Amikacin in Critically Ill Patients: A Review of Population Pharmacokinetic Studies

Marsot, Amélie; Guilhaumou, Romain; Riff, Camille; Blin, Olivier

doi:10.1007/s40262-016-0428-x

Cited by 59 publications

(49 citation statements)

References 46 publications

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“…Amikacin has been used for many years to treat severe infections in critically ill patients . We reviewed one case‐control study that compared an ECMO group with matched critically ill patients not on ECMO (Table ).…”

Section: Resultsmentioning

confidence: 99%

Pharmacokinetic changes of antibiotic, antiviral, antituberculosis and antifungal agents during extracorporeal membrane oxygenation in critically ill adult patients

2017

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SummaryWhat is known and objective: Extracorporeal membrane oxygenation (ECMO) is a life-saving system used for critically ill patients with cardiac and/or respiratory failure.The pharmacokinetics (PK) of drugs can change in patients undergoing ECMO, which can result in therapeutic failure or drug toxicity requiring further management of drug complications. In this review, we discussed changes in the PK of antibiotic, antiviral, antituberculosis and antifungal agents administered to adult patients on ECMO. These drugs are crucial for managing infections, which commonly occur during ECMO. Methods:A literature search was conducted using the PubMed and EMBASE databases with the following keywords: "extracorporeal membrane oxygenation OR extracorporeal membrane oxygenations OR ECMO" and "PK OR pharmacokinetics OR pharmacokinetic*" and "anti infective* OR antibiotic* OR antiviral* OR antituberculosis OR antifungal*."Results and discussion: Generally, the volume of distribution (Vd) increases and drug clearance (CL) and elimination decrease during ECMO. Highly significant changes in drug PK can occur by interactions with the ECMO device itself, drug characteristics, pathological changes and patient characteristics. This may affect the blood concentrations of drugs, which influence the success of therapy. The PK of vancomycin, piperacillin-tazobactam, meropenem, azithromycin, amikacin and caspofungin did not change significantly in adult patients receiving ECMO. However, there were significant changes in the PK of imipenem, oseltamivir, rifampicin and voriconazole. The trough concentrations of imipenem were highly variable; oseltamivir had a decreased CL and increased Vd, and rifampicin concentrations were below therapeutic levels, even when a higher-than-standard dose was used in patients treated with ECMO.Additionally, voriconazole exhibited high mean peak concentrations during ECMO. What is new and conclusion:The impact of ECMO on PK varies among drugs in adult patients, and there is no consistent correlation between the effects observed in adult and infant studies. This review suggested that doses of imipenem, oseltamivir, rifampicin and voriconazole should be adjusted and therapeutic drug monitoring is needed when ECMO is used in adult patients. In the future, large PK trials in adults on ECMO are needed to provide optimal dosing guidelines. A PK/PD modelling approach will be useful for determining the precise impact of ECMO and other factors that *[Correction added on 23 October 2017, after first online publication: Author Contributors section has been added].

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Section: Resultsmentioning

confidence: 99%

Pharmacokinetic changes of antibiotic, antiviral, antituberculosis and antifungal agents during extracorporeal membrane oxygenation in critically ill adult patients

2017

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“…As a result, septic patients have greater Vd values of hydrophilic drugs [10,11]. This altered Vd has been well-documented for amikacin and is associated with albumin plasma concentration, extracellular water body ratio, oxygen ratio, sepsis, cholecystitis, cirrhosis, as well as total body weight [34,35].…”

