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Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness (BALANCE): study protocol for… Daneman, Nick; Rishu, Asgar H; Xiong, Wei; Bagshaw, Sean M; Cook, Deborah J; Dodek, Peter; Hall, Richard; Kumar, Anand; Lamontagne, Francois; Lauzier, Francois; Marshall, John C; Martin, Claudio M; McIntyre, Lauralyn; Muscedere, John; Reynolds, Steven; Stelfox, Henry T; Fowler, Robert A Apr 18, 2015

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STUDY PROTOCOL Open AccessBacteremia Antibiotic Length Actually Needed forClinical Effectiveness (BALANCE): study protocolntrolled trialwhich will evaluate shorter versus longer duration treatment for bacteremia in critically ill patients, and therebyprovide an evidence basis for treatment duration decisions for these infections.TRIALSDaneman et al. Trials  (2015) 16:173 DOI 10.1186/s13063-015-0688-zBayview Ave, Toronto, Ontario M4N 3M5, CanadaFull list of author information is available at the end of the articleTrial registration: The Pilot Trial was registered on 26 September 2014. Trial registration number: NCT02261506.Keywords: intensive care, critically ill, bacteremia, bloodstream infection, antimicrobial, treatment duration,mortality, antimicrobial stewardship* Correspondence: nick.daneman@sunnybrook.ca1Division of Infectious Diseases & Clinical Epidemiology, Sunnybrook HealthSciences Centre, University of Toronto and Adjunct Scientist, Institute forClinical Evaluative Sciences, Sunnybrook Health Sciences Centre, 2075Nick Daneman1*, Asgar H Rishu2, Wei Xiong2, Sean M Bagshaw3, Deborah J Cook4, Peter Dodek5, Richard Hall6,Anand Kumar7, Francois Lamontagne8, Francois Lauzier9, John C Marshall10, Claudio M Martin11,Lauralyn McIntyre12, John Muscedere13, Steven Reynolds14, Henry T Stelfox15, Robert A Fowler16 and on behalf ofthe Canadian Critical Care Trials GroupAbstractBackground: Bacteremia is a leading cause of mortality and morbidity in critically ill adults. No previousrandomized controlled trials have directly compared shorter versus longer durations of antimicrobial treatment inthese patients.Methods/Design: This is a multicenter pilot randomized controlled trial in critically ill patients with bacteremia.Eligible patients will be adults with a positive blood culture with pathogenic bacteria identified while in theintensive care unit. Eligible, consented patients will be randomized to either 7 days or 14 days of adequateantimicrobial treatment for the causative pathogen(s) detected on blood cultures. The diversity of pathogens andtreatment regimens precludes blinding of patient and clinicians, but allocation concealment will be extended today 7 and outcome adjudicators will be blinded. The primary outcome for the main trial will be 90-day mortality.The primary outcome for the pilot trial is feasibility defined by (i) rate of recruitment exceeding 1 patient per siteper month and (ii) adherence to treatment duration protocol ≥ 90%. Secondary outcomes include intensive careunit, hospital and 90-day mortality rates, relapse rates of bacteremia, antibiotic-related side effects and adverseevents, rates of Clostridium difficile infection, rates of secondary infection or colonization with antimicrobial resistantorganisms, ICU and hospital lengths of stay, mechanical ventilation and vasopressor duration in intensive care unit,and procalcitonin levels on the day of randomization, and day 7, 10 and 14 after the index blood culture.Discussion: The BALANCE pilot trial will inform the design and execution of the subsequent BALANCE main trial,for a pilot randomized co© 2015 Daneman et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly credited. The Creative Commons Public DomainDedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,unless otherwise stated.Daneman et al. Trials  (2015) 16:173 Page 2 of 10BackgroundBacteremia is a common and serious problem affecting15% of critically ill patients and resulting in a threefoldhigher mortality [1,2]. Among survivors, bacteremia isassociated with a 2 to 7 day prolongation of intensivecare unit (ICU) length of stay, a 2 to 3 week prolonga-tion of hospital stay, and $25,000 to $40,000 in attribut-able excess costs [3,4].The ICU is the location of greatest antimicrobial usein most hospitals; however, audits have revealed that 30to 50% of antibiotic use in the ICU is unnecessary or in-appropriate [5-7] and leads to avoidable drug side ef-fects. Antibiotics are among the most common cause ofserious adverse drug events [8], which occur in up to 5to 10% of inpatient recipients [9]. Excessive durations ofantibiotic therapy are the greatest contributor to inappro-priate antibiotic use in acute care hospitals, long-term carefacilities, and ambulatory care [6,10-12]. Discontinuing an-tibiotics after achieving clinical cure can potentially reducethe burden of adverse events (allergy and organ toxicity),Clostridium difficile infections, and additional costs andmorbidity related to selection of antimicrobial resistantpathogens [13,14] Antibiotic resistance rates are risingamong pathogens in ICUs [15] at the same time as thedrug discovery pipeline is diminishing with very few