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Fidaxomicin (Fdx) is widely used to treat Clostridioides difficile ( Cdiff ) infections, but the molecular basis of its narrow-spectrum activity in the human gut microbiome remains unknown. Cdiff infections are a leading cause of nosocomial deaths 1 . Fidaxomicin, which inhibits RNA polymerase, targets Cdiff with minimal effects on gut commensals, reducing recurrence of Cdiff infection 2 , 3 . Here we present the cryo-electron microscopy structure of Cdiff RNA polymerase in complex with fidaxomicin and identify a crucial fidaxomicin-binding determinant of Cdiff RNA polymerase that is absent in most gut microbiota such as Proteobacteria and Bacteroidetes. By combining structural, biochemical, genetic and bioinformatic analyses, we establish that a single residue in Cdiff RNA polymerase is a sensitizing element for fidaxomicin narrow-spectrum activity. Our results provide a blueprint for targeted drug design against an important human pathogen. Structural analysis of Clostridioides difficile RNA polymerase in complex with fidaxomicin combined with biochemical, genetic and bioinformatic analyses identifies a key residue that determines fidaxomicin sensitivity.

Background Zika virus (ZIKV) infection is a global health problem, and its complications, including congenital Zika syndrome and Guillain-Barré syndrome, constitute a continued threat to humans. Unfortunately, effective therapeutics against ZIKV infection are not available thus far. Methods We screened the compounds collection consisting of 1789 FDA-approved drugs by a computational docking method to obtain anti-ZIKV candidate compounds targeting ZIKV RNA-dependent RNA polymerase (RdRp). SPR (BIAcore) assay was employed to demonstrate the candidate compounds’ direct binding to ZIKV RdRp, and polymerase activity assay was used to determine the inhibitory effect on ZIKV RdRp-catalyzed RNA synthesis. The antiviral effects on ZIKV in vitro and in vivo were detected in infected cultured cells and in Ifnar1 −/− mice infected by ZIKV virus using plaque assay, western blotting, tissue immunofluorescence, and immunohistochemistry. Results Here, we report that a first-in-class macrocyclic antibiotic, which has been clinically used to treat Clostridium difficile infection, fidaxomicin, potently inhibits ZIKV replication in vitro and in vivo. Our data showed that fidaxomicin was effective against African and Asian lineage ZIKV in a wide variety of cell lines of various tissue origins, and prominently suppressed ZIKV infection and significantly improved survival of infected mice. In addition, fidaxomicin treatment reduced the virus load in the brains and testes, and alleviated ZIKV-associated pathological damages, such as paralysis, hunching, and neuronal necrosis in the cerebra. Furthermore, our mechanistic study showed that fidaxomicin directly bound ZIKV NS5 protein and inhibited the RNA synthesis-catalyzing activity of ZIKV RdRp. Conclusions Our data suggest that fidaxomicin may represent an effective anti-ZIKV agent. In the light that fidaxomicin is already a clinically used drug, there might be a promising prospect in the development of fidaxomicin to be an antiviral therapeutic.

Background Antibiotics are currently the primary treatment of Clostridioides difficile ( C. difficile ) infection. Yet, due to rapid development of resistance and high recurrences rates, there is an unmet need for new antimicrobials for C. difficile infections. This study assessed the in vitro susceptibility of clinical isolates from Israel to two recently developed antibiotics, ridinilazole (RDZ) and ibezapolstat (IBZ), and to standard-of-care antibiotics. Methods C. difficile isolates ( n  = 313) recovered from patients at both community and hospital medical centers across Israel, were typed to different sequence types (ST) by multi-locus sequencing typing (MLST). Susceptibility to metronidazole (MTZ) and vancomycin (VAN) was determined using the gradient strip test (Etest). Susceptibility to fidaxomicin (FDX), RDZ and IBZ was determined by agar dilution. Results ST42 (39; 12.5%) and ST2 (36; 11.5%) were the most prevalent STs. Resistance to MTZ and VAN was low (2.2%, 1.6%, respectively), while 23 (7.35%) isolates were FDX-resistant. RDZ MIC ranged between 0.06 and 0.5 mg/L, and MIC 50/90 was 0.25/0.5 mg/L. IBZ had an MIC 50/90 of 4 mg/L. No significant differences were noted in IBZ MIC of different strains. Conclusions RDZ and IBZ demonstrated potent in vitro activity against 313 C. difficile isolates belonging to different STs. These two antimicrobials may serve as effective agents for C. difficile infection.

