Fidaxomicin Treatment Research Articles

A retrospective budget impact analysis of fidaxomicin treatment for Clostridioides difficile infections (CDI) in Germany

ABSTRACT Background Clostridioides difficile is the most common cause of healthcare-associated diarrhea. Research suggests that treating C. difficile infections (CDI) with fidaxomicin (FDX) is more effective than vancomycin (VAN), with potential cost savings. The objective was to calculate the budget impact of FDX treatment compared to VAN from a German payer perspective. Research design and methods The analysis used real-world data of patients discharged from University Hospital Cologne between Jan-01–2018 and Dec-31–2019. We identified recurrent and non-recurrent CDI cases and calculated direct treatment costs based on G-DRG flat rates. To calculate average costs per treatment and the budget impact, recurrence probabilities for VAN and FDX were taken from published evidence (28-day and 90-day scenarios). Results Totally, 475 cases were analyzed, thereof 421 non-recurrent, causing mean costs of €32,901 per case (95% CI: 27.752–38.050). Thirty-two patients experienced a recurrence within 28 days, yielding mean costs of €10,952 (95% CI: 5.627–16.277) for their additional hospital stay. The resulting budget impact was €1,303 (95% CI: 670–1.937) in favor of FDX, ranging from €148.34 to €2,190.30 in scenario analyses. Conclusion The analysis indicates FDX treatment can lead to cost savings compared to VAN. Future research should focus on specific patient groups, such as refractory CDI patients.

Effective Colonization by Nontoxigenic Clostridioides difficile REA Strain M3 (NTCD-M3) Spores following Treatment with Either Fidaxomicin or Vancomycin.

Colonization with nontoxigenic Clostridioides difficile strain M3 (NTCD-M3) has been demonstrated in susceptible hamsters and humans when administered after vancomycin treatment. NTCD-M3 has also been shown to decrease risk of recurrent C. difficile infection (CDI) in patients following vancomycin treatment for CDI. As there are no data for NTCD-M3 colonization after fidaxomicin treatment, we studied the efficacy of NTCD-M3 colonization and determined fecal antibiotic levels in a well-studied hamster model of CDI. Ten of 10 hamsters became colonized with NTCD-M3 after 5 days of treatment with fidaxomicin when NTCD-M3 was administered daily for 7 days after treatment discontinuation. The findings were nearly identical to 10 vancomycin-treated hamsters also given NTCD-M3. High fecal levels of OP-1118, the major fidaxomicin metabolite, and vancomycin were noted during treatment with the respective agents and modest levels noted 3 days after treatment discontinuation at the time when most of the hamsters became colonized. These findings support the ongoing development of NTCD-M3 for the prevention of recurrent CDI. IMPORTANCE NTCD-M3 is a novel live biotherapeutic, that has been shown in a Phase 2 clinical trial to prevent recurrence of C. difficile infection (CDI) when administered shortly after antibiotic treatment of the initial CDI episode. Fidaxomicin was not, however, in widespread use at the time this study was conducted. A large multi-center Phase 3 clinical trial is now currently in the planning stage, and it is anticipated that many patients eligible for this study will be treated with fidaxomicin. Since efficacy in the hamster model of CDI has predicted success in patients with CDI, we studied the ability of NTCD-M3 to colonize hamsters after treatment with either fidaxomicin or vancomycin.

