Vancomycin Versus Metronidazole for Nonsevere Clostridioides difficile Infection: Are the Data Adequate to Change Practice?

2019 ◽  
Vol 53 (8) ◽  
pp. 845-852
Author(s):  
Katherine V. Sarna ◽  
Alan E. Gross
Keyword(s):  
Cost Effectiveness ◽  
Clinical Studies ◽  
Statistical Significance ◽  
Outcome Data ◽  
Tolerability Profile ◽  
National Guidelines ◽  
Clostridioides Difficile ◽  
Clostridioides Difficile Infection ◽  
Meta Analyses ◽  
Oral Metronidazole

Objective: To compare oral metronidazole and vancomycin for the treatment of mild-to-moderate Clostridioides difficile infection (mmCDI). Data Sources: A MEDLINE literature search (inception to November 2018) was performed using the search terms metronidazole, vancomycin, and Clostridium/Clostridioides difficile. Additional references were identified from a review of literature citations. Study Selection and Data Extraction: All English-language clinical studies (interventional and observational), meta-analyses, and cost-effectiveness analyses comparing the efficacy of metronidazole and vancomycin for mmCDI were evaluated. Data Synthesis: Nine clinical studies, 5 meta-analyses, and 1 cost-effectiveness analysis provided comparative data for metronidazole and vancomycin for the treatment of mmCDI. Improved treatment response with vancomycin as compared with metronidazole in adults with mmCDI reached statistical significance in a few studies; albeit, most studies and pooled analyses have results that numerically favor vancomycin. Furthermore, the cost per case treated appears to be lower with vancomycin compared with metronidazole based on data from hospitalized patients. Relevance to Patient Care and Clinical Practice: Recent updates to national guidelines now give preference to vancomycin over metronidazole for mmCDI; however, this has been a source of controversy. This review provides an appraisal of direct and indirect comparisons of oral metronidazole and vancomycin for mmCDI, including recent literature published after the release of current guidelines. Conclusions: The available outcome data suggesting that vancomycin is more effective than metronidazole, combined with the more favorable pharmacokinetics, safety, and tolerability profile of vancomycin, provide adequate clinical rationale for the preferential use of this agent for the treatment of mmCDI.

scholarly journals Oral Vancomycin May Be Associated With Earlier Symptom Resolution Than Metronidazole for Hospitalized Children With Nonsevere Clostridioides difficile Infections

2019 ◽  
Vol 6 (12) ◽  
Author(s):  
Jianyi Yin ◽  
Larry K Kociolek ◽  
Rebecca G Same ◽  
Alice J Hsu ◽  
Joe Amoah ◽  
...  
Keyword(s):  
Clinical Symptoms ◽  
Propensity Score Analysis ◽  
Hospitalized Children ◽  
National Guidelines ◽  
Oral Vancomycin ◽  
Eligibility Criteria ◽  
Laxative Use ◽  
Clostridioides Difficile ◽  
Clostridioides Difficile Infection ◽  
Oral Metronidazole

Abstract Objective National guidelines recommend oral vancomycin over oral metronidazole as first-line treatment for nonsevere Clostridioides difficile infection (CDI) in adults. Guidelines recommend metronidazole for children with nonsevere CDI, emphasizing that comparative effectiveness studies comparing the relative efficacy of vancomycin and metronidazole are lacking in children. Method We conducted an observational study of hospitalized children with nonsevere CDI treated with metronidazole versus vancomycin using an inverse probability of treatment-weighted propensity-score analysis. All of the following criteria had to be present for children with positive CDI testing for study eligibility: (1) ≥3 new-onset unformed stools within a 24-hour period; (2) 2–17 years of age; (3) hospitalization for ≥48 hours for CDI; (4) no laxative use ≤48 hours; (5) no alternate etiology for diarrhea; (6) no previous episode of CDI ≤3 months; (7) no concurrent non-CDI–targeted antibiotic therapy, and (8) no severe or fulminant CDI. Results One hundred ninety-two patients met eligibility criteria; 141 (73.4%) received oral metronidazole and 51 (26.6%) children received oral vancomycin. Baseline characteristics were similar between the 2 groups in the weighted cohort. Of 141 patients, 101 (71.7%) children receiving metronidazole had clinical improvement by day 5, whereas 44 of 51 (86.3%) cases resolved with vancomycin (odds ratio, 0.40; 95% confidence interval, 0.17–0.97; P = .04). The odds of CDI recurrence within 12 weeks were similar between the groups. Conclusions Our study suggests that children with nonsevere CDI have earlier resolution of clinical symptoms when prescribed vancomycin compared with metronidazole. Large interventional studies are necessary to evaluate the reproducibility of our findings.

