Use of Aerosolized Antibiotics in Patients With Cystic Fibrosis

Abstract

There has been a renewed interest in the use of aerosolized antibiotics in cystic fibrosis (CF) patients during the past decade. Potential benefits of delivering antibiotics by aerosol include the following: direct delivery of antibiotics to the endobronchial site of infection; decreased toxicity as systemic absorption is limited; reduced cost; and less disruption to patients' lives, especially when compared with IV antibiotic administration. Several reviews have summarized the published literature on the subject.1Littlewood JM Smye SW Cunliffe H Aerosol antibiotic treatment in cystic fibrosis.Arch Dis Child. 1993; 68: 788-792Crossref PubMed Scopus (38) Google Scholar2Touw DJ Brimicombe RW Hodson ME et al.Inhalation of antibiotics in cystic fibrosis.Eur Respir J. 1995; 8: 1594-1604PubMed Google Scholar3Smith AL Ramsey BW Aerosol administration of antibiotics.Respiration. 1995; 62: 19-24Crossref PubMed Scopus (24) Google Scholar The authors of this document were convened to discuss the use of aerosolized antibiotics in CF patients. The document attempts to address four major questions: (1) What are the indications for the use of aerosolized antibiotics? (2) What is the appropriate dosage and delivery method for aerosolized agents? (3) How should patients receiving aerosolized antibiotics be monitored? (4) What are the microbiological implications of aerosolized antibiotics? Each section of this document contains a review of the published literature. Whenever possible, evidence-based recommendations are made. The grading of evidence for our recommendations follows the US Preventive Services Task Force system.4United States Preventive Services Task Force Guide to clinical preventive services. Williams & Wilkins, Baltimore, MD1989: 263Google Scholar In addition, words defined in the glossary found in the appendix will be indicated by an asterisk (*) the first time they are used in the text. IEvidence obtained from at least one properly randomized controlled trial.II-1Evidence obtained from well-designed controlled trials without randomization.II-2Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one center or research group.II-3Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of the introduction of penicillin treatment in the 1940s) could also be regarded as this type of evidence.IIIOpinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees. Investigators have primarily examined the efficacy of aerosolized antibiotics in reducing morbidity in patients in stable condition (suppression therapy), a few studies have examined the role of aerosol antibiotics as adjunctive therapy for acute exacerbations of pulmonary disease (treatment), and several have examined their role in delaying chronic Pseudomonas aeruginosainfection/colonization* (prevention). Aerosolized aminoglycosides,β -lactams, and polymyxins have been studied. Aminoglycosides have been the most extensively studied class of aerosolized antibiotics. They are well-suited for inhalation because they remain bioactive when aerosolized and are poorly absorbed across epithelial surfaces. Thus, high concentrations in bronchial secretions can theoretically be achieved with minimal risk for systemic toxicity. In 1981, Hodson and colleagues5Hodson ME Penketh ARL Batten JC Aerosol carbenicillin and gentamicin treatment of Pseudomonas aeruginosa infection in patients with cystic fibrosis.Lancet. 1981; 2: 1137-1139Abstract PubMed Scopus (249) Google Scholar carried out the first (to our knowledge) clinical trial of aerosolized gentamicin (Schering Corp; Kenilworth, NJ) and carbenicillin in 20 adult patients and found lung function to be modestly improved. Following this report, a number of studies with generally positive results were published in the 1980s.5Hodson ME Penketh ARL Batten JC Aerosol carbenicillin and gentamicin treatment of Pseudomonas aeruginosa infection in patients with cystic fibrosis.Lancet. 