Efficacy of linezolid versus a pharmacodynamically optimized vancomycin therapy in an experimental pneumonia model caused by methicillin-resistant Staphylococcus aureus

The British Thoracic Society, American Thoracic Society and Infectious Diseases Society of America guidelines recommend vancomycin for methicillin-resistant Staphylococcus aureus (MRSA) pneumonia, based on evidence suggesting that a vancomycin AUC₀₋₂₄/MIC ratio of 400 predicts clinical success against MRSA pneumonia. The aim of this study was the evaluation of an optimized dose of vancomycin in the treatment of MRSA experimental pneumonia versus linezolid. In vitro activities of vancomycin and linezolid were tested using time-kill curves. Experimental pneumonia in neutropenic C57BL/6 mice was achieved using two clinical MRSA strains, MR30 and MR33 (vancomycin and linezolid MICs of 1 and 4 mg/L, respectively). In vivo dosages were 30 and 110 mg/kg vancomycin (obtaining an AUC₀₋₂₄/MIC ratio lower and higher than 400, respectively), and 30 mg/kg linezolid. Survival rates in controls, and in the groups treated with 120 mg/kg/day vancomycin, 440 mg/kg/day vancomycin and 120 mg/kg/day linezolid were 85.7%, 92.9%, 76.9% and 100%, and 66.7%, 100%, 75% and 100% for MR30 and MR33, respectively. Sterile blood cultures occurred at rates of 21.4%, 64.3%, 100% and 93.8%, and 40%, 66.7%, 100% and 93.3% for MR30 and MR33 strains, respectively. Finally, the respective bacterial lung concentrations (log₁₀ cfu/g) were 8.93 ± 0.78, 6.67 ± 3.01, 3.25 ± 1.59 and 2.87 ± 1.86 for MR30, and 8.62 ± 0.72, 5.76 ± 2.43, 3.97 ± 1.52 and 1.59 ± 1.40 for MR33. These results support that a vancomycin AUC₀₋₂₄/MIC ratio >400 is necessary to obtain a high bacterial lung reduction in MRSA pneumonia, comparable to that achieved with linezolid and better than that with the low dose of vancomycin tested. Linezolid was more efficacious than the pharmacodynamically optimized vancomycin dose in the pneumonia caused by the most virulent strain (MR33).