Pharmacokinetics of high dosage of linezolid in two morbidly obese patients.

Abstract

Sir, Obesity represents a major burden on healthcare as an independent risk factor for mortality in infected patients and its association with comorbidities. Adequate antimicrobial exposure is essential for treatment success, but there are few published data on the pharmacokinetics (PK) of antibiotics in obesity. Furthermore, the degree of alteration depends on several factors: degree of obesity, comorbidities and pharmacological characteristics of the drugs. In addition, the volume of distribution (V) may vary according to the amount of adipose tissue and the lipophilic properties of the antibiotic, resulting in lower serum concentrations. Linezolid is active against Gram-positive bacteria used for skin and lung infections and is a highly lipophilic molecule with a high rate of penetration into tissues. Canut et al. proposed as a PK index predictive of efficacy an AUC/MIC .100 (where AUC1⁄4area under the antimicrobial concentration–time curve for 24 h). The achievement of a Cmin ≥2 mg/L and/or AUC24 .160–200 mg.h/L was proposed as a theoretical threshold to ensure efficacy. Data reported so far show significantly lower concentrations with standard doses of linezolid in obese patients. We report here the main PK parameters in two morbidly obese patients, as defined by BMI, receiving a higher dosage of linezolid. Patient 1 was a male ,50 years old with a BMI of 72 kg/m admitted to the ICU for community-acquired pneumonia with severe sepsis. He had hypoxaemic respiratory failure and later developed methicillin-resistant Staphylococcus epidermidis bloodstream infection (BSI) with a linezolid MIC of 2 mg/L. Patient 2 was a male .60 years old with a BMI of 66 kg/m and acute hypercapnic respiratory failure, admitted to the ICU with a diagnosis of healthcare-associated pneumonia and septic shock. Bronchoalveolar lavage identified an MRSA with a linezolid MIC of 1 mg/L. Plasma concentrations of linezolid were studied at steadystate with a dose of 600 mg every 8 h intravenously by 1 h infusion. The AUC of daily (AUC0 – 24) plasma concentrations was calculated with blood samples collected before (time 0) and at 2, 4, 6 and 8 h after intravenous administration. The Cmin was defined as the concentration before the administration and the maximum plasma concentration (Cmax) as the concentration at the end of the infusion. Linezolid was determined in plasma by a UPLC–photodiode array method. PK data were analysed using Kinetica software (Thermo Scientific, Waltham, MA, USA). AUC0–24 was calculated as 3×AUC0–8. Informed consent was waived due to the clinical need for monitoring plasma levels. The main linezolid PK parameters for Patient 1 were as follows: Cmax 4.83 mg/L, Cmin 0.88 mg/L, AUC0 – 24 55.05 mg.h/L, half-life (t1/2) 3.01 h, clearance (CL) 32.70 L/h, V 141.6 L and 0.51 L/kg, AUC/MIC (MIC1⁄41 mg/L) 55.05 and AUC/MIC (MIC1⁄42 mg/L) 27.52. The main linezolid PK parameters for Patient 2 were as follows: Cmax 15.54 mg/L, Cmin 11.89 mg/L, AUC0 – 24 335.69 mg.h/L, t1/2 10.39 h, CL 5.40 L/h, V 80.98 L and 0.45 L/kg, AUC/MIC (MIC1⁄41 mg/L) 335.69 and AUC/MIC (MIC1⁄42 mg/L) 167.50. See Figure 1. There were satisfactory Cmax and Cmin only in Patient 2, whereas in Patient 1 there was an increased CL and reduced AUC. Since the PK/pharmacodynamic parameter of importance for linezolid activity is the AUC/MIC ratio, assessing changes in AUC exposure by body size is of paramount importance. Only Patient 2 had satisfactory values of AUC and AUC/MIC. Furthermore, since linezolid PK is not related to renal function, the creatinine clearance values of .120 and 40 mL/min in Patients 1 and 2, respectively, are not helpful in understanding the alteration of plasma clearance. Moreover, the observation of higher V (141.6 and 80.9 L in Patients 1 and 2, respectively, when compared with healthy volunteers (52 L) confirms the suggestion of a relationship between weight and V in determining a significant decrease of plasma exposure. Taken together, these data suggest that linezolid PK may be strongly influenced by the degree of obesity and standard doses are not sufficient, further noting that linezolid undergoes slow non-enzymatic oxidation mediated by ubiquitous reactive species in vivo.