Efficacy of fidaxomicin versus vancomycin in the treatment of Clostridium difficile infection: A systematic meta-analysis.

PURPOSE: To compare the efficacy, recurrence rate, adverse event rate and mortality of fidaxomicin compared with vancomycin in treating different types of Clostridium difficile infection (CDI). METHODS: A systematic search was conducted on PubMed, Embase, Web of Science, Cochrane Library and clinical trial registration databases for research on fidaxomicin versus vancomycin in the treatment of CDI and the retrieval period extended from the establishment of the database to July 22, 2022. A total of 15 studies were included, including 8 RCTs and 7 retrospective cohort studies. RESULTS: Results showed that there was no significant difference in the overall efficacy of the treatment between fidaxomicin and vancomycin, and results in the subgroups of CDI hypervirulent strains and recurrent CDI were obtained, but vancomycin was more effective than fidaxomicin in the treatment of severe CDI (RR = 0.94, 95% CI: 0.90-0.98, P < .01). Results showed that fidaxomicin is superior to vancomycin in terms of 40-day recurrence rate (RR = 0.52, 95% CI: 0.38-0.70, P < .01), 60-day recurrence rate (RR = 0.38, 95% CI: 0.21-0.69, P < .01) and 90-day recurrence rate (RR = 0.62, 95% CI: 0.50-0.77, P < .01). For the recurrence rate of the treatment in CDI hypervirulent strains, severe CDI and recurrent CDI, there was no significant difference between the 2 groups. In addition, there was no significant difference in the incidence of clinical adverse reactions, and same outcomes appeared in all-cause mortality at 40-day, severe CDI and recurrent CDI, but fidaxomicin was superior to vancomycin in all-cause mortality over 60-day (RR = 0.57, 95% CI: 0.34-0.96, P = .03). CONCLUSION: There were no significant differences between fidaxomicin and vancomycin in the treatment of CDI in therapeutic effectiveness and adverse reactions, while fidaxomicin was superior to vancomycin in terms of recurrence rate and long-term mortality, and vancomycin is more effective in treating severe CDI.

Is advanced age still a risk factor for recurrence of C. difficile infection in the era of new treatments?

BACKGROUND: Advanced age has been widely identified as a risk factor for recurrent Clostridioides difficile infection (CDI), but most related studies were performed before the introduction of novel therapies. The aim of this study was to compare CDI characteristics and outcomes in patients over and under 80 years old with CDI and their outcomes in the era of new treatments. METHODS: This was a retrospective cohort study of patients diagnosed with CDI from January 2021 to December 2022 in an academic hospital. We compared recurrence and mortality at 12 weeks after the end of treatment. An extension of the Fine and Grey model adjusted for competing events was used to assess the effect of age on recurrence. RESULTS: Four hundred seventy-six patients were considered to have CDI (320 in patients <80 years and 156 in ≥80 years). CDI in older patients was more frequently healthcare-associated and was more severe. Although the Charlson index was almost identical between populations, comorbidities clearly differed. New treatments (bezlotoxumab, fidaxomicin and faecal microbiota transplantation) were more frequently used in older patients without statistical significance (41.3% vs. 33.4%, P = .053). There were 69 (14.5%) recurrences, with no differences by age group after adjusting for competing events. Mortality was greater in the oldest (35.3%) than in the youngest (13.1%); P < .001. CONCLUSIONS: No differences in CDI recurrence rates were found between age groups. However, there was a high mortality rate in patients ≥80 years old, which emphasises the urgent need to improve the prevention and treatment of CDI in this group.

Management of Clostridioides difficile infection: an Italian Delphi consensus.

BACKGROUND: Clostridioides difficile infection (CDI), a leading cause of nosocomial deaths, is a microbiota-mediated disease. As such, the use of broader spectrum antibiotics, such as vancomycin and metronidazole, can prime the gastrointestinal tract to become more prone to CDI recurrences. Fidaxomicin, a narrow-spectrum antibiotic, has been demonstrated to be superior in preventing recurrence and in preserving the intestinal microbiota; however, widespread employment worldwide has been hindered due to high acquisition costs. OBJECTIVES: To integrate the currently available guidelines on the management of CDI and to shed light on the timeliest employment of fidaxomicin. METHODS: An expert panel was gathered to obtain consensus using Delphi methodology on a series of statements regarding the management of CDI and on appropriate antibiotic use. RESULTS: Consensus was reached on 21 of the 25 statements addressing the management of CDI. CONCLUSIONS: Delphi methodology was used to achieve consensus on the management of CDI, on the identification of patients at risk of recurrences or severe infection, and on the most appropriate use of fidaxomicin, with the final aim of fostering clinical practice application of treatment algorithms proposed by previous guidelines, in absolute synergy. It could be an important tool to promote more appropriate and cost-effective CDI treatments in European settings with limited resources, like Italy.

