In vitro activities of daptomycin, arbekacin, vancomycin, and gentamicin alone and/or in combination against glycopeptide intermediate-resistant Staphylococcus aureus in an infection model

Abstract

Daptomycin, a lipopeptide antibiotic, has broad activity against gram-positive organisms, similar to vancomycin; however, its mechanism of action differs, resulting in interference with cell membrane transport and a more rapid bactericidal activity. In light of increasing need for alternative treatments against intermediate-resistant Staphylococcus aureus, there is revitalized interest in this antibiotic. We, therefore, evaluated the activity of daptomycin alone or in combination in an in vitro infection model against two glycopeptide intermediate-resistant S. aureus (GISA) isolates. Newly designed regimens of daptomycin at 4 and 6 mg/kg of body weight every 24 h (q24h) were compared to the previous regimen of 3 mg/kg q12h. Daptomycin MICs and minimal bactericidal concentrations (MBCs) (MIC/MBC) for Mu-50, HIP5836 (992), and MRSA-67 were 0.5/1.0, 0.5/1.0, and 0.125/0.5 microgram/ml, respectively. MICs and MBCs of arbekacin for the three strains were 2.0/8.0, 0. 125/0.5, and 0.125/0.25 microgram/ml, respectively. Vancomycin and gentamicin MICs and MBCs for the three strains were 8.0/8.0, 8.0/8.0, and 0.5/1.0 microgram/ml and 128/128, 0.5/1.0, and 0.25/0.5 microgram/ml, respectively. Our experience with daptomycin in an in vitro infection model has shown significant kill against the two GISA strains (Mu-50 and 992) (P < 0.03). We also noted that kill was related to a total dose effect for 992, in which simulated daptomycin in vivo dosages of 6 mg/kg q24h and 3 mg/kg q12h produced similar kill and 4 mg/kg q24h resulted in significant regrowth (P </= 0.05). Combination therapy with arbekacin resulted in synergistic activity against Mu-50. Daptomycin area under the concentration-time curve/MIC and C(max)/MIC ranges for GISA isolates were 80 to 116 and 6 to 12, respectively, and ranges for MRSA-67 were 320 to 461 and 24 to 48, respectively, and appeared to have an association with kill (i.e., decreased CFU/milliliter) at 24 and 48 h. Therefore, these experiments suggest that daptomycin alone or in combination could provide an alternative for the treatment of GISA.

FIG. 1

Bacteremia model.

FIG. 2

(A) Mu-50. D6, daptomycin at 6 mg/kg q24h (▵); D4, daptomycin at 4 mg/kg q24h (▿); D3, daptomycin at 3 mg/kg q12h (◊); A, arbekacin q12h (■); G, gentamicin q12h (○); V, vancomycin q12h (+); D6+A, daptomycin at 6 mg/kg q24h plus arbekacin q12h (▴); D4+A, daptomycin at 4 mg/kg q24h plus arbekacin q12h (▾); D3+A, daptomycin at 3 mg/kg q12h plus arbekacin q12h (⧫); V+A, vancomycin q12h plus arbekacin q12h (□); GC, growth control (●). (B) 992. D6, daptomycin at 6 mg/kg q24h (▵); D4, daptomycin at 4 mg/kg q24h (▿); D3, daptomycin at 3 mg/kg q12h (◊); A, arbekacin q12h (■); G, gentamicin q12h (○); V, vancomycin q12h (+); GC, growth control (●). (C) MRSA-67. D6, daptomycin at 6 mg/kg q24h (▵); D4, daptomycin at 4 mg/kg q24h (▿); D3, daptomycin at 3 mg/kg q12h (◊); A, arbekacin q12h (■); G, gentamicin q12h (○); V, vancomycin q12h (+); GC, growth control (●).