Clostridioides difficile is the leading cause of nosocomial infections and a worldwide urgent public health threat. Without doubt, there is an urgent need for new effective anticlostridial agents due to the increasing incidence and severity of C. difficile infection (CDI). The aim of the present study is to investigate the in vivo efficacy of auranofin (rheumatoid arthritis FDA-approved drug) in a CDI mouse model and establish an adequate dosage for treatment. The effects of increased C. difficile inoculum, and pre-exposure to simulated gastric intestinal fluid (SGF) and simulated intestinal fluid (SIF), on the antibacterial activity of auranofin were investigated. Auranofin’s in vitro antibacterial activity was stable in the presence of high bacterial inoculum size compared to vancomycin and fidaxomicin. Moreover, it maintained its anti- C. difficile activity after being exposed to SGF and SIF. Upon testing in a CDI mouse model, auranofin at low clinically achievable doses (0.125 mg/kg and 0.25 mg/kg) significantly protected mice against CDI with 100% and 80% survival, respectively. Most importantly, auranofin (0.125 mg/kg and 0.25 mg/kg) significantly prevented CDI recurrence when compared with vancomycin. Collectively, these results indicate that auranofin could potentially provide an effective, safe and quick supplement to the current approaches for treating CDI.

Bezlotoxumab is approved for prevention of recurrent Clostridioides (Clostridium) difficile infection (CDI) in adults receiving antibacterial treatment for CDI who are at high risk for recurrent CDI. Previous studies have shown that although serum albumin levels are an important predictor for bezlotoxumab exposure, this has no clinically meaningful impact on efficacy. This pharmacokinetic modeling study assessed whether hematopoietic stem cell transplant (HSCT) recipients, at increased risk of CDI and exhibiting decreased albumin levels within the first month posttransplant, are at risk of clinically relevant reductions in bezlotoxumab exposure. Observed bezlotoxumab concentration-time data pooled from participants in Phase III trials MODIFY I and II (ClinicalTrials.gov identifiers NCT01241552/NCT01513239) and three Phase I studies (PN004, PN005, and PN006) were used to predict bezlotoxumab exposures in two adult post-HSCT populations: A Phase Ib study of posaconazole including allogeneic HSCT recipients (ClinicalTrials.gov identifier NCT01777763; posaconazole-HSCT population); and a Phase III study of fidaxomicin for CDI prophylaxis (ClinicalTrials.gov identifier NCT01691248; fidaxomicin-HSCT population). The bezlotoxumab PK model used the minimum albumin level for each individual in post-HSCT populations to mimic a “worst-case scenario.” Predicted worst-case bezlotoxumab exposures for the posaconazole-HSCT population (N = 87) were decreased by 10.8% versus bezlotoxumab exposures observed in the pooled Phase III/Phase I data set (N = 1587). No further decrease was predicted for the fidaxomicin-HSCT population (N = 350). Based on published population pharmacokinetic data, the predicted decrease in bezlotoxumab exposure in the post-HSCT populations is not expected to have a clinically meaningful effect on bezlotoxumab efficacy at the recommended 10 mg/kg dose. Dose modification is therefore not required in the hypoalbuminemia setting expected post-HSCT.

The emergence of drug‐resistant viruses and novel strains necessitates the rapid development of novel antiviral therapies. This need was particularly demanding during the COVID‐19 pandemic. While de novo drug development is a time‐consuming process, repurposing existing approved medications offers a more expedient approach. In our prior in silico screening of the DrugBank database, fidaxomicin emerged as a potential SARS‐CoV‐2 papain‐like protease inhibitor. This study extends those findings by investigating fidaxomicin‘s antiviral properties in vitro. Our results support further exploration of fidaxomicin as a therapeutic candidate against SARS‐CoV‐2, given its promising in vitro antiviral activity and favorable safety profile.

Background Recurrent or refractory Clostridioides difficile infection (CDI) often affects older and immunocompromised patients, posing clinical and economic challenges. While fidaxomicin has shown lower recurrence rates than vancomycin in the general population, evidence in this population remains limited. Methods This retrospective, multicentre case-control study compared patients aged > 65 years or immunocompromised patients receiving fidaxomicin (case group) with those treated with vancomycin (control group) for recurrent or refractory CDI. A microcosting approach was used to assess direct treatment costs. Results A total of 344 patients were included (172 per group). Compared to the control group, the fidaxomicin group presented a significantly higher rate of symptom reduction on day 10 ( n  = 163, 95% vs. n  = 147, 86%; p  = 0.004) and lower CDI recurrence rates ( n  = 36, 21% vs. n  = 63, 37%; p  = 0.001). While the mean CDI treatment costs per patient were significantly higher in the fidaxomicin group ( p  < 0.001), the hospitalisation and overall treatment costs were comparable (€19,898, 95% CI €16,151-€23,645 vs. €20,469, 95% CI €16,837-€24,101, p  = 0.811; €17,798, 95% CI €14,620-€20,975 vs. €17,300, 95% CI €14,199-€20,400, p  = 0.840). Key cost drivers were hospitalisation, intensive care unit treatment, and severe initial CDI. Conclusions Despite higher drug acquisition costs of fidaxomicin, overall treatment costs were comparable between the two groups with better clinical outcomes in patients treated with fidaxomicin. Clinical trial number Not applicable.

