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Pharmacologic optimization of antibiotics for Gram-negative infections

Gill, Christian M.a; Nicolau, David P.a,b

Current Opinion in Infectious Diseases: December 2019 - Volume 32 - Issue 6 - p 647–655
doi: 10.1097/QCO.0000000000000601
GRAM-NEGATIVE INFECTIONS: Edited by Matteo Bassetti

Purpose of review 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.

Recent findings 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).

Summary 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.

aCenter for Anti-Infective Research and Development

bDivision of Infectious Diseases, Hartford Hospital, Hartford, Connecticut, USA

Correspondence to David P. Nicolau, PharmD, FCCP, FIDSA, 80 Seymour Street, Hartford, CT 06102, USA. Tel: +1 860 972 3941; fax: +1 860 545 3992; e-mail:

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