Clinical Context

According to the current study by Treggiari and colleagues, Pseudomonas aeruginosa is the predominant organism associated with cystic fibrosis (CF) and results in rapid decline in lung function, increased hospitalizations, and increased mortality rates. Inhaled antibiotics (tobramycin or colistin) may reduce the frequency of colonization or acquisition. However, it is unclear whether the addition of antibiotics or the use of cycled vs culture-based therapy would improve pulmonary and other outcomes in children with CF.

This 18-month randomized controlled trial examines if 4 different regimens are associated with different outcomes of pulmonary exacerbation (PE) and P aeruginosa colonization among children with CF.

Study Synopsis and Perspective

In children with CF, there is no difference in the rate of exacerbation or prevalence of P aeruginosa positivity between cycled and culture-based therapies, with or without ciprofloxacin, according to the results of a randomized controlled trial reported in the September issue of the Archives of Pediatrics & Adolescent Medicine.

"It remains unclear whether clearance of P aeruginosa from airway cultures has any impact on other health indicators such as exacerbation of respiratory symptoms (pulmonary exacerbation [PE]), lung function, hospitalization, and growth," write Miriam M. Treggiari, MD, PhD, MPH, and colleagues from the Early Pseudomonas Infection Control Investigators. "While there is potential to benefit from early intervention, concerns remain regarding the risks of long-term antibiotic exposure and selection of resistant bacterial pathogens. We compared the clinical and microbiological effectiveness as well as the safety of 4 antibiotic treatment strategies for newly identified P aeruginosa infection isolated from respiratory cultures in children with CF."

In this multicenter US trial, 304 children 1 to 12 years old with CF were randomly assigned within 6 months of P aeruginosa detection to receive 1 of 4 antibiotic regimens. Between December 2004 and June 2009, these treatments were administered for 18 months (six 12-week quarters). Cycled therapy consisted of 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. Culture-based therapy consisted of the same treatments only during quarters with positive P aeruginosa culture results.

Analysis was by intent-to-treat, with main study outcomes of time to PE requiring intravenous antibiotics, and proportion of P aeruginosa–positive culture results. No interaction among treatments was detected.

The cycled and culture-based groups did not differ significantly in exacerbation rates (hazard ratio [HR], 0.95; 95% confidence interval [CI], 0.54 - 1.66), nor did ciprofloxacin and placebo (HR, 1.45; 95% CI, 0.82 - 2.54).

Comparing the cycled vs the culture-based therapy group, the odds ratio (OR) of a P aeruginosa–positive culture result was 0.78 (95% CI, 0.49 - 1.23). For ciprofloxacin vs placebo, the OR was 1.10 (95% CI, 0.71 - 1.71). Both groups had similar adverse events.

"No difference in the rate of exacerbation or prevalence of P aeruginosa positivity was detected between cycled and culture-based therapies," the study authors write. "Adding ciprofloxacin produced no benefits."

Limitations of this study were that only 47% of study children were able to perform pulmonary function testing, and only 6% of children were able to expectorate sputum.

"These data also indicate that young children recently acquiring P aeruginosa have a high likelihood of eradication with antibiotic therapy and a prolonged period until reemergence of the pathogen," the study authors conclude.

In an accompanying editorial, Lisa Saiman, MD, MPH, from Columbia University and New York-Presbyterian Hospital in New York, NY, and Mitchell B. Cohen, MD, from Cincinnati Children's Hospital Medical Center in Cincinnati, Ohio, note that this study lacked a placebo group.

"Early treatment to eradicate P aeruginosa is now a well-accepted treatment paradigm for infants and children with CF," Drs. Saiman and Cohen write. "Evidence from the current study combined with data from a prior trial demonstrating efficacy of a 28-day course of therapy in eradicating P aeruginosa leads us to concur with the conclusion of the investigators that judicious use of tobramycin inhalation solution with close microbiologic monitoring of airway cultures is recommended based on current evidence."

The Cystic Fibrosis Foundation; National Heart, Lung, and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases; and the National Center for Research Resources supported this study. Study drugs and devices were supplied free of charge by Novartis Pharmaceutical Corp, Bayer Healthcare AG, and PARI Respiratory Equipment Inc. One of the study authors (Barbara A. Chatfield, MD) has received research grants or contracts from Gilead Pharmaceuticals, Vertex Pharmaceuticals, and the Cystic Fibrosis Foundation. Drs. Saiman and Cohen have disclosed no relevant financial relationships.

Arch Pediatr Adolesc Med. 2011;165:847-856, 867-868.

Clinical Implications

• Use of cycled vs culture-based treatment of P aeruginosa infection is not associated with a reduced rate of PE in children with CF.
• The addition of ciprofloxacin to either a cycled or culture-based regimen is not associated with a reduced rate of PE or positive respiratory culture results in children with CF.

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