Oritavancin Activity Tested against Molecularly Characterized Staphylococci and Enterococci Displaying Elevated Linezolid MIC Results

Abstract

Oritavancin (MIC 50/90 , 0.03/0.06 to 0.12 g/ml) had potent activity against linezolid-resistant staphylococci, as well as Enterococcus faecalis and Enterococcus faecium (oritavancin MIC 50/90 , 0.015/0.12 g/ml against both species). All linezolid-resistant isolates were inhibited by oritavancin at <0.12 g/ml. These results confirmed the absence of cross-resistance between linezolid and oritavancin in staphylococci and enterococci. Staphylococcus aureus (including methicillin-resistant S. aureus [MRSA]), coagulase-negative staphylococci (CoNS), Enterococcus faecium, and multidrug-resistant (MDR) streptococci are frequently isolated pathogens responsible for various clinical infections (1). Several national and local studies have documented a decrease in the incidence of invasive MRSA infections in the United States (2-4). However, MRSA is still estimated to cause ϳ80,000 invasive infections and result in 11,000 deaths annually in the United States (5). Vancomycin-resistant enterococci (VRE) are estimated to cause 20,000 hospital-acquired infections and 1,300 deaths each year (5). Moreover, MRSA and E. faecium are among the defined ESKAPE organisms (E. faecium, S. aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.), which cause the majority of U.S. nosocomial infections and are often refractory to many clinically available agents (6).Linezolid is an anti-Gram-positive agent approved for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) (7), with potent activity against clinical pathogens causing infections worldwide according to large surveillance studies (8, 9). Although uncommon, linezolid resistance does occur, especially after prolonged administration (7, 10), and local investigations have reported occurrences of sporadic outbreaks (11)(12)(13)(14) and dissemination of linezolid-dependent isolates (15,16). Alterations in linezolid binding sites (23S rRNA and L3 and L4 ribosomal proteins) remain the most common mechanisms of oxazolidinone resistance (7). Additionally, transferrable resistance determinants, such as cfr, cfr(B), and optrA, represent newer mechanisms responsible for decreased susceptibility to linezolid (17)(18)(19). This study was conducted to evaluate the in vitro activity of oritavancin, a recently approved lipoglycopeptide for the treatment of ABSSSI (20), against a molecularly characterized collection of isolates displaying elevated linezolid MIC results.A total of 25 S. aureus (linezolid MIC range, 4 to 32 g/ml), 80 CoNS (linezolid MIC range, 4 to Ͼ128 g/ml), and 45 enterococci (linezolid MIC range, 4 to 64 g/ml) were included (see Table S1 in the supplemental material). These isolates were selected based on the presence of linezolid resistance mechanisms, although some staphylococcal isolates showed a linezolid MIC result (4 g/ ml) at the breakpoint for susceptibility (i.e., Յ4 g/ml) (21). Isolates were recovered from a network of medical centers as part of the SENTRY Antimicrobial Surveillance Program and submi...