PurposeThere is a lack of real-world evidence of the comparative effectiveness of fidaxomicin versus vancomycin or metronidazole for treating patients with Clostridium difficile (CDI) infection. No systematic evidence comparing these treatment regimens using real-world observational studies was published up to date. The goal of this study is to compare the fidaxomicin and vancomycin/metronidazole regimens in terms of treatment outcomes in CDI patients.MethodsSystematic and comprehensive search was carried out in the following databases and search engines: EMBASE, Cochrane, MEDLINE, ScienceDirect, and Google Scholar from 1954 until January 2022. Newcastle–Ottawa (NO) scale was used to assess the risk of bias. Meta-analysis was carried out using random effects model, and pooled odds ratios (OR) with 95% confidence interval (CI) were reported.ResultsA total of 10 studies satisfied the inclusion criteria, most of them were with poorer quality. The pooled OR was 0.40 (95% CI: 0.09–1.68; I2 = 82.4%) for clinical cure and 2.02 (95% CI: 0.36–11.39; I2 = 88.4%) for sustained cure. We reported pooled OR of 0.69 (95% CI: 0.40–1.20; I2 = 65.7%) for the recurrence rate, 2.81 (95% CI: 1.08–7.29; I2 = 70.6%) for the treatment failure, and 0.73 (95% CI: 0.50–1.07; I2 = 0%) for all-cause mortality between patients that received fidaxomicin and vancomycin. The pooled OR was 0.71 (95% CI: 0.05–9.47; I2 = 69.6%) in terms of recurrence between patients receiving fidaxomicin and metronidazole.ConclusionFidaxomicin and vancomycin/metronidazole regimens did not have significant difference in terms of treatment outcomes, such as clinical cure, sustained cure, recurrence, and all-cause mortality. However, there was significantly higher risk of treatment failure in CDI patients taking fidaxomicin.

Background Clostridioides ( Clostridium ) difficile is an important pathogen of healthcare- associated diarrhea, however, an increase in the occurrence of C. difficile infection (CDI) outside hospital settings has been reported. The accumulation of antimicrobial resistance in C. difficile can increase the risk of CDI development and/or its spread. The limited number of antimicrobials for the treatment of CDI is matter of some concern. Objectives In order to summarize the data on antimicrobial resistance to C. difficile derived from humans, a systematic review and meta-analysis were performed. Methods We searched five bibliographic databases: (MEDLINE [PubMed], Scopus, Embase, Cochrane Library and Web of Science) for studies that focused on antimicrobial susceptibility testing in C. difficile and were published between 1992 and 2019. The weighted pooled resistance (WPR) for each antimicrobial agent was calculated using a random- effects model. Results A total of 111 studies were included. The WPR for metronidazole and vancomycin was 1.0% (95% CI 0–3%) and 1% (95% CI 0–2%) for the breakpoint > 2 mg/L and 0% (95% CI 0%) for breakpoint ≥32 μg/ml. Rifampin and tigecycline had a WPRs of 37.0% (95% CI 18–58%) and 1% (95% CI 0–3%), respectively. The WPRs for the other antimicrobials were as follows: ciprofloxacin 95% (95% CI 85–100%), moxifloxacin 32% (95% CI 25–40%), clindamycin 59% (95% CI 53–65%), amoxicillin/clavulanate 0% (0–0%), piperacillin/tazobactam 0% (0–0%) and ceftriaxone 47% (95% CI 29–65%). Tetracycline had a WPR 20% (95% CI 14–27%) and meropenem showed 0% (95% CI 0–1%); resistance to fidaxomicin was reported in one isolate (0.08%). Conclusion Resistance to metronidazole, vancomycin, fidaxomicin, meropenem and piperacillin/tazobactam is reported rarely. From the alternative CDI drug treatments, tigecycline had a lower resistance rate than rifampin. The high-risk antimicrobials for CDI development showed a high level of resistance, the highest was seen in the second generation of fluoroquinolones and clindamycin; amoxicillin/clavulanate showed almost no resistance. Tetracycline resistance was present in one fifth of human clinical C. difficile isolates.

Clostridioides difficile is the leading cause of hospital-associated diarrhea and has remained a consistent threat for older patients and those with comorbidities or vulnerabilities. The high rates of treatment failure and recurrence, along with the decreased effectiveness of first-line treatments highlight the urgent need for the development of new anti- C. difficile agents. α-mangostin is a natural compound isolated from the edible mangosteen fruit pericarps that has known antimicrobial activity. α-mangostin is poorly absorbed from the gastrointestinal tract (GIT), which is ideal for treatment of CDI to accumulate at the site of infection at concentrations capable of clearing C. difficile . We found that α-mangostin was as potent as the standard-of-care vancomycin, inhibiting a diverse panel of C. difficile strains at a concentration range of 0.5–2 µg/mL. It exhibited rapid bactericidal activity, completely clearing C. difficile in vitro within 2 hours, surpassing vancomycin and fidaxomicin. Additionally, α-mangostin’s anti- C. difficile activity was not affected by the high C. difficile inoculum. To further understand its mechanism, we investigated α-mangostin’s membrane disruption activity by assessing the leakage of DNA and ATP post-exposure. α-mangostin resulted in a significant leakage of DNA and ATP indicating that its anti- C. difficile activity is mediated by the bacterial cell membrane disruption. Collectively, these findings demonstrate that α-mangostin possesses desirable characteristics for a promising anti- C. difficile which merits further investigation.