The use of nebulised TOBI (tobramycin) in cystic fibrosis

The use of inhaled tobramycin

Prof C Taylor. September, 2002. The use of nebulised tobramycin (TOBI) [online]. Sheffield Children's Hospital, Shefield, UK. Available from http://www.cysticfibrosismedicine.com

Despite tremendous advances in understanding the pathophysiology of cystic fibrosis (CF), chronic respiratory disease remains the principle clinical problem in caring for patients with CF[1] and continues to be the major cause of morbidity and mortality. Chronic endobronchial infection with Pseudomonas aeruginosa is associated with progressive of lung disease leading to bronchiectasis and respiratory failure [2,3,4,5]. Retrospective studies suggest that survival is increased by using an aggressive policy of intravenous anti-pseudomonal antibiotics at regular intervals, irrespective of symptoms[6]. Nebulised anti-pseudomonal antibiotics are also thought to prevent recurrent exacerbations, reduce antibiotic usage and maintain lung function[7], although until recently the evidence for this was based on small non-randomised studies[8,9,10].

A recent Cochrane review of 10 trials with 758 participants by Mukhopadhyay and Singh's concluded that 'nebulised anti-pseudomonal antibiotic treatment improves lung function and reduces the frequency of infective exacerbations in patients with cystic fibrosis' [11]. Most evidence was based on the use of nebulised tobramycin in daily doses of 40 - 1800mg. In the largest trial of this agent involving 520 subjects, the FEV1 was 11.9% predicted (95% confidence interval 8.1 to 15.6) higher in the treated group than in the placebo control group after five months. In three trials with 581 participants the number of subjects having at least one hospital admission during a trial was reduced in the groups treated with nebulised antibiotics, odds ratio 0.69, (95% confidence interval 0.50 to 0.96). Two trials with 591 participants showed that the number of patients having and at least one course of antibiotic therapy was reduced in the treated group, odds ratio 0.62 (95% confidence interval 0.45 to 0.87). Antibiotic resistance increased more in the antibiotic treated group than in the placebo group[12].

Although Mukhopadhyay and Singh's review found no evidence of renal or auditory toxicity with nebulised anti-pseudomonal antibiotic therapy, there is concern that long-term or intermittent use of high dose antibiotics may lead to toxicity [13,14], antibiotic resistance or predisposition to resistant organisms [15]. Mulherin et al found signs of bilateral sensorineural hearing loss consistent with aminoglycoside induced ototoxicity in one in six adult CF patients assessed by pure tone audiometry [16] and Pai and Nahata, while confirming improved pulmonary function and decreased sputum density of P. aeruginosa with tobramycin solution for inhalation (TSI), noted an increased risk of emergence of resistant strains of P. aeruginosa at all doses, after prolonged use [17]. However, a further retrospective review by Graff and Burns found that nebulised tobramycin therapy did not result in a greater risk for isolation of S. maltophilia than standard care alone [18] and MacLeod et al, reported impermeability resistance occurred in only a fraction of the P. aeruginosa population in CF lungs [19].

TSI is licensed in the UK for treating patients >6 years with FEV1's <75% predicted who are P. aeruginosa colonised and likely to comply with treatment. However, an age stratified analysis of phase iii trial data indicated a highly significant effect in adolescents that was three times greater than that observed in other age groups [12], a finding supported by further analysis of subjects who completed up to 24 months open-label follow-on therapy [20]. At the end of the last 'on-drug' period, patients randomised to TSI showed an improvement in FEV1 of 14.3% compared with 1.8% in those randomised to placebo. Thus, most gain may be achieved in younger patients before irreversible lung damage has occurred.

Recent studies have also examined possible effects of TSI on health related quality of life (HRQOL) issues. Quittner and Buu, found improved HRQOL but used a non validated assessment [21]. This requires further corroboration.

Conclusions

Follow up of patients receiving TSI suggests significant long-term benefits from nebulised tobramycin including improved lung function, reduced hospitalisation and IV antibiotic use and increased weight gain. More information on long-term toxicity and antibiotic resistance is needed.

References

1. Tauber E, Eichler I, Gartner C, Halmerbauer G, Gotz M, Rath R, Wojnarowski C, Frischer T. Improvements of lung function in cystic fibrosis. Pediatr Pulmonol 2002 Apr;33(4):263-268.