newantimicrobial agents under development [16,17].Meta-analysis of randomized controlled trials has demon-strated that shorter duration antibiotic therapy is as effect-ive as longer duration antibiotic therapy for a range of mildto moderate infections [18]. Even in critically ill patientswith ventilator-associated pneumonia, mortality rates andrelapse rates were non-inferior among the 402 patients (ofwhich only 7% were bacteremic) randomized to receiveshorter (8 day) versus longer (15 day) courses of antibiotics[19]. However, similar high-grade evidence is lacking forthe treatment of patients with bloodstream infections[1,20,21]. Specific guidelines for treatment durations existfor a variety of infections in ICU, including pneumonia[22,23], intra-abdominal infection [24], catheter-relatedbloodstream infection [25], pyelonephritis [26], and skinand soft tissue infection [27] but no guidelines exist for theoptimal duration of treatment for bacteremic patients.We have performed a systematic review of the existingliterature [21], a national practice survey of InfectiousDiseases (ID) and critical care physicians [28], a singlecenter observational study [29], and a multicenter observa-tional study [Daneman N, Rishu AH, Xiong W, BagshawSM, Dodek P, Hall R, et al: Antibiotic Treatment DurationsAmong Canadian Critically Ill Patients with Bacteremia,forthcoming]. We have identified gaps in current evi-dence, documented extensive practice variation, andconfirmed equipoise for a randomized controlled trialcomparing shorter (7 days) versus longer (14 days) anti-biotic treatment durations for bloodstream infections.The primary aim of the Bacteremia Antibiotic LengthActually Needed for Clinical Effectiveness (BALANCE)main randomized controlled trial will be to determinewhether 7 days (as compared to 14 days) of adequateantibiotic treatment is associated with non-inferior sur-vival for critically ill patients with bacteremia. The aimof this BALANCE pilot randomized controlled trial isto determine whether recruitment and protocol adher-ence rates will be sufficient for the main trial to befeasible.Methods/DesignDesignWe will conduct a multicenter randomized concealed al-location trial of shorter duration (7 days) versus longerduration (14 days) antibiotic treatment for critically illpatients with bacteremia admitted to ICU.SettingTo maximize efficiency, the BALANCE pilot trial will aimto involve a geographically and clinically diverse spectrumof ICUs across Canada. The study will be initiated inOctober 2014 at Sunnybrook Health Sciences Centre(SHSC) in Toronto, Ontario, and then rolled out to add-itional sites, starting with Kingston General Hospital inKingston, Ontario. These two sites will be sufficient toaccrue the intended pilot sample size of 115 patients,but we aim to roll out to 13 additional sites, if sufficientfunding is acquired, to improve external generalizabilityof the pilot trial findings. See Additional file 1 for par-ticipating pilot sites.PopulationAll patients aged ≥18 years will be considered for enrol-ment in this study if they meet all the inclusion and noexclusion criteria.Inclusion criteriaPatient is in the ICU at the time a blood culture result isreported as positive with a pathogenic bacterium.Exclusion criteria1. Patient has severe immune system compromise, asdefined by: absolute neutrophil count <0.5×109/L;or is receiving immunosuppressive treatment forsolid organ or bone marrow or stem cell transplant.2. Patient has a prosthetic valve or syntheticendovascular graft.3. Patient has a suspected or documented syndrome withwell-defined requirement for prolonged treatment(infective endocarditis, osteomylitis/septic arthritis,undrainable/undrained abscess, or unremovable/unremoved prosthetic-associated infection).Consent can be delayed at maximum to the 7th day ofadfrtethstsuptiacamthvipsecoDaneman et al. Trials  (2015) 16:173 Page 3 of 10equate antibiotic treatment. Critically ill patients areequently unable to provide initial consent due to al-red level of consciousness or understanding. Hence,e Canadian Critical Care Trials Group (CCCTG) hasandard operating procedures to seek assistance frombstitute-decision makers on behalf of patients. Thisrocess has been found feasible and acceptable to pa-ents, decision-makers, and research ethics boardsross Canada and has been successfully employedong dozens of CCCTG RCTs [32-35]. We will useis enhanced approach to consent, employing 13 pre-ously described strategies distributed over threehases: preparation for the consent encounter, the con-Ethics and informed consentThe study protocol has been approved by the SunnybrookHealth Sciences Research Ethics Board and the Queen’sUniversity Health Sciences and Affiliated TeachingHospitals Research Ethics Board (for Kingston GeneralHospital), and will be sought at other participating sites.After seeking permission from the treating team, theresearch coordinator/site primary investigator will ap-proach eligible patients (or their substitute decision-makers) as soon as their blood cultures are positive toobtain informed consent (see Additional file 2).4. Patient has a single positive blood culture with acommon contaminant