Addition of Daptomycin to Levofloxacin Increased the Efficacy of Levofloxacin Monotherapy against a Methicillin-Susceptible Staphylococcus aureus Strain in Experimental Meningitis and Prevented Development of Resistance

Abstract

Daptomycin and levofloxacin were tested as monotherapies and in combination against the antibiotic-susceptible S. aureus strain MSSA 1112 in a rabbit meningitis model and the effect of the combination on induction of resistance was determined in vitro. Changes of the susceptibility to fluoroquinolones and daptomycin was determined by the measurement of the MIC and mutations were detected by whole genome sequence comparison of the mutants with the parent strain MSSA 1112. Meningitis was induced by intracisternal inoculation of 105 CFU of MSSA 1112 and treatment was started 10 h later by injection of daptomycin (15 mg/kg) and levofloxacin (10 mg/kg) standard doses. Cerebrospinal fluid (CSF) samples were repeatedly collected during therapy in order to determine killing rates and results of bactericidal activity were expressed in {Delta}log10 CFU/ml over 8 h. The combination of daptomycin with levofloxacin was significantly (p< 0.001) superior to levofloxacin monotherapy and increased the antibacterial activity of daptomycin. In vitro, MSSA 1112 was cycled over six days with either increasing concentrations of levofloxacin or daptomycin or with a combination of levofloxacin with half of the MIC of daptomycin or daptomycin with half of the MIC of levofloxacin leading to mutations in target genes as identified by whole genome sequence analysis. Addition of low concentration of daptomycin (0.25 mg/L) reduced levofloxacin-induced resistance in vitro. Addition of levofloxacin in low concentration (0.125 mg/L) did not influence daptomycin-induced resistance. These findings highlight the lack of reciprocal interference of antibiotics in combination with regard to the development of resistance.