|Year : 2017 | Volume
| Issue : 6 | Page : 28-30
The bacteremia antibiotic length actually needed for clinical effectiveness research program (balance.ccctg.ca)
Nick Daneman, Asgar Rishu, Robert Fowler
Sunnybrook Hospital, the University of Toronto, Toronto, Ontario, Canada
|Date of Web Publication||23-Nov-2017|
MDCM, MS (Epi), FRCP(C), 2075 Bayview Avenue, Room D478, Sunnybrook Hospital, Toronto, Ontario
Source of Support: None, Conflict of Interest: None
A multitude of global health organizations have declared antimicrobial resistance a threat to health, based on rapidly increasing resistance rates and declining new drug development. Up to 30%–50% of antibiotic use is estimated to be inappropriate, and excessive durations of treatment are the greatest contributor to inappropriate use. A landmark trial in critically ill patients with ventilator-associated pneumonia showed that mortality and relapse rates were noninferior in patients who received 8 versus 15 days of treatment, but similar evidence is lacking for the treatment of patients with bloodstream infection, which affects 15% of critically ill patients. The Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness (BALANCE) research program was initiated to provide evidence-based guidance on this question.
Keywords: Bacteremia, critical care, duration, treatment, trial
|How to cite this article:|
Daneman N, Rishu A, Fowler R. The bacteremia antibiotic length actually needed for clinical effectiveness research program (balance.ccctg.ca). Saudi Crit Care J 2017;1, Suppl S2:28-30
|How to cite this URL:|
Daneman N, Rishu A, Fowler R. The bacteremia antibiotic length actually needed for clinical effectiveness research program (balance.ccctg.ca). Saudi Crit Care J [serial online] 2017 [cited 2023 Jun 4];1, Suppl S2:28-30. Available from: https://www.sccj-sa.org/text.asp?2017/1/6/28/219135
| Introduction|| |
A multitude of global health organizations have declared antimicrobial resistance a threat to health,,,, based on rapidly increasing resistance rates and declining new drug development.,, Up to 30%–50% of antibiotic use is estimated to be inappropriate, and excessive durations of treatment are the greatest contributor to inappropriate use.,,, A landmark trial in critically ill patients with ventilator-associated pneumonia showed that mortality and relapse rates were noninferior in patients who received 8 versus 15 days of treatment, but similar evidence is lacking for the treatment of patients with bloodstream infection, which affects 15% of critically ill patients. The Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness (BALANCE) research program was initiated to provide evidence-based guidance on this question.
| Systematic Review of the Evidence Underlying Treatment Durations for Bacteremia in Critically Ill Patients|| |
We performed a systematic review, finding a lack of prior trials evaluating shorter versus longer duration therapy for bacteremia, but among the bacteremic subgroups in trials of fixed-duration treatment for infections commonly complicated by bacteremia, shorter and longer treatments were associated with similar cure rates.
| A Survey of Infectious Diseases and Critical Care Physician Practices for Bacteremia Treatment|| |
Subsequently, we surveyed Canadian infectious diseases and critical care specialists regarding their recommended antibiotic treatment durations for five common bacteremic syndromes. For each syndrome, the most common recommendation was 14 days, yet the majority of respondents recommended durations of ≤10 days. Most respondents would not modify the duration based on host characteristics or measures of clinical response. Among respondents, infectious disease physicians recommended longer durations than critical care physicians for all five syndromes, but the majority of both specialist groups would enroll patients in a trial of shorter (7 days) versus longer (14 days) antibiotic therapy.
| A Mulitcentric Observational Study of Critically Ill Patients With Bacteremia|| |
We then undertook a multicentric observational study of 1202 patients with bloodstream infection in 14 Intensive Care Units (ICUs) in six Canadian provinces, confirming a median treatment duration of 14 days, which was also consistent across the underlying pathogens and sources of bacteremia. The most commonly identified sources for bacteremia were lung (38%), urinary tract (20%), vascular catheters (20%), intra-abdominal (16%), and skin and soft-tissue infection (8%), and ten most common pathogens accounted for the majority of cases, including Escherichia coli (15%), Staphylococcus aureus (12%), coagulase-negative staphylococci (9%), Klebsiella pneumoniae (6%), Streptococcus pneumoniae (6%), Enterococcus faecalis (6%), Pseudomonas aeruginosa (5%), Enterococcus faecium (4%), Candida albicans (4%), and Enterobacter cloacae (3%). Importantly, we found that the risk of bacteremia relapse was similar in those receiving shorter versus longer duration treatment (6% vs. 8%; P = 0.29) and treatment duration was not significantly associated with an adjusted hazard of dying. However, the influence of selection bias and survivor bias renders it impossible to determine how treatment duration impacts survival and highlights the need for a randomized clinical trial as the only valid method to assess the impact of treatment duration on survival.