Real-World Budget Impact of Fidaxomicin versus Vancomycin or Metronidazole for In-Hospital Treatment of Clostridioides difficile Infection

Fidaxomicin, a macrocyclic antibiotic, selectively kills Clostridioides difficile and reduces C. difficile infection (CDI) recurrence compared with vancomycin, but some studies and guidelines report fidaxomicin as being less cost-effective. The aim of this study was to compare the cost-effectiveness and budget impact of fidaxomicin versus vancomycin or metronidazole for treating CDI in a real-world UK setting. Data were retrospectively collected from medical records of 86 patients with CDI treated with vancomycin or metronidazole at a single UK hospital between April 2011 and March 2012, and prospectively from 62 patients with CDI treated with fidaxomicin between August 2012 and July 2013. CDI cases were matched by age, financial year, and healthcare resource use to control cases. CDI recurrence rates were lower with fidaxomicin (6.5%) than vancomycin/metronidazole (19.8%). An estimated 12 additional recurrent CDIs were prevented with fidaxomicin treatment. Patients with CDI had significantly higher healthcare costs than those without CDI, with a mean excess spend of GBP 10,748 and GBP 17,451 per patient in the fidaxomicin (p = 0.015) and vancomycin/metronidazole cohorts (p < 0.001), respectively. A second CDI was associated with mean excess costs of GBP 8373 and GBP 20,249 per patient in the fidaxomicin and vancomycin/metronidazole cohorts, respectively. Despite higher fidaxomicin drug costs, overall cost savings were estimated at GBP 140,292 (GBP 2125 per CDI). In this real-world study, first-line CDI treatment with fidaxomicin reduced healthcare costs versus vancomycin/metronidazole, consistent with previous studies.

Clinical and Economic Outcomes After Implementation of a Fidaxomicin Treatment Optimization and Access Pathway at a US Hospital System.

This study aimed to evaluate the clinical and economic outcomes of implementing a Clostridiodes difficile infection (CDI) Treatment Optimization and Access Pathway (treatment pathway) directing first-line use of fidaxomicin for CDI. This was a retrospective, quasi-experimental study of adult patients with CDI using Electronic Health Record data from a single center. The primary intervention was implementation of a treatment pathway directing first-line use of fidaxomicin for patients with first/second CDI episode and at high risk of recurrence. The primary clinical outcome was CDI recurrence within 30days of completing therapy in patients achieving clinical cure. Secondary clinical outcomes included clinical cure and sustained response evaluated at 90days after completion of CDI treatment. Economic outcomes included costs associated with hospital stay at index admission and 30- and 90-day readmission. Differences between the pre- and post-implementation cohorts were assessed for baseline characteristics, CDI treatment utilization, clinical outcomes, and economic outcomes. The budget impact was calculated for the pre- vs. post-implementation cohorts, each normalized to 100 patients. Post- vs. pre-implementation, 30-day recurrence (6.4% vs. 18.0%., p = 0.001), 90-day recurrence (14.9% vs. 27.1%, p = 0.009), and 30-day (4.6% vs. 12.7%, p = 0.007) and 90-day CDI-related readmissions (8.5% vs. 18.9%, p = 0.007) were lower. The clinical cure (94.1% vs. 84.4%, p = 0.002) and 90-day sustained response rates were higher (73.3% vs. 55.9%, p < 0.001). Median total costs were also lower in the post- vs. pre-implementation cohorts at index admission ($11,934.64 vs. $14,523.27, p = 0.048), and 30-day ($7685.82 vs. $12,424.44, p = 0.102) and 90-day CDI-related readmission episodes ($8246.69 vs. $12,729.57, p = 0.042). The budget impact analyses of 100 patients post- vs. pre-implementation found saving of $222,895 overall and $9432 per CDI-readmission avoided. Implementation of the CDI treatment pathway was associated with better clinical outcomes and hospital cost savings. The findings help validate real-world value of fidaxomicin for CDI disease management.

Microbiota diversity and bacterial load after successful treatment of Clostridioides difficile infection with honey lavage in 4 patients.

In this letter, an experimental therapy in four patients with therapy-resistant Clostridioides difficile infection is described. These four patients were treated with Manuka honey via colon lavage. First, the patients received a three-day fidaxomicin treatment. The colon lavage was performed on the third day. During a subsequent ileocolonoscopy, 300 mL 15% Manuka honey was applied via a spray catheter. Patients remained in bed for two hours after the procedure and did not defecate. The patient’s microbiomes were tested before treatment, after the fidaxomicin treatment, and after honey lavage. A decrease in C. difficile load was found in their microbiomes. Additionally, restoration of microbiota diversity after the honey lavage was also noted. The four patients experienced complete cessation of watery stools and remain symptom free. These results indicate the need for more clinical research into this matter.

