Daptomycin versus placebo as an adjunct to beta-lactam therapy in the treatment of Staphylococcus aureus bacteremia: study protocol for a randomized controlled trial

Daptomycin versus placebo as an adjunct to beta-lactam therapy in the treatment of Staphylococcus... Background: Staphylococcus aureus bacteremia is associated with significant morbidity and mortality. To treat this infection, the current standard of care includes intravenous anti-staphylococcal beta-lactam antibiotics and obtaining adequate source control. Combination therapy with an aminoglycoside or rifampin, despite early promise, can no longer be routinely recommended due to an absence of proven benefit and risk of harm. Daptomycin is a rapidly acting bactericidal antibiotic that is approved for the treatment of Staphylococcus aureus bacteremia as monotherapy but has not been shown to be superior to the current standard of care. As demonstrated in vitro, the addition of daptomycin to beta-lactam therapy may result in enhanced anti-staphylococcal activity. Our objective is to assess the efficacy and safety of prescribing the combination of daptomycin with cefazolin or cloxacillin for the treatment of methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia in adults. We hypothesize that adjunctive therapy with daptomycin will reduce the duration of bacteremia in this population. Methods: The DASH-RCT trial is a randomized, double blind, placebo-controlled trial designed per the Standard Protocol Items: Recommendation for Interventional Trials (SPIRIT) and Consolidated Standards of Reporting Trials (CONSORT) guidelines. We recruit adults with confirmed MSSA bacteremia, at the McGill University Health Center. Patients are eligible if they are 18 years or older, can receive cefazolin or cloxacillin monotherapy, and are enrolled within 72 h of the first blood culture being drawn. Exclusion criteria include anaphylaxis to study drugs, having polymicrobial bacteremia, anticipated hospital admission for < 5 days, and healthcare team refusal. While receiving standard of care, study patients are randomized to a 5-day course of adjunctive daptomycin or placebo. The trial began in December 2016 and is expected to end in December 2018, after recruiting an estimated 102 patients. Discussion: The DASH-RCT will compare the use of daptomycin as an adjunct to an anti-staphylococcal beta-lactam versus placebo in the treatment of MSSA bacteremia. We believe that a short course of dual therapy will result in earlier eradication of bacteremia and that subsequent research could evaluate effects on metastatic infection, relapse, and/or mortality. Ongoing issues in the trial include a delay between presentation of infection, enrollment in the trial, and the potential for unrecognized deep foci of infection at diagnosis. Trial registration: ClinicalTrials.gov, NCT02972983. Registered on 25 November 2016. Trial protocol: http://individual.utoronto.ca/leet/dash/dashprotocol.pdf Keywords: Daptomycin, Staphylococcus aureus, Bacteremia, Beta-lactam * Correspondence: matthew.cheng@mail.mcgill.ca; alexander.lawandi@mail.mcgill.ca; todd.lee@mcgill.ca Division of Infectious Diseases, Department of Medicine, McGill University, 1001 Boulevard Décarie E5-1917, Montreal, QC H4A 3J1, Canada Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Cheng et al. Trials (2018) 19:297 Page 2 of 9 Background cell death [19, 20]. Daptomycin’s synergism with Staphylococcus aureus is a leading cause of bacteremia, various beta-lactams has been demonstrated for several with an annual incidence of 38.2 to 45.7 cases per 100,000 different Gram-positive cocci, notably S. aureus and Entero- people in the USA [1, 2]. Despite effective antibiotics, ap- coccus species [7, 21–26]. The therapeutically active proximately 20% of patients will die from the initial infec- daptomycin-calcium complex has a net positive charge and tion [3–6] and as many as 62% of patients will die within must bind to the cell surface in order to exert its thera- one year [7]. Furthermore, approximately 30% of patients peutic effect. It has been demonstrated that beta-lactams with S. aureus bacteremia will develop metastatic infection can reduce a bacterial cell’s surface charge, thereby enhan- requiring prolonged antibiotic courses and, in certain cases, cing the binding of the daptomycin complex to the cell wall surgical intervention. The rates of these complications are and as a result, increasing its bactericidal effect [24]. These increased in those who remain febrile and/or in those in interactions have even demonstrated restoration of dapto- whom bacteremia does not clear within 48 to 72 h [8]. As mycin susceptibility to previously non-susceptible Entero- such, the timely clearance of bacteremia may be an import- cocci [25]. While much of the potential synergism has been ant component in the management of these patients. demonstrated in Enterococci, there is evidence that this also The current management of methicillin-susceptible S. applies to S. aureus. For example, it has been shown in vitro aureus (MSSA) bloodstream infection consists of adequate that beta-lactams can reduce the net positive charge of the source control and anti-staphylococcal beta-lactam (ASBL) S. aureus cell membrane, resulting in increased drug bind- antibiotics, notably cloxacillin, nafcillin, or cefazolin [9–12]. ing and a subsequent reduction in the organism’s minimum The duration of ASBL therapy is determined by the cause inhibitory concentration (MIC) to daptomycin [22, 27–29]. of MSSA bacteremia per international clinical practice stan- Combinations of oxacillin and daptomycin have demon- dards. In short, uncomplicated MSSA bacteremia is treated strated synergistic activity in vitro against MSSA isolates for 2 weeks, complicated or disseminated infection for at [27] and against MRSA [21, 29]. Thus, treatment with least 4 weeks, and infective endocarditis for a minimum of daptomycin and a beta-lactam appears to result in in- 6 weeks. creased bactericidal activity. The use of adjuvant gentamicin combined with an ASBL Daptomycin is licensed for the treatment of S. aureus was formerly advocated, as this combination was shown to bacteremia including strains that are methicillin-susceptible. reduce the duration of MSSA bacteremia [13]. However, However, it is not currently the standard of care due to a due to aminoglycoside-induced nephrotoxicity without a lack of direct comparison to ASBLs in the treatment of demonstrated reduction in mortality, this combination is methicillin-susceptible S. aureus bacteremia. no longer recommended in the treatment of S. aureus To investigate the potential role of adjuvant daptomycin infections outside of prosthetic valve infective endocarditis in the treatment of MSSA infections, we designed the “Dap- [14]. Nevertheless, finding another synergistic drug that tomycin as Adjunctive therapy for Staphylococcus aureus accelerates bacterial clearance without toxicity could prove Bacteremia” trial (DASH-RCT). Our objective is to assess if a significant finding that could translate into a reduction in the addition of 5 days of adjunctive daptomycin therapy as subsequent metastatic infection, recurrence, and/or mortal- compared to ASBL monotherapy will decrease the total ity. To this end the role of combination therapy in the duration of MSSA bacteremia in hospitalized men and treatment of Staphylococcus aureus infections remains an women 18 years of age or older, with MSSA bacteremia. area of active research interest. The combination of vanco- mycin and beta-lactam therapy for the treatment of Methods methicillin-resistant S. aureus (MRSA) bacteremia has been The DASH-RCT is a randomized, double-blind, demonstrated to shorten the duration of bacteremia [15], placebo-controlled trial enrolling at three McGill University and there is now an ongoing randomized controlled trial to Health Center (MUHC) hospitals: the Montreal General investigate the potential superiority of daptomycin/vanco- Hospital, the Royal Victoria Hospital, and the Montreal mycin in combination with beta-lactams in the treatment Neurological Institute. The research protocol was submit- of MRSA infections with complication-free survival at ted to the MUHC Research and Ethics Board who granted 90 days as the primary endpoint [16]. approval of the study in November 2016. The trial is Daptomycin is a lipopeptide antibiotic active against both funded via internal funds received from the MUHC Associ- MSSA and MRSA [17, 18]. This antibiotic acts in concert ation of Physicians. Please see Additional file 1: SPIRIT with calcium ions to insert itself into the cell membrane of table in the Appendix for a detailed description of the items Gram-positive bacteria, oligomerize, and cause a positive included in our clinical trial protocol. curvature strain on the membrane’sphospholipids.By changing the configuration of the bacterial cellular mem- Study population brane, daptomycin induces rapid depolarization of the Eligible inpatients are aged 18 years or older with docu- microbe and extravasation of cell contents, and results in mented MSSA bacteremia, who are enrolled within a Cheng et al. Trials (2018) 19:297 Page 3 of 9 maximum of 72 h of the culture being drawn and within Table 1 Daptomycin dosing in accordance with patient weight 24 h of the confirmation of S. aureus. Patients are Daptomycin dosing 6 mg/kg body weight excluded if they are moribund due to other illnesses and Weight (kg) Daptomycin dose (mg) are expected to die within 5 days of potential recruit- 38–45 250 ment, are clinically appropriate for admission to a 46–54 300 critical care unit but are not going to receive critical care 55–62 350 due to an advanced directive, or if they are unable to 63–70 400 receive either ASBL monotherapy or a combination of 71–79 450 ASBL and daptomycin exclusively. The latter precludes individuals with known type I hypersensitivity to the 80–87 500 study drugs from participating in the trial and those with 88–95 550 polymicrobial infections requiring additional antimicro- 96–104 600 bial drugs. Patients for whom the use of open-label dap- 105–112 650 tomycin was felt to be indicated by the treating doctors 113–120 700 were also excluded. 