Population Pharmacokinetics and Monte Carlo Dosing Simulations of Meropenem During the Early Phase of Severe Sepsis and Septic Shock in Critically Ill Patients in Intensive Care Units

Introduction:

Severe sepsis/septic shock are one of the most important reasons for admission the critically-ill patient to Intensive Care Units (ICU) and remaining a major causes of high mortality. Evidently, the fluctuation in pathophysiology, particularly during early phase, of this condition may result in PK alteration and lead to the inadequate antibiotic dosed of standard treatment. Therefore, thearly phase treatment with an appropriate antimicrobial doses that achieved pharmacodynamic target for antimicrobial therapy have been the crucial factor for therapeutic.

Meropenem, a carbapenem antibiotic, is a β-lactam antimicrobial agent with a broad spectrum of activity, coverage of gram-negative bacteria including highly resistant pathogens for instance ESBL-producing or AmpC-mediated b-lactamase producing Enterobacteriaceae. This agent, in common with other β-lactams, is characterized by time-dependent antimicrobial activity, and the exposure time during which the free drug concentrations remains above the minimum inhibitory concentration (T>MIC) is the pharmacokinetic/pharmacodynamic (PK/PD) index that best correlates with efficacy. The majority of previous PK/PDs studies on β-lactams in critically ill patients were mostly conducted in the steady-state period of treatment in which during the early phase of severe sepsis/septic shock was still lacking.

Objectives:

To study the population PK of meropenem and assess the probability of target attainment (PTA) of meropenem inthe initial phases of severe sepsis or septic shock patients in order to be able to optimize dosing recommendations.