Challenges to the management of curable sexually transmitted infections

Marcus Y Chen
Sepehr N Tabrizi
Department of Obstetrics and Gynaecology
University of Melbourne
MelbourneAustralia

Department of Microbiology and Infectious Diseases
Royal Women's Hospital
MelbourneAustralia

Challenges to the management of curable sexually transmitted infections
E D I T O R I A L Open Access
Each year, hundreds of millions of new cases of curable sexually transmitted infections (STIs) occur worldwide resulting in reproductive and other serious sequelae, as well as enhanced transmission of HIV. The clinical management and control of these STIs should include as a minimum access to services that provide timely and accurate diagnostic testing together with effective treatment. The provision of appropriate treatment is challenged by the development of increasing antimicrobial resistance, in particular with gonorrhoea and Mycoplasma genitalium infections, requiring new treatments and management algorithms. In addition, infections such as chlamydia, syphilis and trichomoniasis, which show few signs of resistance, are nevertheless highly prevalent and require better public health control measures. While these may be achievable in high income countries, they are still beyond the reach of many low and middle income countries, making substantial improvements in STI management and reductions in STI prevalence challenging.

Editorial

In 2008, the World Health Organization (WHO) estimated that globally there were 499 million new cases of curable sexually transmitted infections (STIs), including gonorrhoea, chlamydia, syphilis, and trichomoniasis, occurring every year. Discouragingly, this was even higher than the estimated 448 million cases reported in 2005 [1]. Each of these cases, mostly detected in young men and women, represents a person diagnosed with what is generally a stigmatizing condition with potentially serious reproductive or other sequelae. These include ectopic pregnancy, pelvic inflammatory disease, preterm birth, female infertility, neonatal death, and enhanced acquisition and transmission of HIV, just to name a few [1,2]. This begs the question, what more can be done to improve the diagnosis, treatment and control these curable infections? This special issue of BMC Infectious Diseases focuses on the challenges confronting the clinical management of several key treatable STI and STI related syndromes with experts in the field offering opinions on where future efforts should be focused. These include infections where antimicrobial resistance is established and increasing as well as infections that show few signs of resistance but are nevertheless highly prevalent with the need for better control.

Over several decades, Neisseria gonorrhoeae has successively developed antimicrobial resistance to multiple classes of antibiotics and has been identified by the United States Center for Disease Control as one of the top urgent antibiotic resistance threats [3]. Case reports of high level resistance to ceftriaxone have rung alarm bells and further stimulated efforts towards the discovery of new alternative treatments [4,5]. In this issue Unemo reviews these and other cases, highlights the need for continued vigilance, and discusses potential new agents in the development pipeline aimed at combatting this mercurial bacterium [6].

Mycoplasma genitalium is a common cause of male urethritis and is found in women with pelvic inflammatory disease [7]. Like gonorrhoea, Mycoplasma genitalium has developed increasing resistance to various antibiotic classes, a problem that is currently under recognized and in pressing need for greater attention. Jensen et al. provide a detailed overview of data pointing to the growing antimicrobial resistance evident with M. genitalium infections [8]. It is difficult to envisage any reversal in these trends without the introduction of fundamental measures such as widespread routine diagnostic testing for M. genitalium, availability of testing for antimicrobial resistance, and ongoing surveillance. In many high income countries these are in place for gonorrhoea but notably absent for M. genitalium.

Moi et al. explore the treatment implications of M. genitalium resistance further in their proposed guidance on the clinical management of men presenting with non-gonococcal urethritis, one of the most common STI related syndromes [9]. This currently presents a major clinical challenge as most urethral chlamydia will clear with azithromycin or doxycycline but both of these antibiotics are becoming increasingly ineffective at eliminating M. genitalium urethritis. Moi et al. float the idea of withholding treatment from men presenting with nongonococcal urethritis until a diagnosis of chlamydia or M. genitalium is confirmed by laboratory testing. This concept is worthy of further exploration and may need to be tailored to different clinical settings. Better drugs and more rational management algorithms for nongonococcal urethritis are needed.

While antimicrobial resistance to chlamydia is fortunately not currently contributing to the treatment failures to any significant extent, there continues to be uncertainty over whether single dose azithromycin, which has been the mainstay of treatment for uncomplicated genital chlamydial infections for many years, or doxycycline, should be the preferred treatment for chlamydia [10]. The question of whether doxycycline should replace single dose azithromycin as first line therapy for non-gonococcal urethritis in men based on efficacy against chlamydia and possible induction of macrolide resistant M. genitalium warrants further investigation [10]. A growing number of observational studies have suggested that azithromycin is inferior to doxycycline for the treatment of rectal chlamydia [11]. Kong et al. delve into these issues in their review of chlamydia treatment and call for randomized controlled trials to definitively determine if doxycycline should replace single dose azithromycin for the treatment of rectal chlamydia [12]. Several studies have pointed to rectal chlamydia being prevalent among not only men who have sex with men, but also women [13].