1981; 2: 1137-1139Abstract PubMed Scopus (249) Google Scholar6Wall MA Terry AB Eisenberg J et al.Inhaled antibiotics in cystic fibrosis [letter].Lancet. 1983; 1: 1325Abstract PubMed Scopus (74) Google Scholar7Carswell F Ward C Cook DA et al.A controlled trial of nebulized aminoglycoside and oral flucloxacillin versus placebo in the outpatient management of children with cystic fibrosis.Br J Dis Chest. 1987; 81: 356-360Abstract Full Text PDF PubMed Scopus (61) Google Scholar8Stead RJ Hodson ME Batten JC Inhaled ceftazidime compared with gentamicin and carbenicillin in older patients with cystic fibrosis infected with Pseudomonas aeruginosa..Br J Dis Chest. 1987; 81: 272-279Abstract Full Text PDF PubMed Scopus (98) Google Scholar9Steinkamp G Tummler B Gappa M et al.Long-term tobramycin aerosol therapy in cystic fibrosis.Pediatr Pulmonol. 1989; 6: 91-98Crossref PubMed Scopus (129) Google Scholar10Kun P Landau LI Phelan PD Nebulized gentamicin in children and adolescents with cystic fibrosis.Aust J Paediatr. 1984; 20: 43-45PubMed Google Scholar11MacLusky IB Gold R Corey M et al.Long-term effects of inhaled tobramycin in patients with Pseudomonas aeruginosa..Pediatr Pulmonol. 1989; 7: 42-48Crossref PubMed Scopus (142) Google Scholar All but one6Wall MA Terry AB Eisenberg J et al.Inhaled antibiotics in cystic fibrosis [letter].Lancet. 1983; 1: 1325Abstract PubMed Scopus (74) Google Scholar of the studies that measured pulmonary function demonstrated significant improvement5Hodson ME Penketh ARL Batten JC Aerosol carbenicillin and gentamicin treatment of Pseudomonas aeruginosa infection in patients with cystic fibrosis.Lancet. 1981; 2: 1137-1139Abstract PubMed Scopus (249) Google Scholar7Carswell F Ward C Cook DA et al.A controlled trial of nebulized aminoglycoside and oral flucloxacillin versus placebo in the outpatient management of children with cystic fibrosis.Br J Dis Chest. 1987; 81: 356-360Abstract Full Text PDF PubMed Scopus (61) Google Scholar8Stead RJ Hodson ME Batten JC Inhaled ceftazidime compared with gentamicin and carbenicillin in older patients with cystic fibrosis infected with Pseudomonas aeruginosa..Br J Dis Chest. 1987; 81: 272-279Abstract Full Text PDF PubMed Scopus (98) Google Scholar9Steinkamp G Tummler B Gappa M et al.Long-term tobramycin aerosol therapy in cystic fibrosis.Pediatr Pulmonol. 1989; 6: 91-98Crossref PubMed Scopus (129) Google Scholar or a slower rate of decline10Kun P Landau LI Phelan PD Nebulized gentamicin in children and adolescents with cystic fibrosis.Aust J Paediatr. 1984; 20: 43-45PubMed Google Scholar11MacLusky IB Gold R Corey M et al.Long-term effects of inhaled tobramycin in patients with Pseudomonas aeruginosa..Pediatr Pulmonol. 1989; 7: 42-48Crossref PubMed Scopus (142) Google Scholar during the study period. A trend toward decreased hospitalization rates was seen in four studies,5Hodson ME Penketh ARL Batten JC Aerosol carbenicillin and gentamicin treatment of Pseudomonas aeruginosa infection in patients with cystic fibrosis.Lancet. 1981; 2: 1137-1139Abstract PubMed Scopus (249) Google Scholar6Wall MA Terry AB Eisenberg J et al.Inhaled antibiotics in cystic fibrosis [letter].Lancet. 1983; 1: 1325Abstract PubMed Scopus (74) Google Scholar8Stead RJ Hodson ME Batten JC Inhaled ceftazidime compared with gentamicin and carbenicillin in older patients with cystic fibrosis infected with Pseudomonas aeruginosa..Br J Dis Chest. 1987; 81: 272-279Abstract Full Text PDF PubMed Scopus (98) Google Scholar10Kun P Landau LI Phelan PD Nebulized gentamicin in children and adolescents with cystic fibrosis.Aust J Paediatr. 1984; 20: 43-45PubMed Google Scholar and improved nutritional status was seen in two studies.8Stead RJ Hodson ME Batten JC Inhaled ceftazidime compared with gentamicin and carbenicillin in older patients with cystic fibrosis infected with Pseudomonas aeruginosa..Br J Dis Chest. 1987; 81: 272-279Abstract Full Text PDF PubMed Scopus (98) Google Scholar9Steinkamp G Tummler B Gappa M et al.Long-term tobramycin aerosol therapy in cystic fibrosis.Pediatr Pulmonol. 