<p><strong>BACKGROUND: </strong>Tobramycin is frequently used for treatment of bronchopneumonia in patients with cystic fibrosis (CF). Variability in tobramycin clearance (CL) is high in this population with few reliable approaches to guide dosing.</p>

<p><strong>OBJECTIVES: </strong>We sought to evaluate the pharmacokinetics of once-daily intravenous tobramycin in patients with CF and test the influence of covariates on tobramycin CL, including serum creatinine (SCr) and urinary biomarkers: neutrophil gelatinase-associated lipocalin (NGAL), retinol-binding protein (RBP) and kidney injury molecule-1 (KIM-1).</p>

<p><strong>METHODS: </strong>This was a prospective, observational cohort study of children/young adults with CF receiving once-daily intravenous tobramycin from October 2012 to May 2014 at Cincinnati Children's Hospital Medical Center. Therapeutic drug monitoring data were prospectively obtained. Population pharmacokinetic analyses were performed using non-linear mixed-effects modelling.</p>

<p><strong>RESULTS: </strong>Thirty-seven patients (median age 15.3 years, IQR 12.7-19.5) received 62 tobramycin courses. A one-compartment model with allometrically scaled weight for tobramycin CL and volume of distribution (V) best described the data. Urinary NGAL was associated with tobramycin CL (P &lt; 0.001), as was urinary RBP (P &lt; 0.001). SCr, estimated glomerular filtration rate and urinary KIM-1 were not significant covariates. The population pharmacokinetic parameter estimates were CL = 8.60 L/h/70 kg (relative standard error 4.3%) and V = 31.3 L/70 kg (relative standard error 4.7%).</p>

<p><strong>CONCLUSIONS: </strong>We describe urinary biomarkers as predictors of tobramycin CL using a population pharmacokinetic modelling approach. Our findings suggest that patient weight and urinary NGAL or RBP could be used to individualize tobramycin therapy in patients with CF.</p>

<p><strong>BACKGROUND: </strong>Aminoglycoside (AG) therapy is a common cause of acute kidney injury (AKI) in cystic fibrosis (CF) patients. The aim of this study was to identify factors associated with AKI during intravenous AG courses in this population.</p>

<p><strong>METHODS: </strong>This was a matched case-control study utilizing two independent cohorts of hospitalized CF patients receiving ≥ 3 days of intravenous AG at Cincinnati Children's Hospital Medical Center and Children's of Alabama. All admissions with AKI (cases, N = 82) were matched to two randomly selected admissions without AKI (controls, N = 164) by center, gender, and age ±3 years of the case. AKI was defined as a 1.5-fold increase in the baseline serum creatinine (SCr) level or by an increase in SCr level of 0.3 mg/dL within 48 h. Admissions with AKI before day 4 or without at least weekly SCr monitoring were excluded from the analysis. Factors were compared between cases and controls using simple and multiple conditional logistic regression.</p>

<p><strong>RESULTS: </strong>Multivariable analysis identified receipt of an AG within 90 days prior to admission, longer duration of AG therapy, low serum albumin, and receipt of trimethoprim/sulfamethoxazole as independent risk factors for developing AKI. Infection with Staphylococcus aureus diminished the odds of developing AKI.</p>

<p><strong>CONCLUSIONS: </strong>This study identifies risk factors contributing to AG-associated AKI in CF patients. These findings can be used to anticipate high-risk scenarios and limit AKI in CF patients under clinical care.</p>

<p><strong>BACKGROUND: </strong>The epidemiology of aminoglycoside-associated acute kidney injury (AG-AKI) has not been well described in pediatric patients with cystic fibrosis (CF). We aimed to assess the impact of daily serum creatinine (SCr) measurement on detection of AG-AKI at our institution.</p>

<p><strong>METHODS: </strong>We examined a cohort of hospitalized patients with CF who received an intravenous (IV) aminoglycoside for ≥ 3 days. We compared the rate, timing, and medical management surrounding detection of AG-AKI during 2 periods: January 2010-May 2011 (Era 1, SCr measured at the discretion of the medical team, N=124) and June 2011-June 2012 (Era 2, SCr measured daily, N=103). Our primary outcome was detection of AG-AKI defined as ≥ 50% increase in SCr from baseline (lowest value in prior 6 months), or ≥ 0.3mg/dL rise within 48 h, occurring after day 2.</p>

<p><strong>RESULTS: </strong>The use of once daily tobramycin (p=0.02) and IV fluids (p&lt;0.001) was higher during Era 2, while AG courses were shorter (p=0.04), and fewer concomitant nephrotoxins (p=0.04) were given; higher daily tobramycin doses (p&lt;0.001) were administered. Although the rate of AG-AKI was not significantly different (12% during Era 1 vs. 20% during Era 2, p=0.09), the number of AG-AKI days detected increased (5.5 vs. 2.9 per 100 AG days, p=0.003), and detection occurred earlier (median 6 vs. 9 days, log rank test p=0.02) during the daily SCr period.</p>

<p><strong>CONCLUSIONS: </strong>Daily SCr measurement promoted earlier and increased detection of AG-AKI in patients with CF at our institution. We suggest systematic evaluation for AKI during aminoglycoside administration in patients with CF.</p>