Use of linezolid susceptibility test results as a surrogate for the susceptibility of Gram-positive pathogens to tedizolid, a novel oxazolidinone

Abstract

Background: Tedizolid is a novel oxazolidinone antibacterial with potent activity against a wide range of Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. Although tedizolid is approved by the US Food and Drug Administration (FDA) for treatment of patients with acute bacterial skin and skin structure infection, commercial susceptibility testing products for tedizolid are not currently available. This study evaluated the usefulness of applying linezolid susceptibility test results as a surrogate for predicting susceptibility to tedizolid in clinically significant Gram-positive pathogens.

Methods: Gram-positive isolates (N = 10,702) were obtained from annual surveillance programs conducted between 2009 and 2012, from 3 tedizolid clinical trials, and from a preclinical study of the antibacterial activity of tedizolid. Susceptibility testing of linezolid and tedizolid was performed using the reference broth microdilution method in accordance with Clinical and Laboratory Standards Institute methods.

Results: The minimum inhibitory concentration (MIC) distribution for tedizolid and linezolid against this set of isolates was consistent with that of previous reports. Scatter plot analysis of relevant subsets of organisms was performed and showed high categorical agreement between linezolid and tedizolid MIC results (>99% for staphylococci and streptococci; >98% for enterococci). Very major error rates (ie, tedizolid false-susceptible errors) were very low and within acceptable limits for a surrogate agent: S. aureus and other staphylococcal species, 0%; Enterococcus spp, 0.2%; and Streptococcus spp, 0%.

Conclusions: High categorical agreement between MIC values for tedizolid and linezolid and low very major error rates were shown for all organism groups tested, supporting the use of linezolid as a reliable surrogate for tedizolid susceptibility testing.

Figure 1

Scatter plot comparing tedizolid and linezolid minimum inhibitory concentration (MIC) values for 7187 Staphylococcus aureus isolates. Dashed lines represent the breakpoints for tedizolid (≤0.5 μg/ml [susceptible], 1 μg/ml [intermediate], and ≥2 μg/ml [resistant]) and linezolid (≤4 μg/ml [susceptible] and ≥8 μg/ml [resistant]).

Figure 2

Scatter plot comparing tedizolid and linezolid minimum inhibitory concentration (MIC) values for 674 staphylococcal isolates other than Staphylococcus aureus. Dashed lines represent the US Food and Drug Administration–approved S. aureus breakpoints for tedizolid generalized for all staphylococci (≤0.5 μg/ml [susceptible], 1 μg/ml [intermediate], and ≥2 μg/ml [resistant]) and the Clinical and Laboratory Standards Institute–approved breakpoints for linezolid (≤4 μg/ml [susceptible] and ≥8 μg/ml [resistant]). These isolates are primarily from coagulase-negative staphylococcal species (eg, S. epidermidis, S. haemolyticus, S. lugdunensis), though some isolates are from coagulase-positive staphylococcal species other than S. aureus.

Figure 3

Scatter plot comparing tedizolid and linezolid minimum inhibitory concentration (MIC) values for 1241 enterococcal isolates. Dashed lines represent the US Food and Drug Administration–approved Enterococcus faecalis breakpoint for tedizolid generalized for all enterococci (≤0.5 μg/ml [susceptible]) and the Clinical and Laboratory Standards Institute–approved breakpoints for linezolid (≤2 μg/ml [susceptible], 4 μg/ml [intermediate], and ≥8 μg/ml [resistant]).

Figure 4

Scatter plot comparing tedizolid and linezolid minimum inhibitory concentration (MIC) values for 1600 streptococcal isolates. Dashed lines represent the US Food and Drug Administration–approved Streptococcus pyogenes and Streptococcus agalactiae breakpoint for tedizolid generalized for all streptococci (≤0.5 μg/ml [susceptible]) and the Clinical and Laboratory Standards Institute–approved breakpoint for linezolid (≤2 μg/ml [susceptible]).

Figure 5

Scatter plot comparing tedizolid and linezolid minimum inhibitory concentration (MIC) values for 91 Streptococcus anginosus group isolates. Dashed lines represent the US Food and Drug Administration–approved breakpoint for tedizolid for S. anginosus group isolates (≤0.25 μg/ml [susceptible]) and the Clinical and Laboratory Standards Institute–approved breakpoint for linezolid (≤2 μg/ml [susceptible]).