High target attainment for β-lactam antibiotics in intensive care unit patients when actual minimum inhibitory concentrations are applied

Woksepp, Hanna; Hällgren, Anita; Borgström, S; Kullberg, F.; Wimmerstedt, A.; Oscarsson, Anna; Nordlund, P.; Lindholm, M-L; Bonnedahl, Jonas; Brudin, Lars; Carlsson, Björn; Schӧn, Thomas

doi:10.1007/s10096-016-2832-4

Cited by 23 publications

(30 citation statements)

References 25 publications

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“…Treatment should therefore target the most likely and the most virulent pathogens involved in neonatal infections, and MIC targets are based upon standard MIC breakpoints from antimicrobial susceptibility testing databases (32,33). With this approach, it is possible that the MIC breakpoint used is higher than the observed gentamicin MIC in individual patient isolates (34). In the present study, MICs up to 1 mg/liter are addressed.…”

Section: Discussionmentioning

confidence: 98%

Quantitative Analysis of Gentamicin Exposure in Neonates and Infants Calls into Question Its Current Dosing Recommendations

Donge

Pfister

Bielicki

et al. 2018

Antimicrob Agents Chemother

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Optimal dosing of gentamicin in neonates is still a matter of debate despite its common use. We identified gentamicin dosing regimens from eight international guidelines and seven Swiss neonatal intensive care units. The dose per administration, the dosing interval, the total daily dose, and the demographic characteristics between guidelines were compared. There was considerable variability with respect to dose (4 to 6 mg/kg), dosing interval (24 h to 48 h), total daily dose (2.5 to 6 mg/kg/day), and patient demographic characteristics that were used to calculate individualized dosing regimens. A model-based simulation study in 1071 neonates was performed to determine the achievement of efficacious peak gentamicin concentrations according to predefined MICs (/MIC ≥ 10) and safe trough concentrations ( ≤ 2 mg/liter) with recommended dosing regimens. MIC targets of 0.5 and 1 mg/liter were used. Dosing optimization was performed giving priority to the first day of treatment and with the goal of simplifying dosing. Current gentamicin neonatal guidelines allow to achieve effective peak concentrations for MICs ≤ 0.5 mg/liter but not higher. Model-based simulations indicate that to attain peak gentamicin concentrations of ≥10 mg/liter, a dose of 7.5 mg/kg should be administered using an extended dosing interval regimen. Trough concentrations of ≤2 mg/liter can be maintained with a dosing interval of 36 to 48 h in neonates according to gestational and postnatal age. For treatment beyond 3 days, therapeutic drug monitoring is advised to maintain adequate serum concentrations.

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Section: Discussionmentioning

confidence: 98%

Quantitative Analysis of Gentamicin Exposure in Neonates and Infants Calls into Question Its Current Dosing Recommendations

Donge

Pfister

Bielicki

et al. 2018

Antimicrob Agents Chemother

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“…In summary, the in vitro MIC assay is insufficiently accurate and reproducible to adequately represent conditions in vivo and therefore cannot be used as an exact concentration to strife for during treatment. Doing so possibly leads to an underestimation of the antibiotic effect in vivo [93,94] or missed treatment options [95]. Secondly, the MIC that is used in the desired PD targets is regarded as static value but should be seen more as a distribution of MICs within a bacterial strain [92].…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and Target Attainment of Antibiotics in Critically Ill Children: A Systematic Review of Current Literature

et al. 2019

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Background Pharmacokinetics (PK) are severely altered in critically ill patients due to changes in volume of distribution (Vd) and/or drug clearance (Cl). This affects the target attainment of antibiotics in critically ill children. We aimed to identify gaps in current knowledge and to compare published PK parameters and target attainment of antibiotics in critically ill children to healthy children and critically ill adults. Methods Systematic literature search in PubMed, EMBASE and Web of Science. Articles were labelled as relevant when they included information on PK of antibiotics in critically ill, non-neonatal, pediatric patients. Extracted PK-parameters included Vd, Cl, (trough) concentrations, AUC, probability of target attainment, and elimination half-life. Results 50 relevant articles were identified. Studies focusing on vancomycin were most prevalent (17/50). Other studies included data on penicillins, cephalosporins, carbapenems and aminoglycosides, but data on ceftriaxone, ceftazidime, penicillin and metronidazole could not be found. Critically ill children generally show a higher Cl and larger Vd than healthy children and critically ill adults. Reduced target-attainment was described in critically ill children for multiple antibiotics, including amoxicillin, piperacillin, cefotaxime, vancomycin, gentamicin, teicoplanin, amikacin and daptomycin. 38/50 articles included information on both Vd and Cl, but a dosing advice was given in only 22 articles. Conclusion The majority of studies focus on agents where TDM is applied, while other antibiotics lack data altogether. The larger Vd and higher Cl in critically ill children might warrant a higher dose or extended infusions of antibiotics in this patient population to increase target-attainment. Studies frequently fail to provide a dosing advice for this patient population, even if the necessary information is available. Our study shows gaps in current knowledge and encourages future researchers to provide dosing advice for special populations whenever possible.

