ADAPTIVE RESISTANCE OF PSEUDOMONAS-AERUGINOSA INDUCED BY AMINOGLYCOSIDES AND KILLING KINETICS IN A RABBIT ENDOCARDITIS MODEL

Adaptive resistance following the first exposure to aminoglycosides is a recently described in vitro phenomenon in Pseudomonas aeruginosa an d other aerobic gram-negative bacilli. We investigated the in vivo rel evance of adaptive resistance in P. aeruginosa following a single dose of amikacin in the experimental rabbit endocarditis model. Rabbits wi th P. aeruginosa endocarditis received either no therapy (control) or a single intravenous (i.v.) dose of amikacin (80 mg/kg of body weight) at 24 h postinfection, after which they were sacrificed at 5, 8, 12, 16, or 24 h postdose. Excised aortic vegetations were subsequently exp osed ex vivo to amikacin at 2.5, 5, 10 or 20 times the MIC for 90 min. In vivo adaptive resistance was identified when amikacin-induced pseu domonal killing within excised aortic vegetations was less in animals receiving single-dose amikacin in vivo than in vegetations from contro l animals not receiving amikacin in vivo. Maximal adaptive resistance occurred between 8 and 16 h after the in vivo amikacin dose, with comp lete refractoriness to ex vivo killing by amikacin seen at 12 h postdo se. By 24 h postdose, bacteria within excised vegetations had partiall y recovered their initial amikacin susceptibility, In a parallel treat ment study, we demonstrated that amikacin given once daily (but not tw ice daily) at a total dose of 80 mg/kg i.v. for 1-day treatment signif icantly reduced pseudomonal densities within aortic vegetations versus those in untreated controls. When therapy was continued for 3 days wi th the same total daily dose (80 mg/kg/day), amikacin given once or tw ice daily significantly reduced intra-vegetation pseudomonal densities versus those in controls. However, amikacin given once daily was stil l more effective than the twice-daily regimen, These data confirm the induction of aminoglycoside adaptive resistance in vivo and further su pport the advantages of once-daily aminoglycoside dosing regimens in t he treatment of serious pseudomonal infections.