2. Gilligan PH. Microbiology of airway disease in patients with cystic fibrosis. Clin Microbiol Rev 1991;4:35-51.

3. Pier GB. Pulmonary disease associated with P. aeruginosa in cystic fibrosis: current status of the host bacterium infection. J Infect Dis 1985;151:575-580.

4. Nixon GM, Armstrong DS, Carzino R, Carlin JB, Olinsky A, Robertson CF, Grimwood K. Clinical outcome after early Pseudomonas aeruginosa infection in cystic fibrosis. J Pediatr 2001 May;138(5):699-704.

5. Henry RI, Mellis CM, Petrovic I. Mucoid Pseudomonas aeruingosa is a marker of poor survival in cystic fibrosis. Pediatr Pulmonol 1992;12:158-161.

6. Hoiby N. Prospects for the prevention and control of pseudomonal infection in children with cystic fibrosis. Paediatr Drugs 2000 Nov-Dec;2(6):451-463.

7. Banerjee D, Stableforth D. The treatment of respiratory pseudomonas infection in cystic fibrosis: what drug and which way? Drugs 2000 Nov;60(5):1053-1064.

8. Mukhopadhyay S, Singh M, Cater JI, Ogston S, Franklin M, Olver RE. Nebulised antipseudomonal antibiotic therapy in cystic fibrosis: a meta-analysis of benefits and risks. Thorax 1996 Apr;51(4):364-368.

9. Conway SP. Evidence for using nebulised antibiotics in cystic fibrosis. Arch Dis Child 1999 Apr;80(4):307-309.

10. Littlewood JM, Miller MG, Ghonheim AT, Ramsden CH. Nebulised colomycin for early pseudomonas colonisation in cystic fibrosis. Lancet 1985 Apr13;1(8433):865.

11. Ryan G, Mukhopadhyay S, Singh M. Nebulised anti-pseudomonal antibiotics for cystic fibrosis. Cochrane Database Syst Rev 2000;(2):CD001021.

12. Ramsey BW, Pepe MS, Quan JM, Otto KL, Montgomery AB, Williams-Warren J, Vasilijev-KM, Borowitz D, Bowman CM, Marshall BC, Marshall S, Smith AL. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group. N Engl J Med 1999 Jan7;340(1):23-30.

13. Samaniego-Picota MD, Whelton A. Aminoglycoside-Induced Nephrotoxicity in Cystic Fibrosis: A Case Presentation and Review of the Literature. Am J Ther 1996 Mar;3(3):248-257.

14. Bald M, Ratjen F, Nikolaizik W, Wingen AM. Ciprofloxacin-induced acute renal failure in a patient with cystic fibrosis. Pediatr Infect Dis J 2001 Mar;20(3):320-321.

15. Doring G, Conway SP, Heijerman HG, Hodson ME, Hoiby N, Smyth A, Touw DJ. Antibiotic therapy against Pseudomonas aeruingosa in cystic fibrosis: a European consensus. Eur Respir J 2000 Oct;16(4):749-767.

16. Mulherin D, Fahy J, Grant W, Keogan M, Kavanagh B, Fitzgerald M. Aminoglycoside induced ototoxicity in patients with cystic fibrosis. Ir J Med Sci 1991 Jun;160(6):173-175.

17. Pai VB, Nahata MC. Efficacy and safety of aerosolized tobramycin in cystic fibrosis. Pediatr Pulmonol 2001 Oct;32(4):314-327.

18. Graff GR, Burns JL. Factors Affecting the Incidence of Stentrophomonas maltophilia isolation in Cystic Fibrosis. Chest 2002 Jun;121(6):1754-1760.

19. MacLeod DL, Nelson LE, Shawar RM, et al. Aminoglycoside-resistance mechanisms for cystic fibrosis Pseudomonas aeruginosa isolates are unchanged by long-erm inhaled tobramycin treatment. J Infect Dis 2000;181:1180-1184.

20. Moss RB. Long-term benefits of inhaled tobramycin in adolescent patients with cystic fibrosis. Chest 2002;121:55-63.

21. Quittner AL, Buu A. Effects of tobramycin solution for inhalation on global ratings of quality of life in patients with cystic fibrosis and Pseudomonas aeruginosa infection. Pediatr Pulmonol 2002;33:269-276.