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Inhaled Tobramycin (TOBI®)

A Review of its Use in the Management of Pseudomonas aeruginosa Infections in Patients with Cystic Fibrosis

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Summary

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 300mg 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 ≥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 300mg 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 300mg 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.

Antibacterial Activity

Tobramycin, an aminoglycoside antibacterial, had good in vitro activity against Pseudomonas aeruginosa in sputum isolates from patients with cystic fibrosis; the minimum concentrations required to inhibit the growth of 90% (MIC90) of strains was 8 μg/mL in the largest study (involving 1240 isolates) [MIC90 = 8–64 μg/mL in smaller studies]. According to breakpoint values for systemic antibacterials issued by the US National Committee for Clinical Laboratory Standards (NCCLS) [MIC ≤4 μg/mL susceptible, MIC 8 μg/mL intermediate, MIC ≥16 μg/mL resistant], 89% of 1240 P. aeruginosa isolates from 508 patients with cystic fibrosis were susceptible to tobramycin and 5.4% were resistant; the range of resistance for other antibacterial agents was 11–21%. Increased resistance of non-mucoid compared with mucoid strains was evident with tobramycin in one study (although statistical analysis was not performed) but not in another study. Tobramycin was active against most (65–84%) nonaminoglycoside single- or multiple-drug resistant isolates. About one- to two-thirds of isolates resistant to tobramycin were susceptible to other agents. Resistance to tobramycin results mostly from impermeability of isolates.

In phase III placebo-controlled trials in patients aged ≥6 years with cystic fibrosis, there was a significant decrease in the tobramycin susceptibility of P. aeruginosa isolates (characterised by an increase in MIC90 from 8 [baseline] to 16 μg/mL [weeks 20 and 24]) and an increase in fungal organisms (Candida albicans and Aspergillus species) during intermittent treatment with tobramycin solution for inhalation (TSI) 300mg twice daily. However, clinical outcome was not adversely affected. Furthermore there was no evidence of selection for the most resistant isolates.

Similarly, improvement in lung function was not affected by tobramycin MIC after 96 weeks of alternating treatment (i.e. 28 days on/28 days off) with TSI 300mg twice daily in patients with cystic fibrosis, despite reduced susceptibility of P. aeruginosa to tobramycin. In a subgroup of adolescent patients, increases were observed in the percentage of resistant isolates (5% [baseline] to 19% [study end]) and MIC90 (from 8 to 32 μg/mL).

Pharmacokinetic Properties

TSI achieved lung concentrations of tobramycin sufficient for an antibacterial effect against P. aeruginosa in most patients aged ≥6 with moderate-to-severe cystic fibrosis, while maintaining minimal systemic exposure. Ten minutes after single-dose TSI 300mg, sputum concentrations of tobramycin were 35–7417 μg/g (mean 1237 μg/g; median 959 μg/g), demonstrating wide interindividual variability. At 60 minutes after TSI, serum tobramycin concentrations remained low (≤3.62 μg/mL, mean 0.95 μg/mL, median 0.91 μg/mL). There was no accumulation of tobramycin in sputum or serum after multiple-dose administration (measured at week 20). The median ratio of serum-to-sputum tobramycin concentrations was 0.01 after TSI administration, demonstrating an improved therapeutic ratio compared with parenteral aminoglycosides.

The estimated bioavailability of tobramycin following administration of TSI 300mg was 11.7% in a population pharmacokinetic analysis using systemic clearance of 5.79 L/h and an apparent clearance of 49.6 L/h.

In children aged <6 years with cystic fibrosis, peak serum drug concentrations (0.6 μg/mL [range <0.2–1.2 μg/mL]) were reached 1 hour after administration of TSI 300mg, and were lower than the maximum accepted trough concentrations (2 μg/mL) for parenteral administration of tobramycin. Lower respiratory tract drug concentrations were within the bactericidal range for P. aeruginosa, with lung epithelial lining fluid concetrations being 16–204 μg/mL (mean 90 μg/mL) and above the target of 20 μg/mL (i.e. 10 times the MIC90 for P. aeruginosa) in 11 of 12 patients.

After inhalation, systemically absorbed tobramycin is assumed to be eliminated primarily by glomerular filtration, and unabsorbed tobramycin residing in the endobronchial space is probably eliminated primarily in expectorated sputum.

Therapeutic Efficacy

In Patients aged ≥6 years with cystic fibrosis and chronic P. aeruginosa respiratory infection, TSI 300mg twice daily significantly improved lung function and sputum P. aeruginosa density versus placebo or baseline in well designed trials. In addition, TSI 300mg twice daily was significantly more effective than colistin for improvement in forced expiratory volume in 1 second (FEV1) in a nonblind trial of short duration (involving only the antibacterial phase of one 28-day on/28-day off cycle of TSI) in 100 patients with cystic fibrosis and chronic P. aeruginosa infection.

In two identically designed, randomised, double-blind, placebo-controlled trials (pooled analysis, n = 520), marked improvements in lung function (≈12% increase from baseline in FEV1) occurred within 2 weeks of treatment initiation and were maintained throughout the treatment period (three 28-day on/28-day off cycles). At treatment end, the total treatment effect (absolute difference between TSI and placebo) was ≈12%. Mean FEV1 was maintained above pretreatment (baseline) for up to 96 weeks in an open-label extension phase. Patients aged 13–17 years were more responsive to treatment than other patient age-groups. There were no observed differences according to gender, disease severity or dornase alfa use. These results can be contextualised when one considers the progressive decline in lung function of ≈2% per year generally observed in patients with cystic fibrosis.

