Adaptive Resistance to Aminoglycoside Antibiotics from First-Exposure Down-Regulation

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Abstract
Adaptive resistance to the bactericidal effect of an aminoglycoside antibiotic was induced in Pseudomonas aeruginosa and other aerobic gram-negative bacilli by initial exposure to the drug. Both subinhibitory and inhibitory concentrations produced resistance in bacterial cells surviving the effects of the initial ionic binding. Development of drug refractoriness required an adaptive period of growth, was enhanced by the continued presence of drug, and reversed after several hours of growth in drug-free medium. Unstable resistance was not explained by selection of mutants. The mechanism of adaptive resistance was down-regulation of aminoglycoside uptake during the period of accelerated energy dependent drug transport (EDP II). Down-regulation induced by gentamicin or tobramycin produced cross-resistance to other aminoglycosides. The kinetics of unstable first-exposure resistance suggest that a continuous drug level might not provide the most effective therapy with aminoglycosides and gives rationale to larger initial and longer interval bolus dosing.