Antibiotic treatment failure of Klebsiella pneumoniae liver abscesses

Over the past three decades, a distinctive pathotype of tissue-invasive hypervirulent Klebsiella pneumoniae (hvKp) has gained attention for its capacity to induce severe infections, such as wound infection and liver abscesses in healthy individuals. Despite appropriate antibiotic therapy, treatment of hvKp liver abscesses is frequently ineffective, leading to complications such as recurrent bacteremia, metastatic infection, or mortality. Despite the clinical significance of hvKp liver abscesses, the bacterial factors necessary for abscess formation and the cause of inadequate antibiotic efficacy are poorly understood. Populations of antibiotic-tolerant cells, defined as phenotypic variants capable of surviving antibiotic challenge, have been implicated in treatment failure of infections caused by other pathogens. However, the contribution of antibiotic-tolerant cells to the treatment failure of hvKp infections is unknown. We have established a novel mouse model of hvKp wound infection which results in systemic infection, including liver abscesses. Initial findings indicate that that clinically relevant antibiotics used to treat hvKp infections, are very effective against wound infection but have poor efficacy against liver abscesses. Treatment failure was not associated with antibiotic resistance but could be a result of inadequate drug penetration or the enrichment of antibiotic tolerant cells within abscesses. In Aim 1 of this proposal, we will employ a combination of quantitative and imaging mass spectrometry to visualize antibiotic distribution into infected livers and decipher the contribution of antibiotic tolerant cells and/or poor drug penetration to treatment failure in this niche. In Aim 2, we will employ RNA sequencing to examine the transcriptional profile of hvKp in the wound infection compared to liver abscesses and assess the ability of mutants in key virulence factors to establish infection. Understanding the factors required to form liver abscesses and the precise nature of treatment failure against abscess populations will aid in future therapeutic development against this clinically challenging indication.