Carbapenem-Resistant Acinetobacter spp Infection in Critically Ill Patients With Limited Treatment Options: A Descriptive Study of Cefiderocol Therapy During the COVID-19 Pandemic.

Background: Carbapenem-resistant Acinetobacter baumannii infections are difficult to treat and are a significant public health threat due to intrinsic/acquired resistance and limited treatment options. Methods: A retrospective, observational cohort study in patients receiving cefiderocol via Shionogi's early access program for Acinetobacter spp infections (1 April 2020-30 April 2021; 27 sites; Italy, Spain, Germany, France). Primary outcome was clinical success, defined as clinical resolution of infection at day 14 or day 28 survival. Results: Overall, 147 patients were included. Primary infection sites were respiratory (65.3%) and bloodstream (unknown source [15.6%]; catheter-related [10.9%]); 24.5% of patients had polymicrobial infection. Of 136 patients in intensive care (92.5%), 85.3% (116/136) received mechanical ventilation. Septic shock (55.6% [70/126]) and coronavirus disease 2019 (COVID-19) (81.6%) were prevalent. Prior to cefiderocol, 85.0% of patients received gram-negative treatment, 61.2% received ≥2 antimicrobials, and most received colistin (58.5%; median duration, 11.5 days). Cefiderocol monotherapy was used in 30.6% of patients. Clinical success rate was 53.1% and was higher in patients without septic shock (62.5%), without COVID-19 (77.8%), and with lower Sequential Organ Failure Assessment (SOFA) scores (quartile 1 [median, 3; range, 0-5]: 82.9%). Day 28 survival was 44.9% and was higher in patients without septic shock (60.7%), without COVID-19 (59.3%), with lower SOFA score (quartile 1: 82.9%), and receiving first-line cefiderocol (68.2% [15/22]). Resolution of infection at day 14 occurred in 39.5% of patients. Conclusions: Despite use in complex patients with limited treatment options and high septic shock/COVID-19 rates, cefiderocol treatment was associated with an overall clinical success rate of 53%.

Intermittent micafungin for prophylaxis in a rat model of chronic Candida albicans gut colonization.

BACKGROUND: During antifungal prophylaxis, micafungin is generally infused IV once daily over 1 h. In practice, less-frequent dosing could improve the quality of life in patients requiring long-term treatment or prophylaxis. The feasibility of this approach was assessed using humanized doses of daily or infrequent micafungin regimens. OBJECTIVES: To evaluate the effectiveness of intermittent high-dose micafungin, simulating human exposure, for prophylaxis of invasive candidiasis in a rat model of chronic Candida albicans gastrointestinal colonization and systemic dissemination. METHODS: Two weeks post-infection with an oral challenge of C. albicans, Sprague-Dawley rats were immunocompromised with a cytotoxic drug and a steroid. Rats received IV infusions of: daily vehicle control; daily subcutaneous micafungin (20 mg/kg SC); high-dose micafungin (20 mg/kg bolus SC + 80 mg/kg infusion/72 h, to simulate intermittent human dosing of 300 mg/72 h); or daily fluconazole by mouth (10 mg/kg PO). The effects of antifungal prophylaxis on faecal fungal burden and systemic C. albicans dissemination were evaluated. RESULTS: A rat model of chronic C. albicans gastrointestinal colonization and systemic dissemination was established, characterized by a sustained microbiological burden over 29 days and fungal recovery from normally sterile tissues. Using this model, intermittent high-dose micafungin (delivered via iPrecio pumps) to simulate humanized doses of 300 mg/72 h was significantly more effective than vehicle control, as effective as once-daily micafungin and similar to daily fluconazole at reducing faecal burden and preventing systemic dissemination. CONCLUSIONS: These data indicate that intermittent high-dose micafungin can be as effective as daily therapy, supporting clinical assessment in high-risk patients requiring long-term antifungal prophylaxis.

