Evaluation of Linezolid Pharmacokinetics in Critically Ill Obese Patients with Severe Skin and Soft Tissue Infections

Abstract

Background: Linezolid standard dosing is fixed at 600 mg q12h for adults. Literature suggests critically-ill, obese patients require higher doses. The study aim is two-fold: (i) to describe linezolid PK and (ii) to evaluate if PK/PD target attainment is achieved with standard dosing in critically-ill, obese patients with severe SSTIs. Methods: Adult patients with a body mass index (BMI) ≥ 30 kg/m2 and receiving IV linezolid from August 2018 to April 2019 were eligible for consent in this prospective study. Severe SSTIs were defined as necrotizing fasciitis, myonecrosis, or SSTI with sepsis syndrome. Four blood samples were collected at steady state at 1, 3, 5 hours post-infusion and as a trough. Target attainment was defined as achieving AUC0-24h/MIC ≥ 100 hr*mg/L. Monte Carlo simulations were used to determine probability of target attainment (PTA). Results: Eleven patients were included in the study. The median BMI was 45.7 kg/m2 and median total body weight (TBW) was 136.0 kg. Seven patients received standard linezolid doses and four received 600 mg q8h. A one-compartment model described linezolid PK. Based on AUC0-24h/MIC targets, for non-cirrhotic patients at 140 kg, PTA with standard linezolid doses was 100%, 98.8%, 34.1%, and 0% for MICs 0.5, 1, 2, and 4 mg/L, respectively. Conclusion: Target attainment ≥ 90% is not achieved with standard linezolid doses for non-cirrhotic patients ≥ 140 kg with MICs ≥ 2 mg/L. This study adds to accumulating evidence that standard linezolid doses may not be adequate for all patients.

WSES/GAIS/WSIS/SIS-E/AAST global clinical pathways for patients with skin and soft tissue infections

“…One recent study included 11 obese patients with severe SSTI, of whom 9 had NSTI, and evaluated the pharmacokinetics of linezolid. Although linezolid has an excellent soft tissue distribution, the probability of target attainment for this antibiotic was low using the standard dosing of 600 mg every 12 h [ 70 ].…”

Antibiotics in Necrotizing Soft Tissue Infections

“…Only one recent study included 11 obese patients with severe SSTI, of whom 9 had NSTI, and evaluated the pharmacokinetics of linezolid. Although thought to have an excellent soft tissue distribution, the probability of target attainment for this drug was low using the standard dosing of 600 mg every 12 h, highlighting the importance of conducting specific studies in this specific population [80].…”

“…Only one recent study included 11 obese patients with severe SSTI, of whom 9 had NSTI, and evaluated the pharmacokinetics of linezolid. Although thought to have an excellent soft tissue distribution, the probability of target attainment for this drug was low using the standard dosing of 600 mg every 12 h, highlighting the importance of conducting specific studies in this specific population [80]. Features of septic shock from any cause (increased distribution volume, altered renal clearance, hypoalbuminemia, and reduced tissue perfusion) abound for optimizing delivery of hydrophilic and time-dependent drugs such as betalactams by using high-loading doses and prolonged infusion with therapeutic drug monitoring.…”

Antimicrobial Dosing in Specific Populations and Novel Clinical Methodologies: Obesity

“…Multiple groups have shown through PK/pharmacodynamic studies that this is not reasonable especially for individuals over 140 kg. [37][38][39] However, in practical terms, it is difficult to overcome this underdosing challenge in obesity when 600 mg tablets are the only available oral formulation for adults. 39 For example, if a decision is made to increase the daily dose from 1,200 mg to 1,800 mg, then dosing options for linezolid would be 600 mg every 8 hours or 900 mg every 12 hours.…”

“…Is a 600 mg twice daily oral regimen of an agent like linezolid based on an 80 kg individual reasonable in a 40 kg and a 240 kg individual as well? Multiple groups have shown through PK/pharmacodynamic studies that this is not reasonable especially for individuals over 140 kg 37–39 . However, in practical terms, it is difficult to overcome this underdosing challenge in obesity when 600 mg tablets are the only available oral formulation for adults 39 .…”