Comparative efficacy and safety of 4 randomized regimens to treat early Pseudomonas aeruginosa infection in children with cystic fibrosis

Abstract

Objective: To investigate the efficacy and safety of 4 antipseudomonal treatments in children with cystic fibrosis with recently acquired Pseudomonas aeruginosa infection.

Design: Randomized controlled trial.

Setting: Multicenter trial in the United States.

Participants: Three hundred four children with cystic fibrosis aged 1 to 12 years within 6 months of P aeruginosa detection.

Interventions: Participants were randomized to 1 of 4 antibiotic regimens for 18 months (six 12-week quarters) between December 2004 and June 2009. Participants randomized to cycled therapy received tobramycin inhalation solution (300 mg twice a day) for 28 days, with oral ciprofloxacin (15-20 mg/kg twice a day) or oral placebo for 14 days every quarter, while participants randomized to culture-based therapy received the same treatments only during quarters with positive P aeruginosa cultures.

Main outcome measures: The primary end points were time to pulmonary exacerbation requiring intravenous antibiotics and proportion of P aeruginosa -positive cultures.

Results: The intention-to-treat analysis included 304 participants. There was no interaction between treatments. There were no statistically significant differences in exacerbation rates between cycled and culture-based groups (hazard ratio, 0.95; 95% confidence interval [CI], 0.54-1.66) or ciprofloxacin and placebo (hazard ratio, 1.45; 95% CI, 0.82-2.54). The odds ratios of P aeruginosa- positive culture comparing the cycled vs culture-based group were 0.78 (95% CI, 0.49-1.23) and 1.10 (95% CI, 0.71-1.71) comparing ciprofloxacin vs placebo. Adverse events were similar across groups.

Conclusions: No difference in the rate of exacerbation or prevalence of P aeruginosa positivity was detected between cycled and culture-based therapies. Adding ciprofloxacin produced no benefits.

Trial registration: ClinicalTrials.gov Identifier: NCT00097773.

Figure 1

Flow diagram of participants through each stage of the randomized trial. TIS indicates tobramycin inhalation solution. * One adverse event resulting in withdrawal was due to skin rash attributed to ciprofloxacin.

Figure 2

Percent of participants prescribed treatment in the cycled (black bars) and culture-based (light gray bars) therapy groups.

Figure 3

Proportion of participants remaining free of exacerbations requiring intravenous antibiotics or hospitalization over time, comparing (a) participants who received cycled therapy (solid line, N=152) to participants who received culture-based therapy (dotted line, N=152); (b) participants who received tobramycin inhalation solution (TIS) and oral ciprofloxacin (solid line, N=152) to participants who received TIS and oral placebo (dotted line, N=152); (c) Proportion of participants who were Pa positive at each study visit comparing participants who received cycled therapy (black bars, N=152) to participants who received culture-based therapy (light gray bars, N=152); and (d) participants who received TIS and oral ciprofloxacin (dark gray bars, N=152) to participants who received TIS and oral placebo (white bars, N=152).