Preclinical Models Provide Critical Foundation for Antibiotic PK/PD Targets

Preclinical models play a vital role in helping researchers understand how antimicrobials behave and which pharmacokinetic/pharmacodynamic (PK/PD) targets may be most effective before therapies reach patients, according to Sean N. Avedissian, PharmD, PhD, MSc, associate professor in the Department of Pharmacy Practice and Science at University of Nebraska Medical Center, during a recent discussion on antibiotic development and clinical application. Avedissian spoke on the topic during the recent MAD-ID and SIDP 2026 annual meeting.

The conversation highlighted how in vitro systems and animal models serve as the initial framework for determining whether antimicrobials are driven by factors such as area under the curve or time above minimum inhibitory concentration. These early studies help researchers establish practical therapeutic targets while balancing safety and efficacy concerns.

“A lot of times, these preclinical models are started as a starting point to figure out what the PK/PD driver is for a lot of these antimicrobials,” Avedissian said.

The discussion also explored why stasis targets—rather than aggressive bacterial kill targets—are commonly used when establishing antimicrobial susceptibility breakpoints. According to Avedissian, higher kill targets may require drug exposures that are unrealistic or potentially toxic in clinical practice, particularly for agents with narrow therapeutic windows.

Avedissian emphasized that preclinical models can oversimplify what occurs in human patients because they often lack important host factors such as immune system contributions. However, advancements in more physiologically relevant systems, including organ-on-a-chip technologies and organoids, are helping improve translational accuracy.

“We treat a patient, not a number, and in the patient, you have all the other factors that help clear bacteria that you don’t always see in these preclinical models,” said Avedissian.

He also addressed the challenge of antibiotic penetration into difficult-to-treat areas such as the central nervous system, lungs, and bone. Avedissian noted that plasma drug levels do not always reflect concentrations achieved within tissues, underscoring the importance of integrating published penetration studies with ongoing clinical assessment when managing critically ill or immunocompromised patients.