# Integrated modeling of Klebsiella pneumoniae infections based on bacterial genotype, patient factors and colonization status

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $410,599

## Abstract

Abstract
Klebsiella pneumoniae is a leading cause of hospital-acquired infections in the United States and the most
common Carbapenem-resistant Enterobacteriaceae (CRE) and Extended-Spectrum Beta-lactamase (ESBL)
species. Infections with CRE cause up to 50% mortality from sepsis, and both ESBL and CRE infections are a
significant cause of excess morbidity and hospital costs. Our preliminary data from 1765 patients indicates that
patients with K. pneumoniae gastrointestinal colonization are at a high risk of subsequent disease (Odds ratio
4.0; p<0.0001) and become infected with their colonizing strain. Antibiotic therapy can be life-saving but
choosing the correct regimen requires antimicrobial susceptibility data that is available days after the onset of
disease. Testing for colonization could provide an ideal opportunity for intervention: physicians can identify at-
risk patients and use antibiotic susceptibility data from their colonizing strain to make rational choices for
empiric therapy. High-risk patients could be targeted for intervention, but how the complex interaction of patient
and bacterial factors leads to disease is unknown. To close this gap in knowledge, we have assembled a multi-
disciplinary team of physician-scientists, epidemiologists, bioinformaticians, and statisticians with expertise in
clinical microbiology, microbial pathogenesis and infectious diseases. The objective of this proposal is to
identify the bacterial and host factors that predict K. pneumoniae infections in colonized patients. Our central
hypothesis is that K. pneumoniae strains vary in their virulence potential, and the combination of K.
pneumoniae genotype and host susceptibility determines the risk of disease in a colonized patient. To test this
hypothesis, we validated a novel genome comparison method called Pathogenicity-Associated Loci
sequencing (PAL-Seq) to identify K. pneumoniae genes in variable genomic regions that are associated with
infection. We also developed a preliminary clinical model of patient risk factors for K. pneumoniae infection. We
will test our hypothesis and meet the objective of this proposal through the following specific aims: Aim 1:
Define patient risk factors for K. pneumoniae infection in colonized patients. We will use electronic medical
records and culture samples in cohorts from three hospitals to build and validate models based on patient
characteristics and colonization density as risk factors for infection in colonized patients, and test the models in
the subgroup of ESBL and CRE colonized patients. Aim 2: Identify K. pneumoniae genes that predict the risk
of disease in colonized patients. Using colonizing and invasive isolates, we will apply our PAL-Seq pipeline to
identify bacterial genes associated with infection, validate them in animal models and an independent cohort,
and test candidate virulence genes in ESBL and CRE colonized patients. The positive impact of this work will
be immediate and substantial. We will r...

## Key facts

- **NIH application ID:** 9852971
- **Project number:** 5R01AI125307-04
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Michael Abbott Bachman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $410,599
- **Award type:** 5
- **Project period:** 2017-02-15 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852971

## Citation

> US National Institutes of Health, RePORTER application 9852971, Integrated modeling of Klebsiella pneumoniae infections based on bacterial genotype, patient factors and colonization status (5R01AI125307-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9852971. Licensed CC0.

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