121–129 750 Our research team is notified of eligible patients via direct page coupled with an automatically generated fax 130–137 800 when a new presumptive S. aureus infection is identified 138–145 850 on blood culture. The microbiologic protocols followed to More than 145 900 identify S. aureus and determine methicillin susceptibility are included in the Appendix: Figure 2. After the organism is identified, patients are assessed for eligibility and of drug allocation. The study drug is delivered to the approached for the study by trained personnel. If patients patient’s admitting unit in the form of a sealed container are unable to consent, the research team approaches their with the patient’s name and unit number and administra- power of attorney for third-party consent. tion instructions. Upon enrollment, each patient is assigned a unique nu- The choice of ASBL, either cloxacillin or cefazolin, is meric study identifier that will be used in the subsequent at the treating team’s discretion. Further management of randomization and statistical analysis. Randomization for the infection is also at the treating team’s discretion. The each unique identifier is performed in advance by per- study protocol does not prescribe the timing of removal muted block with variable block size. The randomization of intravascular devices, performance of echocardiog- table is held in confidence by the central research raphy, ancillary investigations aside from the bloodwork pharmacy, which services all three sites. Investigators and mentioned below, or consultation with an infectious study personnel outside of the research pharmacy do not diseases specialist. Statin therapy may be continued. have access to the randomization table. The study mandates that regular blood samples be ob- tained to document clearance of the infection and monitor Study protocol for drug adverse effects (see Fig. 1). Two sets of aerobic and Enrolled patients are randomized to daptomycin and an anaerobic blood cultures are obtained daily for 5 days or ASBL or placebo and an ASBL. Daptomycin at a dose of until microbiological clearance is documented. As per our 6 mg/kg body weight is administered intravenously once routine hospital practice, the first blood culture set contains daily for 5 days in persons with normal renal function (see both an aerobic and an anaerobic bottle, whereas the sec- Tables 1 and 2 for details). This dose was chosen as it is ond set contains only an aerobic bottle. Complete blood the dose approved by Health Canada for the treatment of counts, creatine kinase, aspartate aminotransferase, alanine S. aureus bacteremia. In obese patients, the actual body aminotransferase, alkaline phosphatase, gamma-glutamyl weight is used as in keeping with the monograph. The transferase, and total and direct bilirubin are drawn on days study drug is dissolved in a 50-mL bag of NaCl 0.9% or in 1 and 5. Electrolytes and creatinine are measured at a an appropriately sized syringe if there is a minibag short- Table 2 Daptomycin dosing interval per patient renal function age. The placebo is NaCl 0.9%, which is provided in the Renal function Dosing interval same container and administered intravenously once daily Creatinine clearance > 30 mL/minute Q24H × 5 doses for 5 days in persons with normal renal function; the dos- ing frequency is adjusted based on the patient’s renal func- Creatinine clearance < 30 mL/minute Q48H × 3 doses tion in the same manner as daptomycin (see Table 2). Continuous renal replacement therapy Q24H × 5 doses The MUHC research pharmacy monitors the creatinine Peritoneal cialysis Q48H × 3 doses clearance of enrolled patients and contacts the research Intermittent hemodialysis Qdialysis × 3 doses team to suggest dosing modifications as needed, regardless Cheng et al. Trials (2018) 19:297 Page 4 of 9 STUDY PERIOD Enrolment Allocation Post-allocation Close-out TIMEPOINT** -t 0 D1 D2 D3 D4 D5 ENROLMENT: Eligibility screen Informed consent Allocation INTERVENTIONS: Daptomycin Placebo ASSESSMENTS: AST Daptomycin MIC Blood cultures XX X X X Complete blood XX counts Creatine kinase XX Hepatic profile XX Electrolytes XX X Creatinine XX X Symptom questionnaire * 1 Fig. 1 Time and events scheduled for patients enrolled into the DASH-RCT. Refers to the first day post-allocation. Routine antimicrobial susceptibility testing is performed on the first methicillin-susceptible Staphylococcus aureus isolate of each patient. The minimal inhibitory concentration (MIC) to daptomycin is performed by Etest® on the first methicillin-susceptible S. aureus isolate of each patient. Two sets of blood cultures are obtained daily for 5 days or until microbiological clearance is documented, whichever is longer. Hepatic profile includes aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, and total bilirubin. Electrolytes include sodium, potassium, chloride, and bicarbonate. A symptom questionnaire is administered on day 5 to assess patients for nausea, vomiting, headaches, and myalgia minimum on days 1, 3, and 5. In addition, each patient’s drug. However, the patient’s allocation arm remains un- first MSSA isolate undergoes full antimicrobial susceptibil- known to the investigators. Such patients are maintained ity testing, and testing of the MIC to daptomycin using the in the intention-to-treat analysis. Daptomycin ETest (BioMérieux, France). The participants’ data are collected and managed using The patients, their clinicians, the investigators assessing REDCap electronic data capture tools hosted at the McGill the primary outcome, and those performing the statistical University Health Center [30]. Data are anonymized and analysis are blinded to the treatment allocation. Unblind- de-identified to ensure patient confidentiality. ing can be requested by the treating physician in the event of a serious adverse event suspected to be due to the study Outcomes drug. The research team is notified that the patient has The primary outcome is to assess if the addition of 5 days been unblinded and excluded from receiving further study of daptomycin adjunctive to an ASBL compared to ASBL Cheng et al. Trials (2018) 19:297 Page 5 of 9 monotherapy will decrease the duration of MSSA apreviouslypublished study[15] and derived from our cen- bacteremia in hospitalized men and women 18 years of age ter’s local epidemiology. or older. The total duration of bacteremia will be Participants will be analyzed according to their treat- determined based on microbiology laboratory reports. The ment allocation in an intention-to-treat analysis. A modi- duration will be defined in days, where day 1 is the day on fied intention-to-treat analysis will exclude participants which the first positive blood culture was drawn and the whose blood cultures were already negative at the time of final day is the last day that yielded a positive blood culture. their first study drug dose. Participants who have received Secondary outcomes are as follows: at least 3 days of therapy according to their treatment allocation will also be analyzed in a per-protocol fashion 1. All cause 30-day mortality will be obtained from as part of the secondary analyses. hospital records and centralized provincial health Primary outcome: the duration of MSSA bacteremia will care databases. be evaluated via time-to-event analysis using Kaplan-Meier 2. Relapsed bacteremia is defined as a blood culture curves reporting the median time to clearance. Compari- specimen positive for MSSA obtained ≥ 48 h and sons will be made using the Tarone-Ware log rank test with ≤ 90 days after obtaining a negative blood culture significant α < 0.05. (negative after 5 days of incubation). Results will be Secondary outcomes are as follows: obtained from the electronic microbiology laboratory records. 1. The proportion of patients who are clear of MSSA 3. Clinically relevant embolic or metastatic MSSA bacteremia at days 3, 5, and 7. disease will be diagnosed within 90 days of the first 2. Relapsed bacteremia will be a binary outcome; positive blood culture by the treating team and proportions will be reported, and will be compared defined as the presence of bone abscess or using Fisher’s exact test. osteomyelitis on computed tomography (CT), 3. Metastatic MSSA disease will be a binary outcome; magnetic resonance imaging (MRI), or bone and proportions will be reported, and will be compared gallium scan; renal emboli or ilio-psoas, splenic, and using Fisher’s exact test. other occult abscesses on ultrasound, CT or MRI; 4. The patient safety outcome will be binary; septic brain emboli on CT of the head or MRI of the proportions will be reported, compared using brain; septic emboli to the lung on chest x-ray or CT; Fisher’s exact test, then we will adjust for or infective endocarditis on echocardiography. confounders using exact logistic regression. 