The correlation of Clostridium difficile infection (CDI) with in-hospital morbidity is important in hospital settings where broad-spectrum antimicrobial agents are routinely used, such as in Greece. ...The C. DEFINE study aimed to assess point-prevalence of CDI in Greece during two study periods in 2013.
There were two study periods consisting of a single day in March and another in October 2013. Stool samples from all patients hospitalized outside the ICU aged ≥18 years old with diarrhea on each day in 21 and 25 hospitals, respectively, were tested for CDI. Samples were tested for the presence of glutamate dehydrogenase antigen (GDH) and toxins A/B of C. difficile; samples positive for GDH and negative for toxins were further tested by culture and PCR for the presence of toxin genes. An analysis was performed to identify potential risk factors for CDI among patients with diarrhea.
5,536 and 6,523 patients were screened during the first and second study periods, respectively. The respective point-prevalence of CDI in all patients was 5.6 and 3.9 per 10,000 patient bed-days whereas the proportion of CDI among patients with diarrhea was 17% and 14.3%. Logistic regression analysis revealed that solid tumor malignancy odds ratio (OR) 2.69, 95% confidence interval (CI): 1.18-6.15, p = 0.019 and antimicrobial administration (OR 3.61, 95% CI: 1.03-12.76, p = 0.045) were independent risk factors for CDI development. Charlson's Comorbidity Index (CCI) >6 was also found as a risk factor of marginal statistical significance (OR 2.24, 95% CI: 0.98-5.10). Median time to CDI from hospital admission was shorter with the presence of solid tumor malignancy (3 vs 5 days; p = 0.002) and of CCI >6 (4 vs 6 days, p = 0.009).
The point-prevalence of CDI in Greek hospitals was consistent among cases of diarrhea over a 6-month period. Major risk factors were antimicrobial use, solid tumor malignancy and a CCI score >6.
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.
Abstract
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 ± 1, 12 ± 1 and 25/26, and post-dose stool samples obtained on Days 5 ± 1, 12 ± 1 and 26 ± 1.
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 ± 1 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 ± 1 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 ± 1. Systemic exposure to fidaxomicin and OP-1118 was low throughout and there was no evidence of accumulation in plasma or stool during treatment.
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.
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.
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.
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.
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.
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.
The article “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)”, written by M.J.G.T. Vehreschild et al., was originally published at Springerlink on 11 August 2018 without open access.
Abstract
Background
In vitro gut model evidence suggests an extended-pulsed fidaxomicin, a narrow-spectrum macrocyclic antibiotic, regimen (EPFX) may be equivalent to standard vancomycin (SV) for ...resolving Clostridium difficile infection (CDI), but with a potentially greater capacity to prevent recurrence by facilitating gut microbiota recovery. EXTEND was the first multicentre study to compare clinical outcomes for EPFX and SV; this sub-group analysis investigated the impact of baseline factors.
Methods
Patients aged ≥60 years with CDI were randomised (1:1) to receive either EPFX 200 mg tablets, twice-daily on Day 1–5 and once-daily on alternate days on Day 6–25; or SV 125 mg capsules, four-times daily on Day 1–10. The primary objective was sustained clinical cure (SCC) of CDI 30 days after end of treatment (EOT): Day 40 for SV and Day 55 for EPFX. Secondary efficacy endpoints included clinical response at Day 12 and at 2 days after EOT, and SCC at Day 40, 55 and 90. Patients who dropped out of the study after starting treatment were considered failures for SCC. Patients were stratified by baseline CDI severity, presence of cancer, and number of CDI episodes in the 3 months before the study. Primary and secondary endpoints were analyzed in these sub-groups. Deaths were also recorded and safety evaluated.
Results
Efficacy was assessed in 356 patients; 58.1% were female, median (range) age 75 (60–95) years. At baseline, 36.5% had severe CDI; 15.4% and 5.6% had one and two prior CDI episodes, respectively. The primary endpoint, SCC at 30 days after EOT, was higher for EPFX than SV in all subgroups (Figures 1–3), but did not reach statistical significance. For the secondary endpoints, differences in clinical response were not statistically significant; differences in SCC with EPFX vs. SV were significant (p value <0.05) for non-severe CDI, no cancer and no prior CDI episode on Day 40, 55 and 90. Incidence of deaths did not differ between the treatment groups: 29/183 (15.8%) EPFX and 36/181 (19.9%) SV patients; P = 0.54. Safety was similar with both treatments.
Conclusion
There was a consistent trend for higher absolute SCC in the EPFX group than the SV group across all sub-groups and time points, which reached statistical significance from Day 40 onwards in some sub-groups.
Disclosures
O. A. Cornely, Astellas Pharma, Inc.: Consultant, Research Contractor and Speaker’s Bureau, Consulting fee, Research grant and Speaker honorarium; M. J. G. T. Vehreschild, Astellas Pharma, Inc.: Investigator, Consulting fee and Research support; N. Adomakoh, Astellas Pharma, Inc.: Employee, Salary; A. Georgopali, Astellas Pharma, Inc.: Employee, Salary; A. Karas, Astellas Pharma, Inc.: Employee and Patent WO2015169451 A1 pending, Salary; G. Kazeem, Astellas Pharma, Inc.: Consultant, Salary; B. Guery, Astellas Pharma, Inc.: Investigator, Consulting fee and Research support
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