Optimizing the Use of Beta-Lactam Antibiotics in Clinical Practice: A Test of Time

Abstract Despite their limitations, the pharmacokinetics (PK) and pharmacodynamics (PD) indices form the basis for our current understanding regarding antibiotic development, selection, and dose optimization. Application of PK-PD in medicine has been associated with better clinical outcome, suppression of resistance, and optimization of antibiotic consumption. Beta-lactam antibiotics remain the cornerstone for empirical and directed therapy in many patients. The percentage of time of the dosing interval that the free (unbound) drug concentration remains above the minimal inhibitory concentration (MIC) (%fT > MIC) has been considered the PK-PD index that best predicts the relationship between antibiotic exposure and killing for the beta-lactam antibiotics. Time dependence of beta-lactam antibiotics has its origin in the acylation process of the serine active site of penicillin-binding proteins, which subsequently results in bacteriostatic and bactericidal effects during the dosing interval. To enhance the likelihood of target attainment, higher doses, and prolonged infusion strategies, with/or without loading doses, have been applied to compensate for subtherapeutic levels of antibiotics related to PK-PD changes, especially in the early phase of severe sepsis. To minimize resistance and maximize clinical outcome, empirical therapy with a meropenem loading dose followed by high-dose-prolonged infusion should be considered in patients with high inoculum infections presenting as severe (Gram negative) sepsis. Subsequent de-escalation and dosing of beta-lactam antibiotics should be considered as an individualized dynamic process that requires dose adjustments throughout the time course of the disease process mediated by clinical parameters that indirectly assess PK-PD alterations.