organism according to theClinical Laboratory & Standards Institute (CLSI)(coagulase negative staphylococci, Bacillus spp.,Corynebacterium spp., Propionobacterium spp.,Aerococcus spp., Micrococcus spp) [30].5. Patient has a positive blood culture withStaphylococcus aureus [31].6. Patient has a positive blood culture with Candidaspp. or other fungal species as the only potentialpathogen.7. Patient already or previously enrolled in the trial.Eligible, nonrandomized patientsWe will maintain a log of all patients who were eligiblebut not randomized due to one of the following reasons:1. Patient or substitute decision maker (SDM) declinedconsent, specifying reason;2. Patient unable to give consent and SDM notavailable;3. ICU physician declined consent, specifying reason; [32]4. Consent not obtained due to other reason,specifying reason.nt encounter, and as follow-up to the consent en-unter [34].Randomization and allocation concealmentRandomization will occur as soon as the consent isobtained. The web-based randomization system forBALANCE will be created using RANDOMIZE.NET(http://www.randomize.net/), and will employ variableblock sizes, stratified by ICU site. After the full sus-ceptibility results become available, the site researchcoordinator along with site co-investigators will deter-mine the date for day 7 unblinding, taking into ac-count the number of days that the patient has alreadyreceived adequate antibiotics after the blood culture col-lection date. At day 7 (date entered by the research coord-inator), another email will be sent with the unblindedtreatment assignment for the patient. At this time the un-blinded treatment for that patient will be displayed in thereports available to the site research coordinator. If a pa-tient is randomized to the shorter (7 day) treatment arm,the treating team will be informed to stop the antibioticsat the completion of 7 days of antibiotics appropriate forthe causative pathogen; if the patient is randomized to thelonger (14 day) arm the team will be instructed to con-tinue the antibiotic until that date.Trial interventionsWe will randomize patients to receive a shorter durationof adequate antimicrobial therapy (7 days) versus a lon-ger duration (14 days). Adequate antimicrobial treat-ment will be defined as a regimen with in vitro activityagainst the organism(s) responsible for the bloodstreaminfection; the duration of adequate treatment will be de-termined as the cumulative number of calendar days forwhich adequate treatment is delivered beyond the dateof collection of the index blood culture specimen- theclock will start from initiation of the first adequate treat-ment dose after the blood culture has been drawn. Theselection of specific antimicrobial agents, doses androute of delivery will initially be at the discretion of thetreating clinical team. Most commonly the patient willalready be receiving some empiric antibiotic treatmentfor suspected infection prior to the blood culture beingdocumented as positive; the study protocol will not ex-pose patients to potential antibiotic treatment delays. Assoon as blood culture results are available (preliminaryGram staining), the research coordinator, in consultationwith the site investigator and site infectious diseases co-investigator if necessary, will review the initial antibioticchoice to ensure adequate empiric coverage for the po-tential culprit organism(s). As blood culture results arefinalized (speciation and sensitivity determination), theywill re-review the antibiotic choice to ensure that thespectrum of activity is adequate. If the spectrum is inad-equate, this will be communicated to the treating physi-cians. To avoid differentially influencing antibioticchoices and clinical decision-making, the randomizationassignment will not be communicated to the study re-search coordinator, study critical care or infectious dis-eases investigators or clinicians until the end of day 7.The ICU research coordinator at each site will visit dailyto ensure protocol adherence (antibiotics are stopped atthe pre-specified date (end of the 7th or 14th day) andnot earlier (Figure 1).Calculating day 7 of adequate antibiotics is a complexprocedure; there are multiple potential scenarios of ad-equate and inadequate antibiotic treatment days priorto the culture results being finalized. Figure 2 demon-strates some of the possible scenarios, to illustrate cal-culation of day 7 from the positive blood culturecollection date. The day 7 unblinding date will be cal-culated as the cumulative number of calendar days thepatient receives adequate antibiotics after the positiveblood culture collection date. Adequacy of antibioticswill only be definable after the final susceptibility reportis available. If a patient received inadequate antibioticsafter the positive blood culture collection and beforethe culture is finalized (Figure 2, scenario 3), day 7 datewill be calculated from the date adequate antibioticswere started, which should be immediately after theculture is finalized. If a patient received adequate anti-biotics for one day after positive blood culture collec-tion and then was switched to inadequate antibioticsuntil the culture was