Effect of Algorithm-Based Therapy vs Usual Care on Clinical Success and Serious Adverse Events in Patients with Staphylococcal Bacteremia: A Randomized Clinical Trial

Abstract

Importance: The appropriate duration of antibiotics for staphylococcal bacteremia is unknown.

Objective: To test whether an algorithm that defines treatment duration for staphylococcal bacteremia vs standard of care provides noninferior efficacy without increasing severe adverse events.

Design, setting, and participants: A randomized trial involving adults with staphylococcal bacteremia was conducted at 16 academic medical centers in the United States (n = 15) and Spain (n = 1) from April 2011 to March 2017. Patients were followed up for 42 days beyond end of therapy for those with Staphylococcus aureus and 28 days for those with coagulase-negative staphylococcal bacteremia. Eligible patients were 18 years or older and had 1 or more blood cultures positive for S aureus or coagulase-negative staphylococci. Patients were excluded if they had known or suspected complicated infection at the time of randomization.

Interventions: Patients were randomized to algorithm-based therapy (n = 255) or usual practice (n = 254). Diagnostic evaluation, antibiotic selection, and duration of therapy were predefined for the algorithm group, whereas clinicians caring for patients in the usual practice group had unrestricted choice of antibiotics, duration, and other aspects of clinical care.

Main outcomes and measures: Coprimary outcomes were (1) clinical success, as determined by a blinded adjudication committee and tested for noninferiority within a 15% margin; and (2) serious adverse event rates in the intention-to-treat population, tested for superiority. The prespecified secondary outcome measure, tested for superiority, was antibiotic days among per-protocol patients with simple or uncomplicated bacteremia.

Results: Among the 509 patients randomized (mean age, 56.6 [SD, 16.8] years; 226 [44.4%] women), 480 (94.3%) completed the trial. Clinical success was documented in 209 of 255 patients assigned to algorithm-based therapy and 207 of 254 randomized to usual practice (82.0% vs 81.5%; difference, 0.5% [1-sided 97.5% CI, -6.2% to ∞]). Serious adverse events were reported in 32.5% of algorithm-based therapy patients and 28.3% of usual practice patients (difference, 4.2% [95% CI, -3.8% to 12.2%]). Among per-protocol patients with simple or uncomplicated bacteremia, mean duration of therapy was 4.4 days for algorithm-based therapy vs 6.2 days for usual practice (difference, -1.8 days [95% CI, -3.1 to -0.6]).

Conclusions and relevance: Among patients with staphylococcal bacteremia, the use of an algorithm to guide testing and treatment compared with usual care resulted in a noninferior rate of clinical success. Rates of serious adverse events were not significantly different, but interpretation is limited by wide confidence intervals. Further research is needed to assess the utility of the algorithm.

Trial registration: ClinicalTrials.gov Identifier: NCT01191840.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Holland (medical monitor) reported serving as a consultant for Basilea Pharmaceutica, Genentech, Motif Bio, The Medicines Company, and Theravance. Dr Raad (site principal investigator) reported holding 3 patents for Novel Anti-Infective Technologies; receiving royalties from Cook and Novel Anti-Infective Technologies; and serving as chair of the scientific advisory board for Citius. Dr Anderson (clinical events committee [CEC] member) reported receiving a Centers for Disease Control and Prevention Epicenter grant study of stewardship and an Agency for Healthcare Research and Quality grant to study surgical infection and receiving royalties from UpToDate royalties for chapters, including chapters on treatment of bloodstream infection. Dr Cosgrove (CEC member) reported serving on infection adjudication committees for Novartis and Theravance. Dr Chu (site principal investigator) reported serving as an author for UpToDate and as an adjudicator for Theravance. Dr Corey (co-investigator) reported receiving scientific advisory board and consultanting fees from Allergan (formerly Cerexa/Forest/Actavis) and receiving personal fees from Arsanis, Basilea, Bayer, Contrafect, Medtronic, Melinta, Merck, Motif, Paratek, Pfizer, Quintiles, SCPharma, Tetraphase, The Medicines Company, and Theravance. Dr Jenkins (site principal investigator) reported receiving consulting fees from Allergan. Dr Levine (site principal investigator) reported receiving grants from AstraZeneca and Allergan; serving as a consultant for Actavis, Allergan, The Medicines Company, Genetech, Theravance, Melinta, and Contrafect; and serving as a speaker for Actavis, Merck, and Sunovian. Dr Miro (site principal investigator) reported receiving consulting honoraria and academic and research grants from AbbVie, Angelini, Bristol-Myers Squibb, Contrafect, Cubist, Genentech, Gilead Sciences, Medtronic, Merck Sharp & Dohme, Novartis, Pfizer, and ViiV Healthcare and receiving a personal 80:20 research grant from Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. Dr Rupp (site principal investigator) reported having research contract with XBioTech and Contrafect and serving on the advisory board for Citius. Dr Schrank (site principal investigator) reported serving on the speakers bureau for Gilead Sciences. Dr Wray (site principal investigator) reported serving on a clinical trial for Theravance Biopharma. Dr Zervos (site principal investigator) reported serving as a consultant for The Medicines Company and having research contracts with Merck, Allergan/Cerexa, Genentech, Cempra, Achaogen, Melinta, Paratek, Rempex, Tetraphase, Pfizer, Durata, and AstraZeneca. Dr Fowler reported serving as chair of the V710 Scientific Advisory Committee for Merck; receiving grant support from Basilea, Cerexa/Actavis, Pfizer, Advanced Liquid Logics, National Institutes of Health (NIH), MedImmune, Cubist/Merck, Karius, Contrafect, Regeneron, and Genentech; having NIH STTR/SBIR grants pending with Affinergy, Locus, and Medical Surface Inc; serving as a paid consultant for Achaogen, Astellas, Arsanis, Affinergy, Basilea, Bayer, Cerexa, Contrafect, Cubist, Debiopharm, Durata, Grifols, Genentech, MedImmune, Merck, The Medicines Company, Pfizer, Novartis, Novadigm, Theravance, xBiotech, and Regeneron; receiving honoraria from Theravance, and Green Cross; and having a patent pending in sepsis diagnostics. No other authors reported disclosures.

Figures

Figure.. Flow of Participants Through the Staphylococcal Bacteremia Trial

aPrior to an amendment allowing inclusion of these patients. bDetails for reasons for exclusion from the per-protocol population are provided in eTable 8 in Supplement 2.