Globally, syphilis remains a pressing concern with international data indicating a resurgence of syphilis among men who have sex with men and unacceptably high rates of congenital syphilis [14,15]. To highlight the magnitude of this, the WHO estimated that in 2008 syphilis infections in pregnancy led to 305,000 fetal and neonatal deaths and 215,000 infants at risk of dying from prematurity, low birth weight or congenital syphilis worldwide [1]. Syphilis also drives acquisition of HIV infections, worrying as both syphilis and HIV are overrepresented in many populations of MSM [16]. In their review on the challenges in the management of adult syphilis, Tuddenham et al. revisit whether standard treatments for syphilis are adequate in HIV positive patients [17]. They also discuss uncertainty over the management of patients who remain serofast following syphilis treatment and developments in laboratory diagnostics.

Given the extraordinarily high global prevalence of Trichomonas vaginalis and its potential to promote HIV transmission, further investment into the optimal diagnosis, treatment, and control of T. vaginalis is clearly needed. Kissinger provides a comprehensive review on the epidemiology, diagnosis and management of this infection [18]. The fact that T. vaginalis screening of HIV positive women in the US alone would save an estimated $160 million in lifetime costs from new HIV infections prevented underscores the public health importance of the optimal detection and management of this protozoal infection [19].

While not usually regarded as a curable STI, bacterial vaginosis is common among women presenting with vaginal discharge and linked to reproductive sequelae and enhanced HIV transmission [20,21]. Bradshaw et al. discuss emerging areas for research into bacterial vaginosis aimed at reducing recurrence of this condition which is common following treatment [22]. These include studies to help elucidate the postulated role of reinfection from sexual partners, vaginal microbiota, and vaginal biofilm in the pathogenesis of bacterial vaginosis and possible interventions targeting these.

The WHO global strategy for the prevention and control of STI stipulates that comprehensive STI management should include as a minimum, accurate diagnosis by syndrome or laboratory diagnosis, plus effective treatment to prevent complications and further transmission [23]. While laboratory testing is taken for granted in high income countries, they are still beyond the reach of many low and middle income countries. Better performing point of care tests and use of self-collected sampling for several STI bring some hope of more access to diagnostic testing. Similarly, while reasonable adherence by health providers to local treatment guidelines governing antibiotic use for STI should be expected in well-resourced countries, less regulated use of antibiotics in resource limited settings threatens to only compound antimicrobial resistance. Stark differences in levels of health funding, health service infrastructure, together with what is often a low priority for STI on the political agenda, means meaningful improvements in STI management with reductions in STI prevalence will for the foreseeable future remain challenging.
 AcknowledgmentsWe wish to thank David Lewis for his comments on the editorial.Competing interestsThe authors declared that they have no competing interests.Authors' contributions MC and ST both contributed to the drafting and writing of the editorial and approve of the final version.
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Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution. Global strategy for the prevention and control of sexually transmitted infections. Submit your manuscript at www.biomedcentral.com/submitWorld Health Organization. Global strategy for the prevention and control of sexually transmitted infections: 2006-2015. Geneva: WHO; 2007. Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit


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

Nick Daneman
on behalf of the Canadian Critical Care Trials Group

Asgar H Rishu
on behalf of the Canadian Critical Care Trials Group

Ruxandra Pinto
on behalf of the Canadian Critical Care Trials Group

Pierre Aslanian
on behalf of the Canadian Critical Care Trials Group

Sean M Bagshaw
on behalf of the Canadian Critical Care Trials Group

Alex Carignan
on behalf of the Canadian Critical Care Trials Group

Emmanuel Charbonney
on behalf of the Canadian Critical Care Trials Group

Bryan Coburn
on behalf of the Canadian Critical Care Trials Group

Deborah J Cook
on behalf of the Canadian Critical Care Trials Group

Michael E Detsky
on behalf of the Canadian Critical Care Trials Group

Peter Dodek
on behalf of the Canadian Critical Care Trials Group

Richard Hall
on behalf of the Canadian Critical Care Trials Group

Anand Kumar
on behalf of the Canadian Critical Care Trials Group

Francois Lamontagne
on behalf of the Canadian Critical Care Trials Group

Francois Lauzier
on behalf of the Canadian Critical Care Trials Group

John C Marshall
on behalf of the Canadian Critical Care Trials Group

Claudio M Martin
on behalf of the Canadian Critical Care Trials Group

Lauralyn Mcintyre
on behalf of the Canadian Critical Care Trials Group

John Muscedere
on behalf of the Canadian Critical Care Trials Group

Steven Reynolds
on behalf of the Canadian Critical Care Trials Group

Wendy Sligl
on behalf of the Canadian Critical Care Trials Group

Henry T Stelfox
on behalf of the Canadian Critical Care Trials Group

M Elizabeth Wilcox
on behalf of the Canadian Critical Care Trials Group

Robert A Fowler
on behalf of the Canadian Critical Care Trials Group

7 versus 14 days of antibiotic treatment for critically ill patients with bloodstream infection: a pilot randomized clinical trial
10.1186/s13063-018-2474-1R E S E A R C H Open Access
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%) vascularcatheter; 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.

