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To evaluate the success of an initial tobramycin dosing regimen to achieve target peak and trough concentrations in adult patients with pulmonary exacerbations of cystic fibrosis (CF).Retrospective single-center medical record review.Large tertiary care academic medical center.A total of 186 patient encounters where 112 patients with CF were treated for acute pulmonary exacerbations with 10 mg/kg/day of tobramycin between January 1, 2009, and December 5, 2014.Baseline demographics, clinical characteristics, tobramycin data, and pharmacokinetic variables were collected. The primary outcome evaluated the success of the initial tobramycin dosing regimen in attaining the target peak concentration. Secondary end points were achievement of the target trough concentration, achievement of combined peak and trough targets, and incidence of nephrotoxicity. Bivariate and multivariate analyses were performed to evaluate factors associated with achieving target concentrations. Of the 186 patient encounters, 41% achieved the target peak with the first dosing regimen, 62% achieved a target trough, and 23% achieved the target peak and trough. Nephrotoxicity occurred in 10% of patient encounters. A body mass index (BMI) of 18.5–24.9 kg/m2 was associated with higher odds of meeting the target peak compared with a BMI lower than 18.5 kg/m2 (odds ratio [OR] 24.5; 95% confidence interval [CI] 5.2–117.2). Conversely, a BMI of 18.5–24.9 kg/m2 was associated with lower odds of attaining the target trough compared with a BMI lower than 18.5 kg/m2 (OR 0.16; 95% CI 0.05–0.56). Higher volume of distribution and elimination rate constants (Kel) were associated with significantly lower odds of achieving the target peak. In addition, higher Kel values were associated with significantly higher odds of achieving the target trough.The current initial tobramycin regimen did not achieve target serum tobramycin concentrations reliably. Optimization of the initial CF tobramycin dosing regimen is warranted.