Robert McCarthy , Pharmacy Student , John Hawboldt , BSP, ACPR, PharmD , Associate Professor , Erin Davis , BSc(Pharm), PharmD , Assistant Professor
The practice of evidence-based medicine involves integrating clinical expertise with the best evidence available.1 Pharmacy schools train students to apply evidence obtained from the literature to real-life patient scenarios to optimize drug therapy. However, although evidence-based medicine is the ideal, the “real world” presents unique challenges to this practice.
During summer 2012, one of us (R.M.) participated in research involving patients with cystic fibrosis. In this patient population, chronic colonization with Pseudomonas aeruginosa is associated with a more rapid decline in lung function2 and increased mortality.3 Guidelines recommend long-term use of tobramycin by inhalation to improve lung function and reduce exacerbations in those with chronic P. aeruginosa colonization.4,5 According to an informal telephone survey of cystic fibrosis clinics across Canada, doses for inhaled tobramycin range from 160 to 300 mg bid on a month-on, month-off schedule. The product used for inhalation is either tobramycin solution for inhalation (300 mg in 5-mL volume) or tobramycin for injection (80 mg in 2-mL volume). To find evidence regarding appropriate dosage, we conducted a literature search (with no restrictions) in the PubMed, International Pharmaceutical Abstracts, and Embase databases, with search terms “tobramycin”, “tobramycin solution for inhalation”, “cystic fibrosis”, “eradication”, “chronic colonization”, and “ Pseudomonas aeruginosa ”. The results of the search indicated that the product predominantly studied and shown to be effective was tobramycin solution for inhalation at a dose of 300 mg bid. Why, then, does practice not always reflect this evidence?
A unique concern with the sputum of patients with cystic fibrosis is that certain concentrations of drug are required to not only reach the target ( P. aeruginosa ), but also kill that target. When administered via inhalation, tobramycin, a positively charged molecule, binds to negatively charged glycoproteins in the sputum.6,7 It has been determined that administration of a certain amount of the drug (300 mg) saturates these proteins, leaving enough free drug to produce bactericidal effects on P. aeruginosa . In addition, pharmacokinetic analyses of inhaled tobramycin indicate that local concentrations of 25 times the minimum inhibitory concentration (i.e., 25 × 4 μg/mL) are required to kill P. aeruginosa .8 At a total dose of 300 mg, sufficient sputum concentrations are achieved to produce a bactericidal effect in 90% of patients.9 Thus, there seems to be a pharmaceutical, pharmacokinetic, and pharmacodynamic rationale for administering 300 mg of the drug.
With regard to clinical efficacy, there is high-quality evidence to support the use of tobramycin solution for inhalation. In a placebo-controlled trial, intermittent tobramycin solution for inhalation (300 mg bid for 28 days on, 28 days off) yielded significant improvements (10% over baseline) in forced expiratory volume in the first second (FEV 1 ) at 20 weeks.10 In an extension of this study, FEV 1 continued to improve until the end of the 92-week study period.11 This trial, which represents the majority of available evidence, also showed that use of tobramycin solution for inhalation significantly reduced the density of P. aeruginosa in the sputum (by 0.8 log 10 colony-forming units), reduced admissions to hospital (by 26%), and decreased the need for IV antibiotics (by 36%).10 Moreover, a recent study indicated that tobramycin solution for inhalation (300 mg), when used consistently, was associated with an absolute mortality reduction of 2.8% at 5 years and 5.1% at 10 years relative to suboptimal use.12 Finally, the safety of inhaled tobramycin 300 mg bid has been demonstrated, with voice alterations and transient tinnitus as the predominant adverse effects reported.9
Given all of the evidence supporting the use of tobramycin solution for inhalation at a dose of 300 mg bid, why aren’t we using this regimen consistently? The main reason appears to be economic. For patients with cystic fibrosis, medication costs can be high, and many rely on government assistance. Tobramycin solution for inhalation is expensive, and as a result, coverage by provincial drug plans is variable, with some preferentially covering tobramycin for injection instead. Practitioners are forced to set aside the principles of evidence-based medicine and use the injectable formulation by inhalation at a dose (160 mg) that is not supported by the literature. In addition to considerations related to provincial drug coverage, another reason may be the time required to nebulize 300 mg of tobramycin for injection (total volume 7.5 mL), which would be prohibitively long compared with nebulization of 300 mg of tobramycin solution for inhalation (total volume 5 mL). This difference in volume might seem small, but not if consideration is given to the multiple time-intensive treatments that patients with cystic fibrosis must complete daily. We should try to improve adherence, not by selecting a regimen for which there is no evidence, but by selecting an available regimen that is evidence-based (even if it is expensive).
