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Mark H Wilcox - One of the best experts on this subject based on the ideXlab platform.
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in vitro activities of mcb3681 and eight comparators against clostridium difficile isolates with known ribotypes and diverse geographical spread
Antimicrobial Agents and Chemotherapy, 2017Co-Authors: Jane Freeman, Jonathan Vernon, Sally Pilling, Mark H WilcoxAbstract:Treatments for Clostridium difficile infection remain limited, despite the introduction of Fidaxomicin, and development of new agents is necessary. We determined the in vitro susceptibilities of 199 prevalent or emerging Clostridium difficile PCR ribotypes to MCB3681, a novel investigational quinolonyl-oxazolidinone, and 8 comparators (metronidazole, vancomycin, Fidaxomicin, moxifloxacin, ciprofloxacin, clindamycin, tigecycline, and linezolid). MCB3681 showed good activity against C. difficile with no evidence of MCB3681 resistance in isolates showing either moxifloxacin or linezolid resistance or both moxifloxacin and linezolid resistance.
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association of Fidaxomicin with c difficile spores effects of persistence on subsequent spore recovery outgrowth and toxin production
PLOS ONE, 2016Co-Authors: Caroline H Chilton, Mark H Wilcox, Christopher Longshaw, Grace S Crowther, Helen AshwinAbstract:Background We have previously shown that Fidaxomicin instillation prevents spore recovery in an in-vitro gut model, whereas vancomycin does not. The reasons for this are unclear. Here, we have investigated persistence of Fidaxomicin and vancomycin on C. difficile spores, and examined post-antibiotic exposure spore recovery, outgrowth and toxin production. Methods Prevalent UK C. difficile ribotypes (n = 10) were incubated with 200mg/L Fidaxomicin, vancomycin or a non-antimicrobial containing control for 1 h in faecal filtrate or Phosphate Buffered Saline. Spores were washed three times with faecal filtrate or phosphate buffered saline, and residual spore-associated antimicrobial activity was determined by bioassay. For three ribotypes (027, 078, 015), antimicrobial-exposed, faecal filtrate-washed spores and controls were inoculated into broth. Viable vegetative and spore counts were enumerated on CCEYL agar. Percentage phase bright spores, phase dark spores and vegetative cells were enumerated by phase contrast microscopy at 0, 3, 6, 24 and 48 h post-inoculation. Toxin levels (24 and 48h) were determined by cell cytotoxicity assay. Results Fidaxomicin, but not vancomycin persisted on spores of all ribotypes following washing in saline (mean = 10.1mg/L; range = 4.0-14mg/L) and faecal filtrate (mean = 17.4mg/L; 8.4–22.1mg/L). Outgrowth and proliferation rates of vancomycin-exposed spores were similar to controls, whereas Fidaxomicin-exposed spores showed no vegetative cell growth after 24 and 48 h. At 48h, toxin levels averaged 3.7 and 3.3 relative units (RU) in control and vancomycin-exposed samples, respectively, but were undetectable in Fidaxomicin-exposed samples. Conclusion Fidaxomicin persists on C. difficile spores, whereas vancomycin does not. This persistence prevents subsequent growth and toxin production in vitro. This may have implications on spore viability, thereby impacting CDI recurrence and transmission rates.
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susceptibility of clostridium difficile isolates of varying antimicrobial resistance phenotypes to smt19969 and 11 comparators
Antimicrobial Agents and Chemotherapy, 2016Co-Authors: Jane Freeman, Jonathan Vernon, Richard Vickers, Mark H WilcoxAbstract:We determined the in vitro activity of SMT19969 and 11 comparators, including metronidazole, vancomycin, and Fidaxomicin, against 107 C. difficile isolates of different antimicrobial resistance phenotypes. Fidaxomicin and SMT19969 were the most active. The Fidaxomicin and SMT19969 geometric mean MICs were highest in ribotypes known to show multiple resistance. Coresistance to linezolid and moxifloxacin was evident in ribotypes 001, 017, 027, and 356. The high-level ceftriaxone resistance in ribotypes 356 and 018 was location linked.
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efficacy of alternative Fidaxomicin dosing regimens for treatment of simulated clostridium difficile infection in an in vitro human gut model
Journal of Antimicrobial Chemotherapy, 2015Co-Authors: Caroline H Chilton, Mark H Wilcox, Sharie L Todhunter, Christopher Longshaw, Grace S Crowther, Helen Ashwin, Andreas KarasAbstract:Background: Fidaxomicin treatment reduces the risk of recurrent Clostridium difficile infection (CDI) compared with vancomycin. Extending duration of Fidaxomicin therapy may further reduce recurrence. We compared the efficacy of four extended Fidaxomicin regimens in an in vitro model of CDI. Methods: Four gut models were primed with human faeces, spiked with C. difficile spores (PCR ribotype 027) and clindamycin instilled (33.9 mg/L, four-times daily, 7 days) to induce simulated CDI. Four extended Fidaxomicin treatment regimens were evaluated: model 1, 20 days, 200 mg/L twice daily; model 2, 5 days 200 mg/L twice daily, 5 days rest, 5 days 200 mg/L twice daily; model 3, 5 days 200 mg/L twice daily, 5 days rest, 10 days 200 mg/L once daily; and model 4, 5 days 200 mg/L twice daily, 20 days 200 mg/L once every other day. C. difficile populations, toxin, gut microbiota and antimicrobial levels were monitored daily. Results: All Fidaxomicin regimens successfully resolved simulated CDI without recurrence. Five days of Fidaxomicin instillation was barely sufficient to resolve CDI (models 2–4). A second pulse or tapered dosing further reduced C. difficile and toxin detection. All regimens were sparing of microbiota, affecting only enterococci and bifidobacteria. Pulsed or tapered regimens allowed greater bifidobacteria recovery than the extended (20 day) regimen. Bioactive Fidaxomicin persisted throughout the experiment in all models at concentrations inhibitory to C. difficile. Conclusions: Pulsed or tapered Fidaxomicin regimens may enhance suppression of C. difficile whilst allowing microbiota recovery; clinical studies are required to ascertain the potential of this approach in further reducing recurrent CDI.