Budget Impact Analysis of Fidaxomicin Versus Vancomycin for the Treatment of Clostridioides difficile Infection in the United States

Fidaxomicin is as effective as vancomycin in treating Clostridioides difficile infection (CDI) but more effective at preventing recurrence. However, because fidaxomicin is more costly than vancomycin, its overall value in managing CDI is not well understood. This study assessed the budget impact of introducing fidaxomicin versus vancomycin for the treatment of adults with CDI from a hospital perspective in the US. A cohort-based decision analytic model was developed over a 1-year horizon. A hospital with 10,000 annual hospitalizations was simulated. The model considered two adult populations: patients with no prior CDI episode and patients with one prior CDI episode. Two scenarios were assessed per population: 15% fidaxomicin/85% vancomycin use and 100% vancomycin use. Model inputs were obtained from published sources and expert opinion. Model outcomes included cost, payment, and revenue at the hospital level, per treated CDI patient, and per admitted patient. Budget impact was calculated as the difference in revenue between scenarios. One-way sensitivity analyses tested the effects of varying model inputs on the budget impact. In patients with no prior CDI episode, treatment with fidaxomicin resulted in potential savings over 1year of $1105 at the hospital level, $14 per treated CDI patient, and $0.11 per admitted patient. In patients with one prior CDI episode, fidaxomicin use was associated with potential savings over 1year of $1150 at the hospital level, $74 per treated CDI patient, and $0.12 per admitted patient. Savings were driven by a reduced rate of CDI recurrence with fidaxomicin treatment and uptake of fidaxomicin. Sensitivity analyses indicated savings when inputs were varied in most scenarios. Budgetary savings can be achieved with fidaxomicin due to reduced CDI recurrence as a result of a superior sustained clinical response. Our results support considering the broader benefits of fidaxomicin, beyond its cost, when making formulary inclusion decisions.

Initial vancomycin versus metronidazole for the treatment of first-episode non-severe Clostridioides difficile infection.

Clostridioides difficile infection (CDI) is the leading cause of infectious nosocomial diarrhea. Although initial fidaxomicin or vancomycin treatment is recommended by most major guidelines to treat severe CDI, there exists varied recommendations for first-episode non-severe CDI. Given the discrepancy in current treatment guidelines, we sought to evaluate the use of initial vancomycin versus metronidazole for first-episode non-severe CDI. We conducted a retrospective cohort study of all adult inpatients with first-episode CDI at our institution from January 2013 to May 2018. The initial vancomycin versus initial metronidazole cohorts were examined using a multivariate logistic regression model. The study cohort of 737 patients had a median age of 72.3 years, and 357 of these patients (48.4%) had hospital-acquired infection. Among 326 patients with non-severe CDI, recurrence, new incident infection, and 30-day mortality rates were 16.2%, 10.9%, and 5.3%, respectively, when treated with initial metronidazole, compared to 20.0%, 1.4%, and 10.0%, respectively, when treated with initial vancomycin. In an adjusted multivariable analysis, the use of initial vancomycin for the treatment of non-severe CDI was associated with a reduction in new incident infection (adjusted odds ratio [ORadj], 0.11; 95% confidence interval [CI], 0.02-0.86; P = .035), compared to initial metronidazole. Initial vancomycin was associated with a reduced rate of new incident infection in the treatment of adult inpatients with first-episode non-severe CDI. These findings support the use of initial vancomycin for all inpatients with CDI, when fidaxomicin is unavailable.

An Analysis of Clostridium difficile Environmental Contamination During and After Treatment for C difficile Infection.