Background

Both antibiotic use and the acquisition of antibioticresistant organisms are high in intensive care units (ICUs), where critically ill patients are vulnerable to bacterial infections and antibiotic complications. Shortened treatment durations offer an appealing opportunity to maximize the benefits while minimizing the harms and reducing the costs of antibiotic therapy [1]. Randomized clinical trials (RCTs) have established that shorter-duration treatments are sufficient for a wide range of bacterial infections [1][2][3][4][5], including some infections among critically ill patients [6], but the optimal treatment duration for bloodstream infections remains understudied.

Our systematic review of the academic literature revealed no trials of shorter-versus longer-duration treatment among adult patients with bloodstream infection, but did uncover 24 studies (of 7595 patients) of shorter versus longer antibiotic treatment for infections commonly complicated by bacteremia. Cure rates were similar in patients receiving shorter (3-7 days) versus longer (7-21 days) treatment (risk ratio 1.00, 95% confidence interval (CI) 0.98-1.01) [7]. Although, subgroup outcome data were only available for small numbers of bacteremic patients across these studies (n = 115), shorter-duration treatment was associated with similar clinical cure (45/52 versus 47/49, risk ratio 0.88, 95% CI 0.77-1.01) and survival rates (15/17 versus 26/29, risk ratio 0.97, 95% CI 0.76-1.23) as longer-duration treatments. Given the absence of evidence to guide treatment durations for these bacteremic patients, we conducted a national practice survey of infectious disease physicians and critical care physicians [8]. Among these clinicians, 14 days was the most commonly reported treatment duration, but shorter treatments (usually 7 or 10 days) were recommended by nearly half of practitioners [8]. In single [9] and multicenter [10] observational studies of actual practice, we confirmed that critically ill patients with bacteremia receive a median of 14 days of treatment, but with wide variability (interquartile range (IQR) 9-17.5 days), further justifying the need for a trial comparing 7 versus 14 days of treatment. If such a trial could establish that 7 days is non-inferior to 14 days of treatment, this could lead to massive reductions in antimicrobial use, resistance and complications, and an estimated annual cost savings of $678 to 798 million in North America and $1.4 to 1.6 billion across Europe [11].

Prior to embarking on a large multicentre trial, we conducted a pilot RCT to test the feasibility of this trial design. We hypothesized that the co-primary feasibility outcomes (recruitment rate and adherence to treatment duration protocol) would confirm that a definitive trial could be conducted to compare 7 versus 14 days of antibiotic treatment for critically ill patients with bloodstream infections.

Methods

General study design

We conducted an open, pilot RCT of 7 versus 14 days of antibiotic treatment, for critically ill patients with bloodstream infection, to test the feasibility and inform the design of an international, non-inferiority RCT. The trial protocol of the Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness (BALANCE) pilot RCT has been previously published [12]; however, the key design elements are summarized below. We have adhered to the Consolidated Standards of Reporting Trials (CONSORT) guideline for pilot trials [13].

Study setting

The study was conducted through the Canadian Critical Care Trials Group (CCCTG) at 11 participating ICUs, across 10 Canadian cities in five provinces. The ICUs

Inclusion criteria

The inclusion criteria were intended to be broad, so as to be generalizable to most critically ill patients with bloodstream infection. All adult patients (aged over 18 years) with any positive blood culture yielding a pathogenic bacterium while in the ICU were included. The blood culture need not have been collected in the ICU, but at the time of detection of the positive result the patient needed to be under ICU care.

Exclusion criteria

We excluded patients who were severely immunocompromised (only neutropenia or bone marrow, solid organ or stem cell transplantation); had prosthetic valves or synthetic endovascular grafts; had a suspected or documented syndrome with an established requirement for prolonged treatment (e.g., infective endocarditis, osteomyelitis/septic arthritis, undrainable/undrained abscess or unremovable/ unremoved prosthetic infection); had a single positive blood culture with coagulase-negative staphylococci, Bacillus spp., Corynebacterium spp., etc. (because these may have represented contamination rather than infection); had positive blood cultures with Staphylococcus aureus or fungal organisms (because observational data suggest that these warrant more prolonged treatment); or patients previously enrolled in this trial.

