United States resistance surveillance results for linezolid (LEADER Program for 2007)

Abstract

The LEADER Program (2007) monitors for emerging linezolid resistance in sampled US medical centers, initiated in 2004. For the current reported year, the number of sites participating was increased from 50 to 60 institutions representing all 9 US census regions with 100 target organisms per site (6305 isolates, 105.1% compliance to protocol design). The organisms tested by reference broth microdilution methods were Staphylococcus aureus (3318), coagulase negative staphylococci (CoNS, 1020), enterococci (705), Streptococcus pneumoniae (622), and viridans group (249) or β-hemolytic streptococci (391); also, D-test was used to determine inducible clindamycin resistance in S. aureus strains. Linezolid remained very potent against all sampled species with MIC₉₀ results ranging from 1 μg/mL (streptococci and CoNS) to 2 μg/mL (S. aureus and enterococci). Only 0.44% of sampled strains were nonsusceptible to linezolid, compared with 0.45% in 2006. The nonsusceptible strains (23) were usually staphylococci (20) or Enterococcus faecium (8), each with defined target mutations (G2576T, 24 strains) or a novel mobile cfr element in staphylococci (2 strains). In conclusion, linezolid activity sampled by the 4th year of this LEADER Program showed sustained potency and spectrum (99.56% susceptibility). Although the nonsusceptible strain isolation rates remained stable, a new plasmid-mediated ribosomal-based resistance mechanism emerged in S. aureus and Staphylococcus epidermidis strains from Arizona and Ohio. The LEADER Program appears to be an effective and sensitive surveillance tool to detect novel resistance phenotypes and genotypes.

Introduction

The LEADER Program, completing its 4th year, is a US-based resistance surveillance project focused on the monitoring of oxazolidinone activity, for example, linezolid (Draghi et al., 2005, Draghi et al., 2006, Jones et al., 2007a, Pillar et al., 2008). This effort extended the earlier US surveillance sampling of linezolid potencies reported for the prelaunch period of 1999 to 2000 by Ballow et al., 2002, Jones et al., 2001. Linezolid, the 1st oxazolidinone in clinical practice, has broad activity against Gram-positive pathogens, including multidrug-resistant subsets of Staphylococcus aureus, coagulase-negative staphylococci (CoNS), Enterococcus faecalis or Enterococcus faecium, Streptococcus pneumoniae, viridans group Streptococcus spp., and various serotypes of β-hemolytic streptococci (Brickner, 1996, Diekema and Jones, 2001, Ford et al., 2001, Zurenko et al., 1996). More recently, in vitro experience has expanded the potential range of linezolid-susceptible species to a volume of rarely isolated yet important Gram-positive pathogens (Jones et al., 2007b).

Linezolid received US Food and Drug Administration approval in 2000 and has demonstrated clinical success against indicated Gram-positive organisms causing a variety of infections including serious cutaneous disease and nosocomial pneumonia (Shorr et al., 2005, Stevens et al., 2002, Weigelt et al., 2005, Wunderink et al., 2003a, Wunderink et al., 2003b, Zyvox Package Insert, 2004). Resistance to linezolid remains very uncommon (<0.5%) among surveyed isolates. However, with wider linezolid use, resistance has been recognized (Gales et al., 2006, Gonzales et al., 2001, Jones et al., 2002, Marshall et al., 2002, Mutnick et al., 2003, Prystowsky et al., 2001, Tsiodras et al., 2001) and characterized as associated with prolonged drug exposure in at-risk patient populations or with breaks in infection control practices (Kainer et al., 2007, Mutnick et al., 2003, Pai et al., 2002, Potoski et al., 2006). The mechanisms of the oxazolidinone resistance has been dominated by mutations in 23S rRNA targets, usually at G2576T in staphylococci and enterococcal organisms (Gonzales et al., 2001, Mutnick et al., 2003); however, a mobile element was recently characterized in various Staphylococcus spp. that encodes resistances to phenicols, Lincosamides, Oxazolidinones, Pleuromutilins, and Streptogramin A (phLOPS_A) agents (Long et al., 2006). This cfr rRNA methyltransferase has subsequently been identified in human cases of staphylococcal infection (Arias et al., 2008, Toh et al., 2007), as well as in the LEADER Program for 2007 (Mendes et al., 2008). In this summary of the entire LEADER Program for 2007, we report the oxazolidinone and comparator resistance trends, details of the emerging resistance mechanisms, and geographic occurrences among a 60-laboratory sample (6305 isolates) processed by reference broth microdilution tests with supporting molecular methods.