BackgroundLower Clostridium difficile spore counts in feces from C difficile infection (CDI) patients treated with fidaxomicin versus vancomycin have been observed. We aimed to determine whether environmental contamination is lower in patients treated with fidaxomicin compared with those treated with vancomycin/metronidazole.MethodsThe CDI cases were recruited at 4 UK hospitals (Leeds, Bradford, and London [2 centers]). Environmental samples (5 room sites) were taken pretreatment and at 2–3, 4–5, 6–8, and 9–12 days of treatment, end of treatment (EOT), and post-EOT. Fecal samples were collected at diagnosis and as often as produced thereafter. Swabs/feces were cultured for C difficile; percentage of C difficile-positive samples and C difficile bioburden were compared between different treatment arms at each time point.ResultsPre-EOT (n = 244), there was a significant reduction in environmental contamination (≥1 site positive) around fidaxomicin versus vancomycin/metronidazole recipients at days 4–5 (30% vs 50% recipients, P = .04) and at days 9–12 (22% vs 49%, P = .005). This trend was consistently seen at all other timepoints, but it was not statistically significant. No differences were seen between treatment groups post-EOT (n = 76). Fidaxomicin-associated fecal positivity rates and colony counts were consistently lower than those for vancomycin/metronidazole from days 4 to 5 of treatment (including post-EOT); however, the only significant difference was in positivity rate at days 9–12 (15% vs 55%, P = .03).ConclusionsThere were significant reductions in C difficile recovery from both feces and the environment around fidaxomicin versus vancomycin/metronidazole recipients. Therefore, fidaxomicin treatment may lower the C difficile transmission risk by reducing excretion and environmental contamination.

Antibiotic fidaxomicin is an RdRp inhibitor as a potential new therapeutic agent against Zika virus

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

The gut microbiome diversity of Clostridioides difficile-inoculated mice treated with vancomycin and fidaxomicin

ObjectiveTo investigate the effect of vancomycin and fidaxomicin on the diversity of intestinal microbiota in a mouse model of Clostridioides difficile infection. MethodsMice were divided into 11 models (4 mice per model): 6 uninoculated models and 5 models inoculated with C. difficile BI/NAP1/027. Inoculated models were prepared using intraperitoneal clindamycin followed by inoculation with C. difficile BI/NAP1/027. Uninoculated and C. difficile-inoculated mice received 2 or 7 days’ vancomycin or fidaxomicin. Clostridium butyricum MIYAIRI 588 probiotic and lactoferrin prebiotic were administered for 10 days to uninoculated mice. Intestinal microbiome composition was investigated by sequence analyses of bacterial 16S rRNA genes from faeces, and microbiota diversity estimated. ResultsIn uninoculated, untreated (‘normal’) mice, Clostridia (57.8%) and Bacteroidia (32.4%) accounted for the largest proportions of gut microbiota. The proportion of Clostridia was numerically reduced in C. difficile-inoculated versus normal mice. Administration of vancomycin to C. difficile-inoculated mice reduced the proportions of Bacteroidia and Clostridia, and increased that of Proteobacteria. Administration of fidaxomicin to C. difficile-inoculated mice reduced the proportion of Clostridia to a lesser extent, but increased that of Bacteroidia. Microbiota diversity was lower in C. difficile-inoculated versus normal mice (164.5 versus 349.1 operational taxonomic units (OTUs), respectively); treatment of C. difficile-inoculated mice with 7 days' vancomycin reduced diversity to a greater extent than did 7 days' fidaxomicin treatment (26.2 versus 134.2 OTUs, respectively). ConclusionsBoth C. difficile inoculation and treatment with vancomycin or fidaxomicin reduced microbiota diversity; however, dysbiosis associated with fidaxomicin was milder than with vancomycin.

Antimicrobial susceptibility and molecular characterisation using whole-genome sequencing of Clostridioides difficile collected in 82 hospitals in Japan between 2014 and 2016.