scholarly journals 1042. Safety of Investigational Microbiota-Based Live Biotherapeutic RBX2660 in Individuals with Recurrent Clostridioides difficile Infection: Data from Five Prospective Clinical Studies

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S611-S611
Author(s):  
Tricia Braun ◽  
Beth Guthmueller ◽  
Adam J Harvey
Keyword(s):  
Clinical Studies ◽  
Ad Hoc ◽  
Safety Data ◽  
Standard Of Care ◽  
Oral Antibiotic ◽  
Open Label ◽  
Two Phase ◽  
Oral Antibiotic Therapy ◽  
Clostridioides Difficile ◽  
Clostridioides Difficile Infection

Abstract Background Microbiota-based treatments have shown promise to reduce recurrence, morbidity, and mortality for recurrent Clostridioides difficile infections (rCDI), but consistent and reliable safety data are needed to support regulatory approvals and broaden patient access. Here we provide cumulative safety data from 5 prospective clinical studies evaluating RBX2660—a standardized, microbiota-based investigational live biotherapeutic—for reducing rCDI. Methods This analysis included three Phase 2 (PUNCH CD, PUNCH CD2, PUNCH CD Open Label) and two Phase 3 trials (PUNCH CD3, PUNCH CD3-OLS ad hoc analysis). Participants were ≥18 years old with documented rCDI who completed standard-of-care oral antibiotic therapy prior to treatment with RBX2660. PUNCH CD3-OLS allowed participants with comorbidities of irritable bowel syndrome (IBS) or inflammatory bowel disease (IBD). Depending on the trial, assigned study treatment was 1 or 2 doses of RBX2660 (or placebo), administered rectally. Participants whose CDI recurred within 8 weeks were eligible for additional RBX2660 treatment. Treatment-emergent adverse events (TEAEs) were recorded for at least 6 months following last study treatment; CD2 and CD Open Label recorded TEAEs for 24 months. Results Among 620 participants who received at least one RBX2660 dose (assigned treatment or after recurrence), 324 (52.3%) received 1, 270 (43.5%) received 2, 14 (2.3%) received 3, and 12 (1.9%) received 4. 83 participants received blinded placebo only. A total of 1980 TEAEs were reported from 432 (69.7%) RBX2660-treated participants, compared to 174 TEAEs in 50 (60.2%) placebo-only treated participants. Most TEAEs were mild or moderate in severity, with diarrhea common in all treatment groups. No potentially life-threatening TEAEs were considered related to RBX2660. Study discontinuation due to TEAEs was minimal (< 1%) with none related to RBX2660. There were no reported infections for which the causative pathogen was traced to RBX2660. Conclusion Across five clinical studies with consistent investigational product, RBX2660 was well-tolerated in rCDI participants. In aggregate, this data provides compelling and consistent safety data for RBX2660. Disclosures Tricia Braun, PharmD, Rebiotix, a Ferring Company (Employee) Beth Guthmueller, AS, Rebiotix Inc, A Ferring Company (Employee) Adam J. Harvey, PhD, Rebiotix, A Ferring Company (Employee)

scholarly journals How robust are findings of pairwise and network meta-analysis in the presence of missing participant outcome data?

