Journal Club

Pharmacokinetics of Linezolid in Obese Patients with Skin Infections

Reviewed by Zeina Kanafani, MD, MS, FIDSA

Linezolid is approved by the Food and Drug Administration for the treatment of complicated skin and soft tissue infections at a standard dose of 600 mg twice daily, orally or intravenously. In the setting of obesity and critical illness, the volume of distribution and drug clearance are increased, which would decrease the likelihood of attaining the pharmacokinetic (PK)/pharmacodynamic (PD) targets. In this study from the University of Maryland Medical Center, the investigators describe the PK of linezolid and the PK/PD target attainment with standard dosing in critically ill obese patients.

A total of 11 patients were included in the analysis, with a median total body weight of 141.3 kg, range 99.9 to 188.0 kg (median body mass index 45.7 kg/m², range 34.6 to 72.6 kg/m²). The most common underlying condition was necrotizing fasciitis in 81.8% of cases. The median sequential organ failure assessment score on admission was 7, range 0 to 17. Four patients received higher doses of linezolid at 600 mg every 8 hours. Linezolid serum levels were obtained at 1, 3, and 5 hours after infusion and as a trough. The main outcome of interest was target attainment, which was defined as achieving area under the concentration-time curve from 0 to 24 h to MIC (AUC_0–24h/MIC) of  100 h*mg/L. A secondary efficacy target was also used, which was the percentage of time above minimum inhibitory concentrations (MICs) higher than 85% (%T > MIC > 85%).

At a weight of 140 kg in non-cirrhotic patients, standard linezolid dosing was associated with a probability of target attainment (PTA) of 100%, 98.8%, 34.1%, and 0% for MICs of 0.5, 1, 2, and 4 mg/L, respectively. At linezolid doses of 600 mg every 8 hours, PTA was suboptimal (6.1%) only for MICs of 4 mg/L. Using the secondary efficacy target at a total body weight of 140 kg, PTA with standard dosing was 100%, 99.8%, 92.1%, and 16.9% for MICs of 0.5, 1, 2, and 4 mg/L, respectively.  At linezolid doses of 600 mg every 8 hours, PTA was more than 99% for all MICs except at 4 mg/L where the PTA was 70.7%.

The data from this study show that in critically ill obese patients, PK/PD target attainment with standard linezolid dosing might not be reached at MICs exceeding 2 mg/L. More studies should be done to determine the effectiveness and safety of higher linezolid dosing in this patient population.

(Blackman et al. Antimicrob Agents Chemother. 2021;65(2):e01619-20.)