# Modifiable Risk Factors for the Emergence of Resistance to Pseudomonas aeruginosa

> **NIH NIH R21** · JOHNS HOPKINS UNIVERSITY · 2022 · $203,381

## Abstract

Project Summary
Carbapenem-resistant Pseudomonas aeruginosa (CR-P. aeruginosa) contributes to significant mortality in
hospitalized patients. Only four β-lactam agents with activity against CR-P. aeruginosa are available in the US,
of which ceftolozane-tazobactam (C-T) is the most frequently used to treat CR-P. aeruginosa. Pre-clinical
investigations indicate C-T had activity against >90% of P. aeruginosa isolates; after clinical use, reports of P.
aeruginosa that initially tested susceptible to C-T but became resistant during therapy emerged.
Our preliminary data indicate that amongst 28 consecutive patients infected with CR-P. aeruginosa with
isolates initially susceptible to C-T, 50% of patients had subsequent P. aeruginosa isolates with > 4-fold
increase in C-T minimum inhibitory concentrations (MICs) up to 30 days after C-T exposure. We identified
genetic markers contributing to resistance through whole genome sequencing (WGS) – notably mutations in
the ampC-ampR region and in PBP3. Alarmingly, 86% of P. aeruginosa isolates initially susceptible to another
novel antibiotic, ceftazidime-avibactam (C-A), exhibited resistance to C-A after C-T exposure - in the absence
of C-A exposure. This is concerning as the emergence of resistance to one novel agent could eliminate the few
remaining treatment options. We explored modifiable risk factors that could reduce the frequency of C-T
resistance and found that 30% of patients who received C-T over 1 hour had subsequent C-T resistant
isolates, whereas no patients who received the drug over 3 hours developed resistant isolates. We would like
to repeat this exploratory work and include experimental validation studies in a cohort of 260 patients across
seven hospitals who have paired P. aeruginosa clinical isolates stored at -80°C and were prescribed C-T.
In Aim 1, WGS will identify the genetic loci associated with C-T resistance comparing paired CR-P. aeruginosa
isolates from the same patient before and up to 30 days after C-T exposure. Validation will occur through
cloning and site-directed mutagenesis work. Broth microdilution will determine susceptibility testing results for
the three other β-lactams with activity against CR-P. aeruginosa to quantify the emergence of cross-resistance.
In Aim 2, we will capitalize on diverse C-T administration strategies at participating sites and develop a
machine learning derived decision tree to inform clinicians how to prescribe C-T most effectively to reduce the
likelihood of acquired resistance. The following are some risk factors that will be investigated for potential
inclusion: (1) infusion of C-T over 3 hours, (2) high-dose C-T, (3) combination antibiotic therapy, (4) dialysis
dependency, (5) source of infection and source control, (6) number of days of C-T exposure.
This work will (1) inform future drug development by identifying areas of the bacterial chromosome highly
prone to resistance and in need of additional reinforcement and (2) identify modifiable r...

## Key facts

- **NIH application ID:** 10425430
- **Project number:** 5R21AI153580-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Pranita Tamma
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $203,381
- **Award type:** 5
- **Project period:** 2021-06-09 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10425430

## Citation

> US National Institutes of Health, RePORTER application 10425430, Modifiable Risk Factors for the Emergence of Resistance to Pseudomonas aeruginosa (5R21AI153580-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10425430. Licensed CC0.

---

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