Pharmacokinetic analysis of an extended-pulsed fidaxomicin regimen for the treatment of Clostridioides (Clostridium) difficile infection in patients aged 60 years and older in the EXTEND randomized controlled trial.

BACKGROUND: Fidaxomicin is a recommended treatment for Clostridioides difficile infection (CDI) and reduces CDI recurrence incidence versus vancomycin. An extended-pulsed fidaxomicin (EPFX) regimen further reduces recurrence frequency. However, the pharmacokinetic profile of fidaxomicin in an EPFX regimen is unknown. OBJECTIVES: To evaluate plasma and stool concentrations of fidaxomicin and its metabolite, OP-1118, after EPFX administration for CDI. METHODS: In the Phase 3b/4 EXTEND trial, patients aged ≥60 years with toxin-confirmed CDI were randomized to receive EPFX (oral fidaxomicin twice daily, Days 1-5; once daily on alternate days, Days 7-25). Fidaxomicin and OP-1118 concentrations were determined using post-dose plasma samples obtained on Days 5 ±âŸ1, 12 ±âŸ1 and 25/26, and post-dose stool samples obtained on Days 5 ±âŸ1, 12 ±âŸ1 and 26 ±âŸ1. RESULTS: Plasma samples from 14 patients were included in the pharmacokinetic analysis; 12 of these patients provided stool samples. Median (range) plasma concentrations of fidaxomicin on Day 5 ±âŸ1 and Day 25/26 were 0.0252 (0.0038-0.1220) mg/L and 0.0069 (0-0.0887) mg/L, respectively, and those of OP-1118 were 0.0648 (0.0142-0.3250) mg/L and 0.0206 (0-0.3720) mg/L, respectively. Median (range) stool concentrations of fidaxomicin and OP-1118 on Day 26 ±âŸ1 were 272.5 (0-524) mg/kg and 280.5 (0-1120) mg/kg, respectively. CONCLUSIONS: EPFX treatment maintained fidaxomicin stool concentrations above the C. difficile MIC90 until Day 26 ±âŸ1. Systemic exposure to fidaxomicin and OP-1118 was low throughout and there was no evidence of accumulation in plasma or stool during 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. METHODS: We 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. RESULTS: All 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. CONCLUSIONS: Testing for presence of copathogens in clinical trials of antibiotics could help to explain clinical failures.

Extended-pulsed fidaxomicin versus vancomycin for Clostridium difficile infection: EXTEND study subgroup analyses.

Poor outcomes following Clostridium difficile infection (CDI) have been associated with advanced age, presence of cancer and C. difficile PCR-ribotype 027. The impact of baseline risk factors on clinical outcomes was evaluated using data from the EXTEND study, in which rate of sustained clinical cure (SCC) in the overall population was significantly higher with an extended-pulsed fidaxomicin (EPFX) regimen than with vancomycin. Patients aged ≥ 60 years received EPFX (fidaxomicin 200 mg twice daily, days 1-5; once daily on alternate days, days 7-25) or vancomycin (125 mg four times daily, days 1-10). We analysed outcomes by advanced age, cancer diagnosis, CDI severity, prior CDI occurrence and infection with PCR-ribotype 027. The primary endpoint was SCC 30 days after end of treatment (EOT; clinical response at test-of-cure with no subsequent recurrence). SCC rates 30 days after EOT did not differ significantly between EPFX (124/177, 70.1%) and vancomycin (106/179, 59.2%) regardless of age, cancer diagnosis, CDI severity and prior CDI. In patients with PCR-ribotype 027, SCC rate 30 days after EOT was significantly higher with EPFX (20/25, 80%) than with vancomycin (9/22, 40.9%) (treatment difference, 39.1%; 95% CI, 13.2-64.9; P = 0.006). Subgroup analyses from the EXTEND study suggest that EPFX is efficacious as a potential treatment for CDI regardless of age, cancer diagnosis, infection with PCR-ribotype 027, CDI severity or prior CDI. ClinicalTrials.gov identifier: NCT02254967.

