Optimal loading dose of meropenem before continuous infusion in critically ill patients: a simulation study

Liebchen, Uwe; Salletmeier, Hanna; Kallee, Simon; Scharf, Christina; Huebner, Lucas; Weber, Alexandra; Zöller, Michael

doi:10.1038/s41598-021-96744-3

Cited by 7 publications

(6 citation statements)

References 21 publications

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“…Liebchen et al [ 55 ] reported on the optimal loading dose of meropenem before continuous infusion in critically ill patients using a previously evaluated pharmacokinetic model of critically ill patients. Maintenance doses administered as continuous infusion of 1.5–6 g/24 h with preceding loading doses (administered in 30 minutes) of 0.15–2 g were investigated.…”

Section: Methodsmentioning

confidence: 99%

“…If all 3 covariates showed extreme values (“worst-case scenario”), a loading dose of 0.5 g was necessary to achieve PK-PD targets. Liebchen et al [ 55 ] recommended the administration of a loading dose of 0.5 g meropenem over 30 minutes immediately followed by continuous infusion. It is interesting to note that a higher loading dose did not lead to further improvements of target attainment (%fT > MIC) [ 55 ].…”

Section: Methodsmentioning

confidence: 99%

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Optimizing the Use of Beta-Lactam Antibiotics in Clinical Practice: A Test of Time

Tilanus¹,

Drusano

2023

Open Forum Infectious Diseases

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Despite their limitations, the PK (pharmacokinetics) and PD (pharmacodynamics) indices form the basis for our current understanding regarding antibiotic development, selection and dose optimization. Application of PK-PD in medicine has been associated with better clinical outcome, suppression of resistance and optimization of antibiotic consumption. Beta-lactam antibiotics remain the cornerstone for empirical and directed therapy in many patients. The percentage of time of the dosing interval that the free (unbound) drug concentration remains above the MIC (Minimal Inhibitory Concentration)(%fT > MIC) has been considered the PK-PD index that best predicts the relationship between antibiotic exposure and killing for the beta-lactam antibiotics. Time dependence of beta-lactam antibiotics has its origin in the acylation process of the serine active site of PBPs (Penicillin Binding Proteins) which subsequently results in bacteriostatic and bactericidal effects during the dosing interval. To enhance the likelihood of target attainment, higher doses, prolonged infusion strategies with/or without loading doses have been applied to compensate for sub-therapeutic levels of antibiotics related to PK-PD changes, especially in the early phase of severe sepsis. To minimize resistance and maximize clinical outcome, empirical therapy with a meropenem loading dose followed by high dose prolonged infusion should be considered in patients with high inoculum infections presenting as severe (Gram negative) sepsis. Subsequent de-escalation and dosing of beta-lactam antibiotics should be considered as an individualized dynamic process that requires dose adjustments throughout the time course of the disease process mediated by clinical parameters that indirectly assess PK-PD alterations.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Optimizing the Use of Beta-Lactam Antibiotics in Clinical Practice: A Test of Time

Tilanus¹,

Drusano

2023

Open Forum Infectious Diseases

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“…Increasing the load dose, extending the infusion time or providing continuous infusion (CI) of BLs can improve PK/PD parameters and the treatment success rate. 22 , 23 , 24 There are few studies on the PK/PD compliance status of CAZ‐AVI in critically ill patients and the optimization of treatment plans. The largest published clinical study to date included multidrug‐resistant (MDR)‐infected patients ( n = 31) receiving CI CAZ‐AVI to investigate the rate of joint PK/PD target achievement and the clinical efficacy.…”

Section: Discussionmentioning

confidence: 99%

A descriptive pharmacokinetic/pharmacodynamic analysis of ceftazidime‐avibactam in a case series of critically ill patients with augmented renal clearance