| A Pilot Randomized Clinical Trial of Shorter Versus Longer Duration Therapy for Bacteremia in Critically Ill Patients|| |
Before undertaking a large definitive clinical trial, it is important to ensure feasibility of the trial protocol. We undertook a multicenter pilot trial  to evaluate adherence to the protocol, finding 85% of patients who received treatment durations within ± 1 days of their assigned duration. The main reason for nonadherence was concurrent or new-onset infection unrelated to the bacteremia, which we expect to occur in 10%–15% of patients in each arm. In addition, we found that the enrollment rate was between 1 and 2 patients per center per month, indicating that, for both protocol adherence and recruitment rate, a larger trial would be feasible to conduct.
| A Randomized Noninferiority International Clinical Trial of Shorter Versus Longer Duration Therapy for Bacteremia in Critically Ill Patients|| |
General study design
BALANCE is a multicentric, randomized, noninferiority, concealed allocation trial of shorter versus longer duration antibiotic treatment for critically ill patients with bloodstream infections.
We will randomize patients to receive 7 days versus 14 days of adequate antimicrobial treatment. Adequate antimicrobial treatment will be defined as a regimen with in vitro activity against the organism(s) responsible for the bloodstream infection, with the duration determined as the number of cumulative days for which adequate treatment is delivered beyond the date of collection of the index-positive blood culture. The selection of antimicrobial agents, doses, and delivery route will be at the discretion of treating physicians.
All patients will have the following inclusion criteria
- Patient has a positive blood culture with pathogenic bacteria
- Patient is in the ICU at time the blood culture result reported positive.
And, none of the following exclusion criteria:
- Already enrolled in this trial
- Severe immune system compromise, as defined by absolute neutrophil count <0.5 × 109/L, or is receiving immunosuppressive treatment for solid organ or stem cell transplant
- Prosthetic heart valve or synthetic endovascular graft
- Suspected or documented source of infection with well-defined requirement for prolonged treatment:
- Infective endocarditis
- Osteomyelitis/septic arthritis
- Undrainable/undrained abscess
- Unremovable/unremoved prosthetic-associated infection
- A single positive blood culture with a common contaminant organism: coagulase-negative staphylococci, Bacillus spp., Corynebacterium spp., Propionibacterium spp., and Micrococcus spp 
- Blood culture grows S. aureus or Staphylococcus lugdunensis
- Blood culture grows rare bacterial organisms requiring prolonged treatment (e.g., Mycobacteria spp., Nocardia spp., Actinomyces spp., and Brucella spp.)
- The blood culture grows fungal species.
Randomization and allocation concealment
After seeking permission from the treating team, eligible patients with positive blood cultures (or substitute decision-makers as appropriate) will be approached for inclusion. Consented patients will be randomized centrally using a computerized random number generator with concealed allocation, variable undisclosed block sizes, and stratification by ICU site. To avoid differentially influencing antibiotic choices and clinical decision-making, the randomization assignment will not be communicated to the study research coordinators, investigators, or clinicians until the end of day 7, a blinding procedure proven feasible in other landmark critical care trials and in our pilot trial.
Primary and secondary outcome measures
The primary outcome will be survival at 90 days from the date of bacteremia, defined by the date of collection of the index-positive blood culture. The secondary outcomes include: (a) Hospital mortality, (b) ICU mortality, (c) relapse of bacteremia, (d) ICU length of stay, (e) hospital length of stay, (f) mechanical ventilation duration, (g) vasopressor duration, (h) antibiotic-free days, (i) Clostridium difficile, (j) antibiotic adverse events, and (k) colonization/infection with antimicrobial-resistant organisms.
