Technical Report: Precautions Regarding the Use of Aerosolized Antibiotics

Abstract

ABSTRACT. In 1998, the Food and Drug Administration (FDA) approved the licensure of tobramycin solution for inhalation (TOBI). Although a number of additional antibiotics, including other aminoglycosides, ␤-lactams, antibiotics in the polymyxin class, and vancomycin, have been administered as aerosols for many years, none are approved by the FDA for administration by inhalation.TOBI was approved by the FDA for the maintenance therapy of patients 6 years or older with cystic fibrosis (CF) who have between 25% and 75% of predicted forced expiratory volume in 1 second (FEV 1 ), are colonized with Pseudomonas aeruginosa, and are able to comply with the prescribed medical regimen. TOBI was not approved for the therapy of acute pulmonary exacerbations in patients with CF nor was it approved for use in patients without CF. Currently, no other antibiotics are approved for administration by inhalation to patients with or without CF.The purpose of this statement is to briefly summarize the data that supported approval for licensure of TOBI and to provide recommendations for its safe use. The pharmacokinetics of inhaled aminoglycosides and problems associated with aerosolized antibiotic treatment, including environmental contamination, selection of resistant microbes, and airway exposure to excipients in intravenous formulations, will be discussed. Pediatrics 2000;106(6). URL: http://www.pediatrics.org/cgi/content/ full/106/6/e89; aerosolized antibiotics, tobramycin solution for inhalation; cystic fibrosis; Pseudomonas aeruginosa.ABBREVIATIONS. TOBI, tobramycin solution for inhalation; CF, cystic fibrosis; FEV 1 , forced expiratory volume in 1 second; FDA, Food and Drug Administration; MIC, minimal inhibitory concentration. APPROVED INDICATION FOR TOBRAMYCIN SOLUTION FOR INHALATION (TOBI)TOBI is approved for maintenance therapy of patients with cystic fibrosis (CF) who are known to be colonized with Pseudomonas aeruginosa. The results of 2 randomized, double-blind, placebo-controlled, multicentered, 24-week clinical studies demonstrated the favorable effects of this therapy. 1,2 Each study enrolled subjects 6 years or older who had Ն25% and Յ75% of predicted forced expiratory volume in 1 second (FEV 1 ). Subjects with serum creatinine concentrations above 2 mg/dL and those colonized with Burkholderia cepacia were excluded. Study participants received alternating 28-day cycles of drug therapy. Two hundred fifty-eight patients received 300 mg of TOBI twice daily and 262 received inhaled saline placebo. Both drug and placebo were delivered by a PARI LC Plus nebulizer (PARI Respiratory Equipment Inc, Monterey, CA) with a Pulmo-Aide compressor (DeVilbiss Air Power Co, Jackson, TN). The drug recipients experienced significant improvement in pulmonary function compared with the placebo recipients; the average improvement in FEV 1 at the end of the study (week 24) relative to baseline (week 0) was 7% to 11% in the treatment group versus 0% to 1% in the placebo group (P Ͻ .001). Furthermore, TOBI resulted in a significant reduction...

Ventilator-Associated Pneumonia in Neonatal and Pediatric Intensive Care Unit Patients

“…Aerosolized antibiotics have been studied most extensively in children in the setting of cystic fibrosis. The FDA approval of tobramycin solution for inhalation is only for maintenance therapy in patients with cystic fibrosis known to be colonized with Pseudomonas aeruginosa (76). In two randomized controlled trials, a modest improvement in the forced expiratory volume in 1 min occurred after 24 weeks of therapy with tobramycin solution for inhalation; there were significant decreases in CFU/ml of Pseudomonas aeruginosa in sputum, decreases in hospital admission days, and decreases in numbers of parenteral antibiotic days for treatment of Pseudomonas aeruginosa infections.…”

“…No ototoxicity or nephrotoxicity has been associated with the use of inhaled aminoglycosides, although many of those studies excluded children with serum creatinine levels greater than 2. The potential disadvantages of use include bronchospasm, increased MICs of the targeted organism, increased isolation of Candida and Aspergillus species from sputum, nebulization of microorganisms, and antibiotic contamination of the environment (76).…”

Microparticles for Inhalational Delivery of Antipseudomonal Antibiotics

“…Co-nebulizing several antibiotics is difficult because some combinations of antibiotic solutions can form precipitates (13). Finally, nebulization disperses antibiotics into the ambient air and generates antibiotic resistance among ubiquitous bacteria (14). The ideal vehicle for inhalational delivery of antibiotics should deliver the effective drug, provide a high FPF, allow for simultaneous delivery of multiple potentially chemically incompatible antibiotics, limit the contamination of ambient air, and be easy to use.…”

“…In CF patients P. aeruginosa often develops resistance if treated with a single antibiotic (such as tobramycin, ceftazidime, or ciprofloxacin), and many clinicians use two or more agents of different classes simultaneously to prevent this (14,(17)(18)(19)(20)(21). Coencapsulating the two compounds in the same particles would assure their co-deposition in the airway at the intended doses.…”

The Prognosis of Cystic Fibrosis - A Clinician's Perspective

“…The Austrian study was in fact very encouraging but the same group reported that longterm gentamicin inhalation in CF children was associated with reversible raised urinary Nacetyl-beta-D-glucosaminidase (NAG) activity, consistent with subtle subclinical renal tubular damage (Ring et al, 1998). Tobramycin and amikacin however have lower renal toxicity than gentamicin and long-term use of high doses of inhaled tobramycin (TOBI) are now considered safe (Prober et al, 2000). There are several theoretical arguments that make long-term inhaled prophylactic antibiotic therapy attractive (Lebecque et al, 2008).…”