Redeploying β-Lactams Against Staphylococcus aureus: Repurposing With a Purpose

The Journal of Infectious Diseases EDITORIAL COMMENTARY Redeploying β-Lactams Against Staphylococcus aureus: Repurposing With a Purpose Arnold S. Bayer1 and Yan Q. Xiong2 1 LA Biomedical Research Institute at Harbor-UCLA, Torrance, and 2David Geffen School of Medicine at UCLA, Los Angeles, California (See the major article by Waters et al on pages 80–7.) Keywords. β-Lactams; MRSA; MSSA; synergy; Staphylococcus aureus. Received and accepted 26 September 2016; published online 14 November 2016. Correspondence: A. S. Bayer, c/o LA Biomedical Research Institute at Harbor-UCLA, 1124 W Carson St, Bldg RB2, Rm 225, Torrance, CA 90502 (). The Journal of Infectious Diseases® 2017;215:11–13 © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail . DOI: 10.1093/infdis/jiw464 laboratories [8, 9] have identified that the key synergic event is likely the capacity of the β-lactams of interest to block penicillin-binding protein1 (PBP1). This synergic event with daptomycin occurs whether the PBP1 blockade is promiscuous (ie, whether, like nafcillin, it binds to PBP1–4) or occurs in a more PBP1specific manner [10]. Of interest, this daptomycin–β-lactam synergy is also seen with other cationic peptides, including those of the innate host defense system (eg, LL-37) [10]. The 2 main theories about the mechanism(s) of this synergy between cationic peptides (eg, calcium daptomycin) and PBP1-targeting β-lactams are (1) enhanced binding of daptomycin to the divisome, its principal site of action; and/or (2) augmentation of the functional activity of daptomycin without increasing binding [6]. In the current issue of The Journal of Infectious Diseases, Waters et al [11] propose yet another role for β-lactams in anti-staphylococcal therapeutics—an antivirulence mechanism to enhance clinical outcomes in MRSA infections, using oxacillin as the proof-of-principle β-lactam. It should be emphasized that defining an agent’s specific antivirulence properties is difficult. This difficulty is because virulence per se potentially encompasses the sum of a complex set of pathophysiologic events and metrics: (1) in vitro effects on growth rates and/or growth yields, (2) organism transmissibility (ie, the ability to colonize and persist on biologic surfaces, such as on nasal epithelium or on damaged cardiac valves), (3) intrinsic pathogenicity at the site of infection (including toxin production and biofilm formation), and (4) the capacity to evade the innate and adaptive immune systems. Repurposing existing compounds for influencing bacterial virulence or the outcomes of bacterial infections has become de rigueur over the past 2 decades. Examples include (1) using statins to improve outcomes in sepsis and bacterial pneumonias [12, 13]; (2) using statins to reduce the capacity of S. aureus to produce carotenoid pigments, thus improve the ability of the host to eliminate this organism via the oxidative limb of the innate immune system [14]; (3) using aspirin and its congeners to enhance antistaphylococcal therapeutics [15]; and (4) using azithromycin and other macrolides as immunomodulating agents in treating infections [16]. The notion of repurposing β-lactams to affect bacterial virulence independently, over and above their intrinsic bactericidal effects, is not new. More than 30 years ago, a number of experimental endocarditis investigations confirmed that subbactericidal exposures of viridans group streptococci to β-lactam agents impeded the capacity of these pathogens to adhere to and colonize cardiac vegetations [17–19]. This nonbactericidal impact of β-lactams against endocarditis-causing pathogens, confirmed experimentally, has been leveraged into the current approach to antimicrobial prophylaxis of endocarditis, as recommended by the American Heart Association [20]. Thus, β-lactam EDITORIAL COMMENTARY • JID 2017:215 (1 January) • 11 β-Lactam antibiotics have been a mainstay of clinical therapeutics for approximately 70 years, especially for methicillin-susceptible Staphylococcus aureus (MSSA) infections. Since approximately one half of S. aureus bacteremias are caused by MSSA [1], the antistaphylococcal β-lactams remain key elements of therapeutic strategies for such infections. Data from a number of clinical trials have documented the therapeutic superiority of antistaphylococcal β-lactams over vancomycin for MSSA bacteremic infections, including endocarditis [2–4]. Further, the American Heart Association has consistently recommended β-lactams as the treatment of choice for MSSA endocarditis [5]. Recently, the antistaphylococcal βlactams have emerged as an additional tool for treating recalcitrant methicillinresistant S. aureus (MRSA) bacteremic infections, often in combination with daptomycin. The β-lactams that have been deployed off label in combination for this scenario include nafcillin, oxacillin, and ceftaroline [6, 7]. This apparent synergy extends to both persistent MSSA infections and persistent MRSA infections, suggesting that a novel mechanism(s) is involved. Studies from several of wall teichoic acid production, which translated into augmentation of C3b complement deposition and enhanced opsonophagocytosis. Again, the readouts of these latter functional assays were performed using human phagocytes; the linkage with outcomes in their murine infection models remains unproven. Finally, in their murine in vivo studies, Waters et al used 2 distinct models, bacteremia and pneumonia. As with most in vivo investigations, the devil is in the details. For example, at 28 hours after infection in the bacteremia model, there was little bacterial load difference in kidneys and only modest differences in spleens of animals treated with 2 oxacillin doses (7.5 and 75 mg/kg). At 7 days after infection, there was significantly reduced virulence in both kidneys and spleens, although in kidneys, there was a heterogeneous outcome from animal to animal, featured by overlapping of untreated control and oxacillin-treated animal bacterial loads. Given that oxacillin exposures will increase opsonophagocytic killing in vitro, it makes sense that the spleen would exhibit the largest readouts. In contrast, in the pneumonia model, there was a significant impact on both blood culture clearances and in vivo survival in the 2 oxacillin dose regimens. Curiously, no lung bacterial load data were presented. The investigations by Waters et al [11] are well done, clearly presented, and hypothesis generating. Further investigations with more animal models and additional MRSA strains should be done. Moreover, advanced randomized clinical trials addressing the effects of β-lactams in MRSA infections need to be performed. It is encouraging that a recent, small (60 patient) open-label and randomized trial in Australia of vancomycin, with or without the β-lactam flucloxacillin, demonstrated reduced duration of bacteremia by approximately (...truncated)