Application of Pharmacodynamic Profiling for the Selection of Optimal β-lactam Regimens in a Large University Hospital

•Gram-negative pathogens are increasingly resistant to beta-lactam antibiotics•Antibiotic dose, dosing interval & duration of infusion (3Ds) can be altered•Manipulation of 3Ds can be employed to improve antibiotic exposures•Utilization of these dosing techniques can revitalize in vivo potency

BackgroundInfections caused by drug-resistant Gram-negative bacteria (GNB) are increasing worldwide and as a result, the selection of appropriate empiric antibiotics (ATBs) has been made increasingly difficult. The present study aimed to identify optimized dosing regimens of intravenous (IV) ATBs, defined by cumulative fraction response (CFR), against E. coli (EC), K. pneumoniae (KP), P. aeruginosa (PA), and A. baumannii (AB) at 2,300-bed University Hospital.Materials and MethodsThe minimum inhibitory concentrations (MIC) of EC, KP, PA, and AB from clinical specimens, 250 each, were determined. Pharmacodynamic profiling using Monte Carlo Simulation was performed for standard, high dosage, and prolonged infusions (PI) of ceftriaxone, cefepime, ceftazidime, imipenem, meropenem, and doripenem. A CFR of ≥90% was targeted as providing a sufficiently high ATB exposure.ResultsWhen considering the Enterobacteriaceae, the % susceptible for the cephalosporins ranged from 60% for ceftriaxone to 86% for cefepime, as a result only the 2 g q8 h regimens of ceftazidime and cefepime provided high CFRs. In contrast, all the carbapenems had % susceptible and CFRs ≥90% for EC and KP. While cefepime and ceftazidime demonstrated higher % susceptibility (82-83%) for PA relative to that of the carbapenems (61-69%) only doripenem 2 g q8 h (4 h PI) achieved an optimal CFR (92%) against this organism. Due to the MIC profiles and dismal susceptibilities of AB (16-22%), none of the regimens studied achieved CFRs > 65%.ConclusionsThe pharmacodynamic profiling undertaken in the current study provides insights that allow prescribers to select more appropriate empirical antibiotic regimens for the treatment of infection caused by these common GNB pathogens at this Thai hospital. While higher doses and PI of β-lactams improve exposures against EC, KP and PA, this approach will not sufficiently enhance their potency against AB, thus alternative therapies should be considered for this organism.