Mean sputum P. aeruginosa density showed marked reductions from baseline during the first two active TSI-treatment periods and tended back towards baseline during the non-treatment phases in these placebo-controlled trials. The effect of TSI on sputum P. aeruginosa density was significantly (p = 0.01) reduced with increasing age.

Fewer TSI than placebo recipients required hospitalisation or intravenous antibacterial treatment, and the mean duration of both was shorter with TSI than placebo, during the controlled phase of clinical trials. Similar trends for hospitalisation rate and duration of stay were recorded during the 96-week open-label extension phase. Reductions in hospitalisation rates and the use of intravenous antibacterials produced cost savings that partially off-set the acquisition cost of TSI in a small UK observational economic evaluation in patients with cystic fibrosis and P. aeruginosa infection. Global ratings for health-related quality of life were significantly (p ≤ 0.03) better for TSI than placebo recipients during each treatment cycle in a retrospective analysis using a nonvalidated single-item questionnaire.

In 21 patients aged <6 years with cystic fibrosis and early P. aeruginosa colonisation in a randomised, double-blind, placebo-controlled trial, TSI 300mg twice daily was more effective than placebo for change in bronchoalveolar lavage (BAL) P. aeruginosa density (primary endpoint; between group difference 5.36 log10 colony forming units/mL, p < 0.0001) and eradication rate at 28 days (p < 0.0001), with all eight patients in the TSI group having a negative BAL culture.

Tolerability

Children and adults generally tolerated TSI treatment well, with recipients in clinical trials showing few of the adverse events associated with parenteral aminoglycosides as a class (ototoxicity, nephrotoxicity, neuromuscular interference and fetal harm in pregnant women). Inhaled aminoglycoside treatment is expected to result in fewer systemic adverse events because of poor absorption through the respiratory epithelium. This was the case in trials with TSI 300mg twice daily where no nephrotoxicity or neuromuscular interference was experienced. The only adverse events that occurred significantly more frequently in TSI than placebo recipients in the largest trials were transient mild or moderate tinnitus (3% vs 0%, p = 0.003) and voice changes (12.8% vs 6.5%, p = 0.02), neither of which increased with subsequent cycles of treatment or were cause for TSI discontinuation. No reproductive toxicology studies have been conducted with TSI.

Objectively measured hearing loss did not occur in TSI-treated patients in clinical trials even if they experienced tinnitus, nor did patients complain of hearing loss. However, in postmarketing experience, some TSI recipients reported hearing loss and this was frequently associated with tinnitus. Some of these patients had had previous or concurrent systemic aminoglycoside treatment.

Bronchospasm observed in patients shortly after administration of TSI was transient and similar to that observed after inhalation of placebo. The TSI formulation does not contain phenol, EDTA (edetic acid) or sodium metabisulphite which may cause airway reactivity.

Dosage and Administration

TSI 300mg twice daily (taken as close to 12 hours apart as possible, but not less than 6 hours apart) for alternating periods (28 days on/28 days off) is indicated for the management of P. aeruginosa infection in patients with cystic fibrosis. Subsequent to publication of the current US label, which states that safety have not been demonstrated in patients <6 years of age, a clinical trial has been conducted in this younger age group. TSI is inhaled over a 15-minute period using the PARI LC PLUS™ reusable nebuliser with a compressor.

TSI should be used with caution in patients with known or suspected renal, auditory, vestibular or neuromuscular dysfunction, and in consultation with a physician in pregnant or breast-feeding women. It should not be used concomitantly with ethacrynic acid, furosemide, urea or mannitol, and/or concurrently or sequentially with other drugs with neurotoxic or ototoxic potential.

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  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland, 1311, New Zealand

    Susan M. Cheer, John Waugh & Stuart Noble

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Correspondence to Susan M. Cheer.

Additional information

Various sections of the manuscript reviewed by: A. Bush, Imperial School of Medicine and Royal Bromptom Hospital, London, UK; M.E. Hodson, Department of Cystic Fibrosis, Royal Brompton & Harefield NHS Trust, London, UK; B. Ramsey, Children’s Hospital & Regional Medical Center, Seattle, Washington, USA; F. Ratjen, Children’s Hospital, University of Essen, Essen, Germany; T. Schülin, University of Nijmegen, Nijmegen, The Netherlands; A. Smith, Seattle Biomedical Research Institute, Seattle, Washington, USA; G. Steinkamp, CF Centre Hamburg-Altona, Hannover, Germany.

Data Selection

Sources: Medical literature published in any language since 1980 on tobramycin, identified using Medline and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: Medline search terms were ‘tobramycin’ and (‘cystic fibrosis’ or ‘inhaled’ or ‘inhalation’ or ‘aerosol’ or ‘aerosolized’). EMBASE search terms were ‘tobramycin’ and (‘cystic fibrosis’ or ‘inhaled’ or ‘inhalation’ or ‘aerosol’ or ‘aerosolized’). AdisBase search terms were ‘tobramycin’ and (‘cystic fibrosis’ or ‘inhal*’ or ‘aerosol*’). Searches were last updated 6 October 2003.

Selection: Studies in patients with cystic fibrosis who received tobramycin solution for inhalation (TOBI®). Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Tobramycin solution for inhalation, cystic fibrosis, Pseudomonas aeruginosa, pharmacodynamics, pharmacokinetics, therapeutic use.

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Cheer, S.M., Waugh, J. & Noble, S. Inhaled Tobramycin (TOBI®). Drugs 63, 2501–2520 (2003). https://doi.org/10.2165/00003495-200363220-00015

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