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“…We defined ICU length of stay (LOS) and 30-day survival from the start of therapy (enrollment) as our secondary endpoints. Factors likely to contribute to these two outcomes were analyzed for association based on clinical relevancy and previously described relationships [ 14 , 24 – 27 ]. These included patient characteristics (age, gender, body mass index (BMI)), illness severity score (Sequential Organ Failure Assessment (SOFA) score at the start of target antibiotic), serum albumin, serum urea, sepsis, estimated glomerular filtration rate (eGFR ≥ 90 mL/min/1.73 m 2 ), and presence of continuous renal replacement therapy (CRRT).…”

Section: Methodsmentioning

confidence: 99%

“…To our knowledge, only a few other studies have attempted to quantify patient characteristics as potential predictors for beta-lactam antibiotics target attainment in critically ill patients [ 14 , 24 – 27 ]. In some of these studies, limited numbers of patients and/or different beta-lactam antibiotics were investigated, while in only two of these studies, target attainment and relevant factors associated with clinical outcomes were investigated [ 24 , 27 ]. However, the relationship between target attainment and the clinical outcomes ICU length of stay (LOS) and mortality has not yet been clarified.…”

Section: Introductionmentioning

confidence: 99%

Failure of target attainment of beta-lactam antibiotics in critically ill patients and associated risk factors: a two-center prospective study (EXPAT)

et al. 2020

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Background Early and appropriate antibiotic dosing is associated with improved clinical outcomes in critically ill patients, yet target attainment remains a challenge. Traditional antibiotic dosing is not suitable in critically ill patients, since these patients undergo physiological alterations that strongly affect antibiotic exposure. For beta-lactam antibiotics, the unbound plasma concentrations above at least one to four times the minimal inhibitory concentration (MIC) for 100% of the dosing interval (100%ƒT > 1–4×MIC) have been proposed as pharmacodynamic targets (PDTs) to maximize bacteriological and clinical responses. The objectives of this study are to describe the PDT attainment in critically ill patients and to identify risk factors for target non-attainment. Methods This prospective observational study was performed in two ICUs in the Netherlands. We enrolled adult patients treated with the following beta-lactam antibiotics: amoxicillin (with or without clavulanic acid), cefotaxime, ceftazidime, ceftriaxone, cefuroxime, and meropenem. Based on five samples within a dosing interval at day 2 of therapy, the time unbound concentrations above the epidemiological cut-off (ƒT > MICECOFF and ƒT > 4×MICECOFF) were determined. Secondary endpoints were estimated multivariate binomial and binary logistic regression models, for examining the association of PDT attainment with patient characteristics and clinical outcomes. Results A total of 147 patients were included, of whom 63.3% achieved PDT of 100%ƒT > MICECOFF and 36.7% achieved 100%ƒT > 4×MICECOFF. Regression analysis identified male gender, estimated glomerular filtration rate (eGFR) ≥ 90 mL/min/1.73 m2, and high body mass index (BMI) as risk factors for target non-attainment. Use of continuous renal replacement therapy (CRRT) and high serum urea significantly increased the probability of target attainment. In addition, we found a significant association between the 100%ƒT > MICECOFF target attainment and ICU length of stay (LOS), but no significant correlation was found for the 30-day survival. Conclusions Traditional beta-lactam dosing results in low target attainment in the majority of critically ill patients. Male gender, high BMI, and high eGFR were significant risk factors for target non-attainment. These predictors, together with therapeutic drug monitoring, may help ICU clinicians in optimizing beta-lactam dosing in critically ill patients. Trial registration Netherlands Trial Registry (EXPAT trial), NTR 5632. Registered on 7 December 2015.

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High target attainment for β-lactam antibiotics in intensive care unit patients when actual minimum inhibitory concentrations are applied

Cited by 23 publications

References 25 publications

Quantitative Analysis of Gentamicin Exposure in Neonates and Infants Calls into Question Its Current Dosing Recommendations

Quantitative Analysis of Gentamicin Exposure in Neonates and Infants Calls into Question Its Current Dosing Recommendations

Pharmacokinetics and Target Attainment of Antibiotics in Critically Ill Children: A Systematic Review of Current Literature

Failure of target attainment of beta-lactam antibiotics in critically ill patients and associated risk factors: a two-center prospective study (EXPAT)

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