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pan european longitudinal surveillance of antibiotic resistance among prevalent clostridium difficile ribotypes
Clinical Microbiology and Infection, 2015Co-Authors: Jane Freeman, Jonathan Vernon, Kirsti Morris, Scott Nicholson, Sharie L Todhunter, Christopher Longshaw, Mark H WilcoxAbstract:Clostridium difficile infection remains a major healthcare burden. Until the recent introduction of Fidaxomicin, antimicrobial treatments were limited to metronidazole and vancomycin. The emergence of epidemic C. difficile PCR ribotype 027 and its potential link to decreased antibiotic susceptibility highlight the lack of large-scale antimicrobial susceptibility and epidemiological data available. We report results of epidemiological and antimicrobial susceptibility investigations of C. difficile isolates collected prior to Fidaxomicin introduction, establishing important baseline data. Thirty-nine sites in 22 countries submitted a total of 953 C. difficile isolates for PCR ribotyping, toxin testing, and susceptibility testing to metronidazole, vancomycin, Fidaxomicin, rifampicin, moxifloxacin, clindamycin, imipenem, chloramphenicol, and tigecycline. Ninety-nine known ribotypes were identified. Ribotypes 027, 014, 001/072, and 078 were most frequently isolated in line with previous European studies. There was no evidence of resistance to Fidaxomicin, and reduced susceptibility to metronidazole and vancomycin was also scarce. Rifampicin, moxifloxacin, and clindamycin resistance (13%, 40%, and 50% of total isolates, respectively) were evident in multiple ribotypes. There was a significant correlation between lack of ribotype diversity and greater antimicrobial resistance (measured by cumulative resistance score). Well-known epidemic ribotypes 027 and 001/072 were associated with multiple antimicrobial resistance, but high levels of resistance were also observed, particularly in 018 and closely related emergent ribotype 356 in Italy. This raises the possibility of antimicrobial exposure as the underlying reason for their appearance, and highlights the need for ongoing epidemiological and antimicrobial resistance surveillance.
Oliver A Cornely - One of the best experts on this subject based on the ideXlab platform.
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extended pulsed Fidaxomicin versus vancomycin for clostridium difficile infection in patients aged 60 years extend analysis of cost effectiveness
Journal of Antimicrobial Chemotherapy, 2018Co-Authors: Oliver A Cornely, Simon D Goldenberg, Maureen Watt, Charles Mccrea, Enrico De NigrisAbstract:Objectives The randomized Phase IIIb/IV EXTEND trial showed that extended-pulsed Fidaxomicin significantly improved sustained clinical cure and reduced recurrence versus vancomycin in patients ≥60 years old with Clostridium difficile infection (CDI). Cost-effectiveness of extended-pulsed Fidaxomicin versus vancomycin as first-line therapy for CDI was evaluated in this patient population. Methods Clinical results from EXTEND and inputs from published sources were used in a semi-Markov treatment-sequence model with nine health states and a 1 year time horizon to assess costs and QALYs. The model was based on a healthcare system perspective (NHS and Personal Social Services) in England. Sensitivity analyses were performed. Results Patients receiving first-line extended-pulsed Fidaxomicin treatment had a 0.02 QALY gain compared with first-line vancomycin (0.6267 versus 0.6038 QALYs/patient). While total drug acquisition costs were higher for extended-pulsed Fidaxomicin than for vancomycin when used first-line (£1356 versus £260/patient), these were offset by lower total hospitalization costs (which also included treatment monitoring and community care costs; £10 815 versus £11 459/patient) and lower costs of managing adverse events (£694 versus £1199/patient), reflecting the lower incidence of CDI recurrence and adverse events with extended-pulsed Fidaxomicin. Extended-pulsed Fidaxomicin cost £53 less per patient than vancomycin over 1 year. The probability that first-line extended-pulsed Fidaxomicin was cost-effective at a willingness-to-pay threshold of £30 000/QALY was 76% in these patients. Conclusions While Fidaxomicin acquisition costs are higher than those of vancomycin, the observed reduced recurrence rate with extended-pulsed Fidaxomicin makes it a more effective and less costly treatment strategy than vancomycin for first-line treatment of CDI in older patients.