Pharmacokinetics and safety of fidaxomicin in patients with inflammatory bowel disease and Clostridium difficile infection: an open-label Phase IIIb/IV study (PROFILE).

Objectives: Inflammatory bowel disease (IBD) poses an increased risk for Clostridium difficile infection (CDI). Fidaxomicin has demonstrated non-inferiority to vancomycin for initial clinical cure of CDI in patients without IBD; however, lack of data has caused concerns regarding potential systemic absorption of fidaxomicin in patients with IBD. Methods: The plasma pharmacokinetics (PK) of fidaxomicin and its primary metabolite OP-1118 were evaluated in a multicentre, open-label, single-arm, Phase IIIb/IV study enrolling patients with active IBD and CDI. Patients received fidaxomicin, 200 mg twice daily for 10 days. The primary and secondary endpoints were, respectively, plasma and stool PK of fidaxomicin and OP-1118 on Days 1, 5 and 10 of treatment. Other secondary endpoints included safety of fidaxomicin treatment (assessed until Day 180). ClinicalTrials.gov identifier: NCT02437591. Results: Median Tmax of fidaxomicin and OP-1118 for the PK analysis set (PKAS; 24 patients) was 1-2 h across Days 1, 5 and 10. Cmax ranges were 1.2-154 ng/mL for fidaxomicin and 4.7-555 ng/mL for OP-1118 across Days 1, 5 and 10 (PKAS). The ranges of concentrations in stool were 17.8-2170 µg/g for fidaxomicin and 0-1940 µg/g for OP-1118. Sixty percent (15/25) of patients experienced treatment-emergent adverse events (TEAEs), none of which led to treatment discontinuation or death. Conclusions: Maximum fidaxomicin and OP-1118 plasma concentrations observed in this study population suggest no increase in absorption, compared with patients without IBD. Incidence of TEAEs was similar to previous Phase III trials, suggesting that fidaxomicin is comparatively well tolerated in patients with IBD.

Two Distinct Patterns of Clostridium difficile Diversity Across Europe Indicating Contrasting Routes of Spread.

Background: Rates of Clostridium difficile infection vary widely across Europe, as do prevalent ribotypes. The extent of Europe-wide diversity within each ribotype, however, is unknown. Methods: Inpatient diarrheal fecal samples submitted on a single day in summer and winter (2012-2013) to laboratories in 482 European hospitals were cultured for C. difficile, and isolates the 10 most prevalent ribotypes were whole-genome sequenced. Within each ribotype, country-based sequence clustering was assessed using the ratio of the median number of single-nucleotide polymorphisms between isolates within versus across different countries, using permutation tests. Time-scaled Bayesian phylogenies were used to reconstruct the historical location of each lineage. Results: Sequenced isolates (n = 624) were from 19 countries. Five ribotypes had within-country clustering: ribotype 356, only in Italy; ribotype 018, predominantly in Italy; ribotype 176, with distinct Czech and German clades; ribotype 001/072, including distinct German, Slovakian, and Spanish clades; and ribotype 027, with multiple predominantly country-specific clades including in Hungary, Italy, Germany, Romania, and Poland. By contrast, we found no within-country clustering for ribotypes 078, 015, 002, 014, and 020, consistent with a Europe-wide distribution. Fluoroquinolone resistance was significantly more common in within-country clustered ribotypes (P = .009). Fluoroquinolone-resistant isolates were also more tightly clustered geographically with a median (interquartile range) of 43 (0-213) miles between each isolate and the most closely genetically related isolate, versus 421 (204-680) miles in nonresistant pairs (P < .001). Conclusions: Two distinct patterns of C. difficile ribotype spread were observed, consistent with either predominantly healthcare-associated acquisition or Europe-wide dissemination via other routes/sources, for example, the food chain.

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.

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 <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. 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.