Basis for Success of Multidrug-Resistant Enterobacteriaceae

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The high incidence of Klebsiella pneumoniae infections in hospitals is compounded by antibiotic resistance, and notably carbapenem resistance. In the United States, carbapenem-resistance is conferred largely by K. pneumoniae carbapenemase (KPC). Strains that produce KPC are resistant to virtually all beta-lactam antibiotics and infections caused by these opportunistic pathogens are difficult to treat. These multidrug resistant (MDR) K. pneumoniae strains are often referred to as classical K. pneumoniae (cKp). Multilocus sequence type 258 (ST258) K. pneumoniae are the most prominent KPC-containing organisms in U.S. hospitals and other regions worldwide. Outside of carbapenem resistance, the molecular underpinnings of the emergence and success of ST258 and other prominent cKp strains remain incompletely determined. Although the majority of K. pneumoniae infections occur in hospitals, a separate group of strains known as hypervirulent K. pneumoniae (hvKp) cause community-acquired infections in otherwise healthy individuals. The molecular phylogeny of hvKp is predominated by three clonal groups (CGs) based on multilocus sequence typing, namely CG23, CG65, and CG86. The hvKp phenotype is attributed largely to specific virulence molecules encoded on plasmids that were historically not present in cKp. However, there has been recent emergence of strains with the combination of multidrug resistance and hypervirulence phenotypes (MDR kvKp). The emergence of such strains in both community and healthcare settings underscores the need for development of alternative approaches for prevention and/or treatment of infections caused by these organisms. We hypothesize that the success of cKp or emerging MDR hvKp is in part due to the ability of these microbes to circumvent destruction by the innate immune system (e.g., killing by host neutrophils and serum complement). Infections with cKp primarily occur in individuals with significant co-morbidities and/or immunosuppression, whereas those caused by hvKp often occur in otherwise healthy subjects. If our hypothesis is correct, bolstering the host response to either of these organisms could be an effective immunoprophylaxis and/or immunotherapy approach.