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clinical efficacy of Fidaxomicin compared with vancomycin and metronidazole in clostridium difficile infections a meta analysis and indirect treatment comparison
Journal of Antimicrobial Chemotherapy, 2014Co-Authors: Oliver A Cornely, Dilip Nathwani, C Ivanescu, Olatunji Odufoworasita, Peny Retsa, Isaac OdeyemiAbstract:Methods: A systematic literature review was conducted in July to August 2011 and updated in July 2013. For Fidaxomicin versus vancomycin, efficacy was evaluated using meta-analysis of data from two Phase III direct comparative studies (n¼1164). As there were no studies comparing Fidaxomicin and metronidazole, an indirect comparison was made using data from three vancomycin versus metronidazole studies (n ¼345), using the methodologyof Bucher et al. (J Clin Epidemiol 1997; 50: 683‐91). This provides an OR for the indirect comparison of Fidaxomicin versus metronidazole when direct evidence of Fidaxomicin versus vancomycin and vancomycin versus metronidazole is available. Results: Clinical cure rates were similar for Fidaxomicin and vancomycin; the OR (95% CI) was 1.17 (0.82, 1.66). Recurrence [0.47 (0.34, 0.65)] was significantly lower and sustained cure rates [1.75 (1.35, 2.27)] significantly higher for Fidaxomicin than vancomycin. Similar results were obtained in patient subgroups with severe CDI and with non-severe CDI. From the indirect comparison, the likelihood of recurrence [0.42 (0.18, 0.96)] and sustained cure [2.55 (1.44, 4.51)] were significantly improved for Fidaxomicin versus metronidazole. Again, similar results were obtained in those with severe and non-severe CDI. Conclusions: Fidaxomicin provides improved sustained cure rates in patients with CDI compared with vancomycin. An indirect comparison indicates that the same is also true for Fidaxomicin versus metronidazole. In view of these data, Fidaxomicin may be considered as first-line therapy for CDI.
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cost effectiveness analysis of Fidaxomicin versus vancomycin in clostridium difficile infection
Journal of Antimicrobial Chemotherapy, 2014Co-Authors: Dilip Nathwani, Oliver A Cornely, Peny Retsa, Anke Van Engen, O Odufoworasita, I A OdeyemiAbstract:Objectives: Fidaxomicin was non-inferior to vancomycin with respect to clinical cure rates in the treatment of Clostridium difficile infections (CDIs) in two Phase III trials, but was associated with significantly fewer recurrences than vancomycin. This economic analysis investigated the cost-effectiveness of Fidaxomicin compared with vancomycin in patients with severe CDI and in patients with their first CDI recurrence. Methods: A 1 year time horizon Markov model with seven health states was developed from the perspective of Scottish public healthcare providers. Model inputs for effectiveness, resource use, direct costs and utilities were obtained from published sources and a Scottish expert panel. The main model outcome was the incremental cost-effectiveness ratio (ICER), expressed as cost per quality-adjusted life year (QALY), for Fidaxomicin versus vancomycin; ICERs were interpreted using willingness-to-pay thresholds of £20000/QALY and £30000/QALY. One-way and probabilistic sensitivity analyses were performed. Results: Total costs were similar with Fidaxomicin and vancomycin in patients with severe CDI (£14515 and £14344, respectively) and in patients with a first recurrence (£16535 and £16926, respectively). Improvements in clinical outcomes with Fidaxomicin resulted in small QALY gains versus vancomycin (severe CDI, +0.010; patients with first recurrence, +0.019). Fidaxomicin was cost-effective in severe CDI (ICER £16529/QALY) and dominant (i.e. more effective and less costly) in patients with a first recurrence. The probability that Fidaxomicin was cost-effective at a willingness-to-pay threshold of £30000/QALYwas 60% for severe CDI and 68% in a first recurrence. Conclusions: Fidaxomicin is cost-effective in patients with severe CDI and in patients with a first CDI recurrence versus vancomycin.
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Fidaxomicin versus vancomycin for clostridium difficile infection meta analysis of pivotal randomized controlled trials
Clinical Infectious Diseases, 2012Co-Authors: Mark A Miller, Oliver A Cornely, Karl Weiss, Derrick W Crook, Sarah A Walker, Yin Kean, Roberto Esposito, Thomas J LouieAbstract:Two recently completed phase 3 trials (003 and 004) showed Fidaxomicin to be noninferior to vancomycin for curing Clostridium difficile infection (CDI) and superior for reducing CDI recurrences. In both studies, adults with active CDI were randomized to receive blinded Fidaxomicin 200 mg twice daily or vancomycin 125 mg 4 times a day for 10 days. Post hoc exploratory intent-to-treat (ITT) time-to-event analyses were undertaken on the combined study 003 and 004 data, using fixed-effects meta-analysis and Cox regression models. ITT analysis of the combined 003/004 data for 1164 patients showed that Fidaxomicin reduced persistent diarrhea, recurrence, or death by 40% (95% confidence interval [CI], 26%-51%; P < .0001) compared with vancomycin through day 40. A 37% (95% CI, 2%-60%; P = .037) reduction in persistent diarrhea or death was evident through day 12 (heterogeneity P = .50 vs 13-40 days), driven by 7 (1.2%) Fidaxomicin versus 17 (2.9%) vancomycin deaths at <12 days. Low albumin level, low eosinophil count, and CDI treatment preenrollment were risk factors for persistent diarrhea or death at 12 days, and CDI in the previous 3 months was a risk factor for recurrence (all P < .01). Fidaxomicin has the potential to substantially improve outcomes from CDI.
