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The aim of this study was to evaluate the in vitro efficacy of ceftobiprole and comparator antibiotics, either alone or in combination, in staphylococcal MBEC™ (minimum biofilm eradication concentration) and colony biofilm assays at dilutions of the maximum free-drug plasma concentration attained during clinical use (fCmax). Staphylococci tested included meticillin-susceptible and meticillin-resistant Staphylococcus aureus (n=6) and Staphylococcus epidermidis (n=2). Relative to no-drug controls, after 7 days of exposure ceftobiprole concentrations from 1/4 fCmax to fCmax generally decreased CFUs in MBEC or colony biofilms of S. aureus isolates by ca. 1.5log10 to ≥2.5log10. Gentamicin reduced colony biofilm CFUs by ≥1.4log10 at these concentrations with gentamicin-susceptible isolates. Following 7 days of exposure, vancomycin and rifampicin were ineffective as single agents or in combination in the colony model, but yielded CFU decreases from 0 to 5log10 in the MBEC model. Treatment of biofilms with rifampicin for 7 days yielded rifampicin-resistant mutants, and the selection of rifampicin resistance was inhibited by co-treatment with ceftobiprole. Thus, ceftobiprole alone or in combination demonstrated promising activity against biofilms of meticillin-susceptible and -resistant staphylococci at clinically relevant concentrations. In contrast, vancomycin and rifampicin, two agents used clinically for the treatment of biofilm infections, tested separately or together gave inconsistent results and generally had little impact on cell viability., (Copyright © 2013 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.)

RWJ-416457 is a novel investigational oxazolidinone with minimum inhibitory concentrations (MICs) to staphylococci and enterococci that are two- to four-fold lower than those of linezolid. Single-step and serial passage in vitro resistance selection experiments were performed for RWJ-416457 and linezolid with Staphylococcus aureus and Enterococcus faecalis laboratory and clinical isolates. RWJ-416457 selected for resistant mutants in single-step selections at a frequency of ≤1×10(-10), similar to that of linezolid. In serial passage selection experiments, a G2576T transversion in the domain V region of the 23S rRNA gene was the predominant mutation observed for both oxazolidinones, suggesting similar 23S rRNA binding sites. The associated development of increasing oxazolidinone resistance in E. faecalis (four 23S rRNA alleles) required fewer passages than with S. aureus isolates (six 23S rRNA alleles), and resistance was generally proportionate to the number of mutated (G2576T) 23S rRNA alleles. Fold changes in MICs were similar for both compounds, and MICs for RWJ-416457 remained two- to four-fold lower than those of linezolid for mutants selected by either compound. Serial passage of linezolid with S. aureus OC 2878 yielded a novel A2572T 23S rRNA mutation, whilst the final passages of S. aureus OC 10517 with RWJ-416457 resulted in the apparent loss of a mutated (G2576T) allele 6., (Copyright © 2010 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.)