# Biofilm antibiotic tolerance in periprosthetic joint infection

> **NIH NIH K08** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $166,016

## Abstract

Abstract
 Total knee arthroplasty (TKA) is the largest major surgical procedure by volume for Medicare, and infection
is the largest reason for TKA revision. Irrigation and debridement (I&D) with long-term antibiotics is the
preferred method to manage periprosthetic joint infection (PJI; infected TKA). I&D fails in approximately 60% of
cases. The high failure rate of I&D is a result of the high tolerance of biofilm to antibiotics. There is a large gap
in knowledge in how biofilm develops antibiotic tolerance, how it is regulated, and there are no strategies to
disrupt this tolerance in PJI. The hypothesis of this proposal is that bacterial persisters, a subpopulation of
bacteria phenotypically resistant to antibiotics, are a major factor responsible for this tolerance and the high
failure rate of I&D. In other diseases of chronic infection (ie tuberculosis and cystic fibrosis), bacterial persisters
have been well-recognized to increase biofilm tolerance to antibiotics and prevent eradication of the infection.
Demonstrating bacterial persisters are present in PJI biofilm is the first step in developing treatment strategies.
 The aims include establishing the presence of bacterial persisters in biofilm of PJI and identify potential
therapeutic strategies to decrease biofilm antibiotic tolerance for later clinical trials. Preliminary results in this
proposal demonstrate bacterial persisters provide a major contribution to biofilm antibiotic tolerance, and that
this tolerance is associated with increased toxin-antitoxin expression in vitro. In Aim 1, a clinical study will be
completed to determine whether these same results are observed on clinical samples. In Aim 2, we will
determine the role of toxin-antitoxin systems in PJI biofilm antibiotic tolerance in the animal model we have
developed. In Aim 3, the efficacy of a new class of antibiotics, ADEP4, that is not dependent on active
metabolism or a positive energy state to eradicate bacteria will be quantified. This will add further evidence to
the role of bacterial persisters in PJI and offer an additional new therapeutic strategy for later clinical trials.
 The research plan is tightly integrated with a five-year career development plan where Dr. Urish will be
mentored by a multidisciplinary team of research and clinical investigators in orthopaedic surgery,
microbiology, and biostatistics. Mentors were selected based on already existing relationships, methodological
expertise, and success in mentoring previous junior investigators. The mentoring team is a tremendous
strength in this proposal as they compromise a diverse and complimentary skill set. To achieve his training
objectives, a combination of classes, workshops, and conferences scheduled throughout the proposal will
provide the foundation to acquire new skills in advanced bacterial genetic techniques, analysis, and their
application into translational clinical studies. Together, the generated preliminary data and mentoring will
create a ...

## Key facts

- **NIH application ID:** 10145486
- **Project number:** 5K08AR071494-05
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** KENNETH L URISH
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $166,016
- **Award type:** 5
- **Project period:** 2017-06-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10145486

## Citation

> US National Institutes of Health, RePORTER application 10145486, Biofilm antibiotic tolerance in periprosthetic joint infection (5K08AR071494-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10145486. Licensed CC0.

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