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Repurposing the Antiamoebic Drug Diiodohydroxyquinoline for Treatment of Clostridioides difficile Infections.

ABSTRACT: Clostridioides difficile, the leading cause of nosocomial infections, is an urgent health threat worldwide. The increased incidence and severity of disease, the high recurrence rates, and the dearth of effective anticlostridial drugs have created an urgent need for new therapeutic agents. In an effort to discover new drugs for the treatment of Clostridioides difficile infections (CDIs), we investigated a panel of FDA-approved antiparasitic drugs against C. difficile and identified diiodohydroxyquinoline (DIHQ), an FDA-approved oral antiamoebic drug. DIHQ exhibited potent activity against 39 C. difficile isolates, inhibiting growth of 50% and 90% of these isolates at concentrations of 0.5??g/ml and 2??g/ml, respectively. In a time-kill assay, DIHQ was superior to vancomycin and metronidazole, reducing a high bacterial inoculum by 3 log10 within 6 h. Furthermore, DIHQ reacted synergistically with vancomycin and metronidazole against C. difficile in vitro. Moreover, at subinhibitory concentrations, DIHQ was superior to vancomycin and metronidazole in inhibiting two key virulence factors of C. difficile, toxin production and spore formation. Additionally, DIHQ did not inhibit the growth of key species that compose the host intestinal microbiota, such as Bacteroides, Bifidobacterium, and Lactobacillus spp. Collectively, our results indicate that DIHQ is a promising anticlostridial drug that warrants further investigation as a new therapeutic for CDIs.

SUBMITTER: Abutaleb NS

PROVIDER: S-EPMC7269495 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Repurposing the Antiamoebic Drug Diiodohydroxyquinoline for Treatment of Clostridioides difficile Infections.

Abutaleb Nader S NS Seleem Mohamed N MN

Antimicrobial agents and chemotherapy 20200521 6

Clostridioides difficile, the leading cause of nosocomial infections, is an urgent health threat worldwide. The increased incidence and severity of disease, the high recurrence rates, and the dearth of effective anticlostridial drugs have created an urgent need for new therapeutic agents. In an effort to discover new drugs for the treatment of Clostridioides difficile infections (CDIs), we investigated a panel of FDA-approved antiparasitic drugs against C. difficile and iden ...[more]

PMID: 32253206

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Project description:Background: Antibiotics targeted against Clostridioides difficile bacteria are necessary, but insufficient, to achieve a durable clinical response because they have no effect on C. difficile spores that germinate within a disrupted microbiome. ECOSPOR-III evaluated SER-109, an investigational, biologically derived microbiome therapeutic of purified Firmicute spores for treatment of rCDI. Herein, we present the interim analysis in the ITT population at 8 and 12 weeks. Methods: Adults ≥18 years with rCDI (≥3 episodes in 12 months) were screened at 75 US and CAN sites. CDI was defined as ≥3 unformed stools per day for <48 hours with a positive C. difficile assay. After completion of 10–21 days of vancomycin or fidaxomicin, adults with symptom resolution were randomized 1:1 to SER-109 (4 capsules × 3 days) or matching placebo and stratified by age (≥ or <65 years) and antibiotic received. Primary objectives were safety and efficacy at 8 weeks. Primary efficacy endpoint was rCDI (recurrent toxin+ diarrhea requiring treatment); secondary endpoints included efficacy at 12 weeks after dosing. Results: Overall, 287 participants were screened and 182 were randomized (59.9% female; mean age, 65.5 years). The most common reason for screen failure was a negative C. difficile toxin assay. A significantly lower proportion of SER-109 participants had rCDI after dosing compared to placebo at week 8 (11.1% vs 41.3%, respectively; relative risk [RR], 0.27; 95% confidence interval [CI], 0.15–0.51; p-value <0.001). Efficacy rates were significantly higher with SER-109 vs placebo in both stratified age groups (Figure 1). SER-109 was well-tolerated with a safety profile similar to placebo. The most common treatment-emergent adverse events (TEAEs) were gastrointestinal and were mainly mild to moderate. No serious TEAEs, infections, deaths, or drug discontinuations were deemed related to study drug. Conclusions: SER-109, an oral live microbiome therapeutic, achieved high rates of sustained clinical response with a favorable safety profile. By enriching for Firmicute spores, SER-109 achieves high efficacy while mitigating risk of transmitting infectious agents, beyond donor screening alone. SER-109 represents a major paradigm shift in the clinical management of patients with recurrent CDI. Clinicaltrials.gov Identifier NCT03183128. These data were previously presented as a late breaker at American College of Gastroenterology 2020. Funding: Seres Therapeutics Disclosures: None Figure 1.

Project description:Importance:Clostridioides difficile infection (CDI) remains a leading cause of health care facility-associated infection. A greater understanding of the regional epidemiologic profile of CDI could inform targeted prevention strategies. Objectives:To assess trends in incidence of health care facility-associated and community-acquired CDI among hospitalized patients over time and to conduct a subanalysis of trends in the NAP1 strain of CDI over time. Design, Setting, and Participants:This long-term multicenter cohort study reviewed records of patients (N = 2?025?678) admitted to a network of 43 regional community hospitals primarily in the southeastern United States from January 1, 2013, through December 31, 2017. Generalized linear mixed-effects models were used to adjust for potential clustering within facilities and changing test method (nucleic acid amplification testing or toxin enzyme immunoassay) over time. Main Outcomes and Measures:Clostridioides difficile infection incidence rates were counted as cases per 1000 admissions for community-acquired and total CDI cases or cases per 10?000 patient-days for health care facility-associated CDI. Long-term trends in the proportion of cases acquired in the community and in NAP1 strain incidence were also evaluated. Results:A total of 2?025?678 admissions and 21?254 CDI cases were included (12 678 [59.6%] female; median [interquartile range] age, 69 [55-80] years). Median (interquartile range) total CDI incidence increased slightly from 7.9 (3.5-12.4) cases per 1000 admissions in 2013 to 9.3 (4.9-13.7) cases per 1000 admissions in 2017. After adjustment, the overall incidence of health care facility-associated CDI declined (incidence rate ratio [IRR], 0.995; 95% CI, 0.990-0.999; P?=?.03), whereas insufficient evidence was found for either an increase or a decrease in community-acquired CDI (IRR, 1.004; 95% CI, 0.999-1.009; P?=?.14). The proportion of cases classified as community acquired increased over time from a mean (SD) of 0.49 (0.28) in 2013 to 0.61 (0.26) in 2017 (odds ratio, 1.010 per month; 95% CI, 1.006-1.015; P?<?.001). Rates of the NAP1 strain of CDI varied widely between facilities, with no statistically significant change in NAP1 strain incidence over time in the community setting (IRR, 1.007; 95% CI, 0.994-1.021) or health care facility setting (IRR, 1.011; 95% CI, 0.990-1.032). Conclusions and Relevance:The findings suggest that, despite the modest improvement in health care facility-associated CDI rates, a better understanding of community-acquired CDI incidence is needed for future infection prevention efforts.

Dataset Information

Repurposing the Antiamoebic Drug Diiodohydroxyquinoline for Treatment of Clostridioides difficile Infections.

Publications

Repurposing the Antiamoebic Drug Diiodohydroxyquinoline for Treatment of Clostridioides difficile Infections.

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