We studied the antimicrobial susceptibility and the molecular characteristics using draft whole-genome sequencing of Clostridioides (Clostridium) difficile strains before and after treatment in adults with C. difficile infection (CDI) enrolled in a Phase III, randomised, nationwide study of fidaxomicin versus vancomycin in Japan (NCT02179658). C. difficile strains were cultured from stool samples collected before and after standard treatment with either fidaxomicin or vancomycin. Overall, 285 C. difficile strains were recovered, with 188 derived from CDI cases at baseline (87 patients received fidaxomicin and 101 received vancomycin). No strains isolated from episodes of CDI at baseline were shown to have reduced susceptibilities to fidaxomicin (MIC ≥1 mg/L), or resistance to vancomycin and metronidazole. Thirty-three sequence types (STs) were identified, the most common being ST17 (n=61; 32.4%), ST8 (n=26; 13.8%) and ST2 (n=21; 11.2%). Core-genome single nucleotide polymorphism analysis showed that outbreaks of C. difficile were unlikely to have occurred at each hospital. The predominant toxin gene profile was tcdA+tcdB+cdtA/cdtB- (n=149; 79.3%). Six of 87 patients who received fidaxomicin harboured C. difficile isolates with reduced fidaxomicin susceptibilities conferred by previously described mutations, Val1143Leu/Gly/Asp in RpoB or Arg89Gly in RpoC or putative mutations, Gln1149Pro in RpoB or Arg326Cys in RpoC. Allelic exchange studies of these putative mutations were not performed. Prior to fidaxomicin use, we found no C. difficile strains with reduced fidaxomicin susceptibilities causing CDI in Japan; however, mutant strains with reduced fidaxomicin susceptibilities were detected after fidaxomicin treatment.

Microbiological Characterization and Clinical Outcomes After Extended-Pulsed Fidaxomicin Treatment for Clostridioides difficile Infection in the EXTEND Study.

Background Clostridioides (Clostridium) difficile infection (CDI) is diagnosed using clinical signs and symptoms plus positive laboratory tests. Recurrence of CDI after treatment is common, and coinfection with other enteric pathogens may influence clinical outcomes.MethodsWe aimed to assess rates of C difficile positivity, by enzyme-linked immunosorbent assay (ELISA) toxin A/B and BioFire FilmArray, and the effect of enteric coinfection on clinical outcomes, using samples from the EXTEND study of extended-pulsed fidaxomicin (EPFX) versus standard vancomycin.ResultsAll 356 randomized and treated patients tested positive for C difficile toxin A/B by local tests; a majority (225 of 356, 63.2%) also tested positive by both ELISA and BioFire. Most stool samples taken at screening tested positive for C difficile only using BioFire (EPFX: 112 of 165, 69.7%; vancomycin: 118 of 162, 72.8%). Of the 5 patients who failed treatment and had stool samples available, all (1) had tested negative for C difficile by BioFire at screening and (2) were negative by ELISA at time of treatment failure. When analyzed by BioFire results at screening, rates of sustained clinical cure at 30 days after end of treatment were numerically higher with EPFX than with vancomycin for almost all patients, except for those who tested negative for C difficile but positive for another pathogen. However, these outcome differences by presence of coinfection did not reach statistical significance. Whole-genome sequencing analysis determined that 20 of 26 paired samples from patients with recurrence were reinfections with the same C difficile strain.ConclusionsTesting for presence of copathogens in clinical trials of antibiotics could help to explain clinical failures.