1989; 6: 91-98Crossref PubMed Scopus (129) Google Scholar Interpretation of these earlier studies is hampered by small sample size, lack of appropriate controls, and failure to mask the taste of the antibiotic. Comparison between studies is difficult due to differences in dose of aminoglycoside, duration of therapy, type of nebulizers, patient ages and disease severity, and whether sputum colonization with P aeruginosa was required for study entry. A multicenter trial of aerosolized tobramycin (Lederle Laboratories; Wayne, NJ) was designed to overcome some of the limitations of previous studies.12Ramsey BW Dorkin HL Eisenberg JD et al.Efficacy of aerosolized tobramycin in patients with cystic fibrosis.N Engl J Med. 1993; 328: 1740-1746Crossref PubMed Scopus (431) Google Scholar Seventy-one CF patients with stable pulmonary status were enrolled in a multicenter, double-blind, placebo-controlled, taste-masked, crossover design study of tobramycin, 600 mg tid, delivered by ultrasonic nebulizer (Ultraneb 100/99; Sunrise Medical HHG; Somerset, PA). This dose effectively achieves sputum tobramycin concentrations > 10 times the minimal inhibitory concentration (MIC*) of all tobramycin-susceptible P aeruginosa,13Smith AL Ramsey BW Hedges DL et al.Safety of aerosol tobramycin administration for 3 months to patients with cystic fibrosis.Pediatr Pulmonol. 1989; 7: 265-271Crossref PubMed Scopus (138) Google Scholar a concentration shown necessary to overcome competitive binding of tobramycin by CF sputum.14Levy J Smith AL Kenny MA et al.Bioactivity of gentamicin in purulent sputum from patients with cystic fibrosis or bronchiectasis: comparison with activity in serum.J Infect Dis. 1983; 148: 1069-1076Crossref PubMed Scopus (97) Google Scholar15Mendelman PM Smith AL Levy J et al.Aminoglycoside penetration, inactivation, and efficacy in cystic fibrosis sputum.Am Rev Respir Dis. 1985; 132: 761-765PubMed Google Scholar A 10% improvement in FEV1 during the first 28-day treatment period was noted during tobramycin administration compared with placebo; FEV1 increased by 3.72% predicted in the treatment group compared with a 5.97% decline in control subjects (p < 0.001). This effect continued during the three-period crossover analysis, although the difference between treatment and placebo was less, 4.32% predicted (p = 0.002). In addition, during the first 28 days of tobramycin therapy, a 100-fold mean reduction in the density of P aeruginosa in sputum was demonstrated. Although the study demonstrated efficacy, the high dose and cumbersome ultrasonic nebulizer were not acceptable to patients and health-care providers. Subsequently, two identical phase III randomized, placebo-controlled parallel design studies were conducted to examine the safety and efficacy of preservative-free, nonpyrogenic, sterile 300-mg solution of tobramycin (TOBI; PathoGenesis; Seattle, WA) designed for administration by a specific nebulizer (Pari LC Plus Jet Nebulizer; Pari; Midlothian, VA) and compressor (Pulmo-Aide; Sunrise Medical HHG).16Ramsey BW Pepe MS Quan JM et al.Intermittent administration of inhaled tobramycin in patients with cystic fibrosis.N Engl J Med. 1999; 340: 23-30Crossref PubMed Scopus (1150) Google Scholar Selection criteria for subjects included age ≥ 6 years, colonized with P aeruginosa, not colonized with Burkholderia cepacia, and FEV1 ≤ 75% and≥ 25% predicted. The primary end points were assessment of FEV1, and sputum bacterial density at 28 days, as well as at the end of three cycles (20 weeks). Secondary end points included FVC, rate of hospitalization, and IV antibiotic usage over the 6-month (20 weeks) study period. In total, 520 patients were enrolled at 69 centers and 464 patients completed the trial. Tobramycin significantly improved pulmonary function, decreased sputum P aeruginosa bacterial density, reduced hospitalizations, and reduced the use of other antipseudomonal antibiotics. The tobramycin