Jeffrey Strich, MD, MHS
National Institutes of Health Clinical Center
Bethesda, MD
Disclosure information not submitted.
Mark Connelly, MD
Physician
Children's National Medical Center, United States
Disclosure information not submitted.
Joanna Swerczek, CMAR
Non-human Primates Project Manager
NIH, United States
Disclosure information not submitted.
Heather Kendall, CMAR
Veterinary Technician
NIHAC, United States
Disclosure information not submitted.
Andrew Platt, MD, PhD,
Clinical Fellow
National Institutes of Health Clinical Center
Bethesda, MD
Disclosure information not submitted.
Daniel Chertow, MD, FCCM
Tenure Track Investigator
National Institutes of Health Clinical Center, United States
Disclosure information not submitted.
Title: Klebsiella pneumoniae Septic Shock in a Non-human Primate Intensive Care Model
Introduction: Sepsis is a leading cause of death in the United States. Clinically relevant models that adequately recapitulate sepsis progression as seen in human intensive care units (ICU) are lacking. Here, we employed our standardized non-human primate ICU model including mechanical ventilation, invasive hemodynamic monitoring, volume resuscitation, vasopressors, and antibiotics to study bacterial sepsis progression induced by Klebsiella pneumoniae, a clinically relevant organism with high propensity to develop antibiotic resistance.
Methods: Six sedated rhesus macaques were infused by a central line with escalating doses of ST258 strain of Klebsiella pneumoniae [two low-dose (1 x 107 CFU/kg), two medium-dose (1 x 108 CFU/kg), two high-dose (1 x 109 CFU/kg)]. Infusion lasted three hours and antibiotics were initiated one-hour post-hypotension onset. Matched blood samples before infusion and post-infusion (p.i.) during illness progression were analyzed longitudinally against clinical parameters such as: mortality, renal function, leukocyte counts, and coagulation.
Results: Animals showed evidence of a dose-dependent transient bacteremia. All animals developed an early tachycardia (~30 minutes p.i.) with five out of six developing hypotension unresponsive to fluids, requiring vasopressors. Low-dose and medium dose pairs resulted in a 50% mortality, while the high dose model was 100% lethal. All deaths occurred 33-47 hours p.i.. Renal failure occurred in 0/2 low-dose, 1/2 medium-dose and 2/2 high dose animals. Leukocytosis occurred at 10 hours in low dose animals (mean=15.1x103 cells/uL) while leukopenia occurred in medium and high-