1496. Bezlotoxumab Administered at the End of a Suppressive Drug Regimen for Patients with Multiply Recurrent Clostridioides difficile Infection

BackgroundRecurrent Clostridioides difficile infection (CDI) remains a public health burden, affecting as many as 35% of patients with primary CDI. Bezlotoxumab, a monoclonal anti-toxin B antibody, was the first FDA-approved agent indicated for the prevention of recurrent CDI, but real-world experience is limited, particularly in patients with multiple CDI recurrences.MethodsWe conducted a retrospective case study of patients with multiple CDI recurrences who failed prior treatments with pulsed and tapered vancomycin and fidaxomicin regimens. Six patients in a single CDI specialty outpatient clinic received a single iv infusion of bezlotoxumab at the end of a suppressive vancomycin or fidaxomicin treatment regimen. The suppressive treatment was stopped immediately after the bezlotoxumab infusion and the patients were followed closely for recurrent symptoms and need for additional CDI treatment.ResultsFour of 6 patients who received bezlotoxumab at the end of a suppressive treatment regimen did not require subsequent CDI treatment and have been followed for 2 weeks to 1.5 years to date. These four patients experienced a single, self-limited episode of diarrhea within 2 weeks of the infusion, and did not require subsequent CDI treatment. Two patients had recurrent symptoms and positive stool C. difficile tests one month after infusion and were re-started on CDI treatment. One of the patients had longstanding underlying irritable bowel syndrome and variable initial response to re-starting vancomycin. The other patient responded to re-starting fidaxomicin.ConclusionBezlotoxumab at the end of a prolonged suppressive treatment regimen may be an effective therapeutic strategy in preventing recurrent CDI in complicated, multiply recurrent CDI patients. Disclosures All authors: No reported disclosures.

Single centre clinical experience with fidaxomicin in the treatment of Clostridium difficile infection in Slovakia

Clostridium difficile infection (CDI) has become one of the most common causes of hospital-acquired infections. Fidaxomicin is one of the latest antibiotics used in the treatment of CDI, however, treatment cost affects recommendations for its use in several countries. We have analysed the treatment of our patients with CDI, treated by fidaxomicin since it was introduced to the market in 2018 and became available in the second biggest Slovak hospital, University Hospital of L. Pasteur. Our aim was to determine efficacy and safety of fidaxomicin in the treatment of CDI in Slovak patients. We reviewed all courses of fidaxomicin use in our hospital (n = 60). Fidaxomicin was used for first recurrence (12 times), second recurrence (4 times), third recurrence (2 times), and fifth recurrence (1 patient). 41 patients received fidaxomicin first-line. Success of fidaxomicin treatment was recorded at 86.7% within the whole cohort. In the recurrent Clostridium difficile infection (rCDI) subgroup, fidaxomicin was 63% effective with three patients dying (15.7%) and two patients developing subsequent rCDI. During the duration of the study, 6 patients in total died. Only one of three patients, with three or more recurrences of CDI, had no further presentations after eight weeks of completion of treatment. The biggest benefit from fidaxomicin treatment was shown in a cohort of patients with primary CDI infection demonstrating a low recurrence rate and significant reduction of fidaxomicin effectiveness in preventing a recurrence when treating patients with multiple rCDI.

500. Efficacy of 30-Day Fidaxomicin for Treatment of Acute Clostridium difficile Infection With History of Multiple Recurrences