finalized (Figure 2, scenario 7),then this one day of adequate antibiotic after positiveculture collection will still be counted in the calculationof the day 7 date. Once the culture is finalized, ad-equate antibiotic treatment should be started/continuedwithout any break until the completion of the assignedtreatment duration based on study arm. Discontinu-ation or missed treatment before the completion of theassigned treatment duration will be considered to be aprotocol violation.Blood samples for procalcitoninBlood samples will be drawn on the randomization dayand at days 7, 10 and 14 from the index blood culturecollection to measure procalcitonin (PCT) levels. ThePCT levels will be batched and measured at the end ofthe study for the sub-study assessing the association be-tween PCT and clinical outcomes among patientsDaneman et al. Trials  (2015) 16:173 Page 4 of 10Figure 1 BALANCE pilot RCT intervention flow diagram.riofteinaDaneman et al. Trials  (2015) 16:173 Page 5 of 10Figure 2 Determination of day 7 of antibiotic treatment. Multiple scenadetermined based on days of receipt of adequate antibiotic treatment aonly be measurable after the culture and susceptibility result has been freceiving 7 versus 14 days of treatment. The results willnot be made available to the treating team, because thiscould unduly influence clinical practice and protocol ad-herence, and is ethical because none of the participatingsites are currently using PCT as part of routine clinicalpractice. Following study completion, we will comparePCT area-under-the-curve (AUC) and day 14 PCT levelsamong patients receiving 7 versus 14 days of antibiotics.We will also confirm whether 7 days of antibiotics isnon-inferior to 14 days of antibiotics for bacteremia, insubgroups with both normal and abnormal PCT levelson day 7.Protecting against sources of biasSelection biasSelection bias (such as bias-by-indication or survivalbias) will be minimized through rigorous concealedrandomization procedures. Although placebo controlshave been used in some RCTs of antibiotic treatmentduration, such as studies examining treatment durationfor cellulitis [36], pyelonephritis [37,38], and community-acquired pneumonia [39-42], they are not appropriate forbacteremia treatment in the ICU. It will not be practical toprovide placebos for each of the many antimicrobials com-monly used alone or in combination to treat bacteremiadue to varied infectious syndromes and pathogens; in ourmulticenter retrospective study more than 100 differentspecies were identified in enrolment blood cultures, ands are provided to determine how day 7 of antibiotic treatment will ber collection of the positive blood culture. Adequacy of treatment willlized.more than 60 different individual antimicrobials were ad-ministered [43]. Even if it were feasible to generate thismany placebos, patients in critical care may developsecondary sources of nosocomial infection, and clini-cians will not agree to be unaware of whether their pa-tients are already receiving active antimicrobialtreatments versus placebo. The successful, landmarkPneumoA trial of shorter versus longer duration treat-ment for ventilator associated pneumonia, did not em-ploy placebos [19].Outcome misclassification biasWe have selected objective outcome measures, and wewill use central adjudication committees blinded totreatment allocation for subjective outcomes includingsecondary infection or colonization with antibiotic re-sistant organisms [44,45].Publication biasWe will prevent publication bias by registering both theBALANCE Pilot Trial and the main BALANCE Trial,and through this publication of the trial protocol.Withdrawal from studyAll consented patients will be followed regardless of ad-herence to the trial protocol. If a patient is withdrawnfrom the study prematurely, a withdrawal form will becompleted. Data will be collected under the informedDaneman et al. Trials  (2015) 16:173 Page 6 of 10consent up to the point of a consent withdrawal. If per-mitted by the patient or substitute-decision maker, datacollection will continue for withdrawn patients. Primaryanalyses will be carried out on the basis of intention-to-treat principle, safety outcomes will be assessed usingper-protocol analyses. Anticipated reasons for with-drawal include patient not meeting inclusion criteria orrelevant exclusion criteria present prior torandomization, consent withdrawn by patient orsubstitute-decision maker, patient’s physician believespatient should be withdrawn from the study, inadvertentduplicate randomization. Detailed rationales for with-drawal will be recorded.Protocol violationA protocol violation form will be completed in case ofthe following violations:1. Adequate antibiotic treatment stopped by treatingphysician before RCT-dictated antibiotic stop date2. Adequate antibiotic treatment continued by treatingphysician after RCT-dictated antibiotic stop dateWe will also document the reason for protocol violation,responsible person for protocol violation (for example,attending physician, trainee physician, nurse, pharmacist,etcetera) and if there were any clinical explanations thatmight have resulted in the protocol violation.Frequency