Fecal microbiota composition is a better predictor of recurrent Clostridioides difficile infection than clinical factors in a prospective, multicentre cohort study.

INTRODUCTION: Clostridioides difficile infection (CDI) is the most common cause of antibiotic-associated diarrhoea. Fidaxomicin and fecal microbiota transplantation (FMT) are effective, but expensive therapies to treat recurrent CDI (reCDI). Our objective was to develop a prediction model for reCDI based on the gut microbiota composition and clinical characteristics, to identify patients who could benefit from early treatment with fidaxomicin or FMT. METHODS: Multicentre, prospective, observational study in adult patients diagnosed with a primary episode of CDI. Fecal samples and clinical data were collected prior to, and after 5 days of CDI treatment. Follow-up duration was 8 weeks. Microbiota composition was analysed by IS-pro, a bacterial profiling technique based on phylum- and species-specific differences in the 16-23 S interspace regions of ribosomal DNA. Bayesian additive regression trees (BART) and adaptive group-regularized logistic ridge regression (AGRR) were used to construct prediction models for reCDI. RESULTS: 209 patients were included, of which 25% developed reCDI. Variables related to microbiota composition provided better prediction of reCDI and were preferentially selected over clinical factors in joint prediction models. Bacteroidetes abundance and diversity after start of CDI treatment, and the increase in Proteobacteria diversity relative to baseline, were the most robust predictors of reCDI. The sensitivity and specificity of a BART model including these factors were 95% and 78%, but these dropped to 67% and 62% in out-of-sample prediction. CONCLUSION: Early microbiota response to CDI treatment is a better predictor of reCDI than clinical prognostic factors, but not yet sufficient enough to predict reCDI in daily practice.

Comparison of fidaxomicin, thuricin CD, vancomycin and nisin highlights the narrow spectrum nature of thuricin CD.

Vancomycin and metronidazole are commonly used treatments for Clostridioides difficile infection (CDI). However, these antibiotics have been associated with high levels of relapse in patients. Fidaxomicin is a new treatment for CDI that is described as a narrow spectrum antibiotic that is minimally active on the commensal bacteria of the gut microbiome. The aim of this study was to compare the effect of fidaxomicin on the human gut microbiome with a number of narrow (thuricin CD) and broad spectrum (vancomycin and nisin) antimicrobials. The spectrum of activity of each antimicrobial was tested against 47 bacterial strains by well-diffusion assay. Minimum inhibitory concentrations (MICs) were calculated against a select number of these strains. Further, a pooled fecal slurry of 6 donors was prepared and incubated for 24 h with 100 µM of each antimicrobial in a mini-fermentation system together with a no-treatment control. Fidaxomicin, vancomycin, and nisin were active against most gram positive bacteria tested in vitro, although fidaxomicin and vancomycin produced larger zones of inhibition compared to nisin. In contrast, the antimicrobial activity of thuricin CD was specific to C. difficile and some Bacillus spp. The MICs showed similar results. Thuricin CD exhibited low MICs (<3.1 µg/mL) for C. difficile and Bacillus firmus, whereas fidaxomicin, vancomycin, and nisin demonstrated lower MICs for all other strains tested when compared to thuricin CD. The narrow spectrum of thuricin CD was also observed in the gut model system. We conclude that the spectrum of activity of fidaxomicin is comparable to that of the broad-spectrum antibiotic vancomycin in vitro and the broad spectrum bacteriocin nisin in a complex community.

Clostridioides Difficile: A Concise Review of Best Practices and Updates.

