Session: P066 Various agents against Gram-positive bacteria

Category: 5a. Mechanisms of action, preclinical data & pharmacology of antibacterial agents

24 April 2017, 12:30 - 13:30 P1340

New insights into tedizolid efficacy against staphylococci

Pierre Delpech*1, Muna Aleryan2, Brian Jones3, Curtis Gemmell4, Sue Lang2

1Glasgow Caledonian University; Health and Life Sciences

2Glasgow Caledonian University; Life Sciences

3Glasgow Royal Infirmary; Department Of Medical Microbiology

4University of Strathclyde

Background: The development of new antibiotics is a major challenge in the face of constantly evolving resistance to classic agents. Tedizolid, a second-generation oxazolidinone, has recently been approved by the U.S. Food and Drug Administration for the treatment of bacterial skin and skin- structure infections caused by susceptible bacteria. Little is known however, about how staphylococci respond to tedizolid. To assess the efficacy of tedizolid, activity was evaluated against clinical staphylococcal isolates and compared to other commonly used antibiotics.

Material/methods: Following EUCAST guidelines, the MIC (Minimum Inhibitory Concentration) and MBC (Minimum Bactericidal Concentration) values of 63 clinical staphylococcal isolates were determined for tedizolid, linezolid (first-generation oxazolidinone), vancomycin and daptomycin. The susceptibility of biofilm-associated cells of 15 robust-biofilm-forming isolates to these antibiotics at 10xMIC was assessed using a 96-well plate and resazurin assay. Further, a checkerboard methodology was used to determine the effect of combinations of tedizolid with vancomycin, daptomycin, linezolid, fusidic acid, oxacillin or rifampicin against 6 Staphylococcus aureus isolates in planktonic culture (calculation of FIC, Fractional Inhibitory Concentration) and in biofilms (resazurin assay).

Results: Consistent with EUCAST data, a lower dose of tedizolid was required to inhibit the isolates compared to linezolid, vancomycin and daptomycin (Table 1). Considering its bacteriostatic activity, MBC values with tedizolid were higher than those obtained with vancomycin and daptomycin, but remained lower than linezolid. The G2576T linezolid-resistance mutation reduced susceptibility to tedizolid, though activity remained against linezolid-resistant cfr+ isolates. Tedizolid at 10xMIC displayed greater efficacy than 10xMIC linezolid, reducing the biofilm by 60% and 42% of the untreated control, respectively, and displayed activity comparable with 10xMIC vancomycin and daptomycin. Finally, results suggested that tedizolid and fusidic acid act synergistically (FIC<0.5) against S. aureus planktonic cultures, however, the susceptibility of biofilm-associated S. aureus cells to tedizolid was not significantly enhanced by the presence of fusidic acid.

Table 1. Antibiotic susceptibility of planktonic staphylococcal cells.

MIC50 (mg/l) MBC50 (mg/l)

MRSA MSSA Sepi MRSA MSSA Sepi n=25 n=25 n=13

Tedizolid 0.25 0.25 0.25 2 4 4

Linezolid 2 2 1 16 16 32

Vancomycin 0.5 0.5 1 1 1 2

Daptomycin 0.5 0.5 0.5 1 1 0.5

MRSA, MSSA; methicillin resistant and sensitive S. aureus; Sepi; Staphylococcus epidermidis

Conclusions: The efficiency of tedizolid against planktonic staphylococci was superior to vancomycin, daptomycin and linezolid and greater then linezolid against pre-formed biofilms. A combination of tedizolid and fusidic acid gave promising results for the treatment of planktonic infections. To the best of our knowledge, this is the first time that tedizolid efficiency has been assessed in combination with other antibiotics. The activity of tedizolid against planktonic and biofilm-associated cells, including cfr+ multidrug-resistant strains, offers a realistic low-dose alternative agent in the treatment of staphylococcal infections.