BackgroundMultiple recurrent Clostridium difficile (mrCDI) infections pose major challenges to patients and to the healthcare system. mrCDI is associated with multiple, prolonged hospitalizations and significantly higher costs. It can also lead to chronic, severe diarrhea, colectomy, or death. Fecal microbiota transplantation (FMT) is an effective treatment, but its long-term safety remains unknown, and approximately 10% of patients do not respond to multiple FMTs. A 30-day course of fidaxomicin was evaluated for treatment of acute episode of CDI superimposed on mrCDI, including those who did not respond to multiple FMTs. Fidaxomicin was chosen because it disrupts the fecal microbiome less than vancomycin.MethodsTwenty-nine adult patients with at least two episodes of recurrent CDI were initiated on fidaxomicin 200 mg when they experienced new episode of CDI (symptoms plus positive for CD toxin gene by polymerase chain reaction). These patients continued with fidaxomicin 200 mg twice daily for 10 days, and 200 mg once daily for 20 additional days in an open-label clinical trial. The primary endpoints were a clinical response at the completion of 30-day course of fidaxomicin and a sustained clinical response at week 8 from the last dose of fidaxomicin. Patient health-related quality of life was evaluated throughout the treatment using the RAND-36 Item Health Survey (copyright© the RAND Corporation).ResultsTwenty-four of the 29 patients (83%) experienced clinical resolution of CDI-related symptoms at the completion of 30-day fidaxomicin treatment. Twenty-two of the 29 patients had a sustained clinical response with the overall cure rate of 76% (22/29). Eleven of the 29 patients had multiple FMTs and were enrolled into this study as they failed FMTs. Eight of the 11 patients (73%) of these patients had a sustained clinical response. Statistically significant improvements (P < 0.05) in multiple domains of quality of life according to the RAND-36 Item Health Survey were also observed.ConclusionAn extended regimen of fidaxomicin is an effective treatment for adults with multiple rCDI and in restoring quality of life, including those who failed FMTs.Disclosures C. Lee, Rebiotix: Board Member and Grant Investigator, Consulting fee and Research grant. Merck: Research Contractor, Research grant. Pfizer: Grant Investigator, Research grant. Seres: Grant Investigator, Grant recipient. P. Kim, Rebiotix: Board Member, Consulting fee.

Proteomic Signatures of Clostridium difficile Stressed with Metronidazole, Vancomycin, or Fidaxomicin.

The anaerobic pathogen Clostridium difficile is of growing significance for the health care system due to its increasing incidence and mortality. As C. difficile infection is both supported and treated by antibiotics, a deeper knowledge on how antimicrobial agents affect the physiology of this important pathogen may help to understand and prevent the development and spreading of antibiotic resistant strains. As the proteomic response of a cell to stress aims at counteracting the harmful effects of this stress, it can be expected that the pattern of a pathogen’s responses to antibiotic treatment will be dependent on the antibiotic mechanism of action. Hence, every antibiotic treatment is expected to result in a specific proteomic signature characterizing its mode of action. In the study presented here, the proteomic response of C. difficile 630∆erm to vancomycin, metronidazole, and fidaxomicin stress was investigated on the level of protein abundance and protein synthesis based on 2D PAGE. The quantification of 425 proteins of C. difficile allowed the deduction of proteomic signatures specific for each drug treatment. Indeed, these proteomic signatures indicate very specific cellular responses to each antibiotic with only little overlap of the responses. Whereas signature proteins for vancomycin stress fulfil various cellular functions, the proteomic signature of metronidazole stress is characterized by alterations of proteins involved in protein biosynthesis and protein degradation as well as in DNA replication, recombination, and repair. In contrast, proteins differentially expressed after fidaxomicin treatment can be assigned to amino acid biosynthesis, transcription, cell motility, and the cell envelope functions. Notably, the data provided by this study hint also at so far unknown antibiotic detoxification mechanisms.

Impact of the use of local fidaxomicin treatment algorithms for managing Clostridium difficile infection in hospitalized patients in southeastern United States

BackgroundClostridium difficile-associated diarrhea (CDAD) is a major public health threat that results in increased length of stay, hospital readmissions, deaths, and economic burden. CDAD treatment is often guided by severity of disease. Although various tools exist to determine CDAD severity, real-world data evaluating the use of such tools in treatment algorithms are sparse.MethodsA local CDAD treatment pathway was developed independently to guide fidaxomicin prescribing at wellStar Health System (WellStar) and at Lee Health (LH) and Sarasota Memorial Hospital (SMH). Each algorithm was designed locally by the stewardship pharmacist and was utilized to identify patients at high risk for C. difficile recurrence. Patient and clinical data was retrospectively gathered to evaluate the utility and outcomes of the treatment pathway.ResultsThere were 262 patients that received fidaxomicin at these three hospitals during the study time period. Only 30% at WellStar and 20% at LH or SMH met the study criteria and adhered to the pathway requirements. After completion of fidaxomicin, 30-day recurrence rates at WellStar was 0 and at LH and SMH 7%. Clinical cure rates were 83% in WellStar and 93% in LH and SMH.ConclusionsThe results from these two pathways show positive outcomes for the use of fidaxomicin in patients at high risk for CDAD recurrence. This data supports the potential utility of fidaxomicin against CDAD.