Clostridioides difficile infection (CDI) is one of the most common and severe nosocomial infections worldwide. It can also affect healthy individuals in the community. The incidence of CDI has been on the rise globally for the past decade, necessitating a proactive approach to combat its spread; new strategies are being developed to enhance diagnostic accuracy and optimize treatment outcomes. Implementing the 2-step testing has increased diagnostic specificity, reducing the usage of CD-specific antibiotics with no concomitant increase in surgical complication rates. In 2021, the Infectious Diseases Society of America/Society for Healthcare Epidemiology of America (IDSA/SHEA) shifted its preference for initial treatment to fidaxomicin over vancomycin and metronidazole due to its lower recurrence rate. It also prioritized fidaxomicin for the treatment of recurrent CDI. There are new developments on the frontiers of fecal microbiota therapies, with RBX2660 and SER-109 approved recently by the FDA for prevention, with other microbiome-based therapies in various development and clinical trials. This review offers providers an updated and practical guide for CDI management.

Fighting against Clostridioides difficile infection: Current medications.

Clostridioides difficile (formerly Clostridium difficile) has been regarded as an 'urgent threat' and a significant global health problem, as life-threatening diarrhoea and refractory recurrence are common in patients with C. difficile infection (CDI). Unfortunately, the available anti-CDI drugs are limited. Recent guidelines recommend fidaxomicin and vancomycin as first-line drugs to treat CDI, bezlotoxumab to prevent recurrence, and faecal microbiota transplantation 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 summarises 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.

Is shorter also better in the treatment of Clostridioides difficile infection?

OBJECTIVES: To assess the effectiveness of shortened regimens of vancomycin or fidaxomicin in the treatment of Clostridioides difficile infection (CDI). METHODS: Adult patients with CDI hospitalized from January 2022 to May 2023 were included in this observational study. In patients with CDI treated with vancomycin or fidaxomicin, antibiotic treatment was discontinued after either 5 or 7 days of vancomycin or 5 days of fidaxomicin if there was a clinical response and improvement in laboratory parameters. The control cohort was treated with the standard 10 day regimen of either vancomycin or fidaxomicin. The follow-up was 60 days. Causative C. difficile strains were characterized by ribotyping and toxin gene detection when available. RESULTS: Twenty-five patients (median age 76 years) received shortened treatment with vancomycin (n = 21), or fidaxomicin (n = 4). Five cases fulfilled the criteria for severe CDI. Twenty-three patients completed follow-up; two died from causes other than CDI, and two developed recurrent CDI (8.0%). Ribotypes (RTs) 001 and 014 were the most prevalent with 20% each. In two C. difficile isolates, binary toxin genes were detected (RTs 078 and 023). In the control group of 22 patients recurrent CDI developed in 5 patients (22.7%). No statistically significant differences were found between the groups. CONCLUSIONS: Shortened treatment regimens for CDI with vancomycin and fidaxomicin were shown to be effective in our cohort of patients compared with 10 days of treatment. The recurrence rate was lower in the study group. A larger, prospective, double-blind, randomized, multicentre study is needed to support our findings.

[Fulminant Clostridioides difficile infection during treatment with FLT3 inhibitor for acute myeloid leukemia].

An 80-year-old man with FLT3-TKD mutation-positive acute myeloid leukemia (AML) relapsed during consolidation therapy with venetoclax/azacitidine and was started on gilteritinib as salvage therapy. On the day after treatment initiation, febrile neutropenia was observed, but the fever resolved promptly after initiation of antimicrobial therapy. On the fifth day after completion of antimicrobial therapy, the patient experienced fever and watery diarrhea over 10 times a day, and a diagnosis of Clostridioides difficile infection (CDI) was made based on stool examination. The patient was treated with intravenous metronidazole, but renal dysfunction, hypotension, and hypoxemia developed, and a CT scan showed pleural and intraperitoneal effusion, significant intestinal wall thickening, and intestinal dilatation. Fidaxomicin was started under general monitoring in the intensive care unit and response was achieved. The patient was discharged from the intensive care unit on the 18th day after the onset of CDI. We report this case not only due to the rarity of fulminant CDI during AML treatment, but also because it is a valuable example of effective treatment of fulminant CDI with fidaxomicin.

Clostridioides difficile Colitis.

Clostridioides difficile colitis is an important source of hospital-acquired diarrhea associated with antibiotic use. Symptoms are profuse watery diarrhea, typically following a course of antibiotics; however, some cases of fulminant disease may manifest with shock, ileus, or megacolon. Nonfulminant colitis is treated with oral fidaxomicin. C difficile colitis has a high potential for recurrence, and recurrent episodes are also treated with fidaxomicin. Bezlotoxumab is another medication that may be used in populations at high risk for further recurrence. Fulminant disease is treated with maximal medical therapy and early surgical consultation. Antibiotic stewardship is critical to preventing C difficile colitis.

