In patients with cystic fibrosis (CF), chronic endobronchial infection with Pseudomonas aeruginosa (Pa) is associated with a greater rate of pulmonary exacerbations, loss of lung function and greater mortality.^1-3 Initial acquisition of Pa is generally from the environment, and early Pa isolates tend to be highly antibiotic- susceptible and present at low density. Thus, a "window of opportunity" exists to eradicate Pa before infection becomes chronic.⁴ The Danish CF Clinic pioneered early Pa eradication therapy more than 20 years ago⁵ and has demonstrated improved long-term outcomes.⁶ While early Pa eradication is now the standard of care around the world, the most effective regimen remains a highly contested topic. In many European countries, a combination of inhaled colistin and oral ciprofloxacin, often for three months, is employed,⁷ while in North America, 28 days of inhaled tobramycin is the most widely employed antibiotic, with or without oral ciprofloxacin.

Over the past several years, the results of several important clinical trials of early Pa eradication therapies have been published. These studies begin to answer the question, "How shall I most safely and effectively treat my patient with new isolation of Pa from a respiratory culture?" As the studies reviewed herein describe, the results have not necessarily been those expected in this era of ever-increasing aggressiveness of care in our CF patients. These four studies all converge on the same conclusion: that 28 days of inhaled tobramycin is in general quite effective in eradicating Pa and that longer or repeated courses of inhaled tobramycin, adding oral ciprofloxacin, or using three months of inhaled colistin and oral ciprofloxacin, are no more effective. All regimens were safe in the short term, though with one potential cautionary note: in both the EPIC trial (comparing four regimens all including inhaled tobramycin) and the trial by Taccetti, et al (comparing 28 days of inhaled tobramycin and oral ciprofloxacin vs 28 days of inhaled colistin and oral ciprofloxacin), up to 20% of participants developed new respiratory infection with Stenotrophomonas maltophilia, a tobramycin-resistant, gram negative organism of unclear pathogenicity. Interestingly, this finding was not seen in the ELITE trial comparing 28 to 56 days of inhaled tobramycin (these three trials are reviewed in this issue). Thus, as is so often the case in CF, treatment directed toward one organism probably alters the homeostasis of the complex polymicrobial community in the CF airway. The impact on clinical outcomes of this microbiologic finding is currently unclear.

It should be mentioned that a limitation of all these studies is the reliance on throat swabs to diagnose Pa respiratory infection, because of the invasive nature of bronchoalveolar lavage. Treatment decisions based on the results of oropharyngeal cultures may lead to "overtreatment," as the low positive predictive value of throat swabs in this population means that throat swabs tend to overestimate the prevalence of Pa in the lower airway.⁸ Nonetheless, in many countries, treatment decisions are based on the results of throat swabs, as the presence of Pa in the upper airway may convey an increased risk of subsequent lower airway infection.³

What are the next steps in studying the safety and efficacy of Pa eradication regimens? First, while in general these regimens are highly effective, 10% to 30% of patients in each of these studies failed eradication therapy. Understanding how to treat these patients is critical to minimizing the burden of morbidity associated with chronic Pa infection. Second, and perhaps tied to the first step, is a better understanding of the role of intravenous antibiotics in early eradication therapy. In a small cohort of clinically stable children with CF and new Pa infection (N = 15, six of whom received IV antibiotics), Noah et al,⁹ performed bronchoalveolar lavage before and four to six weeks after treatment with two weeks of systemic antibiotics or four weeks of inhaled tobramycin. While both groups had similar reductions in bacterial load after therapy, those in the systemic group had a significantly greater reduction in markers of inflammation (Iower airway total cells and percent neutrophils). Though intriguing, a larger study would be required to change clinical practice. Last, longer-term follow-up of patients receiving early eradication therapy will be critical to monitoring both efficacy and safety of this approach. The participants in the clinical trials reviewed in this issue were in general healthy, with relatively preserved lung function and few pulmonary exacerbations. No differences between groups in short-term (up to two years) clinical outcomes was detected, but the effects over much longer time periods are relatively unknown.⁶ Finally, long-term effects on airway microbiology (such as the finding of possibly increased prevalence of Stenotrophomonas maltophilia) must be further evaluated.