Intervention: 7 versus 14 days of adequate antimicrobial treatment

Eligible consenting patients were randomized 1:1 to receive a shorter duration of adequate antimicrobial treatment (7 days) versus a longer duration (14 days). Adequate antimicrobial treatment was defined as a regimen with in vitro activity against the organism(s) responsible for the bloodstream infection. The duration of adequate treatment was determined as the cumulative number of calendar days for which adequate treatment was delivered including and beyond the date of collection of the index blood culture specimen [12]. The selection of antimicrobial agents, doses, intervals and routes of delivery were left to the discretion of the clinical team; only the duration was determined by randomization.

Randomization, blinding, and allocation concealment methods

Randomization was accomplished via a central, web-based system (http://www.randomize.net) using variable block sizes, stratified by ICU site; patients were allocated 1:1 into 7-versus 14-day treatment arms. Although placebo controls have been used in some RCTs of antibiotic treatment duration [3,[14][15][16][17][18][19], we believe that they are not practical or appropriate for bacteremia treatment in ICU because of variable pathogens, sources of bacteremia, mono-and combination antibiotic treatment regimens, and the potential for critically ill patients to develop secondary nosocomial infections requiring ongoing re-assessment of treatment choices. We elected not to protocolize treatment choices given the variety of pathogens and infectious syndromes causing the bacteremia, so as to maximize generalizability of study findings. As a consequence, patients and clinicians were not blinded to treatment assignment. To mitigate selection bias, and prevent clinicians from providing differential treatments to patients in the two arms, we maintained allocation concealment until the end of day 7, an approach used successfully in the PneumoA RCT of shorterversus longer-duration antibiotic treatment for ventilatorassociated pneumonia [6].

Primary feasibility outcomes

The co-primary outcomes of this pilot RCT related to feasibility of the main trial: (1) recruitment rates and (2) adherence to assigned treatment duration protocol. We targeted overall recruitment rates of one patient per ICU site per month; we targeted protocol adherence rates of 90% of antibiotic treatment courses within 7 ± 2 days in the shorter-duration arm, and 14 ± 2 days in the longerduration arm.

Secondary clinical outcomes

Secondary outcomes included 90-day mortality, which is the planned primary outcome of the larger RCT, and the best measure of net treatment efficacy, as well as other measures of net efficacy including ICU and hospital mortality, relapse of bacteremia, ICU and hospital lengths of stay (LOS), mechanical ventilation and vasopressor duration. Other secondary outcomes include antibiotic-free days, as well as measures of antibiotic-related harms, including rates of Clostridium difficile infection, antibiotic adverse events (allergy, anaphylaxis, acute kidney injury, hepatitis) and secondary nosocomial infection with antimicrobial-resistant organisms. Antibiotic-free days were defined as the number of calendar days within 28 days after blood culture collection on which the patient did not receive any antibiotic treatments; any patient dying within 28 days of blood culture collection was assigned zero antibiotic-free days. A composite definition of highly resistant microorganisms was modified from the description by de Smet et al. [20] as previously described [21].

Mechanistic sub-studies

Within the framework of this study, we also piloted two mechanistic sub-studies with plans for expansion within the larger RCT. First, in a procalcitonin (PCT) sub-study, we obtained blood PCT measurements on the day of randomization, and days 7, 10, and 14 from the index blood culture collection. The results were not made available to the treating team because this could have unduly influenced protocol adherence; rather, they were batchtested at the end of the trial using VIDAS® B.R.A.H.M.S. PCT™, BioMérieux (Marcy L'Etoile, France). The outcome of interest was the proportion of patients for whom PCT levels exceeded the usual threshold (0.25 IU/mL) for recommending antibiotic treatment at day 7 and day 14. At a single ICU site, we also collected rectal swabs on the day of enrollment, day 7, day 14, and at either hospital discharge or 28 days post enrollment, for analysis of gut microbial diversity and bacterial community composition by 16S rRNA gene sequencing, with the main outcome being taxonomic diversity (Shannon Diversity Index) [22].

Data collection and follow-up details

Patients were followed daily during the hospital stay, with entry of baseline characteristics, and outcome information into a secure, electronic Case Report Form. The secondary outcome (90-day mortality) was collected by follow-up telephone call at 90 days from the index bacteremia.

Statistical analysis

The analytic plan for the pilot RCT was primarily descriptivedetermining the recruitment rate, overall and by ICU site, and calculating the protocol adherence rate overall, by ICU site, and by source of infection. A pilot RCT is not adequately powered to identify a clinically important difference in safety endpoints or in overall mortality among patients receiving shorter-versus longer-duration treatmentsrather this is the intended goal of the BAL-ANCE main RCT. Therefore, as per the approach of most pilot trials conducted by the CCCTG, we did not un-blind treatment assignment in the BALANCE pilot RCT [23]. Avoiding such underpowered analyses for clinical endpoints decreases the risk of over-interpreting such results, which could unduly influence investigators, clinicians, peer-reviewers, and research ethics boards [23].