and duration of follow-upThe antibiotic treatment durations may extend beyondICU discharge for some patients, and beyond hospitaldischarge for a minority. Our retrospective observationalstudy showed that 27% of patients were discharged fromICU to hospital wards on or before day 7 of adequateantibiotic treatment and 4% were discharged from hos-pital before day 7. Patients will be reviewed daily in ICU,at hospital discharge and at 90 days post-randomization.If a patient is discharged from hospital prior to 90 dayspost-randomization, the research coordinator will con-tact the patient (or substitute decision-maker as appro-priate) by telephone to determine their disposition andvital status.Study drug related daily dataThe research coordinator will assess the patient daily(each morning) for 14 days after randomization to en-sure the clinical team adheres to the study treatmentduration protocol. If the clinical team proposes stoppingantibiotics prior to the assigned stop date, the researchcoordinator and/or site investigator will follow-up withthe clinical team to continue appropriate antibiotics; ifthe team extends antibiotics beyond the assigned stopdate the research coordinator will suggest discontinuingthe antibiotics.Primary and secondary outcome measuresThe primary outcome for the main BALANCE trial is 90-day mortality and the primary outcome for the pilot trialis feasibility as defined by: (a) adherence to treatment dur-ation protocol (proportion of treatment courses); and (b)rate of recruitment (patients per site, per month). We willconsider the main trial to be feasible and worthy ofembarking on a larger mortality-powered non-inferiorityRCT if 90% of antibiotic treatment courses are within 7 ±2 days in the shorter duration treatment arm or 14 ± 2 daysin the longer duration treatment arm; and, if we achieverecruitment rates of at least 1 patient per 4 weeks, onaverage, per participating site. Secondary outcomes in-clude ICU, hospital and 90-day mortality rates, relapserates of bacteremia, antibiotic allergy and adverse events,rates of Clostridium difficile infection in hospital, rates ofsecondary infection or colonization with antimicrobial re-sistant organisms, ICU and hospital lengths of stay, mech-anical ventilation duration, vasopressor duration in ICUand decline in procalcitonin levels.Statistical analysisSample sizeTo estimate our expected adherence rate of 90% withina margin of error of ± 5% (that is, actual adherence 85 to95%), with 95% confidence, we plan to enroll 115 pa-tients. At our expected recruitment rate of 1 patient/sitemonth across 15 sites, we will need approximately 10 to24 months to recruit these 115 patients given variabilityin site trial start-up steps (REB approval, data sharingagreements and contracts). By the time we have re-cruited 115 patients, we will know with 95% confidencethat this number of sites would be able to recruit 95 to138 patients over the same time interval in a future trial;this data will then be used to estimate the number ofcenters needed for the main trial (see Additional file 1for detailed sample size calculation).Loss to follow-upWe anticipate negligible loss of patients to follow-up.The Canadian Critical Care Trials Group (www.ccctg.ca),who endorsed this trial, has achieved virtually 100%follow-up to hospital discharge over all of its landmarkRCTs [46-48]. Although we will be following survivorsto ascertain 90-day mortality and relapse rates, we alsoexpect close to 100% follow-up based on our previousCCCTG experience.Analysis of primary outcomesThe primary outcomes will be analyzed as follows:Daneman et al. Trials  (2015) 16:173 Page 7 of 10(i).Rate of recruitment: We will consider the main trialto be feasible if we achieve recruitment rates of atleast 1 patient per month per participating site. Wewill report recruitment rates with 95% confidenceintervals.(ii).Adherence to treatment duration protocol: We willconsider the main trial to be feasible if 90% ofantibiotic treatment courses are 7 ± 2 days in theshorter duration treatment arm, and at least 90% ofantibiotic treatment courses are 14 ± 2 days in thelonger duration treatment arm. We will reportproportion of adherence with 95% confidenceintervals.Analysis of secondary outcomesMortality rates (at ICU discharge, hospital discharge and90 days) will be measured as the proportion of patientsalive or dead at these time points. We hypothesize thatmortality rates will be non-inferior with 7 days of treat-ment; the main BALANCE trial will be powered to testthis hypothesis. Continuous secondary outcomes, in-cluding lengths of stay in ICU and hospital, and dura-tions of ventilation and vasopressor use, will becompared by Wilcoxon test. We will compare the ‘differ-ence in differences’ between day 7 to 14 procalcitoninlevels in the two treatment groups.Frequency of analysesThe BALANCE Pilot Trial will be conducted and re-ported according to recommendations by the Consoli-dated Standards of Reporting Trials (CONSORT),including analyzing patients in the groups to which theywere originally assigned (intention-to-treat) and explicitprocedures for handling of any missing data [49].Analyses will be conducted at