Inhaled Tobramycin (TOBI??)

Abstract

Specifically formulated for nebulisation using the PARI LC PLUS reusable nebuliser, tobramycin solution for inhalation (TSI) [TOBI] provides a high dose of tobramycin (an aminoglycoside antibacterial with good activity against Pseudomonas aeruginosa) to the lungs of patients with cystic fibrosis, while maintaining low serum concentrations of the drug, thus reducing the risk of systemic toxicity. Intermittent (28-day on/28-day off) treatment with TSI 300 mg twice daily significantly (p < 0.001) improved lung function and sputum P. aeruginosa density compared with placebo (randomised double-blind trials), and was significantly (p = 0.008) more effective than colistin for improvement in forced expiratory volume in 1 second (small nonblind trial) in patients aged > or =6 years with cystic fibrosis and chronic P. aeruginosa infection. Improvements in lung function were most marked in adolescent patients (aged 13-17 years) in placebo-controlled trials. Improvements were maintained for up to 96 weeks in patients in an open-label extension study. Fewer TSI than placebo recipients required parenteral antipseudomonal agents or hospitalisation. In addition, TSI 300 mg twice daily for 28 days reduced P. aeruginosa density in the lower airways of patients aged <6 years with early colonisation and cystic fibrosis, although TSI is not currently indicated in this patient group. A decrease in tobramycin susceptibility of P. aeruginosa isolates and an increase in fungal organisms (Candida albicans and Aspergillus species) during prolonged intermittent treatment with TSI 300 mg twice daily was not associated with adverse clinical outcome. There was no evidence of selection for the most resistant isolates. TSI is generally well tolerated, with no renal toxicity or hearing loss in clinical trials, although transient mild or moderate tinnitus occurred more frequently in TSI than placebo recipients. Bronchospasm after administration of TSI was transient and occurred with a similar incidence to that with placebo; TSI is preservative free and specifically formulated for the lung in terms of osmolality and pH. In conclusion, TSI provides an effective means of delivering tobramycin to the lungs of patients with cystic fibrosis with chronic P. aeruginosa infection, improving lung function and sputum P. aeruginosa density in these patients without the nephrotoxicity or ototoxicity of parenteral aminoglycosides. Further data on the potential for and clinical significance of increased tobramycin resistance and fungal colonisation during TSI treatment would be beneficial, as would longer-term data. In the meantime, TSI represents a valuable option for suppressive antipseudomonal therapy in patients with cystic fibrosis.

Antibiotic Hybrids: the Next Generation of Agents and Adjuvants against Gram-Negative Pathogens?

“…They interact with rRNA to inhibit protein translation at lower concentrations (Յ4 g/ml), while they are known to disrupt the bacterial membrane at higher concentrations (Ն8 g/ml) (256). Tobramycin is a particularly attractive aminoglycoside, as it is currently one of the most active and effective agents for the treatment of P. aeruginosa infections (257).…”

Pharmacokinetics and Pharmacodynamics of Aerosolized Antibacterial Agents in Chronically Infected Cystic Fibrosis Patients

“…treatment of chronic P. aeruginosa infections in CF patients at a dose of 300 mg/ml; its efficacy was summarized by Cheer et al (287). A tobramycin inhalation dry powder formulation (TIP) administered via a novel inhaler has been developed.…”

Nanomedicine Approaches for the Pulmonary Treatment of Cystic Fibrosis

“…Despite the fact that tobramycin is usually well-tolerated, some of the patients treated with TIP experienced cough, bronchospasm, moderate tinnitus and dysphonia (Heijerman et al, 2009;Shteinberg and Elborn, 2015). The approved dose for TIS is 300 mg of antibiotic nebulised by a jet nebulizer twice a day every other month (Cheer et al, 2003;Somayaji and Parkins, 2015), while for TIP the treatment consists in 112 mg (four 28 mg capsules) inhaled twice a day in alternating cycles of 28-day on/off treatment (Döring et al, 2012). These capsules are composed of low-density porous particles, whose absorption is improved using a portable DPI, named Podhaler R that improves flow and dispersion of formulation.…”