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In order to determine the optimal antipseudomonal therapy in patients with cystic fibrosis aztreonam plus amikacin was compared to ceftazidime plus amikacin, and these two-week hospital regimens were followed by oral ciprofloxacin given for four weeks. Fifty-six cases of acute pulmonary exacerbation of the disease in 42 patients associated with isolation of Pseudomonas aeruginosa from the sputum were randomly treated with either aztreonam or ceftazidime (300mg/kg/day i.v.; maximum daily dose 12g) in combination with amikacin (36mg/kg/day i.v.; maximum daily dose 1,500mg). Other aspects of the two-week treatment were constant. The two therapy groups were comparable in all respects. Both regimens were well tolerated and resulted in similar improvements in clinical, bacteriologic, radiologic and laboratory findings, and pulmonary function. Fifty patients could be reevaluated after subsequent outpatient therapy consisting of oral ciprofloxacin (30mg/kg/day; maximum daily dose 1,500mg) given for four weeks. During this period, the clinical and laboratory improvements persisted, and the rate of eradication of Pseudomonas aeruginosa from sputum decreased from 62% to 34%. Ciprofloxacin was well tolerated and there was no drug toxicity or serious adverse effect. In the 25 prepubertal patients there was neither subjective nor objective evidence of skeletal drug toxicity. In patients with cystic fibrosis, aztreonam or ceftazidime in combination with amikacin represents an effective and safe systemic anti-pseudomonal therapy. Subsequent oral ciprofloxacin therapy for four weeks prolongs the beneficial effects and is well tolerated.