In this era of antimicrobial stewardship, we pharmacists have a better understanding of the implications of inappropriate dosing of antibiotics. Given the lack of published evidence to support the efficacy of tobramycin 160 mg bid, we may need to consider that evidence-based therapy for which adherence is more likely (i.e., tobramycin solution for inhalation) is simply the cost of good health care. Moreover, there is also the question of whether, by using 160 mg bid, we are in fact inadequately treating our patients and encouraging the establishment of resistant organisms in patients’ airways. If we don’t advocate on behalf of our patients for the reimbursement of evidence-based therapies, we may get the answer to this question sooner rather than later, possibly at the expense of patient outcomes.
1. Sackett DL, Rosenberg WM, Gray JA, Haynes RB, Richardson WS. Evidence-based medicine: what it is and what it isn’t. BMJ 1996;312(7023):71–72.
2. Emerson J, Rosenfeld M, McNamara S, Ramsey B, Gibson RL. Pseudomonas aeruginosa and other predictors of mortality and morbidity in young children with cystic fibrosis. Pediatr Pulmonol 2002;34(2):91–100.
3. Høiby N, Pressler T. Emerging pathogens in cystic fibrosis. Eur Respir Soc Monogr 2006;35:66–78.
4. Flume PA, O’Sullivan BP, Robinson KA, Goss CH, Mogayzel PJ Jr, Willey-Courand DB, et al.; Cystic Fibrosis Foundation, Pulmonary Therapies Committee. Cystic fibrosis pulmonary guidelines: chronic medications for the maintenance of lung health. Am J Respir Crit Care Med 2007; 176(10):957–969.
5. Heijerman H, Westerman E, Conway S, Touw D, Döring G. Inhaled medication and inhalation devices for lung disease in patients with cystic fibrosis: a European consensus. J Cyst Fibros 2009;8(5):295–315.
6. Hunt BE, Weber A, Berger A, Ramsey B, Smith AL. Macromolecular mechanisms of sputum inhibition of tobramycin activity. Antimicrob Agents Chemother 1995;39(1):34–39.
7. Ramphal R, Lhermitte M, Filliat M, Roussel P. The binding of anti-pseudomonal antibiotics to macromolecules from cystic fibrosis sputum. J Antimicrob Chemother 1988;22(4):483–490.
8. Mendelman PM, Smith AL, Levy J, Weber A, Ramsey B, Davis RL. Amino-glycoside penetration, inactivation, and efficacy in cystic fibrosis sputum. Am Rev Respir Dis 1985;132(4):761–765.
9. Smith AL. Inhaled antibiotic therapy: What drug? What dose? What regimen? What formulation? J Cyst Fibros 2002;1 Suppl 2:189–193.
10. Ramsey BW, Pepe MS, Quan JM, Otto KL, Montgomery AB, Williams-Warren J, et al.; Cystic Fibrosis Inhaled Tobramycin Study Group. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. New Engl J Med 1999;340(1):23–30.
11. Moss RB. Long-term benefits of inhaled tobramycin in adolescent patients with cystic fibrosis. Chest 2002;121(1):55–63.
12. Sawicki GS, Signorovitch JE, Zhang J, Latremouille-Viau D, von Wartburg M, Wu EQ, et al. Reduced mortality in cystic fibrosis patients treated with tobramycin inhalation solution. Pediatr Pulmonol 2012;47(1):44–52.
Dr Hawboldt is cross-appointed to the Faculty of Medicine and Dr Davis is cross-appointed to the Faculty of Medicine, Discipline of Family Medicine, at Memorial University of Newfoundland. ( Return to Text )
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Canadian Journal of Hospital Pharmacy , VOLUME 65 , NUMBER 6 , November-December 2012