treatment effect on FEV1 percent predicted in both trials was approximately 12%. In all subgroups analyzed, stratified by age, gender, disease severity, and concurrent use of rhDNase (Pulmozyme; Genentech; South San Francisco, CA), tobramycin-treated patients had greater improvements in pulmonary function test (PFT) results and greater reductions in P aeruginosa sputum bacterial density than patients receiving standard therapy without tobramycin. Two studies have investigated the addition of aerosolized antibiotics to an antibiotic regimen in patients being treated for a pulmonary exacerbation.17Stephens D Garey N Isles A et al.Efficacy of inhaled tobramycin in the treatment of pulmonary exacerbations in children with cystic fibrosis.Pediatr Infect Dis J. 1983; 2: 209-211Crossref Scopus (90) Google Scholar18Schaad RB Wedgwood-Krucko J Suter S et al.Efficacy of inhaled as adjunct to intravenous combination therapy (ceftazidime and amikacin) in cystic fibrosis.J Pediatr. 1987; 111: 599-605Abstract Full Text PDF PubMed Scopus (90) Google Scholar Both studies found similar improvement in pulmonary function and clinical measurements in the treatment groups whether or not patients received aerosolized aminoglycoside therapy. In one study,18Schaad RB Wedgwood-Krucko J Suter S et al.Efficacy of inhaled as adjunct to intravenous combination therapy (ceftazidime and amikacin) in cystic fibrosis.J Pediatr. 1987; 111: 599-605Abstract Full Text PDF PubMed Scopus (90) Google Scholar a temporary clearance of P aeruginosa from the sputum was seen in 70% of patients receiving inhaled antibiotic as compared to 41% of patients treated with IV antibiotics alone. The significance of this is unknown. To our knowledge, no study has assessed the efficacy of inhaled antibiotics in place of IV antibiotics for treatment of a pulmonary exacerbation. Polypeptide antibiotics of the polymyxin class are poorly absorbed across mucosal surfaces, so that aerosol therapy offers the theoretical advantage of high respiratory tract levels with low systemic absorption, and a low risk of emergence of polymyxin-resistant P aeruginosa.3Smith AL Ramsey BW Aerosol administration of antibiotics.Respiration. 1995; 62: 19-24Crossref PubMed Scopus (24) Google Scholar The therapeutic efficacy of aerosol polymyxin (Parke-Davis; Morris Plains, NJ) as suppression therapy in CF patients has been evaluated in two small clinical studies. Littlewood et al,19Littlewood JM Miller MG Ghoneim AT et al.Nebulised colomycin for use in early pseudomonas colonisation in cystic fibrosis.Lancet. 1985; 1: 865Abstract PubMed Scopus (210) Google Scholar in an open-label case series of young CF patients treated with 500,000 U of colistin bid, suggested that the frequency of isolation of P aeruginosa decreased. Jensen et al20Jensen T Pedersen SS Garne S et al.Colistin inhalation therapy in cystic fibrosis patients with chronic Pseudomonas aeruginosa lung infections.J Antimicrob Chemother. 1987; 19: 831-838Crossref PubMed Scopus (311) Google Scholar randomized 40 patients to receive either colistin, 1 million units bid, or saline solution control for 90 days and found a slower rate of decline in FVC in treated patients. No adverse reactions to colistin were noted. In a nonrandomized trial, 20 CF patients awaiting lung transplantation were begun on a regimen of aerosolized colistin 75 mg twice daily when a multiply antibiotic-resistant P aeruginosa was cultured from their sputum.21Bauldoff GS Nunley DR Manzetti JD et al.Use of aerosolized colistin sodium in cystic fibrosis patients awaiting lung transplantation.Transplantation. 1997; 64: 748-752Crossref PubMed Scopus (44) Google Scholar Ten other patients with multiply resistant P aeruginosa were not offered colistin treatment. The mean FEV1 percent predicted was not significantly different between the treated and untreated patients, but treated patients were more likely to develop sensitive organisms (p < 0.05) more rapidly (p = 0.007) than untreated patients. Such a strategy merits a randomized, placebo-controlled trial. Three studies have evaluated the efficacy of oral ciprofloxacin (Miles Inc; West Haven, CT) used with aerosolized colistin alone22Valerius NH Koch C Høiby N Prevention of chronic Pseudomonas aeruginosa colonisation in cystic fibrosis by early treatment.Lancet. 