PIRATE project: point-of-care, informatics-based randomised controlled trial for decreasing overuse of antibiotic therapy in Gram-negative bacteraemia

Abstract

IntroductionAntibiotic overuse drives antibiotic resistance. The optimal duration of antibiotic therapy for Gram-negative bacteraemia (GNB), a common community and hospital-associated infection, remains unknown and unstudied via randomised controlled trials (RCTs).Methods and analysisThis investigator-initiated, multicentre, non-inferiority, informatics-based point-of-care RCT will randomly assign adult hospitalised patients receiving microbiologically efficacious antibiotic(s) for GNB to (1) 14 days of antibiotic therapy, (2) 7 days of therapy or (3) an individualised duration determined by clinical response and 75% reduction in peak C reactive protein (CRP) values. The randomisation will occur in equal proportions (1:1:1) on day 5 (±1) of efficacious antibiotic therapy as determined by antibiogram; patients, their physicians and study investigators will be blind to treatment duration allocation until the day of antibiotic discontinuation. Immunosuppressed patients and those with GNB due to complicated infections (endocarditis, osteomyelitis, etc) and/or non-fermenting bacilli (Acinetobacter spp, Burkholderia spp, Pseudomonas spp) Brucella spp, Fusobacterium spp or polymicrobial growth with Gram-positive organisms will be ineligible. The primary outcome is incidence of clinical failure at day 30; secondary outcomes include clinical failure, all-cause mortality and incidence of Clostridiumdifficile infection in the 90-day study period. An interim safety analysis will be performed after the first 150 patients have been followed for ≤30 days. Given a chosen margin of 10%, the required sample size to determine non-inferiority is roughly 500 patients. Analyses will be performed on both intention-to-treat and per-protocol populations.Ethics and disseminationEthics approval was obtained from the cantonal ethics committees of all three participating sites. Results of the main trial and each of the secondary endpoints will be submitted for publication in a peer-reviewed journal.Trial registration numberThis trial is registered at www.clinicaltrials.gov (NCT03101072; pre-results).

How representative is a point-of-care randomized trial? Clinical outcomes of patients excluded from a point-of-care randomized controlled trial evaluating antibiotic duration for Gram-negative bacteraemia: a multicentre prospective observational cohort study

“…Patients were eligible for participation in "EPCO" (Excluded Patients' Clinical Outcomes), a prospective observational cohort study, if they had been excluded from the PIRATE trial at two of its three sites (Geneva and St. Gallen). The PIRATE trial's methods and results have been published previously [5,6]; briefly, this RCT was conducted between 2017 and 2019 in three Swiss hospitals. Adult hospitalized patients with Gram-negative bacteremia were randomized on the fifth day of effective antibiotic therapy to 7-day, 14-day, or C-reactiveprotein (CRP)-guided antibiotic durations; in the latter group, antibiotics were discontinued when CRP levels decreased by 75% from peak.…”

Effect of C-Reactive Protein–Guided Antibiotic Treatment Duration, 7-Day Treatment, or 14-Day Treatment on 30-Day Clinical Failure Rate in Patients With Uncomplicated Gram-Negative Bacteremia

“…Patients with fever or hemodynamic instability in the 24 hours prior to recruitment, severe immunosuppression (see eAppendix 1 in Supplement 3), bacteremia with nonfermenting bacilli or polymicrobial, gram-positive growth, recurrent bacteremia (initial bacteremia in the preceding 60 days), or complicated infections (eg, abscess, endocarditis) were not eligible for inclusion. 11 Race or ethnicity was recorded to allow clinician readers to assess the demographic similarity of this trial population with that of their own clinical populations. Race/ ethnicity was determined by self-report when feasible and otherwise requested from the patient's representative, and was reported according to fixed categories per US Food and Drug Administration guidance.…”

“…The median (IQR) number of antibiotic days of therapy throughout the 90-day study period was 9 (8)(9)(10)(11)(12)(13)(14) in the CRPguided group, 9 (7-14) in the 7-day group, and 16 (14-18) in the 14-day group (P < .001 for CRP-guided vs 14-day and 7-day vs 14-day groups). Median (IQR) hospital length of stay was similar across groups, with 10 (6-19) days in the CRP-guided group, 10 (6-17) in the 7-day group, and 9 (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) in the 14-day group. Deviations from the assigned treatment duration were due to the physician's decision in the absence of suspected complication, failure, or adverse effect in 4 of 34 patients (12%) in the CRP-guided group, 10 of 25 (40%) in the 7-day group, and 2 of 20 (10%) in the 14-day group (eTable 3 in Supplement 3).…”

Effects of County Public Hospital Reform on Procurement Costs and Volume of Antibiotics: A Quasi-Natural Experiment in Hubei Province, China

“…The irrational over-use of antibiotics has been identified as a key driver for the rapid development and spread of antibiotic resistance, an alarming global public health threat [ 1 ]. Concern about a potential shortage of effective antibiotics is increasing [ 2 ].…”