β-Lactams Dosing in Overweight Critically Ill Patients: Are We Driving in the Dark?*
The article published in this issue of Critical Care Medicine by Jung et al (7) describes a prospective study in which the authors measured piperacillin-tazobactam (PTZ) plasma concentrations in critically ill severe obese (body mass index [BMI], > 35) and nonobese (BMI, < 30) patients receiving continuous PTZ infusion. In this single center study, patients with severe sepsis or septic shock were administered continuous infusion of 16 g/2 g PTZ per 24 hours after a loading dose of 4 g/0.5 g over 1 hour. Piperacillin (PIP) steady state plasma concentrations measured twice daily for up to 7 days were compared between severely obese and nonobese patients, and PIP PK Monte Carlo simulations were performed to evaluate PK/PD targets achievement (100% of the time over specific Pseudomonas aeruginosa minimal inhibitory concentration [MIC]) when different regimens of PTZ were given. Eleven severely obese patients and 12 nonobese patients were enrolled. The authors found a high variability of PIP plasma concentrations between groups, intragroups and for the same patient over the time confirming major alterations of PIP PK variables in critically ill patients. With a daily dose of 16 g/2 g of PTZ, the median PIP plasma concentrations remained higher than the P. aeruginosa MIC breakpoint of 16 mg/L in all patients; however, when comparing the median of the 12-hourly PIP plasma concentrations between groups, severely obese patients experienced significantly lower concentrations than nonobese patients. Seven patients (30%), including five nonobese (42%) and two severely obese (18%), experienced a PIP plasma concentration in the toxic range. Finally, the Monte Carlo simulations predicted that a 12 g/1.5 g/24 hr PTZ regimen would achieve concentrations of the drug which would be above the breakpoint MIC of 64 mg/L 100% of the time in only 21% of obese patients, whereas a regimen of 20 g/2.5 g/24 hr PTZ would result in toxic concentrations in 18% of obese patients.
PTZ displays time-dependent PD with the optimal target of 100% of time greater than 4 MIC associated with clinical cure in the most severe patients and when PTZ penetration is expected to be poor in the infected site (8). Previous reports have conflicting findings regarding PIP PK changes and their consequences in obese patients, possibly because of the heterogeneity in degree of obesity and in critical illness severity in these studies (9–13). A case-control study after matching for age, gender, renal function, and Sequential Organ Failure Assessment score did not find any differences in PK variables, including Vd and PIP clearance, between obese and nonobese critically ill patients (10). Conversely, in a study including 14 obese and severely obese patients admitted either to the ward or to ICU, changes were reported in antimicrobial Vd of PTZ (11).