4. The patient safety outcome will be a combined 5. Analysis of effect modification of the primary outcome endpoint of nephrotoxicity, as defined by the using Cox regression models: we will analyze patient Kidney Disease: Improving Global Outcomes comorbidities, including immunosuppressive (KDIGO) guidelines [31]; hepatotoxicity, as defined conditions, the presence of endocarditis, source by an increase in liver enzymes three times the control difficulties, metastatic MSSA infection, and an upper limit of normal; and rhabdomyolysis, as infectious diseases consultation. defined by an increase in creatine kinase three times 6. Accounting for confounders: imbalances in potential the upper limit of normal, occurring within the first confounders between study arms will be evaluated for 5 days of therapy. A questionnaire administered on their influence on the relationship between the day 5 post-allocation is used to assess patients for intervention and the time to clearance of bacteremia nausea, vomiting, headaches, and myalgia. using Cox regression models. Exact logistic regression will be used to adjust for confounders of the secondary outcomes (numbers 1 through 4). Statistical analyses 7. Per-protocol analysis of the time to clearance of Sensitivity analysis was performed to determine the sample bacteremia between the study groups: time-to-event size required to achieve 80% power. Assuming that the dur- analysis using Kaplan-Meier curves, comparisons ation of bacteremia was normally, log-normally, or Poisson using the Tarone-Ware log rank test. distributed, with a mean duration of bacteremia of 3 days, and a standard deviation of 2 days (3 for Poisson), a sample An interim analysis is planned upon enrollment of 50 size of approximately 102 participants would be required to patients who continue to have bacteremia at the time of en- detect a1-day differenceindurationof bacteremiaata sig- rollment. This analysis will be reviewed by an independent nificance level of 5%. If the mean duration of bacteremia is Safety Monitoring Board comprising two physicians and 2 days, we would have 70% power for our primary outcome one statistician who are not appointed to the division of assuming the duration of bacteremia was normally or Infectious Diseases and are not involved in the study. They log-normally distributed. Assumptions were adapted from have the authority to stop the study if there is significant Cheng et al. Trials (2018) 19:297 Page 6 of 9 evidence of benefit or harm (primary outcome, primary [17, 35]. As we do not anticipate differential allocation of safety outcome) based on the O’Brien-Fleming patients with early metastatic disease to a specific arm, a alpha-spending approach [32]. difference in clinically relevant events between groups All statistical analyses will be performed using statistical would be suggestive (but not definitive) of a drug effect. software including STATA 15.0 (STATA Corp, College This secondary endpoint should thus remain informative Station, TX, USA), SAS 9.4 (SAS Institute Inc., Cary, NC, despite the absence of additional diagnostic procedures per- USA), and/or R (R Foundation for Statistical Computing, formed throughout the study. Vienna, Austria). To mitigate the previously mentioned limitations, we could have enrolled all patients with presumed staphylo- Discussion coccal infection per the presence of Gram-positive cocci The objective of the DASH-RCT is to assess whether pa- in clusters on Gram stain of positive blood cultures. tients receiving an ASBL and daptomycin are at reduced Rapid enrollment would have reduced the time between risk of prolonged bacteremia. We hope that an improve- presentation and initiation of the study drugs at the cost ment in this endpoint might be associated with a reduc- of increased post-randomization exclusions. Indeed, tion in metastatic infections, recurrence, and mortality. more patients would have been recruited with MRSA Our goal is to assess whether daptomycin is a good candi- blood stream infections or blood culture contamination date to be studied in a larger study powered for those out- due to coagulase-negative Staphylococcus. Advances in comes. Ultimately, we would like to determine whether earlier diagnosis using a molecular microbiologic the standard of care for MSSA bacteremia should become technique could provide the opportunity for earlier combination therapy with an ASBL and daptomycin. enrollment without enrolling patients with non-relevant There are several limitations to the DASH-RCT trial. Gram-positive cocci. First, the identification of MSSA in blood cultures and the Second, many patients enrolled in the trial will be subsequent enrollment of the patient in the trial is delayed expected to be clear of bacteremia by the time of enroll- by the need to identify the microorganism in the laboratory. ment, as only approximately 30–40% of Staphylococcal As a result, patients may be exposed to a variety of bacteremia persists. It is very difficult to predict in open-label broad-spectrum antibiotics prior to trial enroll- advance who these patients will be and the study sample ment for up to 72 h. While we believe there will not be bias size has been chosen to allow for this. Due to the lag in in these between the arms of the study due to identification of bacteremia, it is impossible to avoid the randomization, there is a possibility of such imbalance, enrollment of patients who may have already be clear of which will need to be considered. We have put into place bacteremia at enrollment. Nevertheless, this limitation will techniques (see Appendix) for early identification of MSSA apply to both the study group and the placebo group and from positive blood cultures and enroll on evenings and therefore the role of adjunctive daptomycin in mitigating weekends to minimize delays. Unfortunately, these early complications of the bacteremia will still be of interest. identification techniques could lead to early misidentifica- Moreover, we have also pre-planned a modified tion of MSSA in approximately 3% of patients (based on intention-to-treat analysis to look only at those who still unpublished but extensive local verification studies) and have bacteremia when they start the study drug. those patients would need to be excluded. However, using Despite the aforementioned limitations, we believe that our modified tube coagulase test (Appendix), rapid MRSA the DASH-RCT is founded in rigorous methodology and testing (Appendix), and accounting for known MRSA examines a biologically plausible hypothesis. Our study colonization status [33] allows us to recruit patients into may demonstrate that daptomycin in combination with an the study as close to presentation as possible, while main- ASBL results in faster clearance of MSSA bacteremia than taining specificity. Second, as the organism may have the current standard of care. Prescribing a short course of already disseminated at the time of species identification, daptomycin at the Health Canada and U.S. Food and Drug the ability to evaluate whether daptomycin can limit Administration approved dose will limit potential metastatic spread may be diminished. We chose to assess dose-dependent toxicities. Benefits similar to combination patients for clinically relevant embolic or metastatic MSSA therapy with aminoglycosides may then be demonstrated, disease as evaluated by the treating team, which has been but with reduced rates of adverse events. If our hypotheses previously validated as a clinical outcome in S. aureus trials hold true, further trials to evaluate daptomycin as an [34]. While we record clinically significant metastatic events adjunctive therapy in the treatment of MSSA-associated at enrollment and follow up, for cost and diagnostic diseases will be warranted. However, given that the stewardship reasons we will not perform extensive imaging mortality associated with MSSA bacteremia is approxi- at the time of randomization nor systematically search for mately 20%, a significantly larger randomized controlled embolic disease during the trial, which is in keeping with trial would be required to demonstrate a survival benefit other large randomized controlled trials involving S. aureus of using combination therapy. Cheng et al. Trials (2018) 19:297 Page 7 of 9 Trial status 4. Isolates that are beta hemolytic, gram-positive cocci in The DASH-RCT began enrolling patients on 1 December clusters are then tested for the presence of catalase 2016. The trial is ongoing. Patient recruitment and follow and coagulase using conventional biochemical analysis. up is expected to be completed by 31 December 2018. 5. These isolates are screened for clumping factor using the Staphaurex Latex Agglutination Assay (ThermoFisher Scientific, MA, USA). Appendix 6. A tube coagulase is also performed on these and Presumptive identification of methicillin-susceptible the results read at 4 h. Staphylococcus aureus 7. Isolates are identified as presumptive S. aureus when they are found to be beta-hemolytic, gram-positive 1. Inoculated blood culture bottles (Bactec, Becton, cocci in clusters, which are catalase-positive, latex Dickinson and Company, New Jersey, USA) are agglutination-positive, and tube coagulase-positive. incubated in the Bactec 9000 blood culture 8. Antimicrobial susceptibility and oxacillin screening instrumentation system as per manufacturer is performed on the Vitek 2 system using their instructions until identified as positive. Antimicrobial Susceptibility Cards (AST) 2. Positive bottle are removed from the incubator and (BioMerieux, Marcy-l’Étoile, France). Methicillin- plated onto blood agar. susceptible S. aureus is identified when isolates are 3. Colonies are gram-stained At 24 h. reported as sensitive to oxacillin using this system. Fig. 2 Identification algorithm utilized for methicillin-susceptible Staphylococcus aureus Cheng et al. Trials (2018) 19:297 Page 8 of 9 Additional file 3. Troidle L, et al. Complications associated with the development of bacteremia with Staphylococcus aureus. Hemodial Int. 2007;11(1):72–5. 