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Background: Linezolid (LZD) is active against Grampositive (GP) organisms such as MRSA, drug-resistant (R) S. pneumoniae and vancomycin-R enterococci that are R to conventional drugs. The LEADER program has monitored the activity of LZD and comparator agents since 2004. Molecular characterization of isolates with elevated LZD MICs has been an integral part of this program. Methods: A total of 3,031 S. aureus (SA), 924 coagulasenegative staphylococci (CoNS), 973 enterococci (ENT), 850 S. pneumoniae (SPN), 236 viridans group streptococci (VGS), and 727 β-hemolytic streptococci (BHS) from 60 medical centers were susceptibility (S) tested against LZD and comparator agents by reference broth microdilution methods. LZD-R isolates were confirmed by Etest (bioMérieux, Hazelwood, MO) and repeat reference S testing. PCR and sequencing was performed to detect mutations in the 23S rRNA, L3, L4, and L22 genes, and for the presence of acquired genes (cfr, optrA). Results: LZD activity against 6,741 GP organisms was high (99.8% S). The MIC50/90 for SA, MRSA, and MSSA was at 1/1 μg/ml. The MRSA rate, which has declined each year over the last eight years, was at 45.9%. For CoNS, MRCoNS, and MSCoNS, the MIC50/90 for LZD was 0.5/1 μg/ml. LZD was active against all SPN and BHS with a MIC50/90 of 1/1 μg/ml and VGS with an MIC50/90 of 0.5/1 μg/ml. SPN penicillin non-susceptibility (NS; MIC, ≥0.12 μg/ml) occurred at a rate of 36.8% and ceftriaxone-NS at 1.7%. There was one LZD-R MRSA (MIC, 8 μg/ml), which harbored G2576T alterations. Among CoNS, seven S. epidermidis (0.76% of all 2015 CoNS isolates compared to 0.75% in 2014, 0.52% in 2013 and 0.92% in 2012) demonstrated LZD MIC results of ≥16 μg/ml. Four of these were from a single study site and three of these isolates were clonally-related (two contained cfr in addition to mutations in other drug target sites). The other resistant CoNS had combinations of 23S rRNA/L3/L4 alterations. One E. faecalis harbored optrA, while two E. faecium had G2576T mutations in 23S rRNA. Conclusions: These in vitro results show continued potent activity of LZD. LZD R phenotypes remain uncommon (<1%), and most isolates were S. epidermidis carrying multiple R mechanisms. cfr-carrying isolates remain rare and associated with clonal dissemination, while detection of a newer mobile resistance mechanism (optrA) emphasizes the need for monitoring. Introduction The LEADER surveillance program has monitored linezolid activity, spectrum and resistance rates in the United States (USA) since 2004. This program has provided information on the emergence of resistance mechanisms to linezolid which have included ribosomal mutations and mobile mechanisms such as cfr and optrA. Overall in the LEADER Program, linezolid resistance has remained below 1%. Linezolid was the first oxazolidinone class agent approved (2000) in the USA for clinical use. Linezolid is indicated for the treatment of complicated skin and skin structure infections (cSSSI) and nosocomial pneumonia caused by Gram-positive pathogens. This compound has emerged as a valuable parenteral/oral agent for the treatment of infections caused by Gram-positive organisms, such as methicillinresistant Staphylococcus aureus (MRSA), and vancomycin-resistant enterococci (VRE).

open forum infectious diseases

Activity of Linezolid When Tested against Gram-Positive Isolates from the USA (Linezolid Experience and Accurate Determination of Resistance [LEADER]) from 2015