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treatment of first recurrence of clostridium difficile infection Fidaxomicin versus vancomycin
Clinical Infectious Diseases, 2012Co-Authors: Oliver A Cornely, Mark A Miller, Derrick W Crook, Thomas J Louie, Sherwood L GorbachAbstract:Recurrence of Clostridium difficile infection (CDI) occurs in approximately 25% of successfully treated patients. Two phase 3 randomized, double-blind trials were conducted at 154 sites in the United States, Canada, and Europe to compare Fidaxomicin vs vancomycin in treating CDI. Patients with CDI received Fidaxomicin 200 mg twice daily or vancomycin 125 mg 4 times daily for 10 days. The primary end point was clinical cure of CDI at end of treatment, and a secondary end point was recurrence during the 28 days following clinical cure. In all, 1164 subjects were enrolled, of which a subgroup of 128 in the per-protocol population had another recent episode of CDI prior to the CDI diagnosis at study enrollment. In the analysis of this subgroup, initial response to therapy was similar for both drugs (>90% cure). However, recurrence within 28 days occurred in 35.5% of patients treated with vancomycin and 19.7% of patients treated with Fidaxomicin (-15.8% difference; 95% confidence interval, -30.4% to -0.3%; P = .045). Early recurrence (within 14 days) was reported in 27% of patients treated with vancomycin and 8% of patients treated with Fidaxomicin (P = .003). In patients with a first recurrence of CDI, Fidaxomicin was similar to vancomycin in achieving a clinical response at end of therapy but superior in preventing a second recurrence within 28 days.
Simon D Goldenberg - One of the best experts on this subject based on the ideXlab platform.
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extended pulsed Fidaxomicin versus vancomycin for clostridium difficile infection in patients aged 60 years extend analysis of cost effectiveness
Journal of Antimicrobial Chemotherapy, 2018Co-Authors: Oliver A Cornely, Simon D Goldenberg, Maureen Watt, Charles Mccrea, Enrico De NigrisAbstract:Objectives The randomized Phase IIIb/IV EXTEND trial showed that extended-pulsed Fidaxomicin significantly improved sustained clinical cure and reduced recurrence versus vancomycin in patients ≥60 years old with Clostridium difficile infection (CDI). Cost-effectiveness of extended-pulsed Fidaxomicin versus vancomycin as first-line therapy for CDI was evaluated in this patient population. Methods Clinical results from EXTEND and inputs from published sources were used in a semi-Markov treatment-sequence model with nine health states and a 1 year time horizon to assess costs and QALYs. The model was based on a healthcare system perspective (NHS and Personal Social Services) in England. Sensitivity analyses were performed. Results Patients receiving first-line extended-pulsed Fidaxomicin treatment had a 0.02 QALY gain compared with first-line vancomycin (0.6267 versus 0.6038 QALYs/patient). While total drug acquisition costs were higher for extended-pulsed Fidaxomicin than for vancomycin when used first-line (£1356 versus £260/patient), these were offset by lower total hospitalization costs (which also included treatment monitoring and community care costs; £10 815 versus £11 459/patient) and lower costs of managing adverse events (£694 versus £1199/patient), reflecting the lower incidence of CDI recurrence and adverse events with extended-pulsed Fidaxomicin. Extended-pulsed Fidaxomicin cost £53 less per patient than vancomycin over 1 year. The probability that first-line extended-pulsed Fidaxomicin was cost-effective at a willingness-to-pay threshold of £30 000/QALY was 76% in these patients. Conclusions While Fidaxomicin acquisition costs are higher than those of vancomycin, the observed reduced recurrence rate with extended-pulsed Fidaxomicin makes it a more effective and less costly treatment strategy than vancomycin for first-line treatment of CDI in older patients.