Review article: The epidemiology and management of Clostridioides difficile infection-A clinical update.

BACKGROUND: Clostridioides difficile is the most common cause of healthcare-associated infection, and severe cases can result in significant complications. While anti-microbial therapy is central to infection management, adjunctive therapies may be utilised as preventative strategies. AIM: This article aims to review updates in the epidemiology, diagnosis, and management, including treatment and prevention, of C. difficile infections. METHODS: A narrative review was performed to evaluate the current literature between 1986 and 2023. RESULTS: The incidence of C. difficile infection remains significantly high in both hospital and community settings, though with an overall decline in recent years and similar surveillance estimates globally. Vancomycin and fidaxomicin remain the first line antibiotics for treatment of non-severe C. difficile infection, though due to lower recurrence rates, infectious disease society guidelines now favour use of fidaxomicin. Faecal microbiota transplantation should still be considered to prevent recurrent C. difficile infection. However, in the past year the field has had a significant advancement with the approval of the first two live biotherapeutic products-faecal microbiota spores-live brpk, an oral capsule preparation, and faecal microbiota live-jslm-both indicated for the prevention of recurrent C. difficile infection, with additional therapies on the horizon. CONCLUSION: Although the prevalence of C. difficile infection remains high, there have been significant advances in the development of novel therapeutics and preventative measures following changes in recent practice guidelines, and will continue to evolve in the future.

Management of Clostridioides difficile Infection: Diagnosis, Treatment, and Future Perspectives.

Clostridioides difficile infection is the most common healthcare-associated infection in the United States, with potential life-threatening complications and a significant impact on the costs of care. Antibiotic stewardship as well as discontinuation of chronic acid suppressive therapy are key for its prevention and treatment. Effective infection management requires appropriate interpretation of diagnostic tests, as well as the use of vancomycin and fidaxomicin as first-line treatment. Novel treatments such as Bezlotoxumab, fecal microbiota transplant, and live biotherapeutic products are proven effective in recurrent C. difficile infection and address dysbiosis.

Antibacterial activity of ibezapolstat against antimicrobial-resistant clinical strains of Clostridioides difficile.

Antimicrobial resistance is emerging in clinical strains of Clostridioides difficile. Ibezapolstat (IBZ) is a DNA polymerase IIIC inhibitor that has completed phase II clinical trials. IBZ has potent in vitro activity against wild-type, susceptible strains but its effect on C. difficile strains with reduced susceptibility to metronidazole (MTZ), vancomycin (VAN), or fidaxomicin (FDX) has not been tested. The primary objective of this study was to test the antibacterial properties of IBZ against multidrug-resistant C. difficile strains. The in vitro activity, bactericidal, and time-kill activity of IBZ versus comparators were evaluated against 100 clinical strains of which 59 had reduced susceptibility to other C. difficile antibiotics. Morphologic changes against a multidrug resistance strain were visualized by light and scanning electron microscopy. The overall IBZ MIC50/90 values (µg/mL) for evaluated C. difficile strains were 4/8, compared with 2/4 for VAN, 0.5/1 for FDX, and 0.25/4 for MTZ. IBZ MIC50/90 values did not differ based on non-susceptibility to antibiotic class or number of classes to which strains were non-susceptible. IBZ bactericidal activity was similar to the minimum inhibitory concentration (MIC) and maintained in wild-type and non-susceptible strains. Time-kill assays against two laboratory wild-type and two clinical non-susceptible strains demonstrated sustained IBZ activity despite reduced killing by comparator antibiotics for IBZ and VAN non-susceptible strains. Microscopy visualized increased cell lengthening and cellular damage in multidrug-resistant strains exposed to IBZ sub-MIC concentrations. This study demonstrated the potent antibacterial activity of IBZ against a large collection of C. difficile strains including multidrug-resistant strains. This study highlights the therapeutic potential of IBZ against multidrug-resistant strains of C. difficile.

In vivo evaluation of Clostridioides difficile enoyl-ACP reductase II (FabK) inhibition by phenylimidazole unveils a promising narrow-spectrum antimicrobial strategy.

