Evaluation of Amikacin Pharmacokinetics and Pharmacodynamics for Optimal Initial Dosing Regimen

Abstract

Amikacin has been one of the important antimicrobial agents against Gram-negative pathogens. However, there is discrepancy regarding the amikacin initial dosage, with some reports recently recommending ≥25 mg/kg and others the conventional dosage (15–20 mg/kg). Hence, we evaluated the optimal initial dosing regimen of amikacin. Pharmacokinetic (PK) parameters were estimated using a population PK analysis. The pharmacodynamic (PD) target was a ratio of ≥8 between the concentration achieved 1 h after beginning the infusion (C peak) and the minimal inhibitory concentration (MIC) of the liable bacteria. Based on the population PK parameters, we simulated individual C peak for several dosing regimens by Monte Carlo method and analyzed the C peak/MIC ratio for MICs from 0.5 to 32 μg/mL. This study included 35 infected patients (25 males), with a median (range) age and body weight of 70 (15–95) years and 49.5 (32.5–78) kg, respectively. A two-compartment model was used, and total body clearance (CL) significantly correlated with creatinine clearance, and volume of distribution (V d) with body weight. Regarding the probability to achieve a C peak/MIC of ≥8, the 15 mg/kg regimen was sufficient to achieve the PK/PD target in ≥90% of patients for a MIC of 4 μg/mL or less. The cumulative fraction of response in Pseudomonas aeruginosa was that 76% of patients achieved a C peak/MIC of 8 with the amikacin dosage of 15 mg/kg/day. We suggest that the 15-mg/kg once-daily dosage of amikacin be recommended as the initial dosage. As its maintenance dosage, the 15 mg/kg/day amikacin dosage is needed for a MIC of ≤4 μg/mL, and amikacin monotherapy for a MIC of ≥8 μg/mL should be avoided.

Differential Activity of the Combination of Vancomycin and Amikacin on Planktonic vs. Biofilm-Growing Staphylococcus aureus Bacteria in a Hollow Fiber Infection Model

“…The first antibiotic exposure tested in the HF model simulated the plasma concentrations of patients receiving 15 mg/kg amikacin once a day ( Kato et al, 2017 ) and/or 1 g vancomycin every 12 h ( Nicasio et al, 2012 ). Since the free plasma drug concentration is known to be one of the best surrogates of the concentration at the site of infection ( Liu et al, 2002 ), we exposed the bacteria in the HF model to concentrations similar to the free plasma concentrations obtained in patients after administration of the above dosing regimens.…”

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

“…As with other drugs used in the treatment of CRE infections, the adequacy of the generally recommended dosage for aminoglycosides (5 to 7 mg/kg/day for gentamicin and tobramycin; 15 to 20 mg/kg/day for amikacin) has also been questioned. 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).…”

Effect of Kidney Function on Amikacin Pharmacokinetics on Hospitalized Patients: Knowledge to Improve Therapy

“…As a consequence of glomerular hyper filtration, augmented renal clearance refers to enhanced excretion of hydrophilic compounds (circulating metabolites, toxins, waste products, and drugs including amikacin) in comparison to renal baseline function. There is a variety of clinical conditions leading to augmented renal clearance including sepsis, trauma, particularly burn injury, pancreatitis, autoimmune disorders, ischemia, and major surgery [11,13]. Often these conditions also lead to increased apparent volume of distribution, providing an additional Factor potentially contributing to insufficient antimicrobial concentrations.…”

“…At the hospital level, the amino glycoside amikacin has been one of the most frequently prescribed antimicrobial agents against Gram-negative and multidrug resistant pathogens such as Pseudomonas aeruginosa [10,11]. Although widespread used, amikacin exhibits a narrow therapeutic plasma index, potential nephro-and ototoxic side effects and wide intra-and inter-individual variability.…”

“…The ratio of its peak plasma concentration (Cmax) to the known minimum inhibitory concentration (MIC) of the pathogen (which can be given by local antibiogram data) is the PK/PD index that best link to the drug antibacterial activity and clinical efficacy. Currently, a ratio Cmax/MIC between 8 and 12 has been demonstrated to be necessary to achieve the clinical response [11,13]. On the other hand, due to its toxicity, amikacin should not exhibit excessive predose (trough) concentrations and, therefore, its plasma concentrations should be also monitored before the following administration (Cmin), allowing dose decrease when unnecessarily high exposures have been measured [12].…”