Abstract
The alarming global rise of antimicrobial resistance combined with the lack of new antimicrobial agents has led to a renewed interest in optimization of our current antibiotics. Continuous infusion (CI) of time-dependent antibiotics has certain theoretical advantages toward efficacy based on pharmacokinetic/pharmacodynamic principles. We reviewed the available clinical studies concerning continuous infusion of beta-lactam antibiotics and vancomycin in critically ill patients. We conclude that CI of beta-lactam antibiotics is not necessarily more advantageous for all patients. Continuous infusion is only likely to have clinical benefits in subpopulations of patients where intermittent infusion is unable to achieve an adequate time above the minimal inhibitory concentration (T > MIC). For example, in patients with infections caused by organisms with elevated MICs, patients with altered pharmacokinetics (such as the critically ill) and possibly also immunocompromised patients. For vancomycin CI can be chosen, not always for better clinical efficacy, but because it is practical, cheaper, associated with less AUC24h (area under the curve >24 h)-variability, and easier to monitor.
Highlights
Antimicrobial resistance is emerging worldwide [1]
One of the ways to achieve this is through optimization of antibiotic dosing regimens based on pharmacokinetic/pharmacodynamic (PK/PD) principles
Review β-lactam antibiotics Beta-lactam antibiotics are “time-dependent antibiotics”. Their maximal killing rate is achieved at concentrations that are only about four times the minimal inhibitory concentration (MIC), which is a relatively low concentration if considering the actual serum levels that are achieved by intermittent administration, and the current clinical breakpoints of beta-lactams that rarely exceed 16 mg/L
Summary
Antimicrobial resistance is emerging worldwide [1]. In addition there is a dramatic lack of new antimicrobial agents being explored in phase 2 or 3 clinical trials, especially for Gram-negative organisms, and development of an antimicrobial with a genuinely novel mechanism of action is estimated to take years [2]. A retrospective study by Lorente et al showed a greater clinical cure rate for CI versus II of ceftazidime (and tobramycin) for the treatment of critically ill patients with ventilatorassociated pneumonia (VAP) [52] Both arms received a low total daily dose of 4 g/d (instead of the standard dosage of 6 g/d). It is fair to say that in the small numbers of clinical studies that did show an advantage in favor of CI, this effect was only present or more pronounced in a subpopulation of the most critically ill or patients with infections caused by pathogens with elevated MICs. An important limitation of most of the older studies is that they are primarily designed to prove that a lower dose of an antibiotic given in CI can be effective as a higher dose given in an intermittent bolus regimen and use lower dosages in the CI arm. The clinician should remain aware of this risk, especially if deciding to aim at a high serum levels, because of the presence of an organism with a high MIC
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