BMC Medicine ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Loukia M. Spineli ◽  
Chrysostomos Kalyvas ◽  
Katerina Papadimitropoulou
Keyword(s):  
Sensitivity Analysis ◽  
Systematic Reviews ◽  
Statistical Significance ◽  
Empirical Studies ◽  
Outcome Data ◽  
Sensitivity Analyses ◽  
Logarithmic Scale ◽  
Primary Analysis ◽  
Current Sensitivity ◽  
Meta Analyses

Abstract Background To investigate the prevalence of robust conclusions in systematic reviews addressing missing (participant) outcome data via a novel framework of sensitivity analyses and examine the agreement with the current sensitivity analysis standards. Methods We performed an empirical study on systematic reviews with two or more interventions. Pairwise meta-analyses (PMA) and network meta-analyses (NMA) were identified from empirical studies on the reporting and handling of missing outcome data in systematic reviews. PMAs with at least three studies and NMAs with at least three interventions on one primary outcome were considered eligible. We applied Bayesian methods to obtain the summary effect estimates whilst modelling missing outcome data under the missing-at-random assumption and different assumptions about the missingness mechanism in the compared interventions. The odds ratio in the logarithmic scale was considered for the binary outcomes and the standardised mean difference for the continuous outcomes. We calculated the proportion of primary analyses with robust and frail conclusions, quantified by our proposed metric, the robustness index (RI), and current sensitivity analysis standards. Cohen’s kappa statistic was used to measure the agreement between the conclusions derived by the RI and the current sensitivity analysis standards. Results One hundred eight PMAs and 34 NMAs were considered. When studies with a substantial number of missing outcome data dominated the analyses, the number of frail conclusions increased. The RI indicated that 59% of the analyses failed to demonstrate robustness compared to 39% when the current sensitivity analysis standards were employed. Comparing the RI with the current sensitivity analysis standards revealed that two in five analyses yielded contradictory conclusions concerning the robustness of the primary analysis results. Conclusions Compared with the current sensitivity analysis standards, the RI offers an explicit definition of similar results and does not unduly rely on statistical significance. Hence, it may safeguard against possible spurious conclusions regarding the robustness of the primary analysis results.

scholarly journals Cost-effectiveness of Treatment Regimens for Clostridioides difficile Infection: An Evaluation of the 2018 Infectious Diseases Society of America Guidelines

2019 ◽  
Vol 70 (5) ◽  
pp. 754-762 ◽  
Author(s):  
Radha Rajasingham ◽  
Eva A Enns ◽  
Alexander Khoruts ◽  
Byron P Vaughn
Keyword(s):  
Cost Effectiveness ◽  
Infectious Diseases ◽  
Fecal Microbiota Transplantation ◽  
Cost Effective ◽  
Fecal Microbiota ◽  
Treatment Regimens ◽  
Clostridioides Difficile ◽  
Life Years ◽  
Clostridioides Difficile Infection ◽  
First Recurrence

Abstract Background In 2018, the Infectious Diseases Society of America (IDSA) published guidelines for diagnosis and treatment of Clostridioides (formerly Clostridium) difficile infection (CDI). However, there is little guidance regarding which treatments are cost-effective. Methods We used a Markov model to simulate a cohort of patients presenting with an initial CDI diagnosis. We used the model to estimate the costs, effectiveness, and cost-effectiveness of different CDI treatment regimens recommended in the recently published 2018 IDSA guidelines. The model includes stratification by the severity of the initial infection, and subsequent likelihood of cure, recurrence, mortality, and outcomes of subsequent recurrences. Data sources were taken from IDSA guidelines and published literature on treatment outcomes. Outcome measures were discounted quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs). Results Use of fidaxomicin for nonsevere initial CDI, vancomycin for severe CDI, fidaxomicin for first recurrence, and fecal microbiota transplantation (FMT) for subsequent recurrence (strategy 44) cost an additional $478 for 0.009 QALYs gained per CDI patient, resulting in an ICER of $31 751 per QALY, below the willingness-to-pay threshold of $100 000/QALY. This is the optimal, cost-effective CDI treatment strategy. Conclusions Metronidazole is suboptimal for nonsevere CDI as it is less beneficial than alternative strategies. The preferred treatment regimen is fidaxomicin for nonsevere CDI, vancomycin for severe CDI, fidaxomicin for first recurrence, and FMT for subsequent recurrence. The most effective treatments, with highest cure rates, are also cost-effective due to averted mortality, utility loss, and costs of rehospitalization and/or further treatments for recurrent CDI.

