Abstract
Background: Linezolid is used for the treatment of soft tissue infections in critically ill patients. However, data for characterizing the pharmacokinetics (PK) and assessing whether effective concentrations are reached at the target site are lacking. We hypothesized that current dosing regimens do not lead to effective concentrations in the plasma and interstitial fluid (ISF) of subcutaneous tissue in obese patients. Methods: As a controlled clinical model, critically ill obese and non-obese patients undergoing intra-abdominal surgery received 600 mg linezolid as a single infusion. Concentrations in the plasma and microdialysate from the ISF of subcutaneous tissue were determined up to 8 h after dosing. Pharmacokinetic analysis was performed by non-compartmental methods. As a therapeutic target, we used fAUC/MIC > 80. Results: Fifteen obese (BMI: 48.7 ± 11.2 kg/m2) and 15 non-obese (23.9 ± 2.1 kg/m2) patients were analyzed. AUC0–8 in ISF decreased by −1.69 mg*h/L (95% CI: −2.59 to −0.79, p < 0.001) for every 10 kg increase in weight. PK in obese patients were characterized by lower maximal plasma concentrations (median 3.8 vs. 8.3 mg/L, p < 0.001) and a higher volume of distribution (41.0 vs. 30.8 L, p < 0.001), and the therapeutic target was not reached for MIC ≥ 1 mg/L in ISF and ≥ 2 mg/L in plasma. Conclusions: Increasing the weight led to a decrease of linezolid concentrations in the plasma and subcutaneous tissue. The current dosing regimen does not seem to produce sufficient concentrations to kill bacteria with MIC ≥ 2 mg/L, especially as empirical antimicrobial therapy in critically ill obese patients.
Highlights
Linezolid is used for the treatment of complicated skin and soft tissue infections with methicillin-resistant Staphylococcus aureus [1,2,3] and for toxic shock syndrome [4], and has become an important treatment option in empirical antimicrobial therapy in intensive care medicine, e.g., recommended in German guidelines for septic shock with a risk of methicillin-resistant Staphylococcus aureus (MRSA) infection [5]
The main findings of this study were that linezolid concentrations in soft tissue and plasma depended on the weight and therapeutic targets of f AUC24/MIC > 80 [28,29] were below accepted values in intensive care medicine, for obese patients
Obesity leads to increased extracellular fluid and to an increased volume of distribution with lower plasma concentrations [33,34,35]
Summary
Linezolid is used for the treatment of complicated skin and soft tissue infections with methicillin-resistant Staphylococcus aureus [1,2,3] and for toxic shock syndrome [4], and has become an important treatment option in empirical antimicrobial therapy in intensive care medicine, e.g., recommended in German guidelines for septic shock with a risk of methicillin-resistant Staphylococcus aureus (MRSA) infection [5]. Linezolid is used for the treatment of soft tissue infections in critically ill patients. We hypothesized that current dosing regimens do not lead to effective concentrations in the plasma and interstitial fluid (ISF) of subcutaneous tissue in obese patients. PK in obese patients were characterized by lower maximal plasma concentrations (median 3.8 vs 8.3 mg/L, p < 0.001) and a higher volume of distribution (41.0 vs 30.8 L, p < 0.001), and the therapeutic target was not reached for MIC ≥ 1 mg/L in ISF and ≥ 2 mg/L in plasma. Conclusions: Increasing the weight led to a decrease of linezolid concentrations in the plasma and subcutaneous tissue. The current dosing regimen does not seem to produce sufficient concentrations to kill bacteria with MIC ≥ 2 mg/L, especially as empirical antimicrobial therapy in critically ill obese patients
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