Clostridioides difficile infection (CDI) is a leading cause of hospital-acquired diarrhea, which often stems from disruption of the gut microbiota by broad-spectrum antibiotics. The increasing prevalence of antibiotic-resistant C. difficile strains, combined with disappointing clinical trial results for recent antibiotic candidates, underscores the urgent need for novel CDI antibiotics. To this end, we investigated C. difficile enoyl ACP reductase (CdFabK), a crucial enzyme in de novo fatty acid synthesis, as a drug target for microbiome-sparing antibiotics. To test this concept, we evaluated the efficacy and in vivo spectrum of activity of the phenylimidazole analog 296, which is validated to inhibit intracellular CdFabK. Against major CDI-associated ribotypes 296 had an Minimum inhibitory concentration (MIC90) of 2 µg/mL, which was comparable to vancomycin (1 µg/mL), a standard of care antibiotic. In addition, 296 achieved high colonic concentrations and displayed dosed-dependent efficacy in mice with colitis CDI. Mice that were given 296 retained colonization resistance to C. difficile and had microbiomes that resembled the untreated mice. Conversely, both vancomycin and fidaxomicin induced significant changes to mice microbiomes, in a manner consistent with prior reports. CdFabK, therefore, represents a potential target for microbiome-sparing CDI antibiotics, with phenylimidazoles providing a good chemical starting point for designing such agents.

European Practice for CDI Treatment.

Clostridioides difficile infection (CDI) remains a significant cause of morbidity and mortality worldwide. Historically, two antibiotics (metronidazole and vancomycin) and a recent third (fidaxomicin) have been used for CDI treatment; convincing data are now available showing that metronidazole is the least efficacious agent. The European Society of Clinical Microbiology and Infectious Diseases (ESCMID) management guidance for CDI were updated in 2021. This guidance document outlines the treatment options for a variety of CDI clinical scenarios and for non-antimicrobial management (e.g., faecal microbiota transplantation, FMT). One of the main changes is that metronidazole is no longer recommended as first-line CDI treatment. Rather, fidaxomicin is preferred on the basis of reduced recurrence rates with vancomycin as an acceptable alternative. Recommended options for recurrent CDI now include bezlotoxumab as well as FMT.A 2017 survey of 20 European countries highlighted variation internationally in CDI management strategies. A variety of restrictions were in place in 65% countries prior to use of new anti-CDI treatments, including committee/infection specialist approval or economic review/restrictions. This survey was repeated in November 2022 to assess the current landscape of CDI management practices in Europe. Of 64 respondents from 17 countries, national CDI guidelines existed in 14 countries, and 11 have already/plan to incorporate the ESCMID 2021 CDI guidance, though implementation has not been surveyed in 6. Vancomycin is the most commonly used first-line agent for the treatment of CDI (n = 42, 66%), followed by fidaxomicin (n = 30, 47%). Six (9%) respondents use metronidazole as first-line agent for CDI treatment, whereas 22 (34%) only in selected low-risk patient groups. Fidaxomicin is more likely to be used in high-risk patient groups. Availability of anti-CDI therapy influenced prescribing in six respondents (9%). Approval pre-prescription was required before vancomycin (n = 3, 5%), fidaxomicin (n = 10, 6%), bezlotoxumab (n = 11, 17%) and FMT (n = 10, 6%). Implementation of CDI guidelines is rarely audited.Novel anti-CDI agents are being evaluated; it is not yet clear what will be the roles of these agents. The treatment of recurrent CDI is particularly troublesome, and several different live biotherapeutics are being developed, in addition to FMT.

Bezlotoxumab during the first episode of Clostridioides difficile infection in patients at high risk of recurrence.

