Cadazolid for the treatment of Clostridium difficile infection: results of two double-blind, placebo-controlled, non-inferiority, randomised phase 3 trials

Gerding, Dale N.; Cornely, Oliver A.; Grill, Simon; Kracker, Hilke; Marrast, Anne Claire; Nord, Carl Erik; Talbot, George H.; Buitrago, Martha; Diaconescu, Iulian; Oliveira, Cláudia Murta de; Preoţescu, Liliana; Pullman, John; Louie, Thomas; Wilcox, Mark H.

doi:10.1016/s1473-3099(18)30614-5

Cited by 47 publications

(37 citation statements)

References 25 publications

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“…In pre-clinical studies, cadazolid showed a potent bactericidal in vitro activity against CD (MIC90 of 0.25 mg/L) and a low propensity for resistance development [174][175][176]. The results for the IMPACT I and IMPACT II phase 3, randomized clinical trials were recently published [177]. While safe and well tolerated, cadazolid failed to achieve the primary end-point of non-inferiority vs. vancomycin for clinical cure [177].…”

Section: Question 9 When and How To Report Clinicians The Results Ofmentioning

confidence: 99%

“…The results for the IMPACT I and IMPACT II phase 3, randomized clinical trials were recently published [177]. While safe and well tolerated, cadazolid failed to achieve the primary end-point of non-inferiority vs. vancomycin for clinical cure [177]. As a result, to the best of our knowledge, efforts to commercialize cadazolid for CDI have been halted.…”

Section: Question 9 When and How To Report Clinicians The Results Ofmentioning

confidence: 99%

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Recommendations for the diagnosis and treatment of Clostridioides difficile infection: An official clinical practice guideline of the Spanish Society of Chemotherapy (SEQ), Spaish Society of Internal Medicine (SEMI) and the working group of Postoperative Infection of the Spanish Society of Anesthesia and Reanimation (SEDAR)

Bouza¹,

Aguado²,

Alcalá³

et al. 2020

Rev Esp Quimioter

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ned leukocytosis, even in the absence of classical risk factors. With a few exceptions, a single stool sample is sufficient for diagnosis, which can be sent to the laboratory with or without transportation media for enteropathogenic bacteria. In the absence of diarrhoea, rectal swabs may be valid. The microbiology laboratory should include C. difficile among the pathogens routinely searched in patients with diarrhoea. Laboratory tests in different order and sequence schemes include GDH detection, presence of toxins, molecular tests and toxigenic culture. Immediate determination of sensitivity to drugs such as vancomycin, metronidazole or fidaxomycin is not required. The evolution of toxin persistence is not a suitable test for follow up. Laboratory diagnosis of CDI should be rapid and results reported and interpreted to clinicians immediately. In addition to the basic support of all diarrheic episodes, CDI treatment requires the suppression of antiperistaltic

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Section: Question 9 When and How To Report Clinicians The Results Ofmentioning

confidence: 99%

Section: Question 9 When and How To Report Clinicians The Results Ofmentioning

confidence: 99%

Recommendations for the diagnosis and treatment of Clostridioides difficile infection: An official clinical practice guideline of the Spanish Society of Chemotherapy (SEQ), Spaish Society of Internal Medicine (SEMI) and the working group of Postoperative Infection of the Spanish Society of Anesthesia and Reanimation (SEDAR)

Bouza¹,

Aguado²,

Alcalá³

et al. 2020

Rev Esp Quimioter

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“…A similar decision was observed with cadazolid, which met the primary endpoint in the phase 2 study, but failed to meet the endpoint in the phase 3 trials (IMPACT I and II, NCT01987895 and NCT01983683). 89…”

Section: Discussionmentioning

confidence: 99%

<p>Investigational Treatment Agents for Recurrent <em>Clostridioides difficile</em> Infection (rCDI)</p>

