Adaptive resistance to tobramycin in Pseudomonas aeruginosa lung infection in cystic fibrosis

Abstract

Aminoglycoside antibiotics have been shown to induce adaptive resistance in Pseudomonas aeruginosa in vitro and in a mouse model of infection, but adaptive resistance has not been described in human infections. Seven patients with cystic fibrosis were treated with inhaled tobramycin to determine whether adaptive resistance occurred in P. aeruginosa in their sputum. In three patients who had not recently taken antibiotics, 80 mg tobramycin was administered by nebuliser and resulting peak sputum tobramycin concentrations were 90-240 mg/L (elimination half-life 1.9-2.1 h). Adaptive resistance was detected in P. aeruginosa 1-4 h after the dose of tobramycin. Moderate resistance was present at 24 h and full susceptibility returned between 24 and 48 h. In four other patients on long-term twice-daily inhaled aminoglycoside treatment, adaptive resistance was present before, and 4 h after, 80 mg of tobramycin administered by nebuliser. The presence and time course of adaptive resistance in humans may have implications for improving aminoglycoside dosing regimens.