Section: Discussionmentioning

confidence: 99%

Determinants of amikacin first peak concentration in critically ill patients

Boidin

Jenck

Bourguignon

et al. 2018

Fundamemntal Clinical Pharma

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Amikacin antimicrobial effect has been correlated with the ratio of the peak concentration (C ) to the minimum inhibitory concentration. A target C ≥ 60-80 mg/L has been suggested. It has been shown that such target is not achieved in a large proportion of critically ill patients in intensive care units. A retrospective analysis was performed to examine the determinants of C ≥ 80 mg/L on the first peak in 339 critically ill patients treated by amikacin. The influence of available variables on C target attainment was analyzed using a classification and regression tree (CART) and logistic regression. Mean C in the 339 patients was 73.0 ± 23.9 mg/L, with a target attainment rate (TAR, C ≥ 80 mg/L) of 37.5%. In CART analysis, the strongest predictor of amikacin target peak attainment was dose per kilogram of lean body weight (dose/LBW). TAR was 60.1% in patients with dose/LBW ≥ 37.8 vs. 19.9% in patients with lower dose/LBW (OR = 6.0 (95% CI: 3.6-10.2)). Renal function was a secondary predictor of C . Logistic regression analysis identified dose per kilogram of ideal body weight (OR = 1.13 (95% CI: 1.09-1.17)) and creatinine clearance (OR = 0.993 (95% CI: 0.988-0.998)) as predictors of target peak achievement. Based on our results, an amikacin dose ≥ 37.8 mg/kg of LBW should be used to optimize the attainment of C ≥ 80 mg/L after the first dose in critically ill patients. An even higher dose may be necessary in patients with normal renal function.

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“…TDM of amikacin aims to minimize risks of toxicity and maximize therapeutic efficacy . Since only a limited number of blood concentrations can be ethically obtained from hospitalized pediatric patients, the PopPK approach using nonlinear mixed‐effect modeling to obtain PK parameters is an ideal tool for PK analysis in this population …”

Section: Discussionmentioning

confidence: 99%

“…According to previous pharmacological studies and our own data, a one‐compartment PK model with first‐order elimination adequately described amikacin PK . Use of more complex models (eg two‐compartment models) did not improve the data fit and was therefore not further pursued.…”

Section: Methodsmentioning

confidence: 98%

Population pharmacokinetics of amikacin in patients with pediatric cystic fibrosis

Guido

Pérez

Halac

et al. 2019

Pediatric Pulmonology

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Introduction Amikacin is commonly used in patients with pediatric cystic fibrosis (CF) for the treatment of pulmonary exacerbations. Amikacin efficacy is related to maximum plasma concentration/minimum inhibitory concentration (Cmax/MIC) ratio >8. Pharmacokinetic data in patients with pediatric CF are scarce. The aim of this study was to develop a population pharmacokinetic (PopPK) model describing amikacin disposition in patients with pediatric CF. Methods CF patients under 18 years of age with pulmonary exacerbation who received amikacin were enrolled. Patients received different amikacin regimens (30 mg−1 kg−1 day−1 every 8, 12, or 24 hours) depending on the patient's status and hospital protocols. Amikacin serum levels were obtained for therapeutic drug monitoring. PopPK model was developed using MONOLIX Suite‐2018R1 (Lixoft). Results A total of 39 patients (114 amikacin concentrations) were included in this study. Population estimates for the elimination rate constant (k) and the volume of distribution (V) were 0.541 hours−1 and 0.451 L/kg, respectively. Between‐subject and between‐occasion variability were 53% and 16.5% for k and 31% and 22% for V, respectively. Bodyweight was a significant covariate associated with V. Based on simulations, almost 70% of the patients receiving 30 mg−1 kg−1 day−1 every 24 hours would achieve a Cmax/MIC ratio >8 which is an appropriate therapeutic goal while no patient in the other two groups (Q8 and Q12) would achieve that objective. Conclusions The regimen of 30 mg−1 kg−1 day−1 every 24 hours more adequately fulfilled the therapeutic target for amikacin. Although all our patients had good clinical results and a good adverse‐events profile, further studies are necessary to redefine the optimal treatment strategy.

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Amikacin in Critically Ill Patients: A Review of Population Pharmacokinetic Studies

Cited by 59 publications

References 46 publications

Pharmacokinetic changes of antibiotic, antiviral, antituberculosis and antifungal agents during extracorporeal membrane oxygenation in critically ill adult patients

Pharmacokinetic changes of antibiotic, antiviral, antituberculosis and antifungal agents during extracorporeal membrane oxygenation in critically ill adult patients

Determinants of amikacin first peak concentration in critically ill patients

Population pharmacokinetics of amikacin in patients with pediatric cystic fibrosis

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