Fidaxomicin for the treatment of Clostridium difficile infection (CDI) in at-risk patients with inflammatory bowel disease, fulminant CDI, renal impairment or hepatic impairment: a retrospective study of routine clinical use (ANEMONE)

Information is limited or lacking on fidaxomicin treatment of Clostridium difficile infection (CDI) in patients with inflammatory bowel disease, fulminant or life-threatening CDI, severe renal impairment, moderate-to-severe hepatic impairment and pregnancy. The ANEMONE study investigated fidaxomicin use in a routine clinical setting, focusing on these medical conditions of specific interest (MCSIs). This retrospective, post-authorisation study reviewed hospital records from Austria, Germany, Spain and the UK (June 2012–June 2015), collecting data from hospital admission to 30 days after last fidaxomicin dose. The primary objective was to identify the proportion of fidaxomicin-treated patients with MCSIs. Secondary objectives were to describe 30-day mortality, changes in ECG and laboratory parameters, fidaxomicin exposure and CDI response (resolution of diarrhoea; 30-day recurrence). 45.3% (261/576) of patients had ≥ 1 MCSI. Thirty-day mortality (post-first dose) was 17.0% (98/576) in the total population and slightly higher (24.6–27.6%) in patients with fulminant CDI or severe renal impairment. 29.6% (24/81) deaths of known cause were attributable to CDI. Of changes in laboratory parameters or ECG findings, only a decrease in leucocyte counts appeared associated with fidaxomicin, consistent with a positive treatment response. Diarrhoea resolved in 78.0% (404/518) of treatment episodes; diarrhoea resolution was lowest in patients with fulminant CDI (investigator-defined, 67.5%, 56/88) and severe renal impairment (68.0%, 68/100). Thirty-day recurrence (18.8%, 79/420) was similar across MCSI subgroups. Although almost half of fidaxomicin-treated patients had ≥ 1 MCSI, the majority of patients in all subgroups had positive responses to treatment, and no particular safety concerns were identified.

Evaluation of fidaxomicin usage patterns and outcomes for Clostridium difficile infection across the United States Veterans Health Administration.

Fidaxomicin was recently approved for the treatment of Clostridium difficile infection (CDI). Limited data on its use exist outside of the phase 3 trials. The purposes of this study were to assess the compliance with the Veterans Health Administration (VHA) fidaxomicin criteria for use and describe patient characteristics and outcomes following fidaxomicin treatment for CDI using real-world data within the VHA system. This was a multicentre, retrospective, observational study including all adult patients who received at least 1 dose of fidaxomicin at any Veterans Affairs Medical Center. A total of 880 unique patients received 1098 courses of fidaxomicin, resulting in an overall usage rate per C.difficile-positive laboratory test of 1.98%. The rate of fidaxomicin courses per 1000 C.difficile-positive diagnostic tests increased steadily from 2011 through 2015 and plateaued from 2015 to 2016. Compliance with the VHA criteria for use was low (9.1%). The majority of courses were given for a first recurrence (25.0%), followed by an initial episode (23.9%) of CDI. The failure and recurrence rates were 6.8% and 24.4%, respectively. Although overall use of fidaxomicin was low, compliance with the VHA criteria for use was also low, suggesting that the criteria may need to be revised. Further studies are warranted to clarify the role of fidaxomicin in clinical practice.

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

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. 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 <75 years), and number of previous 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. 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. 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. Astellas Pharma, Inc.