PK/PD targets of amikacin and gentamicin in ICU patients

Coste, Anne; Deslandes, Guillaume; Jalin, Laurence; Corvec, Stéphane; Caillon, Jocelyne; Boutoille, David; Grégoire, Matthieu; Bretonnière, Cédric

doi:10.1016/j.medmal.2019.12.003

Cited by 8 publications

(20 citation statements)

References 28 publications

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“…Four papers used a correction factor of 0.4 [15,16,19,24] whilst Roger et al used 0.43 however the primary source for this correction factor was not cited [17]. Divergence between the papers was observed for the methodology of calculation of IBW, which limits the ability to compare the results (see Supplementary Information – Additional Data)…”

Section: Resultsmentioning

confidence: 99%

“…Of the eight studies reporting target serum amikacin concentrations, seven listed peak [15-17,19,20,21,23,24] and four listed trough [15,17,19,20] concentrations following amikacin dosing (Table 1). Target peak concentrations (C max ) were broadly similar at >60 mg/ L [16,17,21,23], >64 mg/ L [19,20,24] and 60-80 mg/ L [15]. From the six studies reporting peak concentrations, between 56.7 and 81.8% of participants achieved target C max following the first amikacin dose.…”

Section: Resultsmentioning

confidence: 99%

“…Three papers had no exclusions for renal impairment [15,16,21], two papers excluded patients with creatinine clearance (CrCl) <60 mL/min [22,23], and one study excluded patients with CrCl <40 mL/min [24]. Another paper excluded participants requiring renal replacement therapy on critical care [17], while two further papers excluded those with chronic renal failure requiring dialysis [19,20].…”

Section: Resultsmentioning

confidence: 99%

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Systematic review of high-dose amikacin regimens for the treatment of Gram-negative infections based on EUCAST dosing recommendations

Frost

Hamilton

Hughes

et al. 2022

Preprint

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Background Amikacin is an aminoglycoside with activity against Gram negative pathogens. Updated EUCAST amikacin breakpoints for Enterobacterales and Pseudomonas aeruginosa included revised dosing recommendations of 25-30mg/kg to achieve key pharmacokinetic/pharmacodynamic parameters, higher than recommended in the British National Formulary. We undertook a literature review to report preferred dosing regimens, monitoring and toxicities associated with the use of amikacin at doses ≥20mg/kg/day. Methods This literature search was conducted in electronic databases for any study reporting adult participants treated with amikacin at doses ≥20mg/kg/day. Data were extracted for pharmacokinetic parameters and clinical outcomes, while papers were assessed for bias using the ROBINS-I tool. Results Nine papers were identified and included, eight of which were observational studies; assessment of bias showed substantial flaws. Dosing regimens ranged from 25-30mg/kg/day. Six studies adjusted the dose in obesity when participants BMI ≥30 kg/m2. Target peak serum concentrations ranged from 60mg/L-80mg/L and 59.6-81.8% of patients achieved these targets. Two studies reported the impact of high dose amikacin on renal function. No studies reporting auditory or vestibular toxicity were identified. Conclusions Dosing amikacin at 25-30mg/kg achieved peak concentration targets in the majority of patients, but there was no information on clinical outcomes. There is little information about the impact on renal function or ototoxicity; caution with use of high dose regimens in older patients for prolonged periods is recommended. Given the paucity of information, there is a need for a consensus guideline for high dose amikacin or a prospective study.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Systematic review of high-dose amikacin regimens for the treatment of Gram-negative infections based on EUCAST dosing recommendations

Frost

Hamilton

Hughes

et al. 2022

Preprint

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“…The daily dosing regimens of gentamicin as reported in PPK studies in critically ill patients have ranged from 3 mg/kg to 8 mg/kg [57,[76][77][78]. The PK/PD target used varied between these studies; most have used a C max /MIC ≥8-10 as target [57], resulting in a C max target of ≥16-20 mg/L when targeting micro-organisms with a maximum MIC of 2 mg/L [24].…”

