Individualizing aminoglycoside dosage regimens in patients with cystic fibrosis : an evaluation of three methods

dc.contributor.advisorDriever, Carl W.
dc.contributor.committeeMemberMack, Eric J.
dc.contributor.committeeMemberClark, Toby
dc.contributor.committeeMemberSeilheimer, Dan K.
dc.creatorLaine, Gregory A.
dc.description.abstractCystic fibrosis (CF) is an autosomal-recessive disease that is characterized by exocrine gland dysfunction. The primary clinical features of the disease are pancreatic insufficiency and a chronic, diffuse, obstructive, infectious, pulmonary process. Pulmonary infection is one of the most serious complications of CF. Pseudomonas aeruginosa and Staphylococcus aureus are the pathogens most often responsible for pulmonary infections in CF. Antibiotic therapy has played a significant role in the improvement in quality of life and longer life expectancy in patients with CF. The aminoglycoside antibiotics have been mainstays in the treatment of pseudomonal pulmonary infections in CF. Therapeutic success and increased risk of ototoxicity and nephrotoxicity have been correlated with serum aminoglycoside concentrations. Attainment of therapeutic aminoglycoside serum concentrations early in the treatment course has been associated with improved clinical response. The purpose of this study was to investigate the potential cost savings from utilizing pharmacokinetic principles to dose aminoglycosides in patients with CF. Comparative length of hospital stay and number of serum concentrations necessary to optimize the dosage regimen were objective criteria used in the prospective evaluation. Eighteen patients each were randomized into control (empirical dosing) and experimental (dosing with the Sawchuk-Zaske method) groups. Tobramycin was the aminoglycoside prescribed for all patients. Mean length of hospital stay and mean number of tobramycin serum concentrations necessary to optimize the dosage regimen were not significantly different between study groups. Based on these criteria, the results suggest that using the Sawchuk-Zaske method to dose tobramycin may not be a cost-effective approach for some CF patients. Serum tobramycin concentration-time data for 20 patients requiring a dosage regimen change were used for the retrospective phase of the study. Predictive performance of the one-compartment model and a Bayesian tobramycin dosing program in conjunction with 4 simulated serum sampling schemes was examined. The results suggested that a serum sampling scheme using only peak and trough serum tobramycin concentrations performed with similar precision and accuracy as a sampling scheme using 4 concentrations in conjunction with a one-compartment pharmacokinetic model. The mean number of tobramycin levels necessary to optimize the dosage regimen if only peak and trough levels had been used to calculate kinetic variables was estimated for the experimental group. For patients requiring a dosage regimen change, the estimated mean number of tobramycin concentrations to optimize the dosage regimen in the experimental group (4.3+0.9) was significantly less than for the control group (6.4+2.9). The mean estimated cost-savings to the patient was 63 dollars. This suggests that using a one compartment pharmacokinetic model with only peak and trough serum tobramycin concentrations to estimate individual kinetic variables may be a cost-effective approach to dose tobramycin in this subgroup of patients. Several patients exhibited marked differences between observed and predicted serum tobramycin concentrations. Because of this and results from the predictive performance evaluations, the in-vitro delivery of tobramycin from the infusion system was examined. The results indicated that the in-vitro delivery of the drug from the infusion system employed in the study was delayed and the rate of delivery was not zero-order. Clinicians should consider the type of intravenous infusion system used and interlot variation of drug products when interpreting serum concentration data. Further studies are recommended to test the predictive performance of the Bayesian method using a reliable infusion system and the long-term impact of pharmacokinetic dosing on cost-effective care in CF patients.
dc.description.departmentPharmacy, College of
dc.format.digitalOriginreformatted digital
dc.rightsThis item is protected by copyright but is made available here under a claim of fair use (17 U.S.C. Section 107) for non-profit research and educational purposes. Users of this work assume the responsibility for determining copyright status prior to reusing, publishing, or reproducing this item for purposes other than what is allowed by fair use or other copyright exemptions. Any reuse of this item in excess of fair use or other copyright exemptions requires express permission of the copyright holder.
dc.subjectCystic fibrosis--Chemotherapy
dc.titleIndividualizing aminoglycoside dosage regimens in patients with cystic fibrosis : an evaluation of three methods
dc.type.genreThesis of Pharmacy, College of of Houston of Science


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