Population pharmacokinetics of tigecycline in critically ill patients with severe infections [PublishAheadOfPrint]

Objectives: We sought to describe the population pharmacokinetics of tigecycline in critically ill patients and describe optimized dosing regimens of tigecycline for different bacterial infections.

Methods: This prospective study included ten critically ill patients given a standard dose of tigecycline. Blood samples were collected during one dosing interval and analyzed using validated chromatography. Population pharmacokinetics and Monte Carlo dosing simulations were undertaken using Pmetrics. Three target exposures, ratios of 24h area under the curve to minimum inhibitory concentrations (AUC_0-24/MIC), were evaluated (≥17.9 for skin infections, ≥6.96 for intraabdominal infections, ≥4.5 for hospital-acquired pneumonia).

Results: The median age, total body weight and body mass index (BMI) were 67 years, 69.1 kg and 24.7 kg/m², respectively. A two-compartment linear model best described the time course of tigecycline concentrations. The mean±SD parameter estimates from the final model were clearance 7.50±1.11 L/h, volume of central compartment 72.50±21.18 L, rate constant for tigecycline distribution from the central to peripheral compartment 0.31±0.16 h^-1 and from the peripheral to central compartment 0.29±0.30 h^-1. A larger BMI was associated with increased CL of tigecycline. Licensed doses were found to be sufficient for Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, and Methicillin-resistant Staphylococcus aureus for an AUC_0-24/MIC target of 4.5 or 6.96. For a therapeutic target of 17.9, an increase tigecycline dose is required, especially for patients with higher BMI.

Conclusion: Dosing requirements of tigecycline differ with indication, pathogen susceptibility and potentially with patient BMI.

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