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extended pulsed Fidaxomicin versus vancomycin for clostridium difficile infection in patients 60 years and older extend a randomised controlled open label phase 3b 4 trial
Lancet Infectious Diseases, 2017Co-Authors: Benoit Guery, Nicholas Adomakoh, Areti Georgopali, Simon D Goldenberg, Andreas Karas, Francesco Menichetti, Velijukka Anttila, Jose Maria Aguado, Karen Bisnauthsing, Gbenga KazeemAbstract:Summary Background Clostridium difficile infection causes severe complications and frequently recurs. An extended-pulsed Fidaxomicin regimen might facilitate sustained clinical cure by prolonging C difficile suppression and supporting gut microbiota recovery. We aimed to compare clinical outcomes of extended-pulsed Fidaxomicin with standard vancomycin. Methods In this randomised, controlled, open-label, superiority study, we recruited hospitalised adults aged 60 years and older with confirmed C difficile infection at 86 European hospitals. Patients were randomly assigned (1:1) using an interactive web response system to receive extended-pulsed Fidaxomicin (200 mg oral tablets, twice daily on days 1–5, then once daily on alternate days on days 7–25) or vancomycin (125 mg oral capsules, four times daily on days 1–10), stratified by baseline C difficile infection severity, cancer presence, age (≥75 years vs C difficile infection occurrences. The primary endpoint was sustained clinical cure 30 days after end of treatment (day 55 for extended-pulsed Fidaxomicin and day 40 for vancomycin), assessed in all randomised patients who met the inclusion criteria and received at least one dose of study medication (modified full analysis set). Adverse events were assessed in all patients who received at least one dose of study drug. The study is registered with ClinicalTrials.gov, number NCT02254967. Findings Between Nov 6, 2014, and May 5, 2016, 364 patients were enrolled and randomly assigned to receive extended-pulsed Fidaxomicin or vancomycin. 362 patients received at least one dose of study medication (181 in each group). 124 (70%) of 177 patients in the modified full analysis set receiving extended-pulsed Fidaxomicin achieved sustained clinical cure 30 days after end of treatment, compared with 106 (59%) of 179 patients receiving vancomycin (difference 11% [95% CI 1·0–20·7], p=0·030; odds ratio 1·62 [95% CI 1·04–2·54]). Incidence of treatment-emergent adverse events did not differ between extended-pulsed Fidaxomicin (121 [67%] of 181) and vancomycin (128 [71%] of 181) treatment arms. One death in the vancomycin arm was considered by the investigator to be related to study drug. Interpretation Extended-pulsed Fidaxomicin was superior to standard-dose vancomycin for sustained cure of C difficile infection, and, to our knowledge, extended-pulsed Fidaxomicin recurrence rates in this study are the lowest observed in a randomised clinical trial of antibiotic treatment for C difficile infection. Funding Astellas Pharma, Inc.
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reduction in clostridium difficile environmental contamination by hospitalized patients treated with Fidaxomicin
Journal of Hospital Infection, 2015Co-Authors: J S Biswas, Amita Patel, Jonathan A Otter, Paul Wade, William Newsholme, E Van Kleef, Simon D GoldenbergAbstract:Summary Fidaxomicin is sporicidal and may be associated with a reduced time to resolution of diarrhoea when used to treat patients with Clostridium difficile infection (CDI). This study investigated whether Fidaxomicin for treatment of all patients with CDI reduced C. difficile environmental contamination. Surfaces in the rooms of 66 hospitalized patients treated with metronidazole and/or vancomycin and 68 hospitalized patients treated with Fidaxomicin were sampled. Patients treated with Fidaxomicin were less likely to contaminate their environment (25/68, 36.8%) than patients treated with metronidazole and/or vancomycin (38/66 57.6%) ( P = 0.02). Treatment with Fidaxomicin was associated with reduced environmental contamination with C. difficile.
Derrick W Crook - One of the best experts on this subject based on the ideXlab platform.
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whole genome sequencing demonstrates that Fidaxomicin is superior to vancomycin for preventing reinfection and relapse of infection with clostridium difficile
The Journal of Infectious Diseases, 2014Co-Authors: David W Eyre, Jaime Seddon, Farah Babakhani, Sherwood L Gorbach, Derrick W Crook, David Griffiths, Carlos Del Ojo Elias, Tim E A Peto, Sarah A WalkerAbstract:Whole-genome sequencing was used to determine whether the reductions in recurrence of Clostridium difficile infection observed with Fidaxomicin in pivotal phase 3 trials occurred by preventing relapse of the same infection, by preventing reinfection with a new strain, or by preventing both outcomes. Paired isolates of C. difficile were available from 93 of 199 participants with recurrences (28 were treated with Fidaxomicin, and 65 were treated with vancomycin). Given C. difficile evolutionary rates, paired samples ≤2 single-nucleotide variants (SNVs) apart were considered relapses, paired samples >10 SNVs apart were considered reinfection, and those 3-10 SNVs apart (or without whole-genome sequences) were considered indeterminate in a competing risks survival analysis. Fidaxomicin reduced the risk of both relapse (competing risks hazard ratio [HR], 0.40 [95% confidence interval {CI}, .25-.66]; P = .0003) and reinfection (competing risks HR, 0.33 [95% CI, 0.11-1.01]; P = .05).
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Fidaxomicin attains high fecal concentrations with minimal plasma concentrations following oral administration in patients with clostridium difficile infection
Clinical Infectious Diseases, 2012Co-Authors: Pamela Sears, Mark A Miller, Derrick W Crook, Thomas J Louie, Karl WeissAbstract:Fidaxomicin has recently been approved for the treatment of Clostridium difficile infection (CDI). As part of phase III studies, plasma and fecal samples were analyzed for concentrations of Fidaxomicin and its metabolite, OP-1118. Plasma samples were collected before and after dose receipt on the first and last days of therapy, and fecal samples were collected on the last day of therapy. Samples were analyzed for Fidaxomicin and OP-1118 (metabolite), using validated liquid chromatography/tandem mass spectrometric methods. Plasma concentrations were low for both Fidaxomicin (mean [± standard deviation {SD}], 22.8 ± 26.7 ng/mL and 28.5 ± 33.4 ng/mL on the first and last days of therapy, respectively) and OP-1118 (mean [± SD], 44.5 ± 50.4 ng/mL and 85.6 ± 131 ng/mL, respectively). In contrast, fecal levels were >1000 µg/g for Fidaxomicin and >800 µg/g for OP-1118. Fidaxomicin mean fecal levels were >5000 times the minimum inhibitory concentration for C. difficile of 0.25 µg/mL.
