Improved efficacy with nonsimultaneous administration of netilmicin and minocycline against methicillin-resistant Staphylococcus aureus in in vitro and in vivo models

The effect of combined administration of netilmicin and minocycline against methicillin-resistant Staphylococcus nul eus (MRSA) was investigated by using in vitro and in vivo models. Thirty one isolates of MRSA were tested for sensitivity to netilmicin, minocycline, and combination of both by the chequer board method. We used then a dynamic in vitro system, which simulates in vivo serum kinetics, to assess the effect of various combination regimens of these antibiotics against an MRSA isolate with a fractional inhibitory concentration index of 0.25. The following dose regimens were compared: netilmicin even alone; minocycline given alone; both antibiotics given simultaneously; netilmicin followed by minocycline at 2 h; or minocycline followed by netilmicin at 2 h. Netilmicin showed a stronger activity than minocycline. On the other hand, their combination was synergistic against 19% of isolates and additive against 77% of isolates. Against one isolate only, it was indifferent, and no antagonism was observed. In the auto-simulation system, the combination of antibiotics was generally more effective than single drugs, with the regimen netilmicin followed by minocycline at 2 h showing the highest antibacterial effect. In the mouse model of pulmonary infection, the bacterial counts and histopathological findings of the lungs improved by treatment with this regimen. This regimen led also to a significantly high survival rate of mice with systemic infection compared to the other treatment regimens. Therefore, it was concluded that administration of netilmicin followed by minocycline at 2 h may be an effective combination against MRSA infection. (C) 1999 Elsevier Science B.V. and International Society of Chemotherapy. All rights reserved.