Kullar¹,

Tran²,

Goldstein³

2020

JEP

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Clostridioides difficile infection (CDI) is a major cause of nosocomial diarrhea that is deemed a global health threat. C. difficile strain BI/NAP1/027 has contributed to the increase in the mortality, severity of CDI outbreaks and recurrence rates (rCDI). Updated CDI treatment guidelines suggest vancomycin and fidaxomicin as initial first-line therapies that have initial clinical cure rates of over 80%. Unacceptably high recurrence rates of 15-30% in patients for the first episode and 40% for the second recurrent episode are reported. Alternative treatments for rCDI include fecal microbiota transplant and a human monoclonal antibody, bezlotoxumab, that can be used in patients with high risk of rCDI. Various emerging potential therapies with narrow spectrum of activity and little systemic absorption that are in development include 1) Ibezapolstat (formerly ACX-362E), MGB-BP-3, and DS-2969b-targeting bacterial DNA replication, 2) CRS3213 (REP3123)-inhibiting toxin production and spore formation, 3) ramizol and ramoplanin-affecting bacterial cell wall, 4) LFF-571-blocking protein synthesis, 5) Alanyl-L-Glutamine (alanylglutamine)inhibiting damage caused by C. difficile by protecting intestinal mucosa, and 6) DNV3837 (MCB3681)-prodrug consisting of an oxazolidinone-quinolone combination that converts to the active form DNV3681 that has activity in vitro against C. difficile. This review article provides an overview of these developing drugs that can have potential role in the treatment of rCDI and in lowering recurrence rates.

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“…According to the currently postulated pathophysiology, the infectious process occurs following a disturbance to the gut’s normal microbiota, leading to an overgrowth of Clostridioides difficile . While symptoms can range from mild to severe, its complications of toxic mega-colon and shock contribute to high morbidity and mortality rates [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

“…Cadazolid is a highly acidic novel fluoroquinolone-oxazolidinone antibiotic with strong lipophilic properties [ 2 , 4 ]. This organic heterocyclic compound’s quinolone characteristics allow it to act as a potent inhibitor of both DNA and protein synthesis.…”

Section: Introductionmentioning

confidence: 99%

Cadazolid vs Vancomycin for the Treatment of Clostridioides difficile Infection: Systematic Review with Meta-analysis

Aziz

Weissman

Fatima

et al. 2020

CCP

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Background:: Current guidelines recommend the use of vancomycin for the initial treatment of Clostridioides difficile Infection (CDI). Cadazolid, an experimental drug, has been utilized and compared in several studies with varying results. Methods:: A systematic literature search was performed using electronic databases [Medline, Google Scholar and Cochrane] for eligible studies. Randomized Controlled Trials (RCTs) comparing cadazolid with vancomycin for CDI treatment were included. Demographic variables and outcomes (CDI resolution, CDI recurrence, and adverse events) were collected. The primary outcome was clinical cure rate defined as the resolution of CDI at the end of a 10-day course. Results:: 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 the treatment was not statistically significant (pooled OR= 0.82; 95% 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 %). Cadazolid had a lower recurrence rate than vancomycin (pooled OR = 0.71; 95% CI = 0.52 to 0.98; p=0.04; I2 = 13 %). Conclusion:: Cadazolid is non-inferior to vancomycin and offers a promising alternative for the treatment of CDI. More studies including RCTs and longitudinal studies with large and diverse patient population are needed to further confirm this. Furthermore, cadazolid should also be compared with fidaxomicin in a head-to-head trial to evaluate their efficacy for CDI.

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Cadazolid for the treatment of Clostridium difficile infection: results of two double-blind, placebo-controlled, non-inferiority, randomised phase 3 trials

Abstract: This is a repository copy of Cadazolid for the treatment of Clostridium difficile infection: results of two double-blind, placebo-controlled, non-inferiority, randomised phase 3 trials.

Cited by 47 publications

References 25 publications

<p>Investigational Treatment Agents for Recurrent <em>Clostridioides difficile</em> Infection (rCDI)</p>

Cadazolid vs Vancomycin for the Treatment of Clostridioides difficile Infection: Systematic Review with Meta-analysis

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