Assessment of the National French recommendations regarding the dosing regimen of 8mg/kg of gentamicin in patients hospitalised in intensive care units

Allou, Nicolas; Allyn, Jérôme; Levy, Yaël; Bouteau, Astrid; Caujolle, Marie; Delmas, Benjamin; Valance, Dorothée; Brulliard, Caroline; Martinet, Olivier; Vandroux, David; Montravers, Philippe; Augustin, Pascal

doi:10.1016/j.accpm.2015.12.012

Cited by 14 publications

(10 citation statements)

References 17 publications

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“…In conclusion, a gentamicin Cmax of 15 mg L −1 could be considered acceptable in the context of probabilistic antibiotic therapy in community-acquired sepsis when the involvement of P. aeruginosa is supposed to be infrequent. Similar results have been described in previous studies ( 9 ).…”

Section: Discussionsupporting

confidence: 93%

“…Since 2014, several studies have shown that Cmax ≥30 mg L −1 was reached, at first injection, in only 10% of cases, despite the administration of a mean dose of 7 mg kg −1 of actual weight ( 7 – 11 ). Some teams investigated the clinico-biological risk factors for gentamicin underdosing ( 9 , 10 ), which could allow for the development of a corrective formula to improve the use of gentamicin in the context of sepsis/septic shock.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Use of Gentamicin for Sepsis and Septic Shock in Anaesthesia-Intensive Care Unit: A Clinical Practice Evaluation

Pernod

Lamblin

Cividjian

et al. 2020

Turk J Anaesthesiol Reanim

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Use of Gentamicin for Sepsis and Septic Shock in Anaesthesia-Intensive Care Unit: A Clinical Practice Evaluation

Pernod

Lamblin

Cividjian

et al. 2020

Turk J Anaesthesiol Reanim

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“…In the first set of SCTK, we studied three carbapenems (imipenem [ The final set of SCTK was conducted using meropenem (1 mg/liter) with tobramycin (0.25 to 16 mg/liter), amikacin (0.5 to 8 mg/liter), or streptomycin (2 to 64 mg/liter) in monotherapy and combinations. The antibiotic concentrations studied included the range of clinically achievable unbound concentrations of carbapenems and aminoglycosides following standard dosing in patients, i.e., the maximum achievable concentrations, average steady-state concentrations, and trough concentrations (40,(44)(45)(46)(47)(48)(49)(50). We also examined relatively low concentrations of aminoglycosides, which did not have a bacterial killing effect in monotherapy, to quantify their potential beneficial and synergistic effects in combination with a carbapenem, the latter due to the effect of the aminoglycosides on the bacterial outer membrane.…”

Section: Methodsmentioning

confidence: 99%

Aminoglycoside Concentrations Required for Synergy with Carbapenems against Pseudomonas aeruginosa Determined via Mechanistic Studies and Modeling

Yadav

Bulitta

Schneider‐Futschik

et al. 2017

Antimicrob Agents Chemother

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This study aimed to systematically identify the aminoglycoside concentrations required for synergy with a carbapenem and characterize the permeabilizing effect of aminoglycosides on the outer membrane of Monotherapies and combinations of four aminoglycosides and three carbapenems were studied for activity against strain AH298-GFP in 48-h static-concentration time-kill studies (SCTK) (inoculum: 10 CFU/ml). The outer membrane-permeabilizing effect of tobramycin alone and in combination with imipenem was characterized via electron microscopy, confocal imaging, and the nitrocefin assay. A mechanism-based model (MBM) was developed to simultaneously describe the time course of bacterial killing and prevention of regrowth by imipenem combined with each of the four aminoglycosides. Notably, 0.25 mg/liter of tobramycin, which was inactive in monotherapy, achieved synergy (i.e., ≥2-log more killing than the most active monotherapy at 24 h) combined with imipenem. Electron micrographs, confocal image analyses, and the nitrocefin uptake data showed distinct outer membrane damage by tobramycin, which was more extensive for the combination with imipenem. The MBM indicated that aminoglycosides enhanced the imipenem target site concentration up to 4.27-fold. Tobramycin was the most potent aminoglycoside to permeabilize the outer membrane; tobramycin (0.216 mg/liter), gentamicin (0.739 mg/liter), amikacin (1.70 mg/liter), or streptomycin (5.19 mg/liter) was required for half-maximal permeabilization. In summary, our SCTK, mechanistic studies and MBM indicated that tobramycin was highly synergistic and displayed the maximum outer membrane disruption potential among the tested aminoglycosides. These findings support the optimization of highly promising antibiotic combination dosage regimens for critically ill patients.

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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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Assessment of the National French recommendations regarding the dosing regimen of 8mg/kg of gentamicin in patients hospitalised in intensive care units

Cited by 14 publications

References 17 publications

Use of Gentamicin for Sepsis and Septic Shock in Anaesthesia-Intensive Care Unit: A Clinical Practice Evaluation

Use of Gentamicin for Sepsis and Septic Shock in Anaesthesia-Intensive Care Unit: A Clinical Practice Evaluation

Aminoglycoside Concentrations Required for Synergy with Carbapenems against Pseudomonas aeruginosa Determined via Mechanistic Studies and Modeling

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

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