Section: Dosing and Pk/pd Targetsmentioning

confidence: 99%

“…The PK/PD target used varied between these studies; most have used a C max /MIC ≥8-10 as target [57], resulting in a C max target of ≥16-20 mg/L when targeting micro-organisms with a maximum MIC of 2 mg/L [24]. Studies dosing 8 mg/kg used a C max target of 30-40 mg/L, to also target microorganisms with an MIC of 4 mg/L [76][77][78]. Several recent studies have shown unsatisfactory C max target attainment in critically ill patients: 47% reached a target C max of ≥15 mg/L with 4 mg/kg [66], 59% reached a target C max of ≥16 mg/L with a median dose of 6.2 mg/kg [79] and only 0-6% achieved a target C max >30 mg/L when using 8 mg/ kg [76][77][78].…”

Section: Dosing and Pk/pd Targetsmentioning

confidence: 99%

Clinical Pharmacokinetics of Gentamicin in Various Patient Populations and Consequences for Optimal Dosing for Gram-Negative Infections: An Updated Review

et al. 2022

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Gentamicin is an aminoglycoside antibiotic with a small therapeutic window that is currently used primarily as part of shortterm empirical combination therapy. Gentamicin dosing schemes still need refinement, especially for subpopulations where pharmacokinetics can differ from pharmacokinetics in the general adult population: obese patients, critically ill patients, paediatric patients, neonates, elderly patients and patients on dialysis. This review summarizes the clinical pharmacokinetics of gentamicin in these patient populations and the consequences for optimal dosing of gentamicin for infections caused by Gram-negative bacteria, highlighting new insights from the last 10 years. In this period, several new population pharmacokinetic studies have focused on these subpopulations, providing insights into the typical values of the most relevant pharmacokinetic parameters, the variability of these parameters and possible explanations for this variability, although unexplained variability often remains high. Both dosing schemes and pharmacokinetic/pharmacodynamic (PK/PD) targets varied widely between these studies. A gentamicin starting dose of 7 mg/kg based on total body weight (or on adjusted body weight in obese patients) appears to be the optimal strategy for increasing the probability of target attainment (PTA) after the first administration for the most commonly used PK/PD targets in adults and children older than 1 month, including critically ill patients. However, evidence that increasing the PTA results in higher efficacy is lacking; no studies were identified that show a correlation between estimated or predicted PK/PD target attainment and clinical success. Although it is unclear if performing therapeutic drug monitoring (TDM) for optimization of the PTA is of clinical value, it is recommended in patients with highly variable pharmacokinetics, including patients from all subpopulations that are critically ill (such as elderly, children and neonates) and patients on intermittent haemodialysis. In addition, TDM for optimization of the dosing interval, targeting a trough concentration of at least < 2 mg/L but preferably < 0.5-1 mg/L, has proven to reduce nephrotoxicity and is therefore recommended in all patients receiving more than one dose of gentamicin. The usefulness of the daily area under the plasma concentration-time curve for predicting nephrotoxicity should be further investigated. Additionally, more research is needed on the optimal PK/PD targets for efficacy in the clinical situations in which gentamicin is currently used, that is, as monotherapy for urinary tract infections or as part of short-term combination therapy.

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Protective effect of empagliflozin on gentamicin-induced acute renal injury via regulation of SIRT1/NF-κB signaling pathway

Botros

Matouk

Mohamed

et al. 2022

Environmental Toxicology and Pharmacology

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PK/PD targets of amikacin and gentamicin in ICU patients

Cited by 8 publications

References 28 publications

Systematic review of high-dose amikacin regimens for the treatment of Gram-negative infections based on EUCAST dosing recommendations

Systematic review of high-dose amikacin regimens for the treatment of Gram-negative infections based on EUCAST dosing recommendations

Clinical Pharmacokinetics of Gentamicin in Various Patient Populations and Consequences for Optimal Dosing for Gram-Negative Infections: An Updated Review

Protective effect of empagliflozin on gentamicin-induced acute renal injury via regulation of SIRT1/NF-κB signaling pathway

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