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

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

Abstract

Background: Shorter-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.

Methods: We 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.

Results: We 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.

Conclusion: It is feasible to conduct a RCT to determine whether 7 versus 14 days of antibiotic treatment is associated with comparable 90-day survival.

Trial registration: ClinicalTrials.gov , identifier: NCT02261506 . Registered on 26 September 2014.

Keywords: Bacteremia; Bloodstream infection; Critical care; Duration of treatment; Intensive care.

Conflict of interest statement

Ethics approval and consent to participate

Informed consent as approved by the following Research Ethics Boards was obtained from all the participants or substitute decision-maker (SDM) as appropriate.

Research Ethics Committee approval was obtained at the following participating sites:

Sunnybrook Health Sciences Center Research Ethics Board, Toronto, ON.

Research Ethics Board, Queen’s university, Kingston, ON.

Capital Health Research Ethics Board, Halifax, NS.

Ottawa Hospital Research Ethics Boards, Ottawa, ON.

Comité d’éthique de la recherché du CIUSSS de l’Estrie – CHUS, Sherbrooke, QC.

University of Manitoba Health Research Ethics Board, Winnipeg, MB.

Comité d’évaluation scientifique, Centre de Recherche CHUS, Québec, QC.

Research Ethics Board, Mount Sinai Hospital, ON.

Research Ethics Board, University of Western Ontario, London, ON.

Research Ethics Office, University of Alberta, Edmonton, AB

Consent for publication

Not applicable

Competing interests

Dr. Nick Daneman is supported by a Clinician Scientist salary award from the Canadian Institutes of Health Research (CIHR). Dr. Rob Fowler is supported by a personnel award from the Heart and Stroke Foundation, Ontario Provincial Office. Dr. Deborah Cook holds a Canada Research Chair of Research Transfer in Intensive Care. Drs. Lauzier and Lamontagne hold a career award from the Fonds de Recherche du Québec-Santé. Dr. John Marshall is an associate editor for Critical Care. Dr. Sean Bagshaw holds a Canada Research Chair in Critical Care Nephrology. Dr. HT Stelfox is supported by a Population Health Investigator Award from Alberta Innovates and an Embedded Clinician Researcher Award from CIHR. This pilot randomized controlled trial was supported by operating funds from the Ontario Ministry of Health and Long-Term Care Academic Health Sciences Alternate Funding Plan Innovation Fund Award, and bridge funding from the Canadian Institutes of Health Research. The BALANCE main trial is supported by a Project Grant from the Canadian Institutes of Health Research.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Consolidated Standards of Reporting Trials (CONSORT) flow diagram describing eligibility screening and randomization assessments