Sample size calculation
The primary analysis will assess whether 7 days' treatment has noninferior 90-day survival rates in comparison to 14 days and will require 1686 patients per arm to establish a noninferiority margin of − 4% absolute decrement in survival (baseline mortality 22%, power 80%, alpha 0.025, one-sided equivalence test). We have inflated this to account for 5% loss to follow-up, and early stopping rules (coefficient: 1.017), for a total sample size of 3598.
Summary and Relevance
The BALANCE trial will answer the question of whether critically ill patients with bloodstream infection can be treated with a substantially shorter duration of antibiotic therapy. If shorter duration treatment is noninferior to longer duration treatment, annual direct antimicrobial cost savings for bacteremia could range from $678–798 million in North America and $1.4–1.6 billion in Europe. The findings may also be generalizable to nonbacteremic and noncritically ill populations and hence could generate larger health system wide reductions in unnecessary antimicrobial consumption, costs, complications, and resistance.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
World Health Organization Antimicrobial Resistance: Global Report on Surveillance 2014. Geneva, Switzerland: WHO Press; 2014.
Ambrose R. Minister of Health Unveils Plan to Tackle Antimicrobial Resistance in Canada; 2014.
Grant J, Saxinger L, Patrick D. Surveillance of Antimicrobial Resistance and Antimicrobial Utilization in Canada. Winnipeg, Manitoba: National Collaborating Centre for Infectious Diseases, 14 A.D.; 2014.
Centers for Disease Control and Prevention. Antibiotic Resistance Threats in the United States. Department of Human and Health Services; 2013.
Spellberg B, Guidos R, Gilbert D, Bradley J, Boucher HW, Scheld WM, et al.
The epidemic of antibiotic-resistant infections: A call to action for the medical community from the infectious diseases society of America. Clin Infect Dis 2008;46:155-64.
Gaynes RP. Preserving the effectiveness of antibiotics. J Am Med Assoc 2010;303:2293-4.
Boucher HW, Talbot GH, Bradley JS, Edwards JE, Gilbert D, Rice LB, et al.
Bad bugs, no drugs: No ESKAPE! An update from the infectious diseases society of America. Clin Infect Dis 2009;48:1-2.
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;46:491-6.
Hecker MT, Aron DC, Patel NP, Lehmann MK, Donskey CJ. Unnecessary use of antimicrobials in hospitalized patients: Current patterns of misuse with an emphasis on the antianaerobic spectrum of activity. Arch Intern Med 2003;163:972-8.
Hurley HJ, Knepper BC, Price CS, Mehler PS, Burman WJ, Jenkins TC, et al.
Avoidable antibiotic exposure for uncomplicated skin and soft tissue infections in the ambulatory care setting. Am J Med 2013;126:1099-106.
Daneman N, Gruneir A, Bronskill SE, Newman A, Fischer HD, Rochon PA, et al.
Prolonged antibiotic treatment in long-term care: Role of the prescriber. JAMA Intern Med 2013;173:673-82.
Chastre J, Wolff M, Fagon JY, Chevret S, Thomas F, Wermert D, et al.
Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: A randomized trial. JAMA 2003;290:2588-98.
Havey TC, Fowler RA, Daneman N. Duration of antibiotic therapy for bacteremia: A systematic review and meta-analysis. Crit Care 2011;15:R267.
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;38:480-5.
Daneman N, Rishu AH, Xiong W, Bagshaw SM, Dodek P, Hall R, et al.
Duration of antimicrobial treatment for bacteremia in Canadian critically ill patients. Crit Care Med 2016;44:256-64.
Daneman N, Rishu AH, Xiong W, Bagshaw SM, Cook DJ, Dodek P, et al.
Bacteremia antibiotic length actually needed for clinical effectiveness (BALANCE): Study protocol for a pilot randomized controlled trial. Trials 2015;16:173.
O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics 1979;35:549-56.
Jennison C, Turnbull B. Group Sequential Methods with Applications to Clinical Trials. Boca Raton, Florida: CRC Press; 2015.
Daneman N, Rishu A, Xiong W, Palmay L, Fowler RA. Antimicrobial cost savings associated with shorter duration treatment for bloodstream infections. Official Journal of the Association of Medical Microbiology and Infectious Disease Canada. 2016;1:32-4.