PURPOSE: To describe a cohort with a high risk of recurrence who received bezlotoxumab during the first episode of Clostridioides difficile infection (CDI) and to compare this cohort with patients with similar characteristics who did not receive the monoclonal antibody. METHODS: A prospective and multicentre study of patients with a high risk of recurrence (expected recurrence rate>35%) who were treated with bezlotoxumab during their first episode of CDI was conducted. A propensity score-matched model 1:2 was used to compare both cohorts that were weighed according to basal characteristics (hospital-acquisition, creatinine value, and fidaxomicin as a CDI treatment). RESULTS: Sixty patients (mean age:72 years) were prospectively treated with bezlotoxumab plus anti-Clostridioides antibiotic therapy. Vancomycin (48 patients) and fidaxomicin (12 patients) were prescribed for CDI treatment, and bezlotoxumab was administered at a mean of 4.2 (SD:2.1) days from the beginning of therapy. Recurrence occurred in nine out of 54 (16.7%) evaluable patients at 8 weeks. Forty bezlotoxumab-treated patients were matched with 69 non-bezlotoxumab-treated patients. Recurrence rates at 12 weeks were 15.0% (6/40) in bezlotoxumab-treated patients vs. 23.2% (16/69) in non-bezlotoxumab-treated patients (OR:0.58 [0.20-1.65]). No adverse effects were observed related to bezlotoxumab infusion. Only one of 9 patients with previous heart failure developed heart failure. CONCLUSION: We observed that patients treated with bezlotoxumab in a real-world setting during a first episode of CDI having high risk of recurrence, presented low rate of recurrence. However, a significant difference in recurrence could not be proved in comparison to the controls. We did not detect any other safety concerns.

The effect of antibiotic therapy for Clostridioides difficile infection on mortality and other patient-relevant outcomes: a systematic review and meta-analysis.

BACKGROUND: Current practice guidelines favour fidaxomicin over vancomycin and exclude metronidazole from the recommended standard regimen for Clostridioides difficile infection (CDI), based on lower recurrence rates with fidaxomicin, giving little weight to mortality or the clinical implications of recurrences. OBJECTIVES: To compile the effects of metronidazole, glycopeptides (vancomycin or teicoplanin), and fidaxomicin for CDI on mortality and other patient-relevant outcomes. DATA SOURCES: PubMed, the Cochrane Library, ClinicalTrials.gov, conference proceedings, and Google Scholar, until August 2023. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials (RCTs). PARTICIPANTS: Adult patients experiencing primary or recurrent CDI. INTERVENTIONS: Glycopeptides versus fidaxomicin or metronidazole (comparators). ASSESSMENT OF RISK OF BIAS: We used the Risk of Bias 2 (RoB 2) tool for randomized trials, focusing on the outcome of all-cause mortality. METHODS OF DATA SYNTHESIS: Random effects meta-analyses were performed for dichotomous outcomes. Outcomes were summarized preferentially for all randomly assigned patients. RESULTS: Thirteen trials were included. There was no significant difference in all-cause mortality (risk ratio [RR] < 1 favouring the comparator) between vancomycin and fidaxomicin (RR 0.86, 95% CI 0.64-1.14, 8 RCTs, 1951 patients) or metronidazole (RR 0.78, 95% CI 0.46-1.32, 4 RCTs, 808 patients), with low and very low certainty of evidence, respectively. No significant difference in initial treatment failure between fidaxomicin and vancomycin was found, however, initial treatment failure was higher with metronidazole (RR 1.58, 95% CI 1.10-2.27, 5 RCTs, 843 patients). No study reported on symptomatic recurrence necessitating re-treatment among all randomly assigned patients. Among initially cured patients, symptomatic recurrence necessitating re-treatment was lower with fidaxomicin than with vancomycin (RR 0.54, 95% CI 0.42-0.71, 6 RCTs, 1617 patients). None of the studies reported on other CDI complications or the burden of infection on daily activities. CONCLUSIONS: Setting patient-relevant outcomes for CDI independently of the RCT definitions and results might lead to less confidence in the guidance for CDI management.

An Open-Label, Randomized Trial Comparing Fidaxomicin With Oral Vancomycin for the Treatment of Clostridioides difficile Infection in Hospitalized Patients Receiving Concomitant Antibiotics for Concurrent Infections.