4. Bai AD, et al. Impact of infectious disease consultation on quality of care, Additional file 1: SPIRIT 2013 Checklist: Recommended items to address mortality, and length of stay in Staphylococcus aureus bacteremia: results in a clinical trial protocol and related documents*. (DOC 120 kb) from a large multicenter cohort study. Clin Infect Dis. 2015;60(10):1451–61. 5. Goto M, et al. Association of evidence-based care processes with mortality in staphylococcus aureus bacteremia at veterans health administration Abbreviations hospitals, 2003-2014. JAMA Intern Med. 2017;177(10):1489–97. ASBL: Anti-staphylococcal beta-lactam; BSI: Bloodstream infections; CT: Computed tomography; MIC: Minimum inhibitory concentration; 6. Cheng MP, Rene P, Cheng AP, Lee TC. Back to the Future: Penicillin- MRI: Magnetic resonance imaging; MRSA: Methicillin-resistant Staphylococcus Susceptible Staphylococcus aureus. Am J Med. 2016;129(12):1331–33. aureus; MSSA: Methicillin-susceptible Staphylococcus aureus; MUHC: McGill 7. Yahav D, et al. Risk factors for long-term mortality of Staphylococcus aureus University Health Center bacteremia. Eur J Clin Microbiol Infect Dis. 2016;35(5):785–90. 8. Chang FY, et al. A prospective multicenter study of Staphylococcus aureus bacteremia: incidence of endocarditis, risk factors for mortality, and clinical Acknowledgements impact of methicillin resistance. Medicine (Baltimore). 2003;82(5):322–32. The authors gratefully acknowledge the financial assistance of the McGill University Health Center Association of Physicians and the technical and 9. Mermel LA, et al. Guidelines for the management of intravascular catheter- in-kind assistance from the MUHC Microbiology Laboratory and Research related infections. Clin Infect Dis. 2001;32(9):1249–72. Pharmacy. 10. Mermel LA, et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;49(1):1–45. Funding 11. Bai AD, et al. Comparative effectiveness of cefazolin versus cloxacillin as The funding for the DASH-RCT trial is provided through internal funding definitive antibiotic therapy for MSSA bacteraemia: results from a large from the MUHC Association of Physicians. Dr. Lee receives research salary multicentre cohort study. J Antimicrob Chemother. 2015;70(5):1539–46. support from the Fonds de Recherche Santé Québec. 12. McDanel JS, et al. Comparative effectiveness of cefazolin versus nafcillin or oxacillin for treatment of methicillin-susceptible Staphylococcus aureus Availability of data and materials infections complicated by bacteremia: a nationwide cohort study. Clin Data sharing is not applicable to this article as no datasets were generated Infect Dis. 2017;65(1):100–6. or analyzed during the current study. The study investigators will have 13. Korzeniowski O, Sande MA. Combination antimicrobial therapy for access to the final trial dataset. staphylococcus aureus endocarditis in patients addicted to parenteral drugs and in nonaddicts: a prospective study. Ann Intern Med. 1982;97(4):496–503. Publication plans 14. Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis in adults: Data generated from this study will be published in a peer-reviewed journal. diagnosis, antimicrobial therapy, and management of complications: A There are no publication restrictions. Authorship eligibility will be determined scientific statement for healthcare professionals from the American Heart based on contributions to the study. No professional writers will be used. Association. Circulation. 2015;132(15):1435-86. 15. Davis JS, et al. Combination of vancomycin and β-lactam therapy for Authors’ contributions methicillin-resistant Staphylococcus aureus bacteremia: a pilot multicenter MPC and AL drafted and revised this manuscript. MPC and TCL contributed randomized controlled trial. Clin Infect Dis. 2016;62(2):173–80. equally to the theory and conceptualization of the DASH-RCT trial and to the 16. Tong SYC, et al. CAMERA2 – combination antibiotic therapy for methicillin- critical revisions of this manuscript. MPC, AL, and GBL identified, consented resistant Staphylococcus aureus infection: study protocol for a randomised and enrolled the patients in the trial and collected the data. GBL, KP, and controlled trial. Trials. 2016;17(1):170. TCL will perform the statistical analysis and interpretation. All authors read 17. Richter SS, et al. The in vitro activity of daptomycin against Staphylococcus and approved the final version of this manuscript. aureus and Enterococcus species. J Antimicrob Chemother. 2003;52(1):123–7. 18. Fowler VGJ, et al. Daptomycin versus standard therapy for bacteremia Ethics approval and consent to participate and endocarditis caused by Staphylococcus aureus. N Engl J Med. 2006; The DASH-RCT trial was reviewed and approved by the McGill University 355(7):653–65. Health Center Research Ethics Board. Informed consent will be obtained 19. Straus SK, Hancock REW. Mode of action of the new antibiotic for from all patients recruited to the study prior to study participation. Gram-positive pathogens daptomycin: comparison with cationic antimicrobial peptides and lipopeptides. Biochim Biophys Acta Competing interests Biomembr. 2006;1758(9):1215–23. The authors declare that they have no competing interests. 20. Steenbergen JN, et al. Daptomycin: a lipopeptide antibiotic for the treatment of serious Gram-positive infections. J Antimicrob Chemother. 2005;55(3):283–8. Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in 21. Rand KH, Houck HJ. Synergy of daptomycin with oxacillin and other β- published maps and institutional affiliations. lactams against methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2004;48(8):2871–5. Author details 22. Dhand A, et al. Use of antistaphylococcal β-lactams to increase daptomycin Division of Infectious Diseases, Department of Medicine, McGill University, activity in eradicating persistent bacteremia due to methicillin-resistant 1001 Boulevard Décarie E5-1917, Montreal, QC H4A 3J1, Canada. Division of Staphylococcus aureus: role of enhanced daptomycin binding. Clin Infect Neonatology, Department of Pediatrics, Sainte-Justine Hospital, Montréal, QC, Dis. 2011;53(2):158–63. Canada. Clinical Practice Assessment Unit, Department of Medicine, McGill 23. Dhand A, Sakoulas G. Daptomycin in combination with other antibiotics for University Health Centre, Montréal, QC, Canada. the treatment of complicated methicillin-resistant Staphylococcus aureus bacteremia. Clin Ther. 2014;36(10):1303–16. Received: 25 October 2017 Accepted: 3 May 2018 24. Sakoulas G, et al. Ampicillin enhances daptomycin- and cationic host defense peptide-mediated killing of ampicillin- and vancomycin-resistant Enterococcus faecium. Antimicrob Agents Chemother. 2012;56(2):838–44. References 25. Sakoulas G, et al. Ceftaroline restores daptomycin activity against 1. El Atrouni WI, et al. Temporal trends in the incidence of Staphylococcus daptomycin-nonsusceptible vancomycin-resistant Enterococcus faecium. aureus bacteremia in Olmsted County, Minnesota, 1998 to 2005: a Antimicrob Agents Chemother. 2014;58(3):1494–500. population-based study. Clin Infect Dis. 2009;49(12):e130–8. 26. Smith JR, et al. β-Lactam combinations with daptomycin provide synergy 2. Rhee Y, et al. Evolving epidemiology of Staphylococcus aureus bacteremia. against vancomycin-resistant Enterococcus faecalis and Enterococcus Infect Control Hosp Epidemiol. 2015;36(12):1417–22. faecium. J Antimicrob Chemother. 2015;70(6):1738–43. Cheng et al. Trials (2018) 19:297 Page 9 of 9 27. Mehta S, et al. β-Lactams increase the antibacterial activity of daptomycin against clinical methicillin-resistant Staphylococcus aureus strains and prevent selection of daptomycin-resistant derivatives. Antimicrob Agents Chemother. 2012;56(12):6192–200. 28. Snydman DR, McDermott LA, Jacobus NV. Evaluation of in vitro interaction of daptomycin with gentamicin or beta-lactam antibiotics against Staphylococcus aureus and Enterococci by FIC index and timed-kill curves. J Chemother. 2005;17(6):614–21. 29. Werth BJ, et al. Ceftaroline increases membrane binding and enhances the activity of daptomycin against daptomycin-nonsusceptible vancomycin- intermediate Staphylococcus aureus in a pharmacokinetic/pharmacodynamic model. Antimicrob Agents Chemother. 2013;57(1):66–73. 30. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap) – a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42(2):377–81. 31. Ardalan MR, et al. Aspergillosis after renal transplantation. Saudi J Kidney Dis Transpl. 2005;16(3):330–3. 32. DeMets DL, Lan KK. Interim analysis: the alpha spending function approach. Stat Med. 1994;13(13–14):1341–52. discussion 1353-6 33. Butler-Laporte G, et al. Using MRSA screening tests to predict methicillin resistance in Staphylococcus aureus bacteremia. Antimicrob Agents Chemother. 2016;60(12):7444–8. 34. Kang DH, et al. Early surgery versus conventional treatment for infective endocarditis. N Engl J Med. 2012;366(26):2466–73. 35. Thwaites GE, Scarborough M, Szubert A, et al. Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2018;391(10121):668-78. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Trials Springer Journals

Daptomycin versus placebo as an adjunct to beta-lactam therapy in the treatment of Staphylococcus aureus bacteremia: study protocol for a randomized controlled trial