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Fidaxomicin versus vancomycin for clostridium difficile infection meta analysis of pivotal randomized controlled trials
Clinical Infectious Diseases, 2012Co-Authors: Mark A Miller, Oliver A Cornely, Karl Weiss, Derrick W Crook, Sarah A Walker, Yin Kean, Roberto Esposito, Thomas J LouieAbstract:Two recently completed phase 3 trials (003 and 004) showed Fidaxomicin to be noninferior to vancomycin for curing Clostridium difficile infection (CDI) and superior for reducing CDI recurrences. In both studies, adults with active CDI were randomized to receive blinded Fidaxomicin 200 mg twice daily or vancomycin 125 mg 4 times a day for 10 days. Post hoc exploratory intent-to-treat (ITT) time-to-event analyses were undertaken on the combined study 003 and 004 data, using fixed-effects meta-analysis and Cox regression models. ITT analysis of the combined 003/004 data for 1164 patients showed that Fidaxomicin reduced persistent diarrhea, recurrence, or death by 40% (95% confidence interval [CI], 26%-51%; P < .0001) compared with vancomycin through day 40. A 37% (95% CI, 2%-60%; P = .037) reduction in persistent diarrhea or death was evident through day 12 (heterogeneity P = .50 vs 13-40 days), driven by 7 (1.2%) Fidaxomicin versus 17 (2.9%) vancomycin deaths at <12 days. Low albumin level, low eosinophil count, and CDI treatment preenrollment were risk factors for persistent diarrhea or death at 12 days, and CDI in the previous 3 months was a risk factor for recurrence (all P < .01). Fidaxomicin has the potential to substantially improve outcomes from CDI.
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treatment of first recurrence of clostridium difficile infection Fidaxomicin versus vancomycin
Clinical Infectious Diseases, 2012Co-Authors: Oliver A Cornely, Mark A Miller, Derrick W Crook, Thomas J Louie, Sherwood L GorbachAbstract:Recurrence of Clostridium difficile infection (CDI) occurs in approximately 25% of successfully treated patients. Two phase 3 randomized, double-blind trials were conducted at 154 sites in the United States, Canada, and Europe to compare Fidaxomicin vs vancomycin in treating CDI. Patients with CDI received Fidaxomicin 200 mg twice daily or vancomycin 125 mg 4 times daily for 10 days. The primary end point was clinical cure of CDI at end of treatment, and a secondary end point was recurrence during the 28 days following clinical cure. In all, 1164 subjects were enrolled, of which a subgroup of 128 in the per-protocol population had another recent episode of CDI prior to the CDI diagnosis at study enrollment. In the analysis of this subgroup, initial response to therapy was similar for both drugs (>90% cure). However, recurrence within 28 days occurred in 35.5% of patients treated with vancomycin and 19.7% of patients treated with Fidaxomicin (-15.8% difference; 95% confidence interval, -30.4% to -0.3%; P = .045). Early recurrence (within 14 days) was reported in 27% of patients treated with vancomycin and 8% of patients treated with Fidaxomicin (P = .003). In patients with a first recurrence of CDI, Fidaxomicin was similar to vancomycin in achieving a clinical response at end of therapy but superior in preventing a second recurrence within 28 days.