Sample size calculation

Our pilot RCT sample size (n = 115) was calculated such that we would be able to estimate our protocol adherence rate within a margin of error of ± 5%, with 95% confidence, with an adherence rate of 90%; or ± 7%, with 95% confidence, with an anticipated adherence rate of 80%.

Results

Screened, eligible and randomized patients

In total, 1159 critically ill patients with a positive blood culture were screened for eligibility, of whom 358 (31%) were eligible for enrollment ( Fig. 1 CONSORT flow diagram; Additional file 1). Among 801 patients who met the exclusion criteria, the most common reasons for noneligibility were single positive cultures with a common contaminant organism (49%), Staphylococcus aureus bacteremia (19%), suspected or documented syndrome with well-defined requirement for prolonged treatment (16%), severe immuncompromise (9%), prosthetic valve or synthetic endovascular graft (4%) or fungemia (3%). Of the eligible patients, 115/358 (32%) were randomized into the study; the most common reasons for non-randomization were lack of consent by the ICU physician (29%) or the patient or substitute decision-maker (SDM) (20%), or the lack of an available SDM (14%) (Fig. 1). There was no loss to follow-up and no missing outcome data.

Patient, infection, and pathogen characteristics

Patients had a median age of 67 (IQR, 57-78) years and were severely ill with a median Acute Physiology And Chronic Health Evaluation (APACHE II) score of 22 (IQR, [18][19][20][21][22][23][24][25][26]; 63 (55%) were male (Table 1). Most bloodstream infections were community-acquired (60%), with the remainder acquired on hospital wards (17%) or in the ICU (24%). The most common sources of bacteremia were lung (27%), abdomen (25%), and urinary tract (23%); the most common pathogens were Escherichia coli (22%), Klebsiella spp. (14%), and Enterococcus spp. (13%), but there was a total of 25 different bacteria isolated among the index blood cultures of these patients (Table 1).

Treatment characteristics

A total of 31 different antimicrobials were used in treating these patients, with the most common being piperacillintazobactam (in 73.9% of patients), vancomycin (56.5%), ceftriaxone (50.4%), ciprofloxacin (36.5%), and meropenem (30.4%) ( Table 2). Patients received a median of 2 (IQR, 1-2) adequate antimicrobials in the empiric window prior to blood culture finalization, and 3 (IQR 2-3) in the period up to 30 days after blood culture collection. A source control procedure was required for 76/115 (66.1%) patients.

Recruitment rate

The overall average recruitment rate was one patient per site per month. Across individual sites the median (IQR) recruitment rate was 0.7 (0.3-1.5) patients per month, with a range of 0-2.1 patients per month.

Adherence to treatment duration protocol

The overall adherence to assigned treatment duration protocol was 89/115 (77%). Across individual sites the median (IQR) adherence to treatment duration protocol was 71% (50-85%). Adherence to treatment duration varied according to 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 and soft tissue; 2/4 (50%) other; and 11/12 (92%) unknown sources of infection. The most common reasons for protocol nonadherence were re-starting of antibiotics for documented/ suspected recurrence or persistence of the index infection (6), clinical reasons for extended treatment that were not present or unrecognized at time of enrollment (4), a new infection unrelated to the index infection (4), ward physician not agreeing with ICU orders after transfer (2), recent surgery (1), and recent prosthetic valve insertion (1). In the 14-day treatment arm, the most common reasons for protocol non-adherence were clinical reasons for extended treatment that were not present or unrecognized at time of enrollment (2), a new infection unrelated to the index infection (2), physician error (1), new gastrointestinal tract perforation (1), life-sustaining treatment withdrawal (1), and recurrence or persistence of index infection (1). There was a trend towards higher protocol adherence among the second half of the patient group enrolled at each ICU site (82%) as compared to the first half of the enrolled patient group at each site (73%) (p = 0.24).

Other feasibility outcomes

No patients were withdrawn from the trial, and there were no losses to follow-up, with complete ascertainment of all study outcomes in ICU, in hospital, and at 90 days.

Clinical outcomes

The overall mortality rate among randomized patients was 7% in ICU, 13% in hospital, and 15% at 90 days ( Table 3). Relapse of bacteremia with the same pathogen occurred in 4 (3%) patients. Patients experienced a median of 14 antibiotic-free days, with wide variability (IQR 8-17 days), and bimodal distribution (modes at 14 and 21 antibiotic-free days). No patients experienced allergy/ anaphylaxis or acute kidney injury. There was one episode of acute hepatitis (1%), four patients (3%) with Clostridium difficile infection, and 10 (9%) with secondary infection with a highly resistant microorganism, including four with methicillin-resistant Staphylococcus aureus, two with vancomycin-resistant Enterococci, two with extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae, two with multi-drug resistant Enterobacteriaceae and one with multi-drug resistant non-Enterobacteriaceae.

