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Pharmacokinetic/Pharmacodynamic Target Attainment Based on Measured versus Predicted Unbound Ceftriaxone Concentrations in Critically Ill Patients with Pneumonia: An Observational Cohort Study.

ABSTRACT: The impact of ceftriaxone pharmacokinetic alterations on protein binding and PK/PD target attainment still remains unclear. We evaluated pharmacokinetic/pharmacodynamic (PK/PD) target attainment of unbound ceftriaxone in critically ill patients with severe community-acquired pneumonia (CAP). Besides, we evaluated the accuracy of predicted vs. measured unbound ceftriaxone concentrations, and its impact on PK/PD target attainment. A prospective observational cohort study was carried out in adult patients admitted to the intensive care unit with severe CAP. Ceftriaxone 2 g q24h intermittent infusion was administered to all patients. Successful PK/PD target attainment was defined as unbound trough concentrations above 1 or 4 mg/L throughout the whole dosing interval. Acceptable overall PK/PD target attainment was defined as successful target attainment in ≥90% of all dosing intervals. Measured unbound ceftriaxone concentrations (CEFu) were compared to unbound concentrations predicted from various protein binding models. Thirty-one patients were included. The 1 mg/L and 4 mg/L targets were reached in 26/32 (81%) and 15/32 (47%) trough samples, respectively. Increased renal function was associated with the failure to attain both PK/PD targets. Unbound ceftriaxone concentrations predicted by the protein binding model developed in the present study showed acceptable bias and precision and had no major impact on PK/PD target attainment. We showed suboptimal (i.e., <90%) unbound ceftriaxone PK/PD target attainment when using a standard 2 g q24h dosing regimen in critically ill patients with severe CAP. Renal function was the major driver for the failure to attain the predefined targets, in accordance with results found in general and septic ICU patients. Interestingly, CEFu was reliably predicted from CEFt without major impact on clinical decisions regarding PK/PD target attainment. This suggests that, when carefully selecting a protein binding model, CEFu does not need to be measured. As a result, the turn-around time and cost for ceftriaxone quantification can be substantially reduced.

SUBMITTER: Gijsen M

PROVIDER: S-EPMC8151456 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionEarly sepsis results in pharmacokinetic (PK) changes due to physiologic alterations. PK changes can lead to suboptimal drug target attainment, risking inadequate coverage from antibiotics like ceftriaxone. Little is known about how ceftriaxone PK and target attainment quantitatively change over time in patients with sepsis or the association between target attainment and outcomes in critically ill children and young adults.MethodsA retrospective analysis of a prospective study was conducted in a single-center pediatric intensive care unit. Septic patients given at least one ceftriaxone dose (commonly as 50 mg/kg every 12 h) and who had blood obtained in both the first 48 h of therapy (early) and afterwards (late) were included. Normalized clearance and central volume were estimated and compared in both sepsis phases. We evaluated target attainment, defined as concentrations above 1× or 4× the minimum inhibitory concentration (MIC) for 100% of dosing intervals, and investigated the association between target attainment and clinical outcomes.ResultsFifty-five septic patients (median age: 7.5 years) were included. Normalized clearance and central volume were similar in both phases (6.18 ± 1.48 L/h/70 kg early vs. 6.10 ± 1.61 L/h/70 kg late, p = 0.60; 26.6 [IQR 22.3, 31.3] L/70 kg early vs. 24.5 [IQR 22.0, 29.4] L/70 kg late, p = 0.18). Individual percent differences in normalized clearance and central volume between sepsis phases ranged from -39% to 276% and -51% to 212% (reference, late sepsis), respectively. Fewer patients attained the 1× MIC target in late sepsis (82% late vs. 96% early, p = 0.013), which was associated with transition to once daily dosing, typically done due to transfer from the pediatric intensive care unit (PICU) to a lower acuity unit. Failure to attain either target in late sepsis was associated with antibiotic broadening.ConclusionCeftriaxone PK parameters were similar between early and late sepsis, but there were large individual differences. Fewer patients attained MIC targets in late sepsis and all who did not attain the less stringent target received once daily dosing during this period. The failure to attain targets in late sepsis was associated with antibiotic broadening and could be an area for antibiotic stewardship intervention.

Project description:The aim of this study was to develop a population pharmacokinetic model for piperacillin (PIPC)/tazobactam (TAZ) in late elderly patients with pneumonia and to optimize the administration planning by applying pharmacokinetic/pharmacodynamic (PK/PD) criteria. PIPC/TAZ (total dose of 2.25 or 4.5 g) was infused intravenously three times daily to Japanese patients over 75 years old. The plasma concentrations of PIPC and TAZ were determined using high-performance liquid chromatography and modeled using the NONMEM program. PK/PD analysis with a random simulation was conducted using the final population PK model to estimate the probability of target attainment (PTA) profiles for various PIPC/TAZ-regimen-minimum-inhibitory-concentration (MIC) combinations. The PTAs for PIPC and TAZ were determined as the fraction that achieved at least 50% free time > MIC and area under the free-plasma-concentration-time curve over 24 h ? 96 ?g h/mL, respectively. A total of 18 cases, the mean age of which was 86.5 ± 6.0 (75-101) years, were investigated. The plasma-concentration-time profiles of PIPC and TAZ were characterized by a two-compartment model. The parameter estimates for the final model, namely the total clearance, central distribution volume, peripheral distribution volume, and intercompartmental clearance, were 4.58 + 0.061 × (CLcr - 37.4) L/h, 5.39 L, 6.96 L, and 20.7 L/h for PIPC, and 5.00 + 0.059 × (CLcr - 37.4) L/h, 6.29 L, 7.73 L, and 24.0 L/h for TAZ, respectively, where CLcr is the creatinine clearance. PK/PD analysis using the final model showed that in drug-resistant strains with a MIC > 8 ?g/mL, 4.5 g of PIPC/TAZ every 6 h was required, even for the patients with a CLcr of 50-60 mL/min. The population PK model developed in this study, together with MIC value, can be useful for optimizing the PIPC/TAZ dosage in the over-75-year-old patients, when they are administered PIPC/TAZ. Therefore, the findings of present study may contribute to improving the efficacy and safety of the administration of PIPC/TAZ therapy in late elderly patients with pneumonia.

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Pharmacokinetic/Pharmacodynamic Target Attainment Based on Measured versus Predicted Unbound Ceftriaxone Concentrations in Critically Ill Patients with Pneumonia: An Observational Cohort Study.

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