The bacteremia antibiotic length actually needed for clinical effectiveness research program (balance.ccctg.ca)

Nick Daneman; Asgar Rishu; Robert Fowler

doi:10.4103/2543-1854.219135

REVIEW ARTICLE

Year : 2017 | Volume : 1 | 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

Correspondence Address:
Robert Fowler
MDCM, MS (Epi), FRCP(C), 2075 Bayview Avenue, Room D478, Sunnybrook Hospital, Toronto, Ontario
Canada

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/2543-1854.219135

Abstract

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,^{[1],[2],[3],[4]} based on rapidly increasing resistance rates and declining new drug development.^[5],[6],[7] Up to 30%–50% of antibiotic use is estimated to be inappropriate, and excessive durations of treatment are the greatest contributor to inappropriate use.^{[8],[9],[10],[11]} 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,^[12] 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.^[13]

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.^[14] 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.^[15] 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 ^[16] 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.^[16] 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.^[17]

Intervention

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.

Eligibility criteria

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:
1. Infective endocarditis
2. Osteomyelitis/septic arthritis
3. Undrainable/undrained abscess
4. 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 ^[2]
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.^[12]

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)^[18],[19] 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.^[20] 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

Nil.

Conflicts of interest

There are no conflicts of interest.

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