Mechanistic sub-studies

Discussion

The BALANCE pilot RCT has confirmed the feasibility of conducting a large, multicenter RCT comparing 7 versus 14 days of antibiotic treatment for critically ill patients with bloodstream infection. It was feasible to recruit patients into this trial, and adherence to treatment  Coagulase-negative staphylococci 12 (9) Enterobacter spp. 6 (5)

(3)

(3)

(2)

Streptococcus anginosus group 3 (2) a All data are presented as medians and interquartile ranges (IQR) unless otherwise specified b A total of 24 different bacterial species were isolated among the index blood cultures of the 115 patients; the denominator for these percentages is all organisms isolated from patients' index blood cultures Empiric treatment window defined as period between blood culture collection and finalization c Overall treatments received within 30 days after blood culture collection d Adequate antimicrobials defined by in vitro activity against the blood culture pathogen(s) duration protocols was adequate to ensure wide separation in antibiotic treatment between groups. No patients were withdrawn from the trial, and there were no losses to follow-up in ascertainment of any of the study outcomes in ICU, in hospital, or at 90 days.

Although, there was some heterogeneity in recruitment rates across sites, we achieved our overall target recruitment average of one patient per ICU per month. The principle BALANCE trial will seek to test whether 7 days of treatment is associated with a non-inferior survival rate as compared to 14 days of treatment, with a noninferiority margin of 4%; after inflation for two interim analyses and potential losses to follow-up, the sample size requirement will be 3598. Therefore, at the rate of recruitment in our pilot RCT we will require approximately 60 ICUs, recruiting patients over a 4-to 5-year period. A study of this magnitude cannot be conducted within a single country. Through Canadian Institutes of Health Research (CIHR) funding, we have initiated enrollment in 20 Canadian ICUs (http://balance.ccctg.ca). The BALANCE research program has also garnered enthusiastic collaboration from critical care trials groups in other countries including the United States, Australia, New Zealand, Saudi Arabia, France, Germany and the United Kingdom, where enrollment and potential parallel funding applications will help to foster accrual of the remaining 40 ICUs.

The adherence to treatment duration protocol was lower than our initial target of 90%, but it was similar to the landmark PneumoA study of 8 versus 15 days of treatment for ventilator-associated pneumonia, which detected 18% protocol non-adherence in the 8-day treatment arm [6], and was far lower than the non-adherence rates of as high as 50% seen in some studies of biomarker-guided treatment for infections in critically ill patients [24]. Still, non-adherence to treatment duration protocol, particularly in patients in the 7-day treatment arm, represents the main threat to the validity of the principle BALANCE trial. Non-adherence cannot be completely eliminated because some ICU patients will develop secondary infections or persistent sepsis for which antibiotics will be re-initiated or continued, and it is appropriate for those patients to receive treatment, as would occur outside of a trial. We aim for a pragmatic approach to intervention duration, and for patient care. However, several lessons learned from this pilot RCT will enable us to minimize non-adherence in the larger RCT, including: use of delayed randomization when imaging is pending to rule out abscesses or confirm success of initial source control procedures; daily research coordinator contact with the clinical team to monitor for premature or delayed antibiotic discontinuation; and real-time involvement of both infectious diseases and ICU site co-investigators in discussing cases of potential non-adherence. The fact that adherence rates were higher in the second versus the first half of the enrollments at each site suggests that adherence rates may improve significantly over time as the main RCT unfolds. Nevertheless, in the principle BALANCE RCT it will be important to conduct both a primary intention-to-treat analysis and a secondary per-protocol analysis; the strength of the inference of non-inferiority will depend on whether the results of the two analytic approaches are in harmony.

We have not measured treatment group-separated clinical and safety outcomes: the pilot RCT is inadequately powered to assess these outcomes. Spurious differences between groups could lead to unnecessary concerns about embarking on the main RCT, while similar outcomes between groups could lead to premature acceptance of non-inferiority and the adoption of shorter-duration treatment [23]. Instead, this is an internal pilot and the patients enrolled to date will be included and analyzed within the principle RCT. Nevertheless, from the aggregate clinical outcomes in the cohort of 115 randomized patients we have still been able to confirm low rates of antibioticrelated adverse events, and a wide bi-modal distribution of antibiotic-free days. Importantly, the overall rates of Clostridium difficile and secondary infections with antibioticresistant organisms are high enough that we may be able to detect potentially important benefits of shorter treatment  (7) in hospital 15 (13) at 90 days 17 (15) Length of stay (in days)

in ICU 8 (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) in hospital 20  Duration of life support (in days) mechanical ventilation 8 (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21) Relapse of bacteremia 4 (4)

