Optimizing the Initial Amikacin Dosage in Adults

Abstract

bWe report on the pharmacokinetics (PK) and pharmacodynamics (PD) of high-dose (>15 mg/kg of body weight per day) amikacin. A mean (standard deviation [SD]) maximum drug concentration in the serum (C max ) and 24-h area under the concentration-time curve (AUC 24 ) of 101 (49.4) mg/liter and 600 (387) mg · h/liter, respectively, were observed (n ‫؍‬ 73) with 28.0 (8.47) mg/kg/day doses. An initial amikacin dose of 2,500 mg in adults weighing 40 kg to 200 kg with therapeutic drug monitoring to adjust the maintenance dose will optimize its PK and PD.A mikacin is an important component of an initial empirical antimicrobial treatment strategy against major Gram-negative pathogens associated with serious infections. The regulatory approved dose of this aminoglycoside is 15 mg/kg of body weight per day as 2 to 3 divided doses (1). Aminoglycoside dosing has shifted from divided daily dosing to single daily dosing in order to optimize its concentration-dependent pharmacokinetic-pharmacodynamic (PK-PD) profile (2, 3). This dosing paradigm seeks to achieve a maximum concentration of drug in the serum (C max )/ MIC of 8 to 10 and an area under the concentration-time curve (AUC)/MIC of 75 (3-5). As a consequence, currently accepted standard doses of aminoglycosides, such as tobramycin, are now administered 5 to 10 mg/kg once daily in patients with normal kidney function, that is roughly 2-fold higher than the regulatory approved dose of 3 to 5 mg/kg/day in divided doses (5).The typical 4-fold higher MIC 90 (4 to 8 mg/liter) of amikacin against Pseudomonas aeruginosa compared to tobramycin (1 to 2 mg/liter) coupled with the dose proportionality of aminoglycosides led our institution to adopt an initial empirical amikacin dose of 24 mg/kg in noncritically ill patients and 30 to 40 mg/kg in critically ill patients. Two amikacin concentrations are measured, at 1 to 2 h and at 8 to 10 h after the end of infusion of this first dose, to permit dose individualization (6). Recent clinical studies corroborate this approach by suggesting that an initial amikacin dose Ն25 mg/kg is likely needed as empirical therapy of certain Gramnegative infections (7-10). Herein, we report on the amikacin exposure profile observed in our patients with this higher-thanregulatory-approved amikacin treatment strategy (1). We also provide a clear rationale for the consideration of an alternate empirical fixed amikacin dosing strategy in line with the current clinical adult total body weight (TBW) distribution.After institution review board approval, patients Ն21 years of age who received at least one dose of amikacin from 1 January 2012 to 30 June 2014, who had two serial amikacin measurable concentrations, and who had an estimated creatinine clearance (CL CR ) Ͼ30 ml/min based on the Cockcroft-Gault equation were included (11). Information pertaining to patient demographics, laboratory values, amikacin dose, administration and infusion times, amikacin concentration, and sample collection times were collected. Amikacin concentrations were measured by an a...

Amikacin Pharmacokinetic-Pharmacodynamic Analysis in Pediatric Cancer Patients

“…Based on the PTA simulation, a minimum amikacin dose of 60 mg/kg administered once daily is expected to achieve the efficacy target of an fC max /MIC of Ն8 in 80% of pediatric patients weighing 8 to 70 kg, with a 97.5% probability and a safety target of Ͻ10 mg/liter in almost all patients. This dosing recommendation is consistent with other studies that suggest higher single daily doses of amikacin of Ն40 mg/kg in different patient populations, including pediatric cancer patients (7,19,(27)(28)(29). In 1998, the amikacin dose of 20 mg/kg administered once a day was recommended for immunocompromised pediatric patients, including those with cancer (10).…”

“…Likewise, amikacin, an aminoglycoside antibiotic used either alone or in combination with ␤-lactams to treat serious Gram-negative infections, was first approved at 15 mg/kg of body weight in 1 to 3 divided doses a day (5)(6)(7). Over time, as amikacin PK-PD became better understood, dosing changed to larger once-daily doses in order to maximize efficacy and limit toxicity (7)(8)(9)(10). Amikacin is an antibiotic that exhibits a concentration-dependent bactericidal activity, and better clinical outcomes were associated with a high free, unbound plasma concentration-to-MIC ratio (fC max /MIC).…”

Treatment of Infections Caused by Extended-Spectrum-Beta-Lactamase-, AmpC-, and Carbapenemase-Producing Enterobacteriaceae

“…A study of patients with severe sepsis or septic shock who were treated with amikacin at 25 mg/kg/day showed that only 70% reached peak concentrations of Ͼ64 mg/liter, which would be Ն8 times the susceptibility breakpoint against Enterobacteriaceae according to EUCAST (8 mg/liter) (316); the same dose, however, should be enough for isolates with a MIC of 4 mg/liter to reach the same target (317). An initial dose of 2,500 mg followed by therapeutic drug monitoring has been suggested for patients with body weights of Ͼ40 kg (318,319). Importantly, the peak concentration/MIC ratio has been challenged as the only pharmacokinetic-pharmacodynamic target to be considered for aminoglycosides (320).…”

High-dose amikacin for achieving serum target levels in critically ill elderly patients

“…In the study of Gálvez et al, 6 only 39% of patients with 25 mg/kg and 76% with 30 mg/kg of amikacin reached peak amikacin levels >60 µg/mL. White et al 20 in a retrospective investigation reported that with a higher than approved dose for amikacin (ie, >15 mg/kg/d), only 63.0% and 36.9% of patients in their institution reached the target Cmax/MIC of ≥10 and AUC 24 /MIC of ≥75 respectively, but only 45.3% of their patients were critically ill. 20 Our study revealed that with standard doses of amikacin (ie, 15 mg/kg/d), no patient reached target peak levels. Even in the high-dose group, in less than half of the patients did the amikacin peak concentrations reach the target level (>64 µg/mL).…”