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Medicine & Public Health; Medicine/Public Health, general; Biomedicine, general; Statistics for Life Sciences, Medicine, Health Sciences
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Abstract

Background: Staphylococcus aureus bacteremia is associated with significant morbidity and mortality. To treat this infection, the current standard of care includes intravenous anti-staphylococcal beta-lactam antibiotics and obtaining adequate source control. Combination therapy with an aminoglycoside or rifampin, despite early promise, can no longer be routinely recommended due to an absence of proven benefit and risk of harm. Daptomycin is a rapidly acting bactericidal antibiotic that is approved for the treatment of Staphylococcus aureus bacteremia as monotherapy but has not been shown to be superior to the current standard of care. As demonstrated in vitro, the addition of daptomycin to beta-lactam therapy may result in enhanced anti-staphylococcal activity. Our objective is to assess the efficacy and safety of prescribing the combination of daptomycin with cefazolin or cloxacillin for the treatment of methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia in adults. We hypothesize that adjunctive therapy with daptomycin will reduce the duration of bacteremia in this population. Methods: The DASH-RCT trial is a randomized, double blind, placebo-controlled trial designed per the Standard Protocol Items: Recommendation for Interventional Trials (SPIRIT) and Consolidated Standards of Reporting Trials (CONSORT) guidelines. We recruit adults with confirmed MSSA bacteremia, at the McGill University Health Center. Patients are eligible if they are 18 years or older, can receive cefazolin or cloxacillin monotherapy, and are enrolled within 72 h of the first blood culture being drawn. Exclusion criteria include anaphylaxis to study drugs, having polymicrobial bacteremia, anticipated hospital admission for < 5 days, and healthcare team refusal. While receiving standard of care, study patients are randomized to a 5-day course of adjunctive daptomycin or placebo. The trial began in December 2016 and is expected to end in December 2018, after recruiting an estimated 102 patients. Discussion: The DASH-RCT will compare the use of daptomycin as an adjunct to an anti-staphylococcal beta-lactam versus placebo in the treatment of MSSA bacteremia. We believe that a short course of dual therapy will result in earlier eradication of bacteremia and that subsequent research could evaluate effects on metastatic infection, relapse, and/or mortality. Ongoing issues in the trial include a delay between presentation of infection, enrollment in the trial, and the potential for unrecognized deep foci of infection at diagnosis. Trial registration: ClinicalTrials.gov, NCT02972983. Registered on 25 November 2016. Trial protocol: http://individual.utoronto.ca/leet/dash/dashprotocol.pdf Keywords: Daptomycin, Staphylococcus aureus, Bacteremia, Beta-lactam * Correspondence: matthew.cheng@mail.mcgill.ca; alexander.lawandi@mail.mcgill.ca; todd.lee@mcgill.ca Division of Infectious Diseases, Department of Medicine, McGill University, 1001 Boulevard Décarie E5-1917, Montreal, QC H4A 3J1, Canada Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Cheng et al. Trials (2018) 19:297 Page 2 of 9 Background cell death [19, 20]. Daptomycin’s synergism with Staphylococcus aureus is a leading cause of bacteremia, various beta-lactams has been demonstrated for several with an annual incidence of 38.2 to 45.7 cases per 100,000 different Gram-positive cocci, notably S. aureus and Entero- people in the USA [1, 2]. Despite effective antibiotics, ap- coccus species [7, 21–26]. The therapeutically active proximately 20% of patients will die from the initial infec- daptomycin-calcium complex has a net positive charge and tion [3–6] and as many as 62% of patients will die within must bind to the cell surface in order to exert its thera- one year [7]. Furthermore, approximately 30% of patients peutic effect. It has been demonstrated that beta-lactams with S. aureus bacteremia will develop metastatic infection can reduce a bacterial cell’s surface charge, thereby enhan- requiring prolonged antibiotic courses and, in certain cases, cing the binding of the daptomycin complex to the cell wall surgical intervention. The rates of these complications are and as a result, increasing its bactericidal effect [24]. These increased in those who remain febrile and/or in those in interactions have even demonstrated restoration of dapto- whom bacteremia does not clear within 48 to 72 h [8]. As mycin susceptibility to previously non-susceptible Entero- such, the timely clearance of bacteremia may be an import- cocci [25]. While much of the potential synergism has been ant component in the management of these patients. demonstrated in Enterococci, there is evidence that this also The current management of methicillin-susceptible S. applies to S. aureus. For example, it has been shown in vitro aureus (MSSA) bloodstream infection consists of adequate that beta-lactams can reduce the net positive charge of the source control and anti-staphylococcal beta-lactam (ASBL) S. aureus cell membrane, resulting in increased drug bind- antibiotics, notably cloxacillin, nafcillin, or cefazolin [9–12]. ing and a subsequent reduction in the organism’s minimum The duration of ASBL therapy is determined by the cause inhibitory concentration (MIC) to daptomycin [22, 27–29]. of MSSA bacteremia per international clinical practice stan- Combinations of oxacillin and daptomycin have demon- dards. In short, uncomplicated MSSA bacteremia is treated strated synergistic activity in vitro against MSSA isolates for 2 weeks, complicated or disseminated infection for at [27] and against MRSA [21, 29]. Thus, treatment with least 4 weeks, and infective endocarditis for a minimum of daptomycin and a beta-lactam appears to result in in- 6 weeks. creased bactericidal activity. The use of adjuvant gentamicin combined with an ASBL Daptomycin is licensed for the treatment of S. aureus was formerly advocated, as this combination was shown to bacteremia including strains that are methicillin-susceptible. reduce the duration of MSSA bacteremia [13]. However, However, it is not currently the standard of care due to a due to aminoglycoside-induced nephrotoxicity without a lack of direct comparison to ASBLs in the treatment of demonstrated reduction in mortality, this combination is methicillin-susceptible S. aureus bacteremia. no longer recommended in the treatment of S. aureus To investigate the potential role of adjuvant daptomycin infections outside of prosthetic valve infective endocarditis in the treatment of MSSA infections, we designed the “Dap- [14]. Nevertheless, finding another synergistic drug that tomycin as Adjunctive therapy for Staphylococcus aureus accelerates bacterial clearance without toxicity could prove Bacteremia” trial (DASH-RCT). Our objective is to assess if a significant finding that could translate into a reduction in the addition of 5 days of adjunctive daptomycin therapy as subsequent metastatic infection, recurrence, and/or mortal- compared to ASBL monotherapy will decrease the total ity. To this end the role of combination therapy in the duration of MSSA bacteremia in hospitalized men and treatment of Staphylococcus aureus infections remains an women 18 years of age or older, with MSSA bacteremia. area of active research interest. The combination of vanco- mycin and beta-lactam therapy for the treatment of Methods methicillin-resistant S. aureus (MRSA) bacteremia has been The DASH-RCT is a randomized, double-blind, demonstrated to shorten the duration of bacteremia [15], placebo-controlled trial enrolling at three McGill University and there is now an ongoing randomized controlled trial to Health Center (MUHC) hospitals: the Montreal General investigate the potential superiority of daptomycin/vanco- Hospital, the Royal Victoria Hospital, and the Montreal mycin in combination with beta-lactams in the treatment Neurological Institute. The research protocol was submit- of MRSA infections with complication-free survival at ted to the MUHC Research and Ethics Board who granted 90 days as the primary endpoint [16]. approval of the study in November 2016. The trial is Daptomycin is a lipopeptide antibiotic active against both funded via internal funds received from the MUHC Associ- MSSA and MRSA [17, 18]. This antibiotic acts in concert ation of Physicians. Please see Additional file 1: SPIRIT with calcium ions to insert itself into the cell membrane of table in the Appendix for a detailed description of the items Gram-positive bacteria, oligomerize, and cause a positive included in our clinical trial protocol. curvature strain on the membrane’sphospholipids.By changing the configuration of the bacterial cellular mem- Study population brane, daptomycin induces rapid depolarization of the Eligible inpatients are aged 18 years or older with docu- microbe and extravasation of cell contents, and results in mented MSSA bacteremia, who are enrolled within a Cheng et al. Trials (2018) 19:297 Page 3 of 9 maximum of 72 h of the culture being drawn and within Table 1 Daptomycin dosing in accordance with patient weight 24 h of the confirmation of S. aureus. Patients are Daptomycin dosing 6 mg/kg body weight excluded if they are moribund due to other illnesses and Weight (kg) Daptomycin dose (mg) are expected to die within 5 days of potential recruit- 38–45 250 ment, are clinically appropriate for admission to a 46–54 300 critical care unit but are not going to receive critical care 55–62 350 due to an advanced directive, or if they are unable to 63–70 400 receive either ASBL monotherapy or a combination of 71–79 450 ASBL and daptomycin exclusively. The latter precludes individuals with known type I hypersensitivity to the 80–87 500 study drugs from participating in the trial and those with 88–95 550 polymicrobial infections requiring additional antimicro- 96–104 600 bial drugs. Patients for whom the use of open-label dap- 105–112 650 tomycin was felt to be indicated by the treating doctors 113–120 700 were also excluded. 