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

Background: Linezolid (LZD) is active against Gram-positive (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 coagulase-negative staphylococci (CoNS), 973 enterococci (ENT), 850 S. pneumoniae (SPN), 236 viridans group (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 (bioMerieux, Hazelwood, MO) and repeat reference S testing. PCR and sequencing was performed to detect mutations in 23S rRNA, L3, L4, and L22 proteins, and acquired genes (cfr, optrA).

Results: LZD activity against 6,741 GP organisms was high (99.84% S). The MIC_50/90 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, MRSE, and MSSE the MIC_50/90 for LZD was 0.5/1 μg/ml. LZD was active against all SPN and BHS with a MIC_50/90 of 1/1, μg/ml and VGS with an MIC_50/90 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 CoNS strains (0.75% in 2014, 0.52% in 2013, 0.92% in 2012) demonstrated LZD MIC results of ≥16 μg/ml. Four of these were from a single site (3 isolates were clonally-related); 2 of which contained cfr in addition to mutations in other drug target sites. Other CoNS had combinations of 23S rRNA/L3/L4 alterations. One E. faecalis harbored optrA, while two E. faecium had G2576T mutations in 23S rRNA.

Conclusion: These in vitro results show continued potent activity of LZD. LZD R phenotypes remain uncommon (<1%); and most isolates are 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.