the completion of thispilot, given that there is no role for early termination [50].However, we will monitor recruitment and adherencerates weekly, and examine barriers as needed, workingwith participating centers to provide screening and con-senting tips from prior CIHR-funded ICU trials [34]. Cap-turing a minimal dataset of patient, pathogen andbacteremia source characteristics among eligible none-nrolled patients will facilitate this, and comparisons witheligible patients will help to identify selection bias [49].Subgroup analysesTo inform and possibly refine the main BALANCE Trialdesign, we will perform four exploratory subgroup ana-lyses. The main subgroup analysis will be based on theunderlying infectious syndrome causing bacteremia(vascular catheter-related, pneumonia, pyelonephritis,intra-abdominal, skin and soft tissue, other identifiedsource, or unknown source). We will also perform sub-group analyses based on illness severity (APACHE IIscore of ≥25 versus <25), community- versus hospital-acquisition, and vasopressor use on day of randomization.If recruitment rates or protocol adherence are particularlylow for any subgroups, in consultation with the SteeringCommittee and CCCTG, we will consider modifying defi-nitions or procedures appropriately. For safety analyses,we will perform a per-protocol analysis by restricting theanalysis to the participants who adhered perfectly to theprotocol in terms of the eligibility, interventions, and out-come assessment.Steering committeeThe Steering Committee is responsible for developmentand oversight of the BALANCE Pilot and full RCT pro-cedures and operations, funding applications, recruit-ment rates, missing data rates, in addition to advisingthe principal applicants on responses to questions fromthe data safety and monitoring committee or otherstakeholders, and eventual interpretation and compil-ation of study results into reports, scholarly manuscriptsand knowledge translation and exchange activities.The steering committee will meet in-person thriceyearly at CCCTG meetings (November, Ontario; January,Alberta; June, Eastern Canada) and by teleconference asneeded between meetings.Data Safety and Monitoring Committee (DSMC)After broad discussion and engagement of the CCCTGit was determined that a DSMC would not be requiredfor this pilot study, given the short duration of enrol-ment, and that it is underpowered to examine mortality.A DSMC will be instituted for the subsequent mainBALANCE trial [51]. DSMC composition will followaccepted norms of content expertise (critical care, in-fectious diseases, methodology, and biostatistics) andindependence from the investigators and steeringcommittee.DiscussionRationale for studying bacteremiaSome might argue that duration of antibiotic treatmentshould be driven by the underlying infectious focus, ra-ther than the presence or absence of bacteremia. How-ever, in our national practice survey the distributions oftreatment duration recommendations were virtuallyidentical for scenarios of bacteremic pneumonia,bacteremic pyelonephritis, catheter-related bloodstreaminfection, bacteremic intra-abdominal infection, andbacteremic skin and soft tissue infection - highlightingthat bacteremia is a very influential syndromic aspectand the appropriate focus for our research program [28].The advantages of studying bacteremia as a clinical en-tity versus other associated syndromes outweigh any po-tential disadvantages. In contrast to syndromic diagnosesmarkers to further nuance treatment decisions, we willFunding has been obtained for this pilot RCT from thefor the Bacteremia Antibiotic Length Actually Needed for ClinicalEffectiveness (BALANCE) pilot randomized controlled trial.Daneman et al. Trials  (2015) 16:173 Page 8 of 10(ventilator-associated pneumonia for example), all pa-tients with bacteremia have a positive sterile site cultureresult (by definition). Therefore, all bacteremic patients(with noncontaminant species) have true infection,whereas the presence or absence of pneumonia is muchharder to define because cultures may representcolonization rather than infection, and even multiple ad-judications of case definitions provide only moderateagreement, particularly in patients on mechanical venti-lators [52,53]. Given that bacteremia is defined by thepositive blood culture result, all study patients will havean identified pathogen, in contrast to syndromic infec-tions, which are often treated empirically without a de-fined etiology. A corollary is that antibiotic susceptibilitytest results are available for all bacteremic patients, so itwill be clear whether or not patients randomized toshorter versus longer duration antibiotic treatment arereceiving an effective antibiotic. The bacteremic sub-groups of patients with pneumonia, pyelonephritis,intra-abdominal infection, and soft tissue infection, gen-erally have more severe and complicated courses thannon-bacteremic infections. Therefore, if shorter coursetherapy is demonstrated to be effective for bacteremicpatients, the results can be more easily generalized tonon-bacteremic patients than vice versa. Finally, pre-specified subgroup analyses in the main BALANCE RCTcan examine