121–129 750 Our research team is notified of eligible patients via direct page coupled with an automatically generated fax 130–137 800 when a new presumptive S. aureus infection is identified 138–145 850 on blood culture. The microbiologic protocols followed to More than 145 900 identify S. aureus and determine methicillin susceptibility are included in the Appendix: Figure 2. After the organism is identified, patients are assessed for eligibility and of drug allocation. The study drug is delivered to the approached for the study by trained personnel. If patients patient’s admitting unit in the form of a sealed container are unable to consent, the research team approaches their with the patient’s name and unit number and administra- power of attorney for third-party consent. tion instructions. Upon enrollment, each patient is assigned a unique nu- The choice of ASBL, either cloxacillin or cefazolin, is meric study identifier that will be used in the subsequent at the treating team’s discretion. Further management of randomization and statistical analysis. Randomization for the infection is also at the treating team’s discretion. The each unique identifier is performed in advance by per- study protocol does not prescribe the timing of removal muted block with variable block size. The randomization of intravascular devices, performance of echocardiog- table is held in confidence by the central research raphy, ancillary investigations aside from the bloodwork pharmacy, which services all three sites. Investigators and mentioned below, or consultation with an infectious study personnel outside of the research pharmacy do not diseases specialist. Statin therapy may be continued. have access to the randomization table. The study mandates that regular blood samples be ob- tained to document clearance of the infection and monitor Study protocol for drug adverse effects (see Fig. 1). Two sets of aerobic and Enrolled patients are randomized to daptomycin and an anaerobic blood cultures are obtained daily for 5 days or ASBL or placebo and an ASBL. Daptomycin at a dose of until microbiological clearance is documented. As per our 6 mg/kg body weight is administered intravenously once routine hospital practice, the first blood culture set contains daily for 5 days in persons with normal renal function (see both an aerobic and an anaerobic bottle, whereas the sec- Tables 1 and 2 for details). This dose was chosen as it is ond set contains only an aerobic bottle. Complete blood the dose approved by Health Canada for the treatment of counts, creatine kinase, aspartate aminotransferase, alanine S. aureus bacteremia. In obese patients, the actual body aminotransferase, alkaline phosphatase, gamma-glutamyl weight is used as in keeping with the monograph. The transferase, and total and direct bilirubin are drawn on days study drug is dissolved in a 50-mL bag of NaCl 0.9% or in 1 and 5. Electrolytes and creatinine are measured at a an appropriately sized syringe if there is a minibag short- Table 2 Daptomycin dosing interval per patient renal function age. The placebo is NaCl 0.9%, which is provided in the Renal function Dosing interval same container and administered intravenously once daily Creatinine clearance > 30 mL/minute Q24H × 5 doses for 5 days in persons with normal renal function; the dos- ing frequency is adjusted based on the patient’s renal func- Creatinine clearance < 30 mL/minute Q48H × 3 doses tion in the same manner as daptomycin (see Table 2). Continuous renal replacement therapy Q24H × 5 doses The MUHC research pharmacy monitors the creatinine Peritoneal cialysis Q48H × 3 doses clearance of enrolled patients and contacts the research Intermittent hemodialysis Qdialysis × 3 doses team to suggest dosing modifications as needed, regardless Cheng et al. Trials (2018) 19:297 Page 4 of 9 STUDY PERIOD Enrolment Allocation Post-allocation Close-out TIMEPOINT** -t 0 D1 D2 D3 D4 D5 ENROLMENT: Eligibility screen Informed consent Allocation INTERVENTIONS: Daptomycin Placebo ASSESSMENTS: AST Daptomycin MIC Blood cultures XX X X X Complete blood XX counts Creatine kinase XX Hepatic profile XX Electrolytes XX X Creatinine XX X Symptom questionnaire * 1 Fig. 1 Time and events scheduled for patients enrolled into the DASH-RCT. Refers to the first day post-allocation. Routine antimicrobial susceptibility testing is performed on the first methicillin-susceptible Staphylococcus aureus isolate of each patient. The minimal inhibitory concentration (MIC) to daptomycin is performed by Etest® on the first methicillin-susceptible S. aureus isolate of each patient. Two sets of blood cultures are obtained daily for 5 days or until microbiological clearance is documented, whichever is longer. Hepatic profile includes aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, and total bilirubin. Electrolytes include sodium, potassium, chloride, and bicarbonate. A symptom questionnaire is administered on day 5 to assess patients for nausea, vomiting, headaches, and myalgia minimum on days 1, 3, and 5. In addition, each patient’s drug. However, the patient’s allocation arm remains un- first MSSA isolate undergoes full antimicrobial susceptibil- known to the investigators. Such patients are maintained ity testing, and testing of the MIC to daptomycin using the in the intention-to-treat analysis. Daptomycin ETest (BioMérieux, France). The participants’ data are collected and managed using The patients, their clinicians, the investigators assessing REDCap electronic data capture tools hosted at the McGill the primary outcome, and those performing the statistical University Health Center [30]. Data are anonymized and analysis are blinded to the treatment allocation. Unblind- de-identified to ensure patient confidentiality. ing can be requested by the treating physician in the event of a serious adverse event suspected to be due to the study Outcomes drug. The research team is notified that the patient has The primary outcome is to assess if the addition of 5 days been unblinded and excluded from receiving further study of daptomycin adjunctive to an ASBL compared to ASBL Cheng et al. Trials (2018) 19:297 Page 5 of 9 monotherapy will decrease the duration of MSSA apreviouslypublished study[15] and derived from our cen- bacteremia in hospitalized men and women 18 years of age ter’s local epidemiology. or older. The total duration of bacteremia will be Participants will be analyzed according to their treat- determined based on microbiology laboratory reports. The ment allocation in an intention-to-treat analysis. A modi- duration will be defined in days, where day 1 is the day on fied intention-to-treat analysis will exclude participants which the first positive blood culture was drawn and the whose blood cultures were already negative at the time of final day is the last day that yielded a positive blood culture. their first study drug dose. Participants who have received Secondary outcomes are as follows: at least 3 days of therapy according to their treatment allocation will also be analyzed in a per-protocol fashion 1. All cause 30-day mortality will be obtained from as part of the secondary analyses. hospital records and centralized provincial health Primary outcome: the duration of MSSA bacteremia will care databases. be evaluated via time-to-event analysis using Kaplan-Meier 2. Relapsed bacteremia is defined as a blood culture curves reporting the median time to clearance. Compari- specimen positive for MSSA obtained ≥ 48 h and sons will be made using the Tarone-Ware log rank test with ≤ 90 days after obtaining a negative blood culture significant α < 0.05. (negative after 5 days of incubation). Results will be Secondary outcomes are as follows: obtained from the electronic microbiology laboratory records. 1. The proportion of patients who are clear of MSSA 3. Clinically relevant embolic or metastatic MSSA bacteremia at days 3, 5, and 7. disease will be diagnosed within 90 days of the first 2. Relapsed bacteremia will be a binary outcome; positive blood culture by the treating team and proportions will be reported, and will be compared defined as the presence of bone abscess or using Fisher’s exact test. osteomyelitis on computed tomography (CT), 3. Metastatic MSSA disease will be a binary outcome; magnetic resonance imaging (MRI), or bone and proportions will be reported, and will be compared gallium scan; renal emboli or ilio-psoas, splenic, and using Fisher’s exact test. other occult abscesses on ultrasound, CT or MRI; 4. The patient safety outcome will be binary; septic brain emboli on CT of the head or MRI of the proportions will be reported, compared using brain; septic emboli to the lung on chest x-ray or CT; Fisher’s exact test, then we will adjust for or infective endocarditis on echocardiography. confounders using exact logistic regression. 