Xu,

Tang,

Yuan

et al. 2023

Pharmacology Res & Perspec

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To describe the pharmacokinetics/pharmacodynamics (PK/PD) of a 2 h infusion of ceftazidime‐avibactam (CAZ‐AVI) in critically ill patients with augmented renal clearance (ARC). A retrospective review of all critically ill patients with ARC who were treated with CAZ‐AVI between August 2020 and May 2023 was conducted. Patients whose 12‐h creatinine clearance prior to CAZ‐AVI treatment and steady‐state concentration (Css) of CAZ‐AVI were both monitored were enrolled. The free fraction (fCss) of CAZ‐AVI was calculated from Css. The joint PK/PD targets of CAZ‐AVI were considered optimal when a Css/minimum inhibitory concentration (MIC) ratio for CAZ ≥4 (equivalent to 100% fT > 4 MIC) and a Css/CT ratio of AVI >1 (equivalent to 100% fT > CT 4.0 mg/L) were reached simultaneously, quasioptimal when only one of the two targets was reached, and suboptimal when neither target was reached. The relationship between PK/PD goal achievement, microbial eradication and the clinical efficacy of CAZ‐AVI was evaluated. Four patients were included. Only one patient achieved optimal joint PK/PD targets, while the other three reached suboptimal targets. The patient with optimal PK/PD targets achieved microbiological eradication, while the other three patients did not, but all four patients achieved good clinical efficacy. Standard dosages may not enable most critically ill patients with ARC to reach the optimal joint PK/PD targets of CAZ‐AVI. Optimal drug dose adjustment of CAZ‐AVI in ARC patients requires dynamic drug concentration monitoring.

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“…While 3–6 g meropenem per day administered by II is commonly used to achieve 100% fT > MIC of the 4–8 mg/L meropenem, a CI regimen would require only a bolus of 0.5 g meropenem followed by 0.5–1 g meropenem per day. 99,100 Therefore, the CI could cost 4 times less, when considering only the amount of meropenem used per day.…”

Section: Meropenemmentioning

confidence: 99%

“…There are concerns regarding extracorporeal membrane oxygenation (ECMO) and PK-PD parameter modifications that are made due to meropenem degradation. 100,101 Nevertheless, several studies have examined ECMO as a factor related to target attainment. 94,102,103 Supporting the higher VD and CL of meropenem while on ECMO, studies demonstrated that for a typical PD target such as 100% fT > MIC, at least 6 g per day would be needed in patients with renal clearance up to 90 mL/min, compared with an MIC of 2 mg/L.…”

Section: Meropenemmentioning

confidence: 99%

Optimization of Antimicrobial Stewardship Programs Using Therapeutic Drug Monitoring and Pharmacokinetics–Pharmacodynamics Protocols: A Cost-Benefit Review

Telles

Morales

Yamada

et al. 2023

Therapeutic Drug Monitoring

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Purpose:Antimicrobial stewardship programs are important for reducing antimicrobial resistance because they can readjust antibiotic prescriptions to local guidelines, switch intravenous to oral administration, and reduce hospitalization times. Pharmacokinetics–pharmacodynamics (PK-PD) empirically based prescriptions and therapeutic drug monitoring (TDM) programs are essential for antimicrobial stewardship, but there is a need to fit protocols according to cost benefits. The cost benefits can be demonstrated by reducing toxicity and hospital stay, decreasing the amount of drug used per day, and preventing relapses in infection. Our aim was to review the data available on whether PK-PD empirically based prescriptions and TDM could improve the cost benefits of an antimicrobial stewardship program to decrease global hospital expenditures.Methods:A narrative review based on PubMed search with the relevant studies of vancomycin, aminoglycosides, beta-lactams, and voriconazole.Results:TDM protocols demonstrated important cost benefit for patients treated with vancomycin, aminoglycosides, and voriconazole mainly due to reduce toxicities and decreasing the hospital length of stay. In addition, PK-PD strategies that used infusion modifications to meropenem, piperacillin-tazobactam, ceftazidime, and cefepime, such as extended or continuous infusion, demonstrated important cost benefits, mainly due to reducing daily drug needs and lengths of hospital stays.Conclusions:TDM protocols and PK-PD empirically based prescriptions improve the cost-benefits and decrease the global hospital expenditures.

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Optimal loading dose of meropenem before continuous infusion in critically ill patients: a simulation study

Cited by 7 publications

References 21 publications

Optimizing the Use of Beta-Lactam Antibiotics in Clinical Practice: A Test of Time

Optimizing the Use of Beta-Lactam Antibiotics in Clinical Practice: A Test of Time

A descriptive pharmacokinetic/pharmacodynamic analysis of ceftazidime‐avibactam in a case series of critically ill patients with augmented renal clearance

Optimization of Antimicrobial Stewardship Programs Using Therapeutic Drug Monitoring and Pharmacokinetics–Pharmacodynamics Protocols: A Cost-Benefit Review

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