Clinical Data on Daptomycin plus Ceftaroline versus Standard of Care Monotherapy in the Treatment of Methicillin-Resistant Staphylococcus aureus Bacteremia.

CLINICAL THERAPEUTICS crossm Clinical Data on Daptomycin plus Ceftaroline versus Standard of Care Monotherapy in the Treatment of Methicillin-Resistant Staphylococcus aureus Bacteremia Matthew Geriak,a Fadi Haddad,b Khulood Rizvi,c Warren Rose,d Ravina Kullar,e Kerry LaPlante,f Marie Yu,b Logan Vasina,a Krista Ouellette,a Marcus Zervos,c Victor Nizet,f George Sakoulasa,g a Sharp Memorial Hospital, San Diego, California, USA b Sharp Grossmont Hospital, La Mesa, California, USA c Henry Ford Hospital, Detroit, Michigan, USA d University of Wisconsin School of Pharmacy, Madison, Wisconsin, USA e Doctor Evidence, LLC, Santa Monica, California, USA f University of Rhode Island College of Pharmacy, Kingston, Rhode Island, USA g University of California San Diego School of Medicine, La Jolla, California, USA ABSTRACT Vancomycin (VAN) and daptomycin (DAP) are approved as a monotherapy for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. A regimen of daptomycin plus ceftaroline (DAP⫹CPT) has shown promise in published case series of MRSA salvage therapy, but no comparative data exist to compare up-front DAP⫹CPT head-tohead therapy versus standard monotherapy as an initial treatment. In a pilot study, we evaluated 40 adult patients who were randomized to receive 6 to 8 mg/kg of body weight per day of DAP and 600 mg intravenous (i.v.) CPT every 8 h (q8h) (n ⫽ 17) or standard monotherapy (n ⫽ 23) with vancomycin (VAN; dosed to achieve serum trough concentrations of 15 to 20 mg/liter; n ⫽ 21) or 6 to 8 mg/kg/day DAP (n ⫽ 2). Serum drawn on the first day of bacteremia was sent to a reference laboratory post hoc for measurement of interleukin-10 (IL-10) concentrations and correlation to in-hospital mortality. Sources of bacteremia, median Pitt bacteremia scores, Charlson comorbidity indices, and median IL-10 serum concentrations were similar in both groups. Although the study was initially designed to examine bacteremia duration, we observed an unanticipated in-hospital mortality difference of 0% (0/17) for combination therapy and 26% (6/23) for monotherapy (P ⫽ 0.029), causing us to halt the study. Among patients with an IL-10 concentration of ⬎5 pg/ml, 0% (0/14) died in the DAP⫹CPT group versus 26% (5/19) in the monotherapy group (P ⫽ 0.057). Here, we share the full results of this preliminary (but aborted) assessment of early DAP⫹CPT therapy versus standard monotherapy in MRSA bacteremia, hoping to encourage a more definitive clinical trial of its potential benefits against this leading cause of infection-associated mortality. (The clinical study discussed in this paper has been registered at ClinicalTrials.gov under identifier NCT02660346.) KEYWORDS bacteremia, ceftaroline, daptomycin, methicillin-resistant Staphylococcus aureus, mortality, vancomycin Copyright © 2019 Geriak et al. This is an openaccess article distributed under the terms of the Creative Commons Attribution 4.0 International license. Address correspondence to George Sakoulas, . M ethicillin-resistant Staphylococcus aureus (MRSA) bacteremia is associated with a significant disease burden and a high case fataility, ranging from 20% to 30%, which is double that seen in methicillin-susceptible S. aureus (MSSA) bacteremia (1–3). This and other metrics of poor outcomes in patients with MRSA bacteremia are attributed to inferior pharmacotherapeutic properties of vancomycin (VAN), the cornerstone of MRSA therapy, compared with ␤-lactam antibiotics used to treat MSSA bacteremia (4, 5). Clinical May 2019 Volume 63 Issue 5 e02483-18 Citation Geriak M, Haddad F, Rizvi K, Rose W, Kullar R, LaPlante K, Yu M, Vasina L, Ouellette K, Zervos M, Nizet V, Sakoulas G. 2019. Clinical data on daptomycin plus ceftaroline versus standard of care monotherapy in the treatment of methicillin-resistant Staphylococcus aureus bacteremia. Antimicrob Agents Chemother 63:e02483-18. https://doi.org/10.1128/AAC .02483-18. Antimicrobial Agents and Chemotherapy Received 27 November 2018 Returned for modification 23 December 2018 Accepted 3 March 2019 Accepted manuscript posted online 11 March 2019 Published 25 April 2019 aac.asm.org 1 Geriak et al. Antimicrobial Agents and Chemotherapy studies demonstrating such differences have been bolstered by experimental data showing that ␤-lactams not only exert direct antibacterial effects on S. aureus but also synergize with cationic antimicrobial peptides and other arms of the innate immune system to promote pathogen clearance (6). These secondary effects may be noteworthy enough that the addition of antistaphylococcal ␤-lactams (oxacillin, nafcillin, and flucloxacillin) to cornerstone daptomycin (DAP) and VAN can aid in the clearance of refractory MRSA bacteremia, despite the ␤-lactam agents having no direct anti-MRSA activity, as measured by standard susceptibility testing methods (7, 8). Based on a study showing noninferiority of DAP to VAN in treating MRSA bacteremia (9), the Infectious Diseases Society of America (IDSA) 2011 MRSA treatment guidelines recommend initiating one of these two agents as first-line MRSA bacteremia therapy (10). Although definitions vary, initial treatment failure is encountered in up to 50% of cases and is linked to poor outcomes, including a greater likelihood of metastatic infections and increased mortality (11–13). The IDSA guidelines recommend switching to an alternative regimen for persistent MRSA bacteremia of ⱖ7 days or earlier if clinical deterioration is evident (10). Case reports and series have documented high success in the treatment of persistent MRSA bacteremia by combining DAP with antistaphylococcal ␤-lactams or ceftaroline (CPT) (14). Potential mechanisms underlying this advantageous dual therapy are (i) ␤-lactam reduction of cell wall cross-linking, enhancing DAP access to the cell membrane (14); (ii) synergy of ␤-lactams with endogenous cationic host defense peptides against MRSA (6); and (iii) increased NLRP3 inflammasome activation and interleukin-1␤ (IL-1␤)-mediated bacterial clearance induced by altered peptidoglycan synthesized by MRSA under ␤-lactam challenge (15, 16). Despite excellent clinical responses to DAP⫹CPT as salvage therapy in difficult MRSA bacteremia cases, immediate initiation of DAP⫹CPT has not been compared with the current standard of care monotherapy. Furthermore, data are emerging that suggest that VAN monotherapy may be insufficient to treat severe MRSA respiratory infections, whereby a second agent may be needed to the improve outcome (17). We prospectively examined DAP⫹CPT within 72 h of bacteremia onset to standard of care VAN or DAP monotherapy in the treatment of MRSA bacteremia in 3 hospital centers. Due to the fact that the study was not carried out in a blind manner and because an unexpected mortality difference was identified before completion, the study was halted early and the cohort of patients remained small. Serum concentrations of interleukin-10, a strong predictor of mortality in S. aureus (...truncated)