scholarly journals Bezlotoxumab for Preventing Recurrent Clostridioides difficile Infection: A Narrative Review from Pathophysiology to Clinical Studies

2020 ◽  
Vol 9 (3) ◽  
pp. 481-494 ◽  
Author(s):  
Daniele Roberto Giacobbe ◽  
Silvia Dettori ◽  
Stefano Di Bella ◽  
Antonio Vena ◽  
Guido Granata ◽  
...  
Keyword(s):  
Clinical Studies ◽  
Narrative Review ◽  
Clostridioides Difficile ◽  
Clostridioides Difficile Infection

scholarly journals 2423. Cost-effectiveness of core and emerging infection control interventions to reduce hospital-onset Clostridioides difficile infection: An agent-based simulation modeling approach

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S837-S837
Author(s):  
Oguzhan Alagoz ◽  
Anna K Barker ◽  
Elizabeth Scaria ◽  
Nasia Safdar
Keyword(s):  
Cost Effectiveness ◽  
Hand Hygiene ◽  
Infection Control ◽  
Hospital Setting ◽  
Multiple Infection ◽  
Agent Based ◽  
Emerging Infection ◽  
Clostridioides Difficile ◽  
Clostridioides Difficile Infection ◽  
The Cost

Abstract Background Multiple infection control interventions have been recommended to reduce hospital-onset Clostridioides difficile infection (C. difficile; HO-CDI), including contact isolation, environmental disinfection, and hand hygiene. These interventions have differential effects on reducing HO-CDI that change for each hospital setting. In the context of today’s constrained resources, with trade-offs a necessary part of any prevention plan, infection control personnel need information regarding intervention cost-effectiveness that is tailored to their unique hospital setting. Methods We evaluated the cost-effectiveness of nine infection control interventions and eight multiple-intervention bundles using our group’s agent-based model of C. difficile transmission. This previously developed model represents a general 200-bed acute-care adult hospital. Effectiveness was measured from the hospital perspective in terms of both quality-adjusted life years (QALYs) and HO-CDIs. Results Six interventions reduced cost while increasing QALYs and averting HO-CDI, compared with baseline standard hospital practices: daily cleaning (saved an average of $407,854 and 36.8 QALYs annually in a 200-bed hospital), HCW hand hygiene ($181,767; 17.7 QALYs), patient hand hygiene ($25,700; 6.3 QALYs), terminal cleaning ($64,986; 12.8 QALYs), screening at admission ($9,083; 18.5 QALYs), and reducing patient transfers ($27,514; 3.1 QALYs). Adding patient hand hygiene to the HCW hand hygiene intervention was cost saving. When screening, HCW hand hygiene, and patient hand hygiene interventions were sequentially added to daily cleaning to form two, three, and four-pronged bundles, the incremental cost-effectiveness ratios for these additions were $26,588, $44,173, and $123,379 per QALY, respectively. Conclusion Using cost-effectiveness data, institutions may consider streamlining their infection control initiatives and prioritizing a smaller number of highly effective interventions. Our model could be used to evaluate the cost-effectiveness of existing core and emerging infection control interventions for specific hospital settings. Disclosures All authors: No reported disclosures.

scholarly journals SER-109, an Investigational Microbiome Drug to Reduce Recurrence After Clostridioides difficile Infection: Lessons Learned From a Phase 2 Trial

2020 ◽  
Author(s):  
Barbara H McGovern ◽  
Christopher B Ford ◽  
Matthew R Henn ◽  
Darrell S Pardi ◽  
Sahil Khanna ◽  
...  
Keyword(s):  
Bile Acid ◽  
Statistical Significance ◽  
Standard Of Care ◽  
Lessons Learned ◽  
Metagenomic Sequencing ◽  
Double Blind ◽  
Secondary Bile Acid ◽  
Phase 2 Trial ◽  
Clostridioides Difficile ◽  
Clostridioides Difficile Infection