4. The patient safety outcome will be a combined 5. Analysis of effect modification of the primary outcome endpoint of nephrotoxicity, as defined by the using Cox regression models: we will analyze patient Kidney Disease: Improving Global Outcomes comorbidities, including immunosuppressive (KDIGO) guidelines [31]; hepatotoxicity, as defined conditions, the presence of endocarditis, source by an increase in liver enzymes three times the control difficulties, metastatic MSSA infection, and an upper limit of normal; and rhabdomyolysis, as infectious diseases consultation. defined by an increase in creatine kinase three times 6. Accounting for confounders: imbalances in potential the upper limit of normal, occurring within the first confounders between study arms will be evaluated for 5 days of therapy. A questionnaire administered on their influence on the relationship between the day 5 post-allocation is used to assess patients for intervention and the time to clearance of bacteremia nausea, vomiting, headaches, and myalgia. using Cox regression models. Exact logistic regression will be used to adjust for confounders of the secondary outcomes (numbers 1 through 4). Statistical analyses 7. Per-protocol analysis of the time to clearance of Sensitivity analysis was performed to determine the sample bacteremia between the study groups: time-to-event size required to achieve 80% power. Assuming that the dur- analysis using Kaplan-Meier curves, comparisons ation of bacteremia was normally, log-normally, or Poisson using the Tarone-Ware log rank test. distributed, with a mean duration of bacteremia of 3 days, and a standard deviation of 2 days (3 for Poisson), a sample An interim analysis is planned upon enrollment of 50 size of approximately 102 participants would be required to patients who continue to have bacteremia at the time of en- detect a1-day differenceindurationof bacteremiaata sig- rollment. This analysis will be reviewed by an independent nificance level of 5%. If the mean duration of bacteremia is Safety Monitoring Board comprising two physicians and 2 days, we would have 70% power for our primary outcome one statistician who are not appointed to the division of assuming the duration of bacteremia was normally or Infectious Diseases and are not involved in the study. They log-normally distributed. Assumptions were adapted from have the authority to stop the study if there is significant Cheng et al. Trials (2018) 19:297 Page 6 of 9 evidence of benefit or harm (primary outcome, primary [17, 35]. As we do not anticipate differential allocation of safety outcome) based on the O’Brien-Fleming patients with early metastatic disease to a specific arm, a alpha-spending approach [32]. difference in clinically relevant events between groups All statistical analyses will be performed using statistical would be suggestive (but not definitive) of a drug effect. software including STATA 15.0 (STATA Corp, College This secondary endpoint should thus remain informative Station, TX, USA), SAS 9.4 (SAS Institute Inc., Cary, NC, despite the absence of additional diagnostic procedures per- USA), and/or R (R Foundation for Statistical Computing, formed throughout the study. Vienna, Austria). To mitigate the previously mentioned limitations, we could have enrolled all patients with presumed staphylo- Discussion coccal infection per the presence of Gram-positive cocci The objective of the DASH-RCT is to assess whether pa- in clusters on Gram stain of positive blood cultures. tients receiving an ASBL and daptomycin are at reduced Rapid enrollment would have reduced the time between risk of prolonged bacteremia. We hope that an improve- presentation and initiation of the study drugs at the cost ment in this endpoint might be associated with a reduc- of increased post-randomization exclusions. Indeed, tion in metastatic infections, recurrence, and mortality. more patients would have been recruited with MRSA Our goal is to assess whether daptomycin is a good candi- blood stream infections or blood culture contamination date to be studied in a larger study powered for those out- due to coagulase-negative Staphylococcus. Advances in comes. Ultimately, we would like to determine whether earlier diagnosis using a molecular microbiologic the standard of care for MSSA bacteremia should become technique could provide the opportunity for earlier combination therapy with an ASBL and daptomycin. enrollment without enrolling patients with non-relevant There are several limitations to the DASH-RCT trial. Gram-positive cocci. First, the identification of MSSA in blood cultures and the Second, many patients enrolled in the trial will be subsequent enrollment of the patient in the trial is delayed expected to be clear of bacteremia by the time of enroll- by the need to identify the microorganism in the laboratory. ment, as only approximately 30–40% of Staphylococcal As a result, patients may be exposed to a variety of bacteremia persists. It is very difficult to predict in open-label broad-spectrum antibiotics prior to trial enroll- advance who these patients will be and the study sample ment for up to 72 h. While we believe there will not be bias size has been chosen to allow for this. Due to the lag in in these between the arms of the study due to identification of bacteremia, it is impossible to avoid the randomization, there is a possibility of such imbalance, enrollment of patients who may have already be clear of which will need to be considered. We have put into place bacteremia at enrollment. Nevertheless, this limitation will techniques (see Appendix) for early identification of MSSA apply to both the study group and the placebo group and from positive blood cultures and enroll on evenings and therefore the role of adjunctive daptomycin in mitigating weekends to minimize delays. Unfortunately, these early complications of the bacteremia will still be of interest. identification techniques could lead to early misidentifica- Moreover, we have also pre-planned a modified tion of MSSA in approximately 3% of patients (based on intention-to-treat analysis to look only at those who still unpublished but extensive local verification studies) and have bacteremia when they start the study drug. those patients would need to be excluded. However, using Despite the aforementioned limitations, we believe that our modified tube coagulase test (Appendix), rapid MRSA the DASH-RCT is founded in rigorous methodology and testing (Appendix), and accounting for known MRSA examines a biologically plausible hypothesis. Our study colonization status [33] allows us to recruit patients into may demonstrate that daptomycin in combination with an the study as close to presentation as possible, while main- ASBL results in faster clearance of MSSA bacteremia than taining specificity. Second, as the organism may have the current standard of care. Prescribing a short course of already disseminated at the time of species identification, daptomycin at the Health Canada and U.S. Food and Drug the ability to evaluate whether daptomycin can limit Administration approved dose will limit potential metastatic spread may be diminished. We chose to assess dose-dependent toxicities. Benefits similar to combination patients for clinically relevant embolic or metastatic MSSA therapy with aminoglycosides may then be demonstrated, disease as evaluated by the treating team, which has been but with reduced rates of adverse events. If our hypotheses previously validated as a clinical outcome in S. aureus trials hold true, further trials to evaluate daptomycin as an [34]. While we record clinically significant metastatic events adjunctive therapy in the treatment of MSSA-associated at enrollment and follow up, for cost and diagnostic diseases will be warranted. However, given that the stewardship reasons we will not perform extensive imaging mortality associated with MSSA bacteremia is approxi- at the time of randomization nor systematically search for mately 20%, a significantly larger randomized controlled embolic disease during the trial, which is in keeping with trial would be required to demonstrate a survival benefit other large randomized controlled trials involving S. aureus of using combination therapy. Cheng et al. Trials (2018) 19:297 Page 7 of 9 Trial status 4. Isolates that are beta hemolytic, gram-positive cocci in The DASH-RCT began enrolling patients on 1 December clusters are then tested for the presence of catalase 2016. The trial is ongoing. Patient recruitment and follow and coagulase using conventional biochemical analysis. up is expected to be completed by 31 December 2018. 5. These isolates are screened for clumping factor using the Staphaurex Latex Agglutination Assay (ThermoFisher Scientific, MA, USA). Appendix 6. A tube coagulase is also performed on these and Presumptive identification of methicillin-susceptible the results read at 4 h. Staphylococcus aureus 7. Isolates are identified as presumptive S. aureus when they are found to be beta-hemolytic, gram-positive 1. Inoculated blood culture bottles (Bactec, Becton, cocci in clusters, which are catalase-positive, latex Dickinson and Company, New Jersey, USA) are agglutination-positive, and tube coagulase-positive. incubated in the Bactec 9000 blood culture 8. Antimicrobial susceptibility and oxacillin screening instrumentation system as per manufacturer is performed on the Vitek 2 system using their instructions until identified as positive. Antimicrobial Susceptibility Cards (AST) 2. Positive bottle are removed from the incubator and (BioMerieux, Marcy-l’Étoile, France). Methicillin- plated onto blood agar. susceptible S. aureus is identified when isolates are 3. Colonies are gram-stained At 24 h. reported as sensitive to oxacillin using this system. Fig. 2 Identification algorithm utilized for methicillin-susceptible Staphylococcus aureus Cheng et al. Trials (2018) 19:297 Page 8 of 9 Additional file 3. Troidle L, et al. Complications associated with the development of bacteremia with Staphylococcus aureus. Hemodial Int. 2007;11(1):72–5. 