Antibiotic-free days (by day 30) 14 (8)(9)(10)(11)(12)(13)(14)(15)(16)(17) Antimicrobial-related adverse outcomes in the principle RCT. For example, the main trial will have 85% power to detect a reduction in Clostridium difficile to 3% from 5% with 7 versus 14 days of antibiotics. One important limitation of the BALANCE pilot and main RCT is that we will only be able to compare outcomes among patients with two fixed durations of treatment, 7 versus 14 days, rather than giving individual patients the minimum duration necessary for curing their particular infection. However, we believe that there are currently no adequate clinical indicators of cure in critically ill patients with bloodstream infection since host signs of sepsis can persist beyond cure of the triggering infection. Although biomarkers, such as PCT, offer a promising means to individualize and reduce antibiotic treatment durations [25,26], there has been poor adherence to PCT guidance in key trials [24], and this technology has not yet been widely adopted. The results of the BALANCE RCT could be potentially synergistic with prior and subsequent biomarker-focused trials of treatment duration; if 7 days is non-inferior to 14 days of treatment this may lead to greater physician adherence to biomarker-guided stopping rules in the future. Moreover, the blinded PCT results from our study were above the 0.25-IU/mL treatment threshold in the majority of patients at both day 7 and at day 14, suggesting that PCT-guided treatment has the potential to lead to treatment prolongation, rather than reduction, in this clinical context. Finally, as in other studies that compare two arbitrary and fixed intervention thresholds (such as the TRICC trial of transfusion thresholds) [27], an adequately powered trial will provide a benchmark duration of therapy around which to make individualized treatment decisions.

Conclusions

In the BALANCE pilot RCT, we have documented that randomization of patients to 7 versus 14 days of treatment is acceptable and feasible. Based on these findings, CIHR has funded the BALANCE main RCT to be conducted in both Canadian and international ICUs, with parallel funding applications in progress or under review in collaborating critical care trials groups in other countries. The BALANCE main RCT will provide foundational evidence regarding treatment duration for our sickest and most vulnerable patients. If 7 days is non-inferior to 14 days of treatment, the result could be a paradigm shift in antibiotic treatment durations for these patients, with immediate substantial healthcare savings, and downstream reductions in Clostridium difficile and antimicrobial resistant pathogens.

started in staggered fashion (Sunnybrook Health Sciences Centre, Toronto, ON (October 2014); Kingston General Hospital, Kingston, ON (January 2015); Queen Elizabeth II, Halifax, NS (March 2015); The Ottawa Hospital, Ottawa, ON (June 2015); Université de Sherbrooke, Sherbrooke, Québec, QC (July 2015); St. Boniface Hospital, Winnipeg, MB (January 2016); L'Hôpital de l'Enfant-Jesus, Laval, Québec, QC (January 2016); CHUM, Montréal, Québec, QC (April 2016); Mount Sinai Hospital, Toronto, ON (April 2016); London Health Sciences Centre, London, ON (May 2016); and University of Alberta Hospital, Edmonton, AB (June 2016)). Patient enrollment was completed in July 2016, and thus individual ICUs participated for durations ranging from 1 to 22 months. Institutional Research Ethics Board approval was obtained at these participating sites.

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

The majority of patients (101/115, 88%) consented to optional blood testing for procalcitonin (PCT) measurements. The median (IQR) PCT levels were 5.0 (2.0-22.5) IU/mL on the day of randomization, 1.3 (0.3-4.3) on day 7, 0.46 (0.15-1.55) on day 10, and 0.28 (0.10-1.19) on day 14. Only a minority of patients had PCT levels below the 0.25 threshold at which PCT algorithms would recommend antibiotic discontinuation, including 12/71 (17%) on the day 7 measurement, and 21/47 (45%) on the day-14 measurement. Most patients(27/  37, 73%) at the central study site consented to rectal swabs for microbiome testing, which confirmed the adequacy of this sampling method for bacterial community testing, and considerable range in the Shannon Diversity Index, with a median (range) of 4.1 (0.2-5.5) across all specimens.

are presented as medians and interquartile ranges (IQR) unless otherwise specified. ICU intensive care unit

1: CONSORT 2010 Checklist of information to include when reporting a pilot or feasibility trial*. (DOC 226 kb) Abbreviations APACHE: Acute Physiology And Chronic Health Evaluation; CCCTG: Canadian Critical Care Trials Group; ICU: Intensive care unit; IQR: Interquartile range; LOS: Lengths of stay; PCT: Procalcitonin; RCT: Randomized clinical trial

Table 1
1Patient, infection, and pathogen characteristics among critically ill patients with bloodstream infectionCharacteristic a
N (%), Median (IQR)

Patient characteristic

Male sex
63 (55)

