Pharmacologic optimization of antibiotics for Gram-negative infections

Antimicrobial resistance among Gram-negative organisms is a rapidly escalating global challenge. Pharmacologic dose optimization based on pharmacokinetic/pharmacodynamic principles is essential for managing Gram-negative infections. High-risk patient populations may receive nonoptimized antimicrobial dosing because pf physiologic changes in acute illness and/or medical interventions. The purpose of this review is to discuss opportunities for pharmacologic optimization of new agents and highlight patient populations that are often associated with poor drug exposure profiles.

Dose optimization of the novel β-lactam-β-lactamase inhibitor combinations has been evaluated through optimizing exposure at the site of infection, evaluating target attainment of both the β-lactam and the β-lactamase-inhibitor in critically ill patients, and evaluating drug exposure to prevent the development of resistance. Plazomicin, a novel aminoglycoside, has pharmacodynamic optimization potential via therapeutic drug monitoring and nomogram-based dosing. Recent studies have evaluated the adequacy of dosing in varying degrees of renal function specifically acute kidney injury, continuous renal replacement therapy (CRRT), and augmented renal clearance (ARC).

The application of fundamental pharmacokinetic/pharmacodynamic principles is required to optimize new antimicrobials in the treatment of serious Gram-negative infections. Exposure at the site of infection, pharmacokinetics in critically ill patients, and exposures to prevent resistance are all considerations to improve microbiologic and clinical outcomes. Therapeutic drug monitoring may be needed for high-risk patients.