the impact of treatment duration withineach specific syndrome.Rationale for studying fixed duration therapy versusindividualized durations based on clinical or biomarkerbased stopping rulesIdeally antibiotic treatment duration should be individual-ized, and patients should be treated until their infectionhas been cured (and likely no longer) [24]. Unfortunately,a randomized controlled trial based on a clinical stoppingrule is not feasible in ICU patients, because there are nospecific markers of persistent infection during critical ill-ness. The difficulty in diagnosing infection in ICU andmonitoring clinical response to treatment, has generatedconsiderable interest in the use of novel biomarkers toguide antibiotic treatment duration [42,54]. One bio-marker, procalcitonin, has been used successfully to re-duce average treatment durations in sepsis [42]. However,only a minority of these patients were bacteremic. More-over, more than half of patients randomized to the procal-citonin group, were not given algorithm-guided treatmentbecause the attending physician believed a biomarker-informed duration was inappropriate [54].Instead, we favor a randomized trial of fixed shorterversus longer duration antibiotic therapy, guided by ourpreliminary studies, as the most easily transferrable re-sult to immediately inform clinical practice. This ap-proach has been successful in more than two dozenAdditional file 2: Informed Consent Form. Informed consent form forthe Bacteremia Antibiotic Length Actually Needed for ClinicalEffectiveness (BALANCE) pilot randomized controlled trial.AbbreviationsAPACHE: Acute physiology and chronic health evaluation; CCCTG: Canadiancritical care trials group; CIHR: Canadian institutes of health research;CLSI: Clinical laboratory & standards institute; CONSORT: Consolidatedstandards of reporting trials; DSMC: Data safety and monitoring committee;ICU: Intensive care unit; ID: Infectious diseases; RCT: Randomized control trial;SDM: Substitute decision maker.Ministry of Health and Long-Term Care Academic HealthSciences Alternative Funding Plan Innovation FundAward (Ontario, Canada). The case report forms (paperand electronic) have been finalized. Training will be donefor all the participating sites through webinar beforestarting recruitment. The study is registered with rando-mize.net and randomization of test patients has been suc-cessfully achieved. The trial is expected to begin enrollingpatients in October 2014. Recruitment of patients willstart at Sunnybrook Health Sciences Centre (coordinatingcenter) and then roll out successively to the othersites after obtaining REB approval at the individualsites, and finalizing data sharing agreements. Withthe planned recruitment, we expect to complete thispilot trial in the summer of 2016 and then enroll fur-ther Canadian and International centers for the mainBALANCE RCT. If the pilot RCT does not identify aneed for any substantive protocol changes, this willbe an internal pilot trial, and patients will be rolledinto the main trial.Additional filesAdditional file 1: Participating Sites. List of potential participating sitesmeasure procalcitonin levels and trajectory in both treat-ment arms to see if it could provide incremental prog-nostic value [49].Trial statusThe study protocol is approved by the Sunnybrook HealthSciences Centre and Kingston General Hospital REBs.randomized controlled trials of infectious diseases thatare potentially complicated by bacteremia [21]. Mostnotably, a trial in ventilator-associated pneumonia hasaltered the standard of care for this infection to shorterduration therapy (8 days) [19]. However, appreciatingthe future promise of individual patient focused bio-Competing interestsThe authors declare that they have no competing interests.Daneman et al. Trials  (2015) 16:173 Page 9 of 10Authors’ contributionsND conceived and designed the study, obtained funding, developed thestatistical analysis plan, database development, drafted the manuscript and isresponsible for trial management and overall supervision. AHR participatedin the study design, helped develop paper and electronic CRF, and webrandomization and drafting of the manuscript. WX contributed to the studydesign, provided statistical and methodological expertise and helpeddrafting the manuscript. SMB participated in the study design, contributed tothe writing grant application and helped in reviewing and revising themanuscript for intellectual content. DC participated in the study design,contributed to the writing grant application and helped in reviewing andrevising the manuscript for intellectual content. PD participated in the studydesign, contributed to the writing grant application and helped in reviewingand revising the manuscript for intellectual content. RH participated in thestudy design, contributed to the writing grant application and helped inreviewing and revising the manuscript for intellectual content. AKparticipated in the study design, contributed to the writing grant applicationand helped in reviewing and revising the manuscript for intellectual content.FL (Lauzier) participated in the study design, contributed to the writing grantapplication and