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The emergence of carbapenem-resistant Pseudomonas aeruginosa in the lung of a patient with cystic fibrosis was evaluated. A single strain of P. aeruginosa persisted during a 3-year study despite antipseudomonal treatment. A stepwise decrease in carbapenem susceptibility leading to resistance was observed in the absence of carbapenem treatment. These data suggest that chronic exposure to unrelated drug classes may be an important determinant for the emergence of carbapenem resistance in P. aeruginosa.