Pharmacodynamic optimization of β-lactams in the patient care setting

David P Nicolau

In order to eradicate an infecting organism, it is necessary to achieve or maintain concentrations of an antibiotic in vivo that exceed the minimum inhibitory concentration (MIC) for the organism. Duration of exposure, or time above MIC, was recognized as being important for beta-lactam antibiotics more than 60 years ago. Continuous infusion regimens are associated with higher clinical response rates, improvement in surrogate markers of outcome, and lower cost of therapy compared with intermittent infusion regimens, because the MIC can be exceeded for an entire dosing interval. However, for carbapenem antibiotics, it appears that the MIC must only be exceeded for 40% of the dosing interval for bactericidal activity in vivo. Therefore, a promising strategy to optimize carbapenem use is to administer the same dose at the same frequency of administration but to extend the infusion time. Extended infusion regimens take full advantage of a drug's exposure potential within the context of in vivo potency without altering the dose or dosing schedule and with no increase in toxicity or cost. Administering higher doses by extended infusion allows one to manage organisms with high MICs. Optimizing the pharmacokinetics/pharmacodynamics of an antibiotic allows one to 'make good drugs better'.