Age in years
67 (57-78)

APACHE II Score
22 (18-26)

Baseline vasopressor use
60 (52)

Admission category

Medical
78 (68)

Surgical
24 (21)

Trauma
6 (5)

Neurological/neurosurgical
6 (5)

Burns
1 (1)

Comorbidity

Coronary artery disease
23 (20)

Congestive heart failure
16 (14)

Arrhythmia
15 (13)

Peripheral vascular disease
14 (12)

Diabetes mellitus
40 (35)

Renal insufficiency
13 (11)

Dialysis dependency
4 (4)

Chronic obstructive pulmonary disease
16 (14)

Liver disease
8 (7)

Obesity
16 (14)

Solid malignancy
18 (16)

Leukemia/lymphoma
1 (1)

Steroids/immunosuppression
10 (9)

Infection characteristics

Acquisition of bacteremia

Community-acquired
69 (60)

Hospital-acquired
19 (17)

ICU-acquired
27 (24)

Source of bacteremia

Lung
31 (27)

Intra-abdominal/hepato-biliary
29 (25)

Urinary tract
26 (23)

Vascular-catheter-related
9 (8)

Skin and/or soft tissue
4 (3)

Other
4 (3)

Undefined/unknown
12 (10)

Top 10 most commonly isolated pathogens in blood cultures b

Escherichia coli
28 (22)

Klebsiella spp.
18 (14)

Enterococcus spp.
17 (13)

Streptococcus pneumoniae
13 (10)

Table 1
1Patient, infection, and pathogen characteristics among critically ill patients with bloodstream infection (Continued)Characteristic a
N (%), Median (IQR)

Table 2
2Treatment characteristics among critically ill patients with bacteremiaTreatment characteristics a
N (%), Median
(IQR)

Empiric antimicrobial treatment b

Number of unique empiric antimicrobials
administered

2 (2-3)

Number of unique adequate d empiric
antimicrobials administered

2 (1-2)

Overall antimicrobial treatments c

Number of unique antimicrobials
administered

3 (3-5)

Number of unique adequate d antimicrobials
administered

3 (2-3)

Top 10 most commonly administered
antimicrobials

Piperacillin-tazobactam
85 (73.9%)

Vancomycin
65 (56.5%)

Ceftriaxone
58 (50.4%)

Ciprofloxacin
42 (36.5%)

Meropenem
35 (30.4%)

Metronidazole
22 (19.1%)

Cefazolin
20 (17.4%)

Ampicillin
19 (16.5%)

Tobramycin
14 (12.2%)

Amoxicillin-clavulanate
11 (9.6%)

Underwent a source control procedure
76 (66.1%)

a

All data are presented as medians and interquartile ranges (IQR) unless
otherwise specified

b

Table 3
3Clinical outcomes among critically ill patients with bacteremiaOutcome a
N (%), Median (IQR)

Mortality

in ICU
8
AcknowledgementsWe would like to acknowledge the extraordinary efforts of the research coordinators at each participating site in screening and enrolling eligible patients, including: Miranda Hunt, Ilinca Georgescu, Eileen Campbell, Lisa Julien, Rebecca Porteous, Irene Watpool, Brigette Gomes, Marie-Helene Masse, Hélène Fournier, Marie-Claude Tremblay, Danny Barriault/Gabrielle, Orla Smith, Gyan Sandhu, Stacy Ruddell, Joshua Booth, Nadia Baig, Nicole Marten, Suzette Willems, Victoria Alcuaz, Martine Lebrasseur, Sumesh Shah, Lia Stenyk, Barbara Kosky. We also like to acknowledge the crucial contributions of Lisa Buckingham and Nicole Zytaruk at the CLARITY methods center in helping to develop the electronic Case Report Form and database.FundingSupported by grants from Ontario Ministry of Health and Long-Term Care Academic Health Sciences Centre Alternative Funding Plan (AFP) Innovation Fund Awards and Canadian Institute of Health Research (CIHR). Dr. Fowler's work was supported by a personnel award from the Heart and Stroke Foundation, Ontario Provincial Office.Availability of data and materialsThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.Authors' contributions ND and RAF conceived and designed the study, obtained funding, developed the statistical analysis plan, database development, drafted the manuscript, and are responsible for overall management and supervision. AHR participated in the study design, helped develop the paper and electronic CRF, and web randomization and drafting of the manuscript. RP contributed to the study design, provided statistical and methodological expertise, and helped draft the manuscript. AP, SMB, AC, EC, BC, DC, MD, PD, RH, AK, FL, FL, JM, CMM, LM, JM, SR, WS, HTS, and MEW participated in the study design, contributed to writing grant applications and helped in reviewing and revising the manuscript for intellectual content. All the authors have reviewed and approved the manuscript for publication.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.Competing interests
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