Tobramycin disposition in ICU patients receiving a once daily regimen: population approach and dosage simulations

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT? • It is well known that tobramycin given as an once daily dose according to the usual recommendations needs therapeutic drug monitoring by measurement of peak and trough concentrations. In the literature, there are only few published studies on the population pharmacokinetics of once daily tobramycin in critically ill patients. Glomerular filtration rate and bodyweight were identified as covariates contributing to the inter‐individual variability in the disposition of aminoglycosides. The study, by Peris‐Marti et al. [24], only evaluated the pharmacodynamic effectiveness of a 4 mg kg−1 dose of tobramycin given once daily in critically ill patients. The authors concluded with a simulation showing that for a theoretical MIC of 1 or 2 mg l−1, a 7 mg kg−1 dose was required. WHAT THIS STUDY ADDS? • Our results confirm the high variability of tobramycin disposition in intensive care patients and consequently the possible lack of effectiveness. • By using a population pharmacokinetic approach, two explicative covariates (height and Cockcroft creatinine clearance) added to a two‐compartment model with proportional error, explained much of the inter‐individual variability of tobramycin disposition in the critically ill patient population. • In a median ICU patient, simulations were performed at various dosage regimens and peak and AUC pharmacodynamic targets could not be reached simultaneously in more than 45% of the ICU patient population. Drug monitoring is required to manage efficacy and toxicity. AIM The aim of this study was to evaluate the disposition of tobramycin (TOB) in critically ill patients (ICU) by a population pharmacokinetic approach, to determine the covariates involved, and to simulate tobramycin dosage regimens. METHODS Forty‐nine adult ICU patients received TOB (5 mg kg−1) once daily. NonMem modelling was performed on 32 patients. The 17 other patients were used for the qualification process by normalized prediction distribution error. Then Monte Carlo simulations (MCS) were performed. RESULTS A two‐compartment model with a proportional error best fitted the data. TOB total clearance (CLTOB) was significantly correlated with Cockcroft creatinine clearance (COCK) and height. TOB clearance was 4.8 ± 1.9 l h−1 (range 1.22–8.95), the volume of distribution of the central compartment was 24.7 ± 3.7 l (range 17.34–32.83) and that of the peripheral compartment and the inter‐compartmental clearance were 30.6 l and 4.74 l h−1, respectively. Only 29% of the patients presented a target AUC between 80 and 125 mg l–1 h and 61% were lower than 80 mg l−1 h. After considering COCK and height, MCS showed that only 50% of the population could achieve the target AUC for the 375 and 400 mg dosages. CONCLUSION Even after taking into account COCK and height, for strains with an MIC ≤ 1 mg l−1, MCS doses evidenced that peak and AUC pharmacodynamic targets could not be reached simultaneously in more than 45% of the ICU patient population. Combination therapy in addition to drug mo...

Resistance suppression by high-intensity, short-duration aminoglycoside exposure against hypermutable and non-hypermutablePseudomonas aeruginosa

“…four times the suggested fAUC/MIC breakpoint of 42 for bactericidal effect, 24 did not inhibit the regrowth of bacteria at the initial inoculum of 10 6 cfu/mL. An fAUC/MIC of 168 would be expected to be achieved in patients for MICs up to 0.5 mg/L following a tobramycin dose of 5 -6 mg/kg in critically and non-critically ill patients 32,46 and 8 -11 mg/kg in patients with CF (both based on a 70 kg patient). 47,48 However, according to EUCAST, 46% of the 25 002 evaluated isolates had an MIC ≥1 mg/L.…”

“…24 For MICs ≤1 mg/L (83% of P. aeruginosa isolates reported by EUCAST), 31 the two lower exposures are achievable at common clinical doses, whereas fAUC/MIC of 168 requires a high clinical dose in ICU patients. 32 The tobramycin agar dilution MIC using the CLSI method 33 was 0.5 mg/L for PAO1 and ATCC 27853; while for PAODmutS it was 1 mg/L due to the resistant bacterial subpopulations. 34 Overall exposures were achieved by exposing the bacteria to appropriate tobramycin concentrations for the durations of 1, 4, 10 and 24 h, as reported in Table 1.…”

Novel Approach To Optimize Synergistic Carbapenem-Aminoglycoside Combinations against Carbapenem-Resistant Acinetobacter baumannii

“…For our Monte Carlo simulations, we combined the mechanism-based combination PD model with published population pharmacokinetic (PK) models of tobramycin and imipenem in critically ill patients (26,27). These Monte Carlo simulations accounted for between-patient variability in the PK of each antibiotic and the between-curve variability of the population PD model parameters.…”

“…The antibiotic concentrations studied included the highest clinically achievable average unbound plasma concentrations at steady state. A tobramycin concentration of 4 mg/liter and isepamicin concentrations of 8 to 16 mg/liter represent the average unbound plasma concentrations in humans over a 24-h dosing interval for tobramycin at 7 mg/kg of body weight and 15 or 25 mg/kg isepamicin given once daily (17,26). Additional experimental arms with 12 mg/ liter tobramycin and 64 mg/liter isepamicin represent the average free plasma concentration of aminoglycosides during the first 6 h. For the highest clinically approved imipenem doses of 4 g per day, our Monte Carlo simulations predicted the unbound average steady-state concentrations to range from 7.61 to 22.6 mg/liter in adult critically ill patients (27).…”

More DNA–Aptamers for Small Drugs: A Capture–SELEX Coupled with Surface Plasmon Resonance and High-Throughput Sequencing

“…The chosen target for the proof-of-concept SELEX is the aminoglycoside tobramycin (molecular weight: 467 Da), for which some RNA aptamers are available for comparison. 15,18 Moreover, tobramycin concentration in patients' blood needs to be routinely controlled due to high patient variability in tobramycin pharmacokinetics, 19 therefore prompting the development of a monitoring device addressed to this application.…”