Comparative pharmacokinetics of the three echinocandins in ICU patients

International audienceAbstract Background We conducted a prospective study in ICU patients of two tertiary hospitals in order to determine basic pharmacokinetic (PK) parameters, associated variation and target attainment rates for anidulafungin, micafungin and caspofungin. Methods Serum samples from patients treated for 7 days with the standard doses of anidulafungin (N = 13), micafungin (N = 14) or caspofungin (N = 7) were analysed by validated chromatographic methods. PK parameters determined with non-compartmental analysis were correlated with demographic, laboratory and disease severity characteristics. The percentages of patients attaining drug exposures described in the summary of product characteristics (SmPC) documents and preclinical PK/PD targets for stasis were estimated. Results The median (range) AUC24 was 101.46 (54.95–274.15) mg·h/L for anidulafungin, 79.35 (28.00–149.30) mg·h/L for micafungin and 48.46 (19.44–103.69) mg·h/L for caspofungin. The interindividual variability of anidulafungin, micafungin and caspofungin AUC24 was 46%–58%, attributed mainly to variability in volume of distribution (V), clearance (CL) and in both V and CL, respectively. Significant correlations were found between anidulafungin AUC24 and BMI (rs = −0.670, P = 0.012) and liver enzymes (rs = 0.572–0.665, P = 0.013–0.041) and between caspofungin Cmin and transaminase levels (rs = −0.775 to −0.786, P = 0.036–0.041). Less than 50% of our patients attained the corresponding SmPC median AUC24s and none of the patients attained the PK/PD targets for Candida albicans and Candida parapsilosis. Conclusions Anidulafungin exposure in ICU patients was comparable with that reported in non-ICU patients and in healthy volunteers. Micafungin exposure was comparable to that of other patients but ∼30% lower than that in healthy volunteers, whereas caspofungin exposure was rather low (∼50% lower than in healthy volunteers). Larger interindividual variability (50%–60%) was recorded in ICU patients compared with other groups for all three echinocandins

Evaluation of a quality improvement intervention to reduce anastomotic leak following right colectomy (EAGLE): pragmatic, batched stepped-wedge, cluster-randomized trial in 64 countries

Background Anastomotic leak affects 8 per cent of patients after right colectomy with a 10-fold increased risk of postoperative death. The EAGLE study aimed to develop and test whether an international, standardized quality improvement intervention could reduce anastomotic leaks. Methods The internationally intended protocol, iteratively co-developed by a multistage Delphi process, comprised an online educational module introducing risk stratification, an intraoperative checklist, and harmonized surgical techniques. Clusters (hospital teams) were randomized to one of three arms with varied sequences of intervention/data collection by a derived stepped-wedge batch design (at least 18 hospital teams per batch). Patients were blinded to the study allocation. Low- and middle-income country enrolment was encouraged. The primary outcome (assessed by intention to treat) was anastomotic leak rate, and subgroup analyses by module completion (at least 80 per cent of surgeons, high engagement; less than 50 per cent, low engagement) were preplanned. Results A total 355 hospital teams registered, with 332 from 64 countries (39.2 per cent low and middle income) included in the final analysis. The online modules were completed by half of the surgeons (2143 of 4411). The primary analysis included 3039 of the 3268 patients recruited (206 patients had no anastomosis and 23 were lost to follow-up), with anastomotic leaks arising before and after the intervention in 10.1 and 9.6 per cent respectively (adjusted OR 0.87, 95 per cent c.i. 0.59 to 1.30; P = 0.498). The proportion of surgeons completing the educational modules was an influence: the leak rate decreased from 12.2 per cent (61 of 500) before intervention to 5.1 per cent (24 of 473) after intervention in high-engagement centres (adjusted OR 0.36, 0.20 to 0.64; P < 0.001), but this was not observed in low-engagement hospitals (8.3 per cent (59 of 714) and 13.8 per cent (61 of 443) respectively; adjusted OR 2.09, 1.31 to 3.31). Conclusion Completion of globally available digital training by engaged teams can alter anastomotic leak rates. Registration number: NCT04270721 (http://www.clinicaltrials.gov)