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Fidaxomicin versus vancomycin for infection with clostridium difficile in europe canada and the usa a double blind non inferiority randomised controlled trial
Lancet Infectious Diseases, 2012Co-Authors: Oliver A Cornely, Pamela Sears, Karl Weiss, Derrick W Crook, Roberto Esposito, Andre Poirier, Michael S Somero, Sherwood L GorbachAbstract:Summary Background Infection with Clostridium difficile is the primary infective cause of antibiotic-associated diarrhoea. We aimed to compare efficacy and safety of Fidaxomicin and vancomycin to treat patients with C difficile infection in Europe, Canada, and the USA. Methods In this multicentre, double-blind, randomised, non-inferiority trial, we enrolled patients from 45 sites in Europe and 41 sites in the USA and Canada between April 19, 2007, and Dec 11, 2009. Eligible patients were aged 16 years or older with acute, toxin-positive C difficile infection. Patients were randomly allocated (1:1) to receive oral Fidaxomicin (200 mg every 12 h) or oral vancomycin (125 mg every 6 h) for 10 days. The primary endpoint was clinical cure, defined as resolution of diarrhoea and no further need for treatment. An interactive voice-response system and computer-generated randomisation schedule gave a randomisation number and medication kit number for each patient. Participants and investigators were masked to treatment allocation. Non-inferiority was prespecified with a margin of 10%. Modified intention-to-treat and per-protocol populations were analysed. This study is registered with ClinicalTrials.gov, number NCT00468728. Findings Of 535 patients enrolled, 270 were assigned Fidaxomicin and 265 vancomycin. After 26 patients were excluded, 509 were included in the modified intention-to-treat (mITT) population. 198 (91·7%) of 216 patients in the per-protocol population given Fidaxomicin achieved clinical cure, compared with 213 (90·6%) of 235 given vancomycin, meeting the criterion for non-inferiority (one-sided 97·5% CI −4·3%). Non-inferiority was also shown for clinical cure in the mITT population, with 221 (87·7%) of 252 patients given Fidaxomicin and 223 (86·8%) of 257 given vancomycin cured (one-sided 97·5% CI −4·9%). In most subgroup analyses of the primary endpoint in the mITT population, outcomes in the two treatment groups did not differ significantly; although patients receiving concomitant antibiotics for other infections had a higher cure rate with Fidaxomicin (46 [90·2%] of 51) than with vancomycin (33 [73·3%] of 45; p=0·031). Occurrence of treatment-emergent adverse events did not differ between groups. 20 (7·6%) of 264 patients given at least one dose of Fidaxomicin and 17 (6·5%) of 260 given vancomycin died. Interpretation Fidaxomicin could be an alternative treatment for infection with C difficile , with similar efficacy and safety to vancomycin. Funding Optimer Pharmaceuticals.
Sherwood L Gorbach - One of the best experts on this subject based on the ideXlab platform.
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Fidaxomicin versus vancomycin in the treatment of clostridium difficile infection canadian outcomes
Canadian Journal of Infectious Diseases & Medical Microbiology, 2016Co-Authors: Christine H Lee, Thomas Louie, Karl Weiss, Louis Valiquette, Marvin Gerson, Wendy Arnott, Sherwood L GorbachAbstract:Background. This analysis examined the efficacy of Fidaxomicin versus vancomycin in 406 Canadian patients with Clostridium difficile infection (CDI), based on data from 2 randomized, clinical trials. Methods. Patients received Fidaxomicin or vancomycin 1. Patients were assessed for clinical response recurrence of infection and sustained clinical response for 28 days after treatment completion. Patients at increased risk of recurrence were subjected to subgroup analyses. Results. Clinical response rates for Fidaxomicin (90.0%) were noninferior to those with vancomycin (92.2%; 95% confidence interval for difference: -7.7, 3.5). However, Fidaxomicin-treated patients had lower recurrence (14.4% versus 28.0%, p = 0.001) and higher sustained clinical response (77.1% versus 66.3%, p = 0.016). Compared with vancomycin, Fidaxomicin was associated with lower recurrence rates in all subgroups, reaching statistical significance in patients with age ≥ 65 years (16.0% versus 30.9%, p = 0.026), concomitant antibiotic use (16.2% versus 38.7%, p = 0.036), and non-BI strains (11.8% versus 28.3%, p = 0.004). Higher sustained clinical response rates were observed for Fidaxomicin compared with vancomycin in all subgroups; this was statistically significant in the non-BI subgroup (82.8% versus 69.1%, p = 0.021). Conclusions. In Canadian patients, Fidaxomicin was superior to vancomycin in sustaining clinical response and reducing CDI recurrence.
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whole genome sequencing demonstrates that Fidaxomicin is superior to vancomycin for preventing reinfection and relapse of infection with clostridium difficile
The Journal of Infectious Diseases, 2014Co-Authors: David W Eyre, Jaime Seddon, Farah Babakhani, Sherwood L Gorbach, Derrick W Crook, David Griffiths, Carlos Del Ojo Elias, Tim E A Peto, Sarah A WalkerAbstract:Whole-genome sequencing was used to determine whether the reductions in recurrence of Clostridium difficile infection observed with Fidaxomicin in pivotal phase 3 trials occurred by preventing relapse of the same infection, by preventing reinfection with a new strain, or by preventing both outcomes. Paired isolates of C. difficile were available from 93 of 199 participants with recurrences (28 were treated with Fidaxomicin, and 65 were treated with vancomycin). Given C. difficile evolutionary rates, paired samples ≤2 single-nucleotide variants (SNVs) apart were considered relapses, paired samples >10 SNVs apart were considered reinfection, and those 3-10 SNVs apart (or without whole-genome sequences) were considered indeterminate in a competing risks survival analysis. Fidaxomicin reduced the risk of both relapse (competing risks hazard ratio [HR], 0.40 [95% confidence interval {CI}, .25-.66]; P = .0003) and reinfection (competing risks HR, 0.33 [95% CI, 0.11-1.01]; P = .05).