1991; 338: 725-726Abstract PubMed Scopus (440) Google Scholar23Frederiksen 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: 330-335Crossref PubMed Scopus (429) Google Scholar or with aerosolized colistin and tobramycin together24Vazquez C Municio M Corera M et al.Early treatment of Pseudomonas aeruginosa colonization in cystic fibrosis.Acta Paediatr. 1993; 82: 308-309Crossref PubMed Scopus (48) Google Scholar to delay chronic P aeruginosa infection. Because historical controls were used and oral ciprofloxacin was administered concomitantly, the effect of aerosolized colistin is difficult to determine from these trials. These preliminary studies suggest that aerosolized polymyxins may have a therapeutic role alone or in combination with other aerosolized or oral antibiotics. To our knowledge, however, no published studies have examined the biological activity or particle size distribution of polymyxins in aerosol form or measured sputum drug concentrations. Coly-Mycin, the most commonly prescribed polymyxin for aerosolization in CF, is a pro-drug that must be hydrolyzed to the bioactive form, colistin, and the rate of hydrolysis in airway secretions is unknown. Furthermore, studies of prophylactic polymyxin for the prevention of Gram-negative bacillary pneumonia in the ICU raised serious concerns about overgrowth by bacterial species inherently resistant to polymyxins such as B cepacia and Serratia marcescens.25Feeley TW du Moulin GC Hedley-Whyte J et al.Aerosol polymyxin and pneumonia in seriously ill patients.N Engl J Med. 1975; 293: 471-475Crossref PubMed Scopus (201) Google Scholar To date, though, overgrowth of B cepacia has not been a practical problem with long-term use of aerosolized polymyxins in England.26Simmonds EJ Conway SP Ghonheim ATM et al.Pseudomonas cepacia : a new pathogen in patients with cystic fibrosis referred to a large centre in the United Kingdom.Arch Dis Child. 1990; 65: 874-877Crossref PubMed Scopus (50) Google Scholar Studies examining aerosolized β-lactams are limited. Hodson et al5Hodson ME Penketh ARL Batten JC Aerosol carbenicillin and gentamicin treatment of Pseudomonas aeruginosa infection in patients with cystic fibrosis.Lancet. 1981; 2: 1137-1139Abstract PubMed Scopus (249) Google Scholar carried out a crossover study of aerosolized carbenicillin and gentamicin administered for 6 months and found significant improvement in pulmonary function and a trend toward decreased hospitalizations. Of note, carbenicillin and gentamicin are incompatible in solution as inactivation of the gentamicin may occur.27Trissel LA Handbook on injectable drugs. 4th ed. 1996Google Scholar Nolan and colleagues28Nolan G McIvor P Levison H et al.Antibiotic prophylaxis in cystic fibrosis: inhaled cephaloridine as an adjunct to oral cloxacillin.J Pediatr. 1982; 101: 626-630Abstract Full Text PDF PubMed Scopus (81) Google Scholar examined the efficacy of aerosolized cephaloridine in patients with mild-to-moderate lung disease and found no beneficial effects. Evidence-based recommendations for aerosolized antibiotic use in CF are possible only regarding their use as suppressive therapy. Although aminoglycosides, semisynthetic penicillins, and Coly-Mycin have demonstrated a variable clinical benefit, adequately powered trials have not been performed, with the exception of studies of preservative-free 300-mg per dose tobramycin.16Ramsey BW Pepe MS Quan JM et al.Intermittent administration of inhaled tobramycin in patients with cystic fibrosis.N Engl J Med. 1999; 340: 23-30Crossref PubMed Scopus (1150) Google Scholar This preparation has undergone the most extensive clinical, safety, and pharmacokinetic testing.