BACKGROUND: Recurrent Clostridioides difficile infection (rCDI) occurs frequently, and concomitant antibiotic (CA) during the initial episode for treatment of non-CDI is a major risk factor. We sought to address the comparative efficacy of fidaxomicin versus vancomycin in the setting of CA during the initial CDI episode. METHODS: We conducted a randomized, controlled, open-label trial at 2 hospitals in Ann Arbor, Michigan. We consecutively consented and enrolled hospitalized patients ≥18 years old with diarrhea, a positive test for C. difficile, and ≥1 qualifying CA. Complicated CDI, CDI treatment for >24 hours prior to enrollment, and planned long-term (>12 weeks) CA use were notable exclusions. Clinical cure was defined as resolution of diarrhea for 2 consecutive days maintained until 2 days after therapy, and rCDI as recurrent diarrhea with positive testing ≤30 days after initial treatment. Patients were randomized to fidaxomicin or vancomycin. RESULTS: Baseline characteristics were similar in the 2 groups of 144 patients. Rates of clinical cure (73% vs 62.9%, P = .195) and rCDI (3.3% vs 4.0%; P > .99) were similar for fidaxomicin and vancomycin in the intention-to-treat and per-protocol cohorts, respectively. Only 4 patients developed rCDI. CONCLUSIONS: In this study of patients with CDI receiving CA, a numerically higher proportion were cured with fidaxomicin versus vancomycin, but this result did not reach statistical significance. Overall recurrence was lower than anticipated in both arms compared with previous studies that did not extend duration of CDI treatment during CA. CLINICAL TRIALS REGISTRATION: www.clinicaltrials.gov (NCT02692651).

Clostridioides difficile infections; new treatments and future perspectives.

PURPOSE OF REVIEW: As a significant cause of global morbidity and mortality, Clostridioides difficile infections (CDIs) are listed by the Centres for Disease Control and prevention as one of the top 5 urgent threats in the USA. CDI occurs from gut microbiome dysbiosis, typically through antibiotic-mediated disruption; however, antibiotics are the treatment of choice, which can result in recurrent infections. Here, we highlight new treatments available and provide a perspective on different classes of future treatments. RECENT FINDINGS: Due to the reduced risk of disease recurrence, the microbiome-sparing antibiotic Fidaxomicin has been recommended as the first-line treatment for C. difficile infection. Based on the success of faecal microbiota transplantations (FMT) in treating CDI recurrence, defined microbiome biotherapeutics offer a safer and more tightly controlled alterative as an adjunct to antibiotic therapy. Given the association between antibiotic-mediated dysbiosis of the intestinal microbiota and the recurrence of CDI, future prospective therapies aim to reduce the dependence on antibiotics for the treatment of CDI. SUMMARY: With current first-in-line antibiotic therapy options associated with high levels of recurrent CDI, the availability of new generation targeted therapeutics can really impact treatment success. There are still unknowns about the long-term implications of these new CDI therapeutics, but efforts to expand the CDI treatment toolbox can offer multiple solutions for clinicians to treat this multifaceted infectious disease to reduce patient suffering.

Ribotypes and antimicrobial susceptibility profiles of clinical Clostridioides difficile isolates: A multicenter, laboratory-based surveillance in Taiwan, 2019-2021.

BACKGROUND: The clinical burden of Clostridioides difficile infections (CDIs) remains substantial globally. This study aimed to investigate the ribotypes (RTs) and antimicrobial susceptibility of C. difficile isolates collected in Taiwan. METHODS: C. difficile isolates were prospectively collected from four medical centers in Taiwan from 2019 to 2021. In a reference laboratory, in vitro susceptibility to clindamycin, moxifloxacin, metronidazole, vancomycin, fidaxomicin, and rifaximin were tested, and ribotyping was conducted to determine their genetic diversity. RESULTS: A total of 568 C. difficile isolates were included. Metronidazole resistance was not observed, and the susceptibility rate of vancomycin was 99.5 %. Clindamycin showed poor activity against these isolates, with a resistance rate of 74.8 %. Fidaxomicin exhibited potent activity and 97.4 % of isolates were inhibited at 0.25 µg/mL. Rifaximin MIC90 increased from 0.015 µg/mL in 2019 to 0.03 µg/mL in 2020 and 2021. Of 40 RTs identified, two predominant RTs were RT 078/126 (78, 14 %) and 014/020 (76, 13 %). RT 017, traditional harboring truncated tcdA, accounted for 3 % (20 isolates) and there was no isolate belonging to RT 027. The proportions of RT 078 increased from 11.2 % in 2019 to 17.1 % in 2021, and the predominance of RT 078/126 was more evident in central Taiwan. CONCLUSIONS: Vancomycin, fidaxomicin, and metronidazole remain in vitro effective against clinical C. difficile isolates in Taiwan. The reservoirs and genetic relatedness of two major RTs with zoonotic potentials, RT 078/126 and 014/020, warrant further investigations.