(264) Tobramycin pharmacodynamic optimization and impact on exposure and nephrotoxicity in children and young adult with Cystic Fibrosis

Background: Tobramycin, an aminoglycoside with a narrow therapeutic index is commonly used in the management of cystic fibrosis (CF) exacerbations to target Pseudomonas aeruginosa. CF patients often receive multiple courses of tobramycin over their lifetime and are at high risk for drug induced toxicity. Careful tobramycin therapeutic monitoring to optimize efficacy and minimize adverse drug events is of particular importance. Tobramycin exhibits concentration-dependent activity with peak over minimum inhibitory concentration ratio (Cmax/MIC) of 8-10 best predicts efficacy. Toxicity has been correlated with high trough levels and overall drug exposure. The CF Foundation recommends once-daily or extended-interval (EI) dosing of aminoglycosides over multiple daily dosing (MDD).

Beginning in 2018, a therapeutic monitoring protocol (protocol group, PG) targeting optimal Cmax 20-40mg/L or 8-10 x MIC and daily area-under-concentration time curve (AUC24) of 50-200mg*h/L was established to optimize tobramycin PD parameters. Between 2013-2017, tobramycin therapeutic monitoring targeted a time-of-undetectable level (t< 0.5mg/L) of 2-6 hours in addition to optimal Cmax (pre-protocol, pPG). Our study objectives are to compare differences in tobramycin exposure, rate of nephrotoxicity and forced expiratory volume in 1 sec (FEV1) between the two monitoring protocols.

Methods: Retrospective cohort study included patients under 21 years admitted for a CF exacerbation who received IV tobramycin from March 2013 – June 2021. Patients with chronic kidney disease, ascites, or pregnancy were excluded. Tobramycin 10mg/kg every 24 hour was initiated empirically in patients without previous dosing history. Drug levels were obtained on day 3 of treatment at 2- and 10-hour post dose for pharmacokinetics (PK) determination and dosage adjustment. All patients received concurrent anti-pseudomonal agent, most commonly a beta-lactam. Primary endpoints include AUC24, Cmax, and nephrotoxicity as defined per pediatric RIFLE (pRIFLE) criteria. Secondary outcome assessed changes in FEV1 from baseline to end of treatment.

Results: A total of 49 patients were included, 28 in the pPG and 21 in the PG. Mean age, sex, weight, baseline serum creatinine, and use of concurrent nephrotoxins were similar in both groups. Of the 21 patients who received tobramycin monitoring in PG, 10 (47.6%) were male, mean age 12.5 (range 0.06 – 20 years) and weighed 39.8 ± 16 kg (mean ± SD). Compared to pPG, patients who received tobramycin therapeutic monitoring in the PG experienced significantly lower tobramycin AUC24 (164 vs. 96 mg*h/L, p< 0.001), and less nephrotoxicity (10/28 (35.7%) vs. 2/21 (9.5%), p=0.01). Mean AUC24 in patients who experienced nephrotoxicity was significantly higher than those who did not (167 vs. 126 mg*h/L, p=0.026). Patients who received dosage adjustment in pPG were more likely to received MDD regimen (Table 1). Patients in both groups achieved similar Cmax (29.8 vs. 28.8 mg/L, p=0.741) and a similar proportion of patients experienced an FEV1 increase of greater than 10% (9/19, 47.4% vs. 11/17, 64.7%, p=0.296).

Conclusions: Tobramycin therapeutic monitoring with optimized peak and daily exposure (AUC24) target rather than time-of-undetectable drug level resulted in similar Cmax, significantly lower drug exposure and risk of nephrotoxicity. Return of lung function reflected by changes in FEV1 was also similar.

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