# In vitro Pharmacokinetic/pharmacodynamic models for dose de-escalation of antibiotics

> **NIH NIH R03** · OHIO STATE UNIVERSITY · 2024 · $78,750

## Abstract

Project Summary/Abstract:
 Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are problematic because of
associated high treatment failures and elevated mortality rates. Staphylococci including MRSA are the major
cause of medical device infections (MDIs) due to their strong capability to form biofilms. These bacterial biofilms
resist removal by the host immune system and lead to antibiotic-treatment failures due to bacterial tolerance,
development of antibiotic resistance, and limited antibiotic penetration. Vancomycin is the recommended therapy
for MRSA MDIs and the antibiotic daptomycin is the primary antibiotic alternative to vancomycin for these
infections; however, the development of daptomycin resistance especially post vancomycin therapy has been
reported with increasing frequency. Dalbavancin is the so called “last line antibiotic”, a new lipoglycopeptide
being used to treat MRSA infections. Our preliminary data furthermore have shown that neither daptomycin nor
dalbavancin monotherapies are effective in eradicating high MRSA bacterial loads. In this context, the first aim
of this project investigates the impact of a single dose of dalbavancin in combination with a single dose of
daptomycin in biofilm state (in vitro pharmacokinetic/pharmacodynamic (PK/PD) model with components of
prosthetic material for biofilm growth). This aim is particularly important for combating MRSA infections
associated with MDIs in out-patient settings.
 Bacteriophages (phages) have been found to readily serve as anti-biofilm agents, and in some cases can
also encode biofilm matrix hydrolyzing depolymerases. Therefore, the second aim proposes a single dose of
dalbavancin adjunctive to a single dose of daptomycin (day 1) and daily administration of bacteriophage Sb-1 to
eradicate MRSA infections in biofilm state (in vitro PK/PD models as stated in aim 1). We will use
pharmacokinetic monitoring to achieve dose de-escalation of antibiotics in antibiotic-phage treatment.
 Collectively, this proposal will apply pharmacokinetic measurements, such as area under the concentration-
time curve to achieve dose-de-escalation in phage-antibiotic treatment regimens. The proposed research is
significant in the context of preserving current and future antibiotics and provides critical information regarding
resistance prevention/re-sensitization using antibiotic-phage co-treatments. We will test our central hypotheses
by evaluating the susceptibility of biofilm embedded MRSA to the various proposed antibacterial combinations
and then perform in vitro two-compartment PK/PD biofilm models with humanized pharmacokinetics to optimize
these novel therapies. We expect that through optimizing therapy of MRSA-biofilm infections, we will improve
patient care and prolong the useful life of dalbavancin and daptomycin for the management of MRSA MDIs.

## Key facts

- **NIH application ID:** 10871138
- **Project number:** 1R03AI183164-01
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Razi Kebriaei
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $78,750
- **Award type:** 1
- **Project period:** 2024-05-17 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10871138

## Citation

> US National Institutes of Health, RePORTER application 10871138, In vitro Pharmacokinetic/pharmacodynamic models for dose de-escalation of antibiotics (1R03AI183164-01). Retrieved via AI Analytics 2026-06-16 from https://api.ai-analytics.org/grant/nih/10871138. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*