title: Survival of Carbapenem-Resistant Klebsiella pneumoniae Sequence Type 258 in Human Blood.
abstract: Klebsiella pneumoniaeis a prominent cause of nosocomial infections worldwide. Bloodstream infections caused by carbapenem-resistantK. pneumoniae, including the epidemic lineage known as multilocus sequence type 258 (ST258), are difficult to treat, and the rate of mortality from such infections is high. Thus, it is imperative that we gain a better understanding of host defense against this pathogen as a step toward developing novel therapies. Here we tested the hypothesis that the resistance of ST258 to bactericidal components of human blood, such as serum complement, is linked to virulence capacity in the context of bacteremia. There was significant variance in the survival of ST258 clinical isolates in heparinized human blood or normal human serum. The rate of survival of ST258 isolates in human blood was, in general, similar to that in normal human serum, suggesting a prominent role for complement (rather than leukocytes) in the healthy host defense against ST258 isolates and related organisms. Indeed, deposition of serum complement-the C5b to C9 (C5b-C9) membrane attack complex-onto the surface of ST258 isolates accompanied serum bactericidal activity. Human serum treated with pharmacological inhibitors of complement, depleted of antibody, or heated at 56°C for 30 min had significantly reduced or absent bactericidal activity. In contrast to heparinized blood from humans, that from BALB/c mice lacked bactericidal activity toward the ST258 isolates tested, but the virulence of these ST258 isolates in a mouse bacteremia model was inexplicably limited. Our data highlight the importance of the complement system in host defense against ST258 bacteremia, and we propose that there is the potential to enhance complement-mediated bactericidal activity using an antibody-based approach.
authors.affiliation: Laboratory of Bacteriology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA fdeleo@niaid.nih.gov.
authors.forename: Frank R
authors.initials: FR
authors.lastname: DeLeo
authors.affiliation: Laboratory of Bacteriology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Kobayashi
authors.affiliation: Laboratory of Bacteriology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA.
authors.forename: Adeline R
authors.initials: AR
authors.lastname: Porter
authors.affiliation: Laboratory of Bacteriology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA.
authors.forename: Brett
authors.initials: B
authors.lastname: Freedman
authors.affiliation: Research Technologies Branch, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Dorward
authors.affiliation: Public Health Research Institute Tuberculosis Center, New Jersey Medical School-Rutgers University, Newark, New Jersey, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.affiliation: Public Health Research Institute Tuberculosis Center, New Jersey Medical School-Rutgers University, Newark, New Jersey, USA.
authors.forename: Barry N
authors.initials: BN
authors.lastname: Kreiswirth
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016470:Bacteremia / Q000188:drug therapy / Q000382:microbiology; D015780:Carbapenems / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D006801:Humans; D007711:Klebsiella pneumoniae / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D058885:Multilocus Sequence Typing; D014774:Virulence / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems
keywords: Klebsiella pneumoniae; antibiotic resistance; bactericidal activity; bloodstream infections; carbapenem resistance; complement