Tobramycin in cystic fibrosis

Nikolaizik WH, Trociewicz K, Ratjen F. Bronchial reactions to the inhalation of high-dose tobramycin in cystic fibrosis. Eur Respir J 2002 20(l) 122-6. 

Geller DE, Pitlick WH, Nardella PA, Tracewell WG, Ramsey BW. Pharmacokinetics and bioavaUabihty of aerosolized tobramycin in cystic fibrosis. Chest 2002 122(l) 219-26. 

Le Brun PPH, de Boer AH, Gjaltema D, Hagedoom P, Heijeman HGM, Frijlink HW (1999) Inhalation of tobramycin in cystic fibrosis. Part 2 optimization of the tobramycin solution for a jet and an ultrasonic nebulizer. Int J Pham 189(2) 215-225... 

Scheenstra RJ, Rijntjes E, Tavy DL, Kingma H, Heijerman HG. Vestibulotoxi-city as a consequence of systemically administered tobramycin in cystic fibrosis patients. Acta Otolaryngol 2009 129(1) 4—7. 

Ramagopal M, Lands LC. Inhaled tobramycin and bronchial hyperactivity in cystic fibrosis. Pediatr Pulmonol 2000 29(5) 366-70. 

Hoffmann IM, Rubin BK, Iskandar SS, Schechter MS, Nagaraj SK, Bitzan MM. Acute renal failure in cystic fibrosis association with inhaled tobramycin therapy. Pediatr Pulmonol 2002 34(5) 375-7. 

Elidemir O, Maciejewski SR, Oermann CM. Falsely elevated serum tobramycin concentrations in cystic fibrosis patients treated with concurrent intravenous and inhaled tobramycin. Pediatr Pulmonol 2000 29(l) 43-5. 

Based on the clinical evidence of benefit from inhaled antibiotic suppressive therapy, the consensus conference recommendation [14] supports the use of the commercially available inhaled tobramycin on a cyclic schedule in cystic fibrosis patients colonized with P. aeruginosa. Other inhaled antibiotics may provide benefit as suppressive therapy as well, although the most compelling data support inhaled tobramycin. 

Steinkamp G, Trummler B, Gappa M. Long-term tobramycin aerosol therapy in cystic fibrosis. Pediatr Pulmonol 6 91 98, 1989. 

Mpller NE, Eriksen KR, Feddersen C, et al. Chemotherapy against Pseudomonas aeruginosa in cystic fibrosis A study of carbenicillin, azlocillin, or piperacillin in combination with tobramycin. Eur J Respir Dis 1982 63 130-139. 

Govoni M, Poli G, Acerbi D, Santoro D, Cicirello H, Annoni O, et al. Pharmacokinetic and tolerability profiles of tobramycin nebuhser solution 300mg/4 ml administered by PARI eFlow((R)) rapid and PARI LC Plus((R)) nebuhsers in cystic fibrosis patients. Pulm Pharmacol Ther 2013 26(2) 249-55. 

The use of the aerosol route for delivery of antibiotics for pulmonary infections remains controversial. The majority of pediatric studies have been conducted in children with cystic fibrosis. In these patients distribution of the antibiotic to the desired tissue site is impeded because of the viscosity of the sputum in patients with acute exacerbations of their pulmonary infections [91,92], Long-term studies have demonstrated preventive benefits of aerosolized antibiotics in children with cystic fibrosis who are colonizing Pseudomonas aeruginosa in their lungs but are not acutely ill [93,94], Cyclic administration of tobramycin administered by nebulizer has received FDA approval [95],... 

Newer examples of aminoglycoside antibiotics include amikacin, neomycin (Neosporin, Cortisporin), and tobramycin (TOBI, TobraDex). Injectable tobramycin is used in the treatment of serious infections at many body sites. It has also been formulated in an inhalable dosage form that has a very specific use to treat cystic fibrosis patients having Pseudomonas aeruginosa lung infections. In the form suitable for inhalation by the patient, it delivers the antibiotic directly to the site of infection. 

Patients suffering from cystic fibrosis often use various aerosolized drugs. To reduce the viscosity of the mucus in the airways, recombinant human deoxyribonuclease is used. This enzyme is the first recombinant protein that has been developed for specific delivery to the lungs via the airways. It has a local action on the mucus in the airways and its absorption is minimal. Another drug that decreases the viscosity of the mucus is acetylcysteine. Aerosolized antibiotics are a further group of therapeutics that is widely used by cystic fibrosis patients. Solutions of antibiotics like tobramycin or colistin are used in nebulizers to prevent exacerbation of the disease. Pentamidine has been used for the prophylaxis of Pneumocystis pneumonia in patients infected with HIV virus, while chronic rejection of lung transplants provided a reason to develop an aerosol formulation of cyclosporine A. 