4. Bai AD, et al. Impact of infectious disease consultation on quality of care, Additional file 1: SPIRIT 2013 Checklist: Recommended items to address mortality, and length of stay in Staphylococcus aureus bacteremia: results in a clinical trial protocol and related documents*. (DOC 120 kb) from a large multicenter cohort study. Clin Infect Dis. 2015;60(10):1451–61. 5. Goto M, et al. Association of evidence-based care processes with mortality in staphylococcus aureus bacteremia at veterans health administration Abbreviations hospitals, 2003-2014. JAMA Intern Med. 2017;177(10):1489–97. ASBL: Anti-staphylococcal beta-lactam; BSI: Bloodstream infections; CT: Computed tomography; MIC: Minimum inhibitory concentration; 6. Cheng MP, Rene P, Cheng AP, Lee TC. Back to the Future: Penicillin- MRI: Magnetic resonance imaging; MRSA: Methicillin-resistant Staphylococcus Susceptible Staphylococcus aureus. Am J Med. 2016;129(12):1331–33. aureus; MSSA: Methicillin-susceptible Staphylococcus aureus; MUHC: McGill 7. Yahav D, et al. Risk factors for long-term mortality of Staphylococcus aureus University Health Center bacteremia. Eur J Clin Microbiol Infect Dis. 2016;35(5):785–90. 8. Chang FY, et al. A prospective multicenter study of Staphylococcus aureus bacteremia: incidence of endocarditis, risk factors for mortality, and clinical Acknowledgements impact of methicillin resistance. Medicine (Baltimore). 2003;82(5):322–32. The authors gratefully acknowledge the financial assistance of the McGill University Health Center Association of Physicians and the technical and 9. Mermel LA, et al. Guidelines for the management of intravascular catheter- in-kind assistance from the MUHC Microbiology Laboratory and Research related infections. Clin Infect Dis. 2001;32(9):1249–72. Pharmacy. 10. Mermel LA, et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;49(1):1–45. Funding 11. Bai AD, et al. Comparative effectiveness of cefazolin versus cloxacillin as The funding for the DASH-RCT trial is provided through internal funding definitive antibiotic therapy for MSSA bacteraemia: results from a large from the MUHC Association of Physicians. Dr. Lee receives research salary multicentre cohort study. J Antimicrob Chemother. 2015;70(5):1539–46. support from the Fonds de Recherche Santé Québec. 12. McDanel JS, et al. Comparative effectiveness of cefazolin versus nafcillin or oxacillin for treatment of methicillin-susceptible Staphylococcus aureus Availability of data and materials infections complicated by bacteremia: a nationwide cohort study. Clin Data sharing is not applicable to this article as no datasets were generated Infect Dis. 2017;65(1):100–6. or analyzed during the current study. The study investigators will have 13. Korzeniowski O, Sande MA. Combination antimicrobial therapy for access to the final trial dataset. staphylococcus aureus endocarditis in patients addicted to parenteral drugs and in nonaddicts: a prospective study. Ann Intern Med. 1982;97(4):496–503. Publication plans 14. Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis in adults: Data generated from this study will be published in a peer-reviewed journal. diagnosis, antimicrobial therapy, and management of complications: A There are no publication restrictions. Authorship eligibility will be determined scientific statement for healthcare professionals from the American Heart based on contributions to the study. No professional writers will be used. Association. Circulation. 2015;132(15):1435-86. 15. Davis JS, et al. Combination of vancomycin and β-lactam therapy for Authors’ contributions methicillin-resistant Staphylococcus aureus bacteremia: a pilot multicenter MPC and AL drafted and revised this manuscript. MPC and TCL contributed randomized controlled trial. Clin Infect Dis. 2016;62(2):173–80. equally to the theory and conceptualization of the DASH-RCT trial and to the 16. Tong SYC, et al. CAMERA2 – combination antibiotic therapy for methicillin- critical revisions of this manuscript. MPC, AL, and GBL identified, consented resistant Staphylococcus aureus infection: study protocol for a randomised and enrolled the patients in the trial and collected the data. GBL, KP, and controlled trial. Trials. 2016;17(1):170. TCL will perform the statistical analysis and interpretation. All authors read 17. Richter SS, et al. The in vitro activity of daptomycin against Staphylococcus and approved the final version of this manuscript. aureus and Enterococcus species. J Antimicrob Chemother. 2003;52(1):123–7. 18. Fowler VGJ, et al. Daptomycin versus standard therapy for bacteremia Ethics approval and consent to participate and endocarditis caused by Staphylococcus aureus. N Engl J Med. 2006; The DASH-RCT trial was reviewed and approved by the McGill University 355(7):653–65. Health Center Research Ethics Board. Informed consent will be obtained 19. Straus SK, Hancock REW. Mode of action of the new antibiotic for from all patients recruited to the study prior to study participation. Gram-positive pathogens daptomycin: comparison with cationic antimicrobial peptides and lipopeptides. Biochim Biophys Acta Competing interests Biomembr. 2006;1758(9):1215–23. The authors declare that they have no competing interests. 20. Steenbergen JN, et al. Daptomycin: a lipopeptide antibiotic for the treatment of serious Gram-positive infections. J Antimicrob Chemother. 2005;55(3):283–8. Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in 21. Rand KH, Houck HJ. Synergy of daptomycin with oxacillin and other β- published maps and institutional affiliations. lactams against methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2004;48(8):2871–5. Author details 22. Dhand A, et al. Use of antistaphylococcal β-lactams to increase daptomycin Division of Infectious Diseases, Department of Medicine, McGill University, activity in eradicating persistent bacteremia due to methicillin-resistant 1001 Boulevard Décarie E5-1917, Montreal, QC H4A 3J1, Canada. Division of Staphylococcus aureus: role of enhanced daptomycin binding. Clin Infect Neonatology, Department of Pediatrics, Sainte-Justine Hospital, Montréal, QC, Dis. 2011;53(2):158–63. Canada. Clinical Practice Assessment Unit, Department of Medicine, McGill 23. Dhand A, Sakoulas G. Daptomycin in combination with other antibiotics for University Health Centre, Montréal, QC, Canada. the treatment of complicated methicillin-resistant Staphylococcus aureus bacteremia. Clin Ther. 2014;36(10):1303–16. Received: 25 October 2017 Accepted: 3 May 2018 24. Sakoulas G, et al. Ampicillin enhances daptomycin- and cationic host defense peptide-mediated killing of ampicillin- and vancomycin-resistant Enterococcus faecium. Antimicrob Agents Chemother. 2012;56(2):838–44. References 25. Sakoulas G, et al. Ceftaroline restores daptomycin activity against 1. El Atrouni WI, et al. Temporal trends in the incidence of Staphylococcus daptomycin-nonsusceptible vancomycin-resistant Enterococcus faecium. aureus bacteremia in Olmsted County, Minnesota, 1998 to 2005: a Antimicrob Agents Chemother. 2014;58(3):1494–500. population-based study. Clin Infect Dis. 2009;49(12):e130–8. 26. Smith JR, et al. β-Lactam combinations with daptomycin provide synergy 2. Rhee Y, et al. Evolving epidemiology of Staphylococcus aureus bacteremia. against vancomycin-resistant Enterococcus faecalis and Enterococcus Infect Control Hosp Epidemiol. 2015;36(12):1417–22. faecium. J Antimicrob Chemother. 2015;70(6):1738–43. Cheng et al. Trials (2018) 19:297 Page 9 of 9 27. Mehta S, et al. β-Lactams increase the antibacterial activity of daptomycin against clinical methicillin-resistant Staphylococcus aureus strains and prevent selection of daptomycin-resistant derivatives. Antimicrob Agents Chemother. 2012;56(12):6192–200. 28. Snydman DR, McDermott LA, Jacobus NV. Evaluation of in vitro interaction of daptomycin with gentamicin or beta-lactam antibiotics against Staphylococcus aureus and Enterococci by FIC index and timed-kill curves. J Chemother. 2005;17(6):614–21. 29. Werth BJ, et al. Ceftaroline increases membrane binding and enhances the activity of daptomycin against daptomycin-nonsusceptible vancomycin- intermediate Staphylococcus aureus in a pharmacokinetic/pharmacodynamic model. Antimicrob Agents Chemother. 2013;57(1):66–73. 30. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap) – a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42(2):377–81. 31. Ardalan MR, et al. Aspergillosis after renal transplantation. Saudi J Kidney Dis Transpl. 2005;16(3):330–3. 32. DeMets DL, Lan KK. Interim analysis: the alpha spending function approach. Stat Med. 1994;13(13–14):1341–52. discussion 1353-6 33. Butler-Laporte G, et al. Using MRSA screening tests to predict methicillin resistance in Staphylococcus aureus bacteremia. Antimicrob Agents Chemother. 2016;60(12):7444–8. 34. Kang DH, et al. Early surgery versus conventional treatment for infective endocarditis. N Engl J Med. 2012;366(26):2466–73. 35. Thwaites GE, Scarborough M, Szubert A, et al. Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2018;391(10121):668-78.

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TrialsSpringer Journals

Published: May 29, 2018

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