References

    1. Rice LB. The Maxwell Finland Lecture: for the duration-rational antibiotic administration in an era of antimicrobial resistance and Clostridium difficile. Clin Infect Dis. 2008;46(4):491–496. doi: 10.1086/526535.
    1. el MR, de Borgie CA, den BP V, et al. Effectiveness of discontinuing antibiotic treatment after three days versus eight days in mild to moderate-severe community acquired pneumonia: randomised, double blind study. BMJ. 2006;332(7554):1355. doi: 10.1136/bmj.332.7554.1355.
    1. Hepburn MJ, Dooley DP, Skidmore PJ, Ellis MW, Starnes WF, Hasewinkle WC. Comparison of short-course (5 days) and standard (10 days) treatment for uncomplicated cellulitis. Arch Intern Med. 2004;164(15):1669–1674. doi: 10.1001/archinte.164.15.1669.
    1. Eliakim-Raz N, Yahav D, Paul M, Leibovici L. Duration of antibiotic treatment for acute pyelonephritis and septic urinary tract infection—7 days or less versus longer treatment: systematic review and meta-analysis of randomized controlled trials. J Antimicrob Chemother. 2013;68(10):2183-91.
    1. Rafailidis PI, Pitsounis AI, Falagas ME. Meta-analyses on the optimization of the duration of antimicrobial treatment for various infections. Infect Dis Clin N Am. 2009;23(2):269–276. doi: 10.1016/j.idc.2009.01.009.
    1. Chastre J, Wolff M, Fagon JY, et al. Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial. JAMA. 2003;290(19):2588–2598. doi: 10.1001/jama.290.19.2588.
    1. Havey TC, Fowler RA, Daneman N. Duration of antibiotic therapy for bacteremia: a systematic review and meta-analysis. Crit Care. 2011;15(6):R267. doi: 10.1186/cc10545.
    1. Daneman N, Shore K, Pinto R, Fowler R. Antibiotic treatment duration for bloodstream infections in critically ill patients: a National Survey of Canadian Infectious Diseases and Critical Care Specialists. Int J Antimicrob Agents. 2011;38:480–485. doi: 10.1016/j.ijantimicag.2011.07.016.
    1. Havey T, Fowler R, Pinto R, Elligsen M, Daneman N. Duration of antibiotic therapy in intensive care unit bloodstream infections. Can J Infect Dis Med Microbiol. 2013;24(3):129–137.
    1. Daneman N, Rishu AH, Xiong W, et al. Duration of Antimicrobial Treatment for Bacteremia in Canadian Critically Ill Patients. Crit Care Med. 2016;44(2):256–264. doi: 10.1097/CCM.0000000000001393.
    1. Daneman N, Rishu A, Xiong W, Palmay L, Fowler RA. Antimicrobial cost savings associated with shorter duration treatment for bloodstream infections. JAMMI. 2016;1(2):33-34.
    1. Daneman N, Rishu AH, Xiong W, et al. Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness (BALANCE): study protocol for a pilot randomized controlled trial. Trials. 2015;16(1):173. doi: 10.1186/s13063-015-0688-z.
    1. Eldridge SM, Chan CL, Campbell MJ, et al. CONSORT 2010 statement: extension to randomised pilot and feasibility trials. Pilot Feasibility Stud. 2016;2:64. doi: 10.1186/s40814-016-0105-8.
    1. Sandberg T, Skoog G, Hermansson AB, et al. Ciprofloxacin for 7 days versus 14 days in women with acute pyelonephritis: a randomised, open-label and double-blind, placebo-controlled, non-inferiority trial. Lancet. 2012;380(9840):484–490. doi: 10.1016/S0140-6736(12)60608-4.
    1. Jernelius H, Zbornik J, Bauer CA. One or three weeks’ treatment of acute pyelonephritis? A double-blind comparison, using a fixed combination of pivampicillin plus pivmecillinam. Acta Med Scand. 1988;223(5):469–477. doi: 10.1111/j.0954-6820.1988.tb15899.x.
    1. Agarwal G, Awasthi S, Kabra SK, Kaul A, Singhi S, Walter SD. Three day versus five day treatment with amoxicillin for non-severe pneumonia in young children: a multicentre randomised controlled trial. BMJ. 2004;328(7443):791. doi: 10.1136/.
    1. Clinical efficacy of 3 days versus 5 days of oral amoxicillin for treatment of childhood pneumonia: a multicentre double-blind trial. Lancet. 2002;360(9336):835-841.
    1. Dunbar LM, Wunderink RG, Habib MP, et al. High-dose, short-course levofloxacin for community-acquired pneumonia: a new treatment paradigm. Clin Infect Dis. 2003;37(6):752–760. doi: 10.1086/377539.
    1. Tellier G, Niederman MS, Nusrat R, Patel M, Lavin B. Clinical and bacteriological efficacy and safety of 5 and 7 day regimens of telithromycin once daily compared with a 10 day regimen of clarithromycin twice daily in patients with mild to moderate community-acquired pneumonia. J Antimicrob Chemother. 2004;54(2):515–523. doi: 10.1093/jac/dkh356.
    1. de Smet AM, Kluytmans JA, Blok HE, et al. Selective digestive tract decontamination and selective oropharyngeal decontamination and antibiotic resistance in patients in intensive-care units: an open-label, clustered group-randomised, crossover study. Lancet Infect Dis. 2011;11(5):372–380. doi: 10.1016/S1473-3099(11)70035-4.
    1. Savage RD, Fowler RA, Rishu AH, et al. The effect of inadequate initial empiric antimicrobial treatment on mortality in critically ill patients with bloodstream infections: a multi-centre retrospective cohort study. PLoS One. 2016;11(5):e0154944. doi: 10.1371/journal.pone.0154944.
    1. Dethlefsen L, Relman DA. Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc Natl Acad Sci U S A. 2011;108(Suppl 1):4554–4561. doi: 10.1073/pnas.1000087107.
    1. Arnold DM, Burns KE, Adhikari NK, Kho ME, Meade MO, Cook DJ. The design and interpretation of pilot trials in clinical research in critical care. Crit Care Med. 2009;37(1 Suppl):S69–S74. doi: 10.1097/CCM.0b013e3181920e33.
    1. Bouadma L, Luyt CE, Tubach F, et al. Use of procalcitonin to reduce patients’ exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial. Lancet. 2010;375(9713):463–474. doi: 10.1016/S0140-6736(09)61879-1.
    1. Kopterides P, Siempos II, Tsangaris I, Tsantes A, Armaganidis A. Procalcitonin-guided algorithms of antibiotic therapy in the intensive care unit: a systematic review and meta-analysis of randomized controlled trials. Crit Care Med. 2010;38(11):2229–2241. doi: 10.1097/CCM.0b013e3181f17bf9.
    1. Prkno A, Wacker C, Brunkhorst FM, Schlattmann P. Procalcitonin-guided therapy in intensive care unit patients with severe sepsis and septic shock—a systematic review and meta-analysis. Crit Care. 2013;17(6):R291. doi: 10.1186/cc13157.
    1. Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med. 1999;340(6):409–417. doi: 10.1056/NEJM199902113400601.

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