P. aeruginosa is commonly found in the bronchial secretions of patients with cystic fibrosis. In one study, daily inhalation of large doses of tobramycin decreased the colonization by this organism 100-fold and significantly improved pulmonary function. 

Cheer SM, Waugh J, Noble S Inhaled tobramycin (TOBI) A review of its use in the management of Pseudomonas aeruginosa infections in patients with cystic fibrosis. Drugs 2003 63 2501. [PMID 14609360]... 

Bums, J.L., Van Dalfsen, J.M., Shawar, R.M., Otto, K.L., Garber, R.L., Quan, J.M., Montgomery, A.B., Albers, G.M., Ramsey, B.W., Smith, A.L. Effect of chronic intermittent administration of inhaled tobramycin on respiratory microbial flora in patients with cystic fibrosis. J Infect Dis 179 (1999) 1190-1196. 

Ramsey, B. W., Pepe, M. S., Quan, J. M., et al. (1999), Intermittent administration of inhaled tobramycin in patients with cystic fibrosis, cystic fibrosis inhaled tobramycin study group, N. Engl. J. Med.., 340,23-30. 

Topical uses. Neomycin and framycetin, whilst too toxic for systemic use, are effective for topical treatment of infections of the conjunctiva or external ear. They are sometimes used in antimicrobial combinations selectively to decontaminate the bowel of patients who are to receive intense immunosuppressive therapy. Tobramycin is given by inhalation for therapy of infective exacerbations of cystic fibrosis. 

The pharmacokinetics of once-daily intravenous tobramycin have been investigated in seven children with cystic fibrosis (162). All responded well. There was one case of transient ototoxicity but no nephrotoxicity. 

Bragonier R, Brown NM. The pharmacokinetics and toxicity of once-daily tobramycin therapy in children with cystic fibrosis. J Antimicrob Chemother 1998 42(l) 103-6. 

In a randomized comparison of nebulized tobramycin and nebulized colistin in patients with cystic fibrosis, 26 of 53 patients treated with tobramycin had at least one respiratory adverse event, most commonly pharyngitis (3). In 520 patients, inhaled tobramycin (300 mg bd for three 28-day cycles, each cycle being separated by a 28-day period of no treatment) was compared with placebo. Respiratory function was significantly improved as early as the second week and remained so for the rest of the study, even dnring periods withont aerosol treatment. There was also a parallel rednetion in the relative risk of hospitalization, the number of days of hospitalization, and the number of days of intravenous antibiotic treatment (4). 

Inhalation of the intravenous formulation of tobramycin can cause bronchoconstriction, as has been confirmed in 26 children with mild to moderate cystic fibrosis (11). Nevertheless, while bronchoconstriction did occur, many patients did not have bronchoconstriction in response to the standard intravenous formulation. The risk of bronchoconstriction may further be reduced by pretreatment with salbutamol. 

Of 60 adult patients with cystic fibrosis randomized to tobramycin, either 10 mg/kg/day or 3.3 mg/kg tds, two patients (one in each group) had bilateral impairment in pure tone audiography after treatment (20). 

Nephrotoxicity due to inhaled tobramycin has recently been described in a 20-year-old patient with cystic fibrosis who developed acute non-oliguric renal insufficiency after taking inhaled tobramycin 300 mg bd for 1 week the clinical and renal biopsy findings were consistent with aminoglycoside-induced changes (36). 

Intermittent administration of inhaled tobramycin has been recommended in patients with cystic fibrosis, as it improves pulmonary function, reduces the density of P. aeruginosa in sputum, and reduces the risk of hospitalization. The proportion of patients with isolates of P. aeruginosa with higher minimal inhibitory concentrations of tobramycin may increase (39). Treatment with inhaled tobramycin does not increase isolation of Burkholderia cepacia, Stenotrophomonas maltophilia, or Alcaligenes xylosoxidans however, isolation of Candida albicans and Aspergillus species may increase (40). 

The pharmacokinetics of tobramycin in patients with cystic fibrosis is significantly altered after lung transplantation, and early and close drug monitoring is recommended (43). 

The efficacy of nebulized tobramycin 300 mg bd for 4 weeks has been studied in a randomized, double-blind, placebo-controlled trial in 74 patients with bronchiectasis and Pseudomonas infection, without cystic fibrosis (31). 

Whitehead A, Conway SP, Etherington C, Caldwell NA, Setchfield N, Bogle S. Once-daily tobramycin in the treatment of adult patients with cystic fibrosis. Eur Respir J 2002 19(2) 303-9. 

Adams JP, Conway SP, Wilson C. Hypomagnesaemic tetany associated with repeated courses of intravenous tobramycin in a patient with cystic fibrosis. Respir Med 1998 92(3) 602-4. 

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