Abstract Background Recurrent Clostridioides difficile infection (rCDI) is associated with loss of microbial diversity and microbe-derived secondary bile acids, which inhibit C. difficile germination and growth. SER-109, an investigational microbiome drug of donor-derived, purified spores, reduced recurrence in a dose-ranging, phase (P) 1 study in subjects with multiple rCDIs. Methods In a P2 double-blind trial, subjects with clinical resolution on standard-of-care antibiotics were stratified by age (< or ≥65 years) and randomized 2:1 to single-dose SER-109 or placebo. Subjects were diagnosed at study entry by PCR or toxin testing. Safety, C. difficile–positive diarrhea through week 8, SER-109 engraftment, and bile acid changes were assessed. Results 89 subjects enrolled (67% female; 80.9% diagnosed by PCR). rCDI rates were lower in the SER-109 arm than placebo (44.1% vs 53.3%) but did not meet statistical significance. In a preplanned analysis, rates were reduced among subjects ≥65 years (45.2% vs 80%, respectively; RR, 1.77; 95% CI, 1.11–2.81), while the <65 group showed no benefit. Early engraftment of SER-109 was associated with nonrecurrence (P < .05) and increased secondary bile acid concentrations (P < .0001). Whole-metagenomic sequencing from this study and the P1 study revealed previously unappreciated dose-dependent engraftment kinetics and confirmed an association between early engraftment and nonrecurrence. Engraftment kinetics suggest that P2 dosing was suboptimal. Adverse events were generally mild to moderate in severity. Conclusions Early SER-109 engraftment was associated with reduced CDI recurrence and favorable safety was observed. A higher dose of SER-109 and requirements for toxin testing were implemented in the current P3 trial. Clinical Trials Registration NCT02437487, https://clinicaltrials.gov/ct2/show/NCT02437487?term=SER-109&draw= 2&rank=4.

scholarly journals Cost-effectiveness of bezlotoxumab and fidaxomicin for initial Clostridioides difficile infection

2021 ◽  
Author(s):  
Jiahe Chen ◽  
Cynthia L. Gong ◽  
Matthew M. Hitchcock ◽  
Marisa Holubar ◽  
Stanley Deresinski ◽  
...  
Keyword(s):  
Cost Effectiveness ◽  
Clostridioides Difficile ◽  
Clostridioides Difficile Infection

scholarly journals Risk factors and treatment outcomes of severe Clostridioides difficile infection in Singapore

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
H. L. Tay ◽  
A. Chow ◽  
T. M. Ng ◽  
D. C. Lye
Keyword(s):  
Risk Factors ◽  
Treatment Outcomes ◽  
Apache Ii Score ◽  
Reactive Protein ◽  
Clostridioides Difficile ◽  
Major Complications ◽  
Clostridioides Difficile Infection ◽  
Independent Risk Factors ◽  
Complications And Mortality ◽  
Oral Metronidazole

Abstract Severe Clostridioides difficile infection (CDI) is associated with poorer outcomes. We aimed to identify risk factors and treatment outcomes of severe CDI. This was a retrospective cohort study. Eligible patients from January to December 2012 were recruited. Severity definitions were in accordance with SHEA/IDSA 2010 guideline. Treatment outcomes were (1) diarrhoea persistence, (2) CDI recurrence, (3) major complications despite treatment and (4) 30-day mortality. Two hundred and seventy-two patients were included and 40% had severe CDI. High APACHE II score (aOR 1.112, 95% CI 1.014–1.219; p < 0.05), high C-reactive protein (aOR 1.011; 95% CI 1.004–1.019; p < 0.01) and carbapenem usage in past 90 days (aOR 3.259; 95% CI 1.105–9.609; p < 0.05) were independent risk factors of severe CDI. Majority received oral metronidazole as sole treatment (92.6% for mild-moderate, 83.9% for severe, 77% for severe-complicated). Diarrhoea persistence was 32% versus 50% (p < 0.01), CDI recurrence 16.6% versus 16.5% (p > 0.05), major complications 1.2% versus 11% (p < 0.001) and 30-day mortality 7.4% versus 20.2% (p < 0.01) in mild-moderate CDI and severe CDI groups respectively. Oral metronidazole for severe CDI was associated with persistent diarrhoea, major complications and mortality. Risk factors for severe CDI can guide doctors in diagnosing severe CDI earlier and instituting oral vancomycin treatment to improve outcomes from severe CDI.

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