7 versus 14\xa0days of antibiotic treatment for critically ill patients with bloodstream infection: a pilot randomized clinical trial

Nick Daneman,Wendy Sligl,Steven Reynolds,John C Marshall,Richard Hall,M Elizabeth Wilcox,Claudio M Martin,Sean M Bagshaw,Alex Carignan,Lauralyn Mcintyre,Bryan Coburn,Michael E Detsky,François Lauzier ,Emmanuel Charbonney,John Muscedere,Henry T Stelfox,Peter Dodek,Asgar Rishu ,Anand Kumar,Deborah J Cook,François Lamontagne ,Pierre Aslanian,Ruxandra Pinto,Robert Fowler

doi:10.1186/s13063-018-2474-1

Abstract

BackgroundShorter-duration antibiotic treatment is sufficient for a range of bacterial infections, but has not been adequately studied for bloodstream infections. Our systematic review, survey, and observational study indicated equipoise for a trial of 7 versus 14 days of antibiotic treatment for bloodstream infections; a pilot randomized clinical trial (RCT) was a necessary next step to assess feasibility of a larger trial.MethodsWe conducted an open, pilot RCT of antibiotic treatment duration among critically ill patients with bloodstream infection across 11 intensive care units (ICUs). Antibiotic selection, dosing and route were at the discretion of the treating team; patients were randomized 1:1 to intervention arms consisting of two fixed durations of treatment – 7 versus 14 days. We recruited adults with a positive blood culture yielding pathogenic bacteria identified while in ICU. We excluded patients with severe immunosuppression, foci of infection with an established requirement for prolonged treatment, single cultures with potential contaminants, or cultures yielding Staphylococcus aureus or fungi. The primary feasibility outcomes were recruitment rate and adherence to treatment duration protocol. Secondary outcomes included 90-day, ICU and hospital mortality, relapse of bacteremia, lengths of stay, mechanical ventilation and vasopressor duration, antibiotic-free days, Clostridium difficile, antibiotic adverse events, and secondary infection with antimicrobial-resistant organisms.ResultsWe successfully achieved our target sample size (n = 115) and average recruitment rate of 1 (interquartile range (IQR) 0.3–1.5) patient/ICU/month. Adherence to treatment duration was achieved in 89/115 (77%) patients. Adherence differed by underlying source of infection: 26/31 (84%) lung; 18/29 (62%) intra-abdominal; 20/26 (77%) urinary tract; 8/9 (89%) vascular-catheter; 4/4 (100%) skin/soft tissue; 2/4 (50%) other; and 11/12 (92%) unknown sources. Patients experienced a median (IQR) 14 (8–17) antibiotic-free days (of the 28 days after blood culture collection). Antimicrobial-related adverse events included hepatitis in 1 (1%) patient, Clostridium difficile infection in 4 (4%), and secondary infection with highly resistant microorganisms in 10 (9%). Ascertainment was complete for all study outcomes in ICU, in hospital and at 90 days.ConclusionIt is feasible to conduct a RCT to determine whether 7 versus 14 days of antibiotic treatment is associated with comparable 90-day survival.Trial registrationClinicalTrials.gov, identifier: NCT02261506. Registered on 26 September 2014.

Highlights

Shorter-duration antibiotic treatment is sufficient for a range of bacterial infections, but has not been adequately studied for bloodstream infections
Both antibiotic use and the acquisition of antibioticresistant organisms are high in intensive care units (ICUs), where critically ill patients are vulnerable to bacterial infections and antibiotic complications
Randomized clinical trials (RCTs) have established that shorter-duration treatments are sufficient for a wide range of bacterial infections [1,2,3,4,5], including some infections among critically ill patients [6], but the optimal treatment duration for bloodstream infections remains understudied

Summary

Introduction

Shorter-duration antibiotic treatment is sufficient for a range of bacterial infections, but has not been adequately studied for bloodstream infections. In single [9] and multicenter [10] observational studies of actual practice, we confirmed that critically ill patients with bacteremia receive a median of 14 days of treatment, but with wide variability (interquartile range (IQR) 9–17.5 days), further justifying the need for a trial comparing 7 versus 14 days of treatment If such a trial could establish that 7 days is non-inferior to 14 days of treatment, this could lead to massive reductions in antimicrobial use, resistance and complications, and an estimated annual cost savings of $678 to 798 million in North America and $1.4 to 1.6 billion across Europe [11]

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Results

Conclusion