helped in reviewing and revising the manuscript forintellectual content. FL (Lamontagne) participated in the study design,contributed to the writing grant application and helped in reviewing andrevising the manuscript for intellectual content. JM (Marshall) participated inthe study design, contributed to the writing grant application and helped inreviewing and revising the manuscript for intellectual content. CMMparticipated in the study design, contributed to the writing grant applicationand helped in reviewing and revising the manuscript for intellectual content.LM participated in the study design, contributed to the writing grantapplication and helped in reviewing and revising the manuscript forintellectual content. JM (Muscedere) participated in the study design,contributed to the writing grant application and helped in reviewing andrevising the manuscript for intellectual content. SR participated in the studydesign, contributed to the writing grant application and helped in reviewingand revising the manuscript for intellectual content. HTS participated in thestudy design, contributed to the writing grant application and helped inreviewing and revising the manuscript for intellectual content. RAFconceived and designed the study, obtained funding, developed thestatistical analysis plan, database development, drafted the manuscript and isresponsible for trial management and overall supervision. All the authorsreviewed and approved the final manuscript for publication.AcknowledgementsThe authors would like to thank the Ministry of Health and Long-Term CareAcademic Health Sciences Alternative Funding Plan Innovation Fund Award,Toronto, Canada for funding this study. The authors would like to thank Dr.Ruxandra Pinto (a member of steering committee) and the site coordinators:B. Ashley (St. Paul’s Hospital, Vancouver), L. Julien (Queen Elizabeth II HealthSciences Centre, Halifax), O. Smith (St. Michael’s Hospital, Toronto), E. Campbell(London Health Sciences Centre, London), I. Watpool (Ottawa hospital-Generalcampus, Ottawa), S. Fleury (Kingston General Hospital, Kingston), S. Ruddell(Foothills Medical Centre, Calgary), C. Langevin (Sherbrooke University Hospital,Quebec), S. Taylor (University of Alberta Hospital, Alberta), O. Gutierrez(Winnipeg Regional Health Authority, Winnipeg) and S. Willems (RoyalColumbian Hospital, Vancouver).Author details1Division of Infectious Diseases & Clinical Epidemiology, Sunnybrook HealthSciences Centre, University of Toronto and Adjunct Scientist, Institute forClinical Evaluative Sciences, Sunnybrook Health Sciences Centre, 2075Bayview Ave, Toronto, Ontario M4N 3M5, Canada. 2Department of CriticalCare Medicine, Sunnybrook Health Sciences Center, 2075 Bayview Ave,Toronto, ON M4N 3M5, Canada. 3Division of Critical Care Medicine, Universityof Alberta Edmonton, 2-124E 8440-112 ST NW, Edmonton, AB T6G 2B7,Canada. 4Division of Critical Care Medicine, Department of Medicine,McMaster University, 1280 Main Street West, Hamilton, ON L8S 4L8, Canada.5Division of Critical Care Medicine and Center for Health Evaluation andOutcome Sciences, St Paul’s Hospital and University of B.C, 1081 BurrardStreet, Vancouver, BC V6Z 1Y6, Canada. 6Division of Critical Care Medicine,Department of Anesthesiology, Dalhousie University and the Capital District,Health Authority, 5790 University Avenue, Halifax, NS B3H 1V7, Canada.7Section of Critical Care Medicine, University of Manitoba, 710 Park BlvdSouth, Winnipeg, MB R3P 0X1, Canada. 8Centre de recherche CliniqueÉtienne-Le Bel, 2500 boul. de l’Université, Université de Sherbrooke,Sherbrooke, QC J1K 2R1, Canada. 9Centre de recherche FRQS du Centrehospitalier affilié universitaire de Québec, Axe Traumatologie - urgence -soins intensifs, Division de soins intensifs adultes, départements de médecineet d’anesthésiologie, Université Laval, 1401, 18e Rue, Québec, QC G1J 1Z4,Canada. 10Departments of Surgery and Critical Care Medicine, St. Michael’sHospital, University of Toronto, 30 Bond Street, Toronto, ON M5B 1W8,Canada. 11Department of Medicine, London Health Sciences Centre,University of Western Ontario, 800 Commissioners Rd. E, London, ON N6A4G5, Canada. 12Division of Critical Care, Department of Medicine, The OttawaHospital, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada. 13Department ofMedicine, Kingston General Hospital, Queen’s University, 76 Stuart Street,Kingston, ON K7L 2V7, Canada. 14Department of Medicine, Royal ColumbianHospital, University of British Columbia, 260 Sherbrook Street, NewWestminster, Vancouver, BC V3L 3M2, Canada. 15Department of Critical CareMedicine, Institute of Public Health, University of Calgary, 1403 29 Street NW,Calgary, AB T2N 2T9, Canada. 16Departments of Medicine and Critical CareMedicine, Sunnybrook Health Sciences Center, University of Toronto, 2075Bayview Ave, Toronto, ON M4N 3M5, Canada.Received: 20 November 2014 Accepted: 26 March 2015References1. Vincent JL, Rello J, Marshall J, Silva E, Anzueto A, Martin CD, et al.International study of the prevalence and outcomes of infection in intensivecare units. JAMA. 2009;302:2323–9.2. Renaud B, Brun-Buisson C. 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