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advances in the treatment of clostridium difficile with Fidaxomicin a narrow spectrum antibiotic
Annals of the New York Academy of Sciences, 2013Co-Authors: Pamela Sears, Yoshitaka Ichikawa, Nancy Ruiz, Sherwood L GorbachAbstract:Clostridium difficile infection, also known as C. difficile-associated diarrhea (CDAD), is the most common cause of nosocomial diarrhea, typically initiated by the use of broad-spectrum antibiotics that disrupt gut flora, thereby allowing C. difficile to proliferate. It is an increasing cause of morbidity and mortality, especially in hospitals and long-term care facilities. A particularly challenging aspect to treating CDAD has been maintenance of clinical response: following initial treatment success, recurrence occurs in approximately 15-30% of patients after the first episode and up to 50-60% subsequently. Fidaxomicin, marketed as DIFICID® in the United States, is approved in multiple countries and is the first new drug to be approved for this indication in over 25 years. It is a novel, narrow spectrum antibiotic with potent bactericidal activity against C. difficile and low activity against the normal gut microbiota. In clinical trials, Fidaxomicin has been shown to be noninferior in initial clinical response to CDAD compared to vancomycin, and superior in limiting recurrence and providing sustained clinical response. In this review, the development and characteristics of Fidaxomicin are described.
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treatment of first recurrence of clostridium difficile infection Fidaxomicin versus vancomycin
Clinical Infectious Diseases, 2012Co-Authors: Oliver A Cornely, Mark A Miller, Derrick W Crook, Thomas J Louie, Sherwood L GorbachAbstract:Recurrence of Clostridium difficile infection (CDI) occurs in approximately 25% of successfully treated patients. Two phase 3 randomized, double-blind trials were conducted at 154 sites in the United States, Canada, and Europe to compare Fidaxomicin vs vancomycin in treating CDI. Patients with CDI received Fidaxomicin 200 mg twice daily or vancomycin 125 mg 4 times daily for 10 days. The primary end point was clinical cure of CDI at end of treatment, and a secondary end point was recurrence during the 28 days following clinical cure. In all, 1164 subjects were enrolled, of which a subgroup of 128 in the per-protocol population had another recent episode of CDI prior to the CDI diagnosis at study enrollment. In the analysis of this subgroup, initial response to therapy was similar for both drugs (>90% cure). However, recurrence within 28 days occurred in 35.5% of patients treated with vancomycin and 19.7% of patients treated with Fidaxomicin (-15.8% difference; 95% confidence interval, -30.4% to -0.3%; P = .045). Early recurrence (within 14 days) was reported in 27% of patients treated with vancomycin and 8% of patients treated with Fidaxomicin (P = .003). In patients with a first recurrence of CDI, Fidaxomicin was similar to vancomycin in achieving a clinical response at end of therapy but superior in preventing a second recurrence within 28 days.
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Fidaxomicin versus vancomycin for infection with clostridium difficile in europe canada and the usa a double blind non inferiority randomised controlled trial
Lancet Infectious Diseases, 2012Co-Authors: Oliver A Cornely, Pamela Sears, Karl Weiss, Derrick W Crook, Roberto Esposito, Andre Poirier, Michael S Somero, Sherwood L GorbachAbstract:Summary Background Infection with Clostridium difficile is the primary infective cause of antibiotic-associated diarrhoea. We aimed to compare efficacy and safety of Fidaxomicin and vancomycin to treat patients with C difficile infection in Europe, Canada, and the USA. Methods In this multicentre, double-blind, randomised, non-inferiority trial, we enrolled patients from 45 sites in Europe and 41 sites in the USA and Canada between April 19, 2007, and Dec 11, 2009. Eligible patients were aged 16 years or older with acute, toxin-positive C difficile infection. Patients were randomly allocated (1:1) to receive oral Fidaxomicin (200 mg every 12 h) or oral vancomycin (125 mg every 6 h) for 10 days. The primary endpoint was clinical cure, defined as resolution of diarrhoea and no further need for treatment. An interactive voice-response system and computer-generated randomisation schedule gave a randomisation number and medication kit number for each patient. Participants and investigators were masked to treatment allocation. Non-inferiority was prespecified with a margin of 10%. Modified intention-to-treat and per-protocol populations were analysed. This study is registered with ClinicalTrials.gov, number NCT00468728. Findings Of 535 patients enrolled, 270 were assigned Fidaxomicin and 265 vancomycin. After 26 patients were excluded, 509 were included in the modified intention-to-treat (mITT) population. 198 (91·7%) of 216 patients in the per-protocol population given Fidaxomicin achieved clinical cure, compared with 213 (90·6%) of 235 given vancomycin, meeting the criterion for non-inferiority (one-sided 97·5% CI −4·3%). Non-inferiority was also shown for clinical cure in the mITT population, with 221 (87·7%) of 252 patients given Fidaxomicin and 223 (86·8%) of 257 given vancomycin cured (one-sided 97·5% CI −4·9%). In most subgroup analyses of the primary endpoint in the mITT population, outcomes in the two treatment groups did not differ significantly; although patients receiving concomitant antibiotics for other infections had a higher cure rate with Fidaxomicin (46 [90·2%] of 51) than with vancomycin (33 [73·3%] of 45; p=0·031). Occurrence of treatment-emergent adverse events did not differ between groups. 20 (7·6%) of 264 patients given at least one dose of Fidaxomicin and 17 (6·5%) of 260 given vancomycin died. Interpretation Fidaxomicin could be an alternative treatment for infection with C difficile , with similar efficacy and safety to vancomycin. Funding Optimer Pharmaceuticals.