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Pharmacology of antimicrobial agents for treatment of methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococcus

Author
Richard H Drew, PharmD, MS, FCCP
Section Editor
David C Hooper, MD
Deputy Editor
Elinor L Baron, MD, DTMH

INTRODUCTION

The pharmacologic properties of alternatives to vancomycin for use in treatment of invasive infections due to methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococcus will be reviewed here. Drugs discussed include daptomycin, linezolid, ceftaroline, telavancin, dalbavancin, oritavancin, tedizolid, tigecycline, and quinupristin-dalfopristin. Issues related to the role of these agents for treatment of specific infections are discussed in detail separately. (See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of bacteremia and osteomyelitis" and "Treatment of enterococcal infections".)

DAPTOMYCIN

Daptomycin is a cyclic lipopeptide that is active against gram-positive organisms including streptococci, enterococci (including vancomycin-resistant enterococci), methicillin-sensitive S. aureus, and methicillin-resistant S. aureus (MRSA) [1,2]. While S. aureus isolates with complete or intermediate resistance to vancomycin in vitro have maintained susceptibility to daptomycin, MRSA isolates with increased minimum inhibitory concentrations (MICs) or prior exposure to vancomycin may also exhibit reduced susceptibility to daptomycin [3,4].

Daptomycin is US Food and Drug Administration (FDA)-approved for the treatment of complicated skin and skin structure infections and for bacteremia with or without right-sided endocarditis due to MRSA and other selected gram-positive pathogens [5,6].

Mechanism and pharmacodynamics — Daptomycin is rapidly bactericidal. Its primary mechanism of action is calcium-dependent depolarization of bacterial cell wall [7,8]. Daptomycin has a lipophilic tail, which binds and inserts itself into the bacterial membrane and forms a channel that causes efflux of intracellular potassium with subsequent depolarization of the cell membrane. The antimicrobial activity of daptomycin is concentration dependent and is associated with a prolonged postantibiotic effect [8-10]. Daptomycin is inactivated by alveolar surfactants and therefore should not be used for pulmonary infections [11].

The mechanisms of resistance to daptomycin are not fully understood [12]. Daptomycin resistance appears to emerge gradually via multiple steps, resulting in a heteroresistant subpopulation with elevated MIC to daptomycin [3]. Altered cell membrane potential due to changes in cell membrane surface charge has been shown to lead to reduced daptomycin binding to the cell membrane and reduced susceptibility to daptomycin-induced depolarization [13].

                                                                       

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