Re-Setting the Antibiotic Course - this time using a map and a compass
We read the analysis by Llewelyn and colleagues, entitled “The antibiotic course has had its day” with interest and shared enthusiasm. We agree that the ‘complete the course’ dogma is outdated - as the authors argue because individual patient and pathogen factors should logically influence the course; and, also because there is still little to no evidence informing the duration of the default “course” for many infections.(1) Selecting resistance in the target pathogen is indeed a flimsy argument to lengthen antibiotic treatment, whereas selecting resistance in bystander flora is a strong argument to shorten antibiotic treatment. We also agree that ‘stop when you feel better’ is a more patient-centered approach to antibiotic treatment in many circumstances, and could lead to broad reductions in antimicrobial use for many types of infection.
However, we would like to point out that this approach could paradoxically lead to unnecessary increased durations of treatment for many types of infection in which clinical signs and symptoms of inflammation persist beyond cure of the inciting pathogen. A classic example is cellulitis, in which pain, redness and swelling can endure long after the last pathogenic Streptococcus is dead. We are particularly concerned about prolonged antibiotic treatment of critically ill patients, among whom infection often incites prolonged systemic inflammatory response. Ongoing fever, leukocytosis, ventilator dependence and other organ dysfunction can persist after the triggering microbe is quashed, and so there is no clinical test of cure or stopping rule to guide cessation of treatment. The future may lie in biomarker-based tests, but the currently best studied of these (procalcitonin) is associated with limited accuracy and poor clinician adherence.(2,3,4) From a global perspective, access to biomarker-based tests of cure will likely remain limited in most low- and many middle-income settings. While further efforts are being made towards a precision medicine approach to antibiotic treatment duration, we believe it is important to establish a better evidence base for treatment courses by challenging the current recommendations.
Therefore, we have recently launched the Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness (BALANCE) Randomized Controlled Trial of 7 versus 14 days of treatment for critically ill patients with bloodstream infection (clinicaltrials.gov NCT03005145). The BALANCE trial was justified and shaped by extensive preparatory work including a systematic review, national practice survey, multicentre observational study, and pilot randomized controlled trial.(1,5,6,7) Together these studies demonstrated an absence of prior evidence to guide treatment duration, wide variability in actual and stated treatment durations, and the equipoise and feasibility for a trial of shorter versus longer treatment. BALANCE is an investigator-initiated, international trial, in which antibiotic selection, dose, route and duration are left to the treating team, but duration will be randomized to fixed shorter (7 days) or longer (14 days) treatment. The large sample size (n=3600) is intended to provide the statistical power to establish non-inferior 90-day survival with 7 days of treatment, but should also provide power to examine (i) variability in time-to-symptom and sign resolution among all patients, (ii) the performance of biomarkers such as procalcitonin in identifying safe stopping points, and (iii) secondary antimicrobial resistance and diversity of the gut microbiome in patients receiving shorter versus longer treatment. If BALANCE establishes a new and shorter optimal average treatment duration for this infectious syndrome, then additional tailored approaches will help us work at further individualizing treatment duration at the margins. It is time to re-set the antibiotic course, with a map to know the duration to go, and a compass to know if we are heading in the right direction.
Dr. Nick Daneman and Dr. Rob Fowler
Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada
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.
2. Tang BM, Eslick GD, Craig JC, McLean AS. Accuracy of procalcitonin for sepsis diagnosis in critically ill patients: systematic review and meta-analysis. Lancet Infect Dis 2007;7(3):210-217.
3. 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.
4. Chu DC, Mehta AB, Walkey AJ. Practice Patterns and Outcomes Associated With Procalcitonin Use in Critically Ill Patients With Sepsis. Clin Infect Dis 2017;64(11):1509-1515.
5. 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.
6. 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.
7. 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.
Competing interests: No competing interests