinilazole, have shown exceptional anti-C. difficile and spore-inhibiting effects that can be expected to not only treat CDI but also prevent its recurrence in the future."

Journal • Review • Gastrointestinal Disorder • Infectious Disease

In vitro and in vivo activities, absorption, tissue distribution and excretion studies of OBP-4, a potential anti-Clostridioides difficile agent. (PubMed, Antimicrob Agents Chemother) - "However, cadazolid (CZD) and vancomycin (VAN) showed less protection for infected mice than did OBP-4 in terms of diarrhea and weight loss, especially VAN. Subsequently, ADE investigations of OBP-4 with a reliable LC-MS/MS method showed a extremely low systemic exposure and predominant fecal excretion, thus resulting in a high local concentration of OBP-4 in the intestinal tract - the site of CDI. These results demonstrated that OBP-4 possess good activity against C. difficile and favorable ADE characteristics for oral treatment of CDI, which support further development of OBP-4 as a potential anti-CDI agent."

Journal • Preclinical

Structural basis of translation inhibition by cadazolid, a novel quinoxolidinone antibiotic. (PubMed, Sci Rep) - "Here we show that cadazolid binds with its oxazolidinone moiety in a binding pocket in close vicinity of the PTC as observed previously for linezolid, and that it extends its unique fluoroquinolone moiety towards the A-site of the PTC. In this position, the drug inhibits protein synthesis by interfering with the binding of tRNA to the A-site, suggesting that its chemical features also can enable the inhibition of linezolid-resistant strains."

Journal • Gastroenterology • Gastrointestinal Disorder

Cadazolid for the treatment of Clostridium difficile infection: results of two double-blind, placebo-controlled, non-inferiority, randomised phase 3 trials. (PubMed, Lancet Infect Dis) - P3 | "Cadazolid was safe and well tolerated but did not achieve its primary endpoint of non-inferiority to vancomycin for clinical cure in one of two phase 3 C difficile infection trials. Therefore, further commercial development of cadazolid for C difficile infection is unlikely."

Clinical • Head-to-Head • Journal • P3 data • Immunology

Multidrug resistance in anaerobes. (PubMed, Future Microbiol) - "MDR was present in >1/2 of Clostridioides difficile isolates, most often in epidemic/hypervirulent strains and unusually high metronidazole or vancomycin resistance has been reported in single studies. Resistance in the anaerobes tends to be less predictable and anaerobic microbiology is required in more laboratories. New hopes may be new antibiotics such as eravacycline, cadazolid, surotomycin, ridinilazol or C. difficile toxoid vaccines; however, more efforts are needed to track the MDR in anaerobes."

Journal

Cadazolid vs. Vancomycin for Treatment of Clostridioides difficile Infection: Systematic Review With Meta-Analysis (ACG 2019) - "Two studies with three RCTs met the inclusion criteria with a total of 1283 patients with CDI who received either cadazolid 250 mg twice daily (624 patients) or vancomycin 125 mg four times daily (659 patients). Clinical cure rate at the end of treatment was not statistically significant (pooled odds ratio (OR)= 0.82; 95% confidence interval (CI) = 0.61 to 1.11; p=0.20; I2= 0%). Sustained clinical response at clinical follow-up was also not significantly different (pooled OR = 1.14; 95% CI = 0.91 to 1.43; p=0.27; I2 = 0 %)."

Retrospective data • Review

Treatment of acute and recurrent Clostridium difficile infections : What is new? (PubMed, Internist (Berl)) - "Fidaxomicin is as effective as vancomycin but has the advantage of a lower rate of recurrence. Furthermore, recent clinical studies were able to demonstrate that significantly fewer recurrences occurred in patients who additionally received the monoclonal antibody bezlotoxumab. In recent years, several new antibiotics with narrow-spectrum acitivity and low intestinal resorption have been developed for the treatment of CDI, including surotomycin, cadazolid, and ridinilazol. Novel toxoid vaccines are expected to become an efficacious tool in the prevention of CDI; however, pivotal clinical trials have so far not been completed."

Journal • Review

Cadazolid vs Vancomycin for Treatment of Clostridioides difficile Infection: Systematic Review with Meta-Analysis. (PubMed, Curr Clin Pharmacol) - "Cadazolid is non-inferior to vancomycin and offers a promising alternative for the treatment of CDI."

Journal • Retrospective data • Review

Emerging drugs for the treatment of Clostridium difficile. (PubMed, Expert Opin Emerg Drugs) - "...Orally administered vancomycin and fidaxomicin are the therapeutic options of choice for initial C difficile infection and fecal microbiota transplant for the recurrence infection. Furthermore, in recent years several new antibiotics with narrow-spectrum activity and low intestinal resorption have been developed, including surotomycin, cadazolid, and ridinilazol, and novel toxoid vaccines are expected to be efficacious in the prevention of C difficile infection...Expert opinion We have today a wide spectrum of promising therapeutic possibilities against infection. Pivotal future clinical trials may be crucial in developing effective strategies to optimize outcomes, mainly in high-risk population."

Journal • Review

New antibiotics in infection treatment (PubMed, Pol Merkur Lekarski) - "...Ceftazidime with avibactam and ceftolozane with tazobactam show exceptional efficacy in severe infections. Karbavans is a combination of meropenem and a new boron beta-lactamase inhibitor, as well as the combination of avibactam and aztreonam, are a hope for the treatment of infections caused by Klebsiella pneumoniae resistant to the majority of available antibiotics. S649266 is itself an inhibitor of beta-lactamases...Solithromycin, a new ketolide, has immunomodulatory effects and a broad antiinflammatory spectrum, with no side effects caused by older generations of macrolides. New fluoroquinolones (delafloxacin, zabofloxacin, finefloxacin, nemonoxacin, zoliflodacin) show a wide spectrum of action with less and less side effects. The new MRX-1 preapplate, alongside tedizolid and cadazolid, are further oxazolidinones that show significant activity against multi-resistant Gram-positive pathogens. The presented palette of new molecules with antimicrobial activity will..."

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