Article

Placebo-controlled, double-blind, randomized study for early treatment of Pseudomonas aeruginosa colonization in patients with cystic fibrosis

Department of Pediatrics, University Hospital, Essen, Germany.
Pediatric Pulmonology (Impact Factor: 2.3). 02/1998; 25(2):88-92. DOI: 10.1002/(SICI)1099-0496(199802)25:2<88::AID-PPUL3>3.0.CO;2-J
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ABSTRACT In chronic Pseudomonas aeruginosa pulmonary infection of patients with cystic fibrosis (CF), antibiotic therapy generally fails to eradicate the bacterial pathogen. The mucoid bacterial phenotype, high sputum production by the host, and low airway levels of antibiotics seem to be responsible for the observed decrease in antibiotic efficacy. We hypothesized that early antibiotic treatment by inhalation in CF patients may be able to prevent or at least delay airway infection. In a prospective placebo-controlled, double-blind, randomized multicenter study, 22 CF patients received either 80 mg b.i.d. of aerosolized tobramycin or placebo for a period of 12 months shortly after the onset of P. aeruginosa pulmonary colonization. Two patients in the tobramycin and six patients in the placebo group stopped inhalation before the 12 month treatment period. Using life table analysis, the time to conversion from a P. aeruginosa-positive to a P. aeruginosa-negative respiratory culture was significantly shorter in the tobramycin-treated group than in the placebo group (P < 0.05, log rank test). Lung function parameters and markers of inflammation did not change in either group during treatment. The results of this study suggest that early tobramycin inhalation may prevent and/or delay P. aeruginosa pulmonary infection in CF patients.

