The Emerging Role of β-Lactams in the Treatment of Methicillin-Resistant Staphylococcus aureus Bloodstream Infections.

MINIREVIEW crossm The Emerging Role of ␤-Lactams in the Treatment of Methicillin-Resistant Staphylococcus aureus Bloodstream Infections Kyle C. Molina,a,b Taylor Morrisette,a,b Matthew A. Miller,a,b Vanthida Huang,c Douglas N. Fisha a Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, Colorado, USA b Department of Pharmacy-Infectious Diseases, University of Colorado Hospital, Aurora, Colorado, USA c Department of Pharmacy Practice, Midwestern University College of Pharmacy–Glendale, Glendale, Arizona, USA ABSTRACT Methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSI) are associated with substantial morbidity and mortality. Monotherapy with first-line antimicrobials such as vancomycin (VAN; glycopeptide) and daptomycin (DAP; lipopeptide) are inadequate in some cases due to reduced antibiotic susceptibilities or therapeutic failure. In recent years, ␤-lactam antibiotics have emerged as a potential option for combination therapy with VAN and DAP that may meet an unmet therapeutic need for MRSA BSI. Ceftaroline (CPT), the only commercially available ␤-lactam in the United States with intrinsic in vitro activity against MRSA, has been increasingly studied in the setting of VAN and DAP failures. Novel combinations of first-line agents (VAN and DAP) with ␤-lactams have been the subject of many recent investigations due to in vitro findings such as the “seesaw effect,” where ␤-lactam susceptibility may be improved in the presence of decreased glycopeptide and lipopeptide susceptibility. The combination of CPT and DAP, in particular, has become the focus of many scientific evaluations, due to intrinsic anti-MRSA activities and potent in vitro synergistic activity against various MRSA strains. This article reviews the available literature describing these innovative therapeutic approaches for MRSA BSI, focusing on preclinical and clinical studies, and evaluates the potential benefits and limitations of each strategy. KEYWORDS beta-lactams, combination therapy, ceftaroline, Staphylococcus aureus bacteremia M ethicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSI) remain a substantial cause of morbidity, mortality, and health care expenditures (1). Despite a decreasing incidence of MRSA BSI, a recent study concluded that no improvement in rates of 30-day mortality was observed between 2007 and 2015 (2). The 2011 Infectious Diseases Society of America clinical practice guidelines for the treatment of MRSA recommend the use of vancomycin (VAN) or daptomycin (DAP) as a first-line agent for treatment of MRSA BSI (3). However, clinical failures with VAN and the emergence of strains with various degrees of VAN nonsusceptibility, such as heterogeneous vancomycin-intermediate S. aureus (hVISA) and VISA, have led to ongoing concerns regarding the efficacy of VAN (4). Moreover, the emergence of isolates with reduced DAP susceptibility and the observation of apparent cross-resistance between DAP and VAN may prevent the use of DAP in the setting of VAN failure (5). The utility of DAP for treatment of MRSA BSI is further diminished by a lack of activity for MRSA BSI secondary to respiratory sources due to inactivation by pulmonary surfactant within brochoalveoli (6). The limitations of current first-line agents and lack of new anti-MRSA agents approved for the treatment of MRSA BSI leave clinicians with few July 2020 Volume 64 Issue 7 e00468-20 Antimicrobial Agents and Chemotherapy Citation Molina KC, Morrisette T, Miller MA, Huang V, Fish DN. 2020. The emerging role of β-lactams in the treatment of methicillinresistant Staphylococcus aureus bloodstream infections. Antimicrob Agents Chemother 64:e00468-20. https://doi.org/10.1128/AAC .00468-20. Copyright © 2020 American Society for Microbiology. All Rights Reserved. Address correspondence to Douglas N. Fish, . Accepted manuscript posted online 20 April 2020 Published 23 June 2020 aac.asm.org 1 Minireview Antimicrobial Agents and Chemotherapy effective treatment options for resistant or refractory infections, underscoring the need for novel therapeutic approaches. There is a growing body of experimental and clinical data that suggest a role for ␤-lactam antimicrobials in the treatment of MRSA BSI (7). Many studies have evaluated the off-label use of the anti-MRSA cephalosporin ceftaroline (CPT). Other novel treatment approaches stem from the in vitro phenomenon known as the “seesaw effect,” whereby ␤-lactam susceptibility may be enhanced as glycopeptide and lipopeptide susceptibility decreases. Several studies have consequently explored synergistic combinations of VAN or DAP and a variety of ␤-lactams to enhance bacterial eradication and/or mitigate drug resistance during treatment of MRSA BSI. The purpose of this review is to examine emerging ␤-lactam therapeutic strategies, describe their limitations, and provide future directions for the investigation of novel approaches to the treatment of MRSA BSI. Ceftaroline. Ceftaroline, the active moiety of the prodrug ceftaroline fosamil, is a broad-spectrum cephalosporin which exhibits potent in vitro activity against Grampositive organisms, including notable activity against MRSA due to a high binding affinity for penicillin-binding protein 2a (PBP2a) (8–10). The Food and Drug Administration (FDA) approved CPT in 2010 for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP) at a dosage of 600 mg intravenously every 12 h (q12h). Higher dosing (600 mg q8h) has been advocated for and is presently recommended by the Clinical and Laboratory Standards Institute (CLSI) for S. aureus isolates with CPT MICs of 2 to 4 mg/liter (susceptible dose dependent [SDD]) (11). Since FDA approval, many in vitro investigations have evaluated the potential utility of CPT as it relates to MRSA BSI. The in vitro activity of CPT was assessed against an extensive collection (n ⫽ 4,426) of clinical MRSA isolates causing BSI from U.S. hospitals between 2009 and 2013 (12). CPT demonstrated activity against 95.4% of isolates at the CLSI susceptibility breakpoint of ⱕ1 mg/liter, and the remaining 4.6% had MICs of 2 mg/liter, which is within the recently adopted SDD category. CPT retained significant activity against subsets of isolates resistant to other agents, including strains with reduced susceptibility to VAN and DAP (12). Another study evaluating in vitro CPT activity against MRSA blood culture isolates (n ⫽ 103), including 60 hVISA and VISA isolates, showed inhibition of 100% of isolates at ⱕ1 mg/liter (13). In that study, an inverse correlation was observed between CPT and VAN MICs (seesaw effect), and notably, CPT had lower MICs among hVISA isolates (13). Collectively, these data demonstrate the potent in vitro activity of CPT against MRSA isolates causing BSI and suggest a potential role in patients with MRSA isolates harb (...truncated)