In summary, on the whole, these studies demonstrate that early Pa eradication regimens are relatively effective, and that "less may be more," in that 28 days of inhaled tobramycin (or possibly colistin) appears as effective as any other regimen tested. Hopefully, we are ushering in an era in which early Pa eradication delays or prevents chronic Pa infection, resulting in fewer hospitalizations and better long-term outcomes for our CF patients.^6,10

Commentary References

1.	Emerson J, Rosenfeld M, McNamara S, Ramsey B, Gibson RL. Pseudomonas aeruginosa and other predictors of mortality and morbidity in young children with cystic fibrosis. Pediatr Pulmonol. 2002;34(2):277-287.
2.	Kosorok MR, Zeng L, West SE, Rock MJ, Splaingard ML, Laxova A, Green CG, Collins J, Farrell PM. Acceleration of lung disease in children with cystic fibrosis after Pseudomonas aeruginosa acquisition. Pediatr Pulmonol. 2001;32(4):277-287.
3.	Li Z, Kosorok MR, Farrell PM, Laxova A, West SE, Green CG, Collins J, Rock MJ, Splaingard ML. Longitudinal development of mucoid Pseudomonas aeruginosa infection and lung disease progression in children with cystic fibrosis.JAMA 2005;293 5:581-588.
4.	Rosenfeld M, Ramsey BW, Gibson RL. Pseudomonas acquisition in young patients with cystic fibrosis: pathophysiology, diagnosis, and management. Curr Opin Pulm Med. 2003;9(6):492-497.
5.	Steinkamp G, Tummler B, Malottke R, von der Hardt H. Treatment of Pseudomonas aeruginosa colonisation in cystic fibrosis. Arch Dis Child. 1989;64:1022-1028.
6.	Frederiksen B, Koch C, Hoiby N. Antibiotic treatment of initial colonization with Pseudomonas aeruginosa postpones chronic infection and prevents deterioration of pulmonary function in cystic fibrosis. Pediatr Pulmonol. 1997;23(5):330-335.
7.	Elborn JS, Hodson M, Bertram C. Implementation of European standards of care for cystic fibrosis - provision of care. J Cyst Fibros. 2009;8:348-355.
8.	Rosenfeld M, Emerson J, Accurso F, Armstrong D, Castile R, Grimwood K, Hiatt P, McCoy K, McNamara S, Ramsey B, Wagener J. Diagnostic accuracy of oropharyngeal cultures in infants and young children with cystic fibrosis. Pediatr Pulmonol. 1999;28(5):321-328.
9.	Noah TL, Ivins SS, Abode KA, Stewart PW, Michelson PH, Harris WT, Henry MM, Leigh MW. Inhaled versus systemic antibiotics and airway inflammation in children with cystic fibrosis and Pseudomonas. Pediatr Pulmonol. 2010;45(3):281-290.
10.	Lillquist YP, Cho E, Davidson AG. Economic effects of an eradication protocol for first appearance of Pseudomonas aeruginosa in cystic fibrosis patients: 1995 vs. 2009. .J Cyst Fibros. 2011;10(3):175-180.

Treggiari MM, Retsch-Bogart G, Mayer-Hamblett N, et al. Comparative efficacy and safety of 4 randomized regimens to treat early Pseudomonas aeruginosa infection in children with cystic fibrosis. Arch Pediatr Adolesc Med. 2011;165(9):847-856. (For non-subscribers to this journal, an additional fee may apply to obtain full-text articles.)

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The aim of the Early Pseudomonas Infection Control (EPIC) Trial was to compare the efficacy and safety of 4 anti-pseudomonal antibiotic regimens in children with CF with new Pseudomonas aeruginosa (Pa) infection. The study was a four-arm, randomized study conducted at 35 US centers between 2004 and 2009. Duration of study participation was 18 months. Participants had to be 1 to 12 years of age with new isolation of Pa from a respiratory tract culture within the six months preceding randomization. New isolation of Pa was defined as first lifetime documented pa-positive culture or a Pa-positive culture after at least a two-year absence of Pa. Participants were allowed one course of intravenous or inhaled antipseudomonal antibiotics before enrollment.

The study was designed to compare culture-based therapy (antibiotics administered quarterly regardless of results of respiratory cultures) vs cycled therapy (antibiotics administered only during quarters in which respiratory cultures were positive for Pa) as well as the addition of systemic antibiotics (ciprofloxacin) to inhaled antibiotics (tobramycin inhalation solution, TIS). Thus, participants were randomized equally to one of four groups: (1) cycled TIS and oral ciprofloxacin, (2) cycled TIS and oral placebo, (3) culture-based TIS and oral ciprofloxacin, (4) culture-based TIS and oral placebo. The antibiotic regimen administered during treatment cycles consisted of TIS 300 mg nebulized twice daily for 28 days and either ciprofloxacin 15 to 20 mg/kg twice daily or oral placebo for the first 14 days. At the beginning of the study, all participants received an initial treatment cycle according to their assigned group, and a second consecutive 28-day course of TIS if cultures obtained during the third week of the first cycle were positive for Pa. The primary clinical endpoint was time to first pulmonary exacerbation requiring IV antibiotics or hospital admission. The primary microbiological endpoint was the proportion of Pa-positive respiratory cultures among all quarterly cultures obtained after the initial treatment cycle.

A total of 304 participants were randomized equally to each of the 4 treatment groups (76 per arm) and included in the intent-to-treat population. While all study participants, as defined by the eligibility criteria, had a Pa-positive respiratory culture within six months before enrollment, 46% received antipseudomonal therapy during the six months preceding enrollment, and only 40% had Pa-positive cultures at the time of randomization. After the initial course of TSI, participants in the cycled-therapy group received on average six additional 28-day courses of TSI over the 18 month study period, while those in the culture-based group received on average only one additional course.

Overall, there was no difference between groups in the proportion of participants experiencing a pulmonary exacerbations requiring IV antibiotics or hospitalization: 24/152 (16%) in the cycled therapy group, 26/152 (17%) in the culture-based group, 29/152 (19%) in the ciprofloxacin group, and 21/152 (14%) in the placebo group. Similarly, the odds of a Pa-positive culture were similar between treatment groups (OR 0.78, 95% CI 0.49 to 1.23 comparing cycled vs culture-based therapy and OR 1.10, 95% CI 0.71 to 1.71 comparing ciprofloxacin vs placebo). All four regimens were effective in eradicating Pa. The majority of participants had no Pa-positive cultures after the first treatment cycle (57 to 74%, depending on the arm), and among those who did have recurrence of Pa, the majority had no more than two Pa positive cultures over the 18-month study. Growth and lung function outcomes were also similar between groups. The emergence of mucoid Pa, tobramycin-resistant and ciprofloxacin-resistant Pa was low and similar in all 4 groups (0 to 4%). Although not different between groups, the rate of treatment-emergent acquisition of Stenotrophomonas maltophilia was up to 20%. The clinical implications of acquiring this tobramycin-resistant gram-negative organism are unclear. Adverse events and safety were similar between groups, except participants assigned to ciprofloxacin had a greater frequency of cough than those assigned to placebo.

This study demonstrates that cycled and culture-based therapy are equally effective in terms of clinical endpoints (pulmonary exacerbations, growth, lung function) and microbiologic efficacy. All treatment regimens were highly effective, and the addition of oral ciprofloxacin to inhaled tobramycin did not improve outcomes. Thus, this study suggests that treatment of new Pa with inhaled tobramycin monotherapy is as effective as more aggressive culture-based regimens or adding oral ciprofloxacin.