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    • "These objective culture results allow comparisons between different studies for corresponding time points in relation to the end of treatment. After 2 early placebo-controlled eradication studies, the second of which was stopped early due to evidence of efficacy [5] [10], subsequent trials have been open-label without a placebo arm (note that although the EPIC study [31] was placebo-controlled for oral ciprofloxacin, all patients received open-label TIS). A randomized , blinded, placebo-controlled trial is difficult to recruit given the accepted need and current consensus guidelines recommendations for prompt Pa eradication treatment. "
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    ABSTRACT: Background Consensus guidelines recommend early treatment to eradicate newly acquired Pseudomonas aeruginosa (Pa) infection in cystic fibrosis (CF) patients although there is no single preferred regimen. Aztreonam for inhalation solution (AZLI) significantly reduces sputum Pa density in CF patients with chronic Pa infection and has been well tolerated in the pediatric population. This single-arm, open-label Aztreonam Lysine for Pseudomonas Infection Eradication (ALPINE) study was conducted to evaluate the safety and efficacy of a 28-day treatment course of AZLI to eradicate newly acquired Pa infection in pediatric CF patients. Methods CF patients (3 months to < 18 years) with new onset Pa infection were treated with AZLI 75 mg 3 times daily for 28 days. New onset Pa infection was defined as first lifetime Pa-positive respiratory tract culture (throat swab, sputum) or Pa-positive culture after a ≥ 2-year history of Pa-negative cultures (≥ 2 cultures/year). Sputum or throat swab cultures were collected at study entry (baseline) and at weeks 4 (end of treatment), 8, 16, and 28. Primary endpoint was the percentage of patients with cultures negative for Pa at all post-treatment time points. Results A total of 105 pediatric CF patients enrolled (3 months to < 2 years, n = 24; 2 to < 6 years, n = 25; 6 to < 18 years, n = 56). Of the 101 patients who completed treatment, 89.1% (n = 90) were free of Pa at the end of treatment and 75.2% (n = 76) were free of Pa 4 weeks after the end of treatment. Of the 79 patients evaluable for the primary endpoint, 58.2% were free of Pa at all post-treatment time points. Conclusions AZLI was effective and well tolerated in eradicating Pa from newly infected pediatric patients with CF. These eradication rates are consistent with success rates reported in the literature for various antibiotic regimens, including other inhaled antibiotics studied for eradication. ClinicalTrials.gov: NCT01375049.
    Journal of Cystic Fibrosis 08/2014; 14(1). DOI:10.1016/j.jcf.2014.06.003 · 3.82 Impact Factor
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    • "A Cochrane review (CR) [36] including 2 RCTs [37] [38], and another new RCT [39] were analyzed. Evidence from two trials [37] [38] showed treatment of early P. aeruginosa infection with inhaled tobramycin results in microbiological eradication of theorganism from respiratory secretions more often than placebo (OR 0.15 (95% CI 0.03 to 0.65)) and that this effect may persist for up to 12 months. In a recent trial [39], 58 patients with median age of 9 years were randomized to treatment with tobramycin inhalation solution (TIS) for 28 days or inhaled sodium colistimethate (2 × 2 million units/d) plus oral ciprofloxacin (30 mg/kg/day) for 3 months (CC). "
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    ABSTRACT: The optimal antibiotic regimen is unclear in management of pulmonary infections due to pseudomonas and staphylococcus in cystic fibrosis (CF). We systematically searched all the published literature that has considered the evidence for antimicrobial therapies in CF till June 2013. The key findings were as follows: inhaled antipseudomonal antibiotic improves lung function, and probably the safest/most effective therapy; antistaphylococcal antibiotic prophylaxis increases the risk of acquiring P. aeruginosa; azithromycin significantly improves respiratory function after 6 months of treatment; a 28-day treatment with aztreonam or tobramycin significantly improves respiratory symptoms and pulmonary function; aztreonam lysine might be superior to tobramycin inhaled solution in chronic P. aeruginosa infection; oral ciprofloxacin does not produce additional benefit in those with chronic persistent pseudomonas infection but may have a role in early or first infection. As it is difficult to establish a firm recommendation based on the available evidence, the following factors must be considered for the choice of treatment for each patient: antibiotic related (e.g., safety and efficacy and ease of administration/delivery) and patient related (e.g., age, clinical status, prior use of antibiotics, coinfection by other organisms, and associated comorbidities ones).
    The Scientific World Journal 12/2013; 2013:645653. DOI:10.1155/2013/645653 · 1.73 Impact Factor
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    • "Several early eradication protocols and randomized clinical trials report a delay in chronic infection with Psa and in some cases achieved eradication [7] [8] [9] [10] [11] [12] [13]. "
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    ABSTRACT: Acquisition of Pseudomonas aeruginosa (Psa) and infection with mucoid strains is associated with repeated pulmonary exacerbations which often require intravenous and long-term nebulised antibiotic treatments, repeated hospitalizations and leads to a more precipitous decline in lung function. Anti-Psa antibiotic therapy early in the course of Psa infection in patients with cystic fibrosis (CF) may result in eradication of Psa and prevention or delay of colonization with the organism. From January 1995 to December 2009 our paediatric CF clinic has followed an early eradication protocol for the first appearance of Psa. In this paper we report on the economic effects after 15 years as reflected in hospitalization and antibiotic usage and cost. The Psa-eradication protocol includes 2 weeks of IV piperacillin and tobramycin, followed by oral ciprofloxacin for 3 weeks, and nebulised colistimethate for 6 months. The same protocol is used for newly diagnosed CF patients who grow Psa on their first visit or who grow a mucoid strain, multiresistant strain of Psa or whose Psa co-cultured with Burkholderia cepacia complex, and for patients in whom Psa recurs after initial clearance. 195 Psa eradication courses were completed from 1995 to 2009 with an overall Psa clearance rate of 90%. Patients that only cultured a Psa classic (non-mucoid) strain had a clearance rate was 96.5%. The percentage of children chronically infected with Psa has declined from 44% in 1994 to 15% in 2009.Total days spent in hospital for all reasons declined by 43%; chronic Psa hospital days declined by 75%; IV and nebulised anti-Psa antibiotic costs reduced by 44%. Results indicate that application of a Pseudomonas eradication protocol as described in this report has economic and resource utilization benefits in addition to clinical benefits.
    Journal of cystic fibrosis: official journal of the European Cystic Fibrosis Society 02/2011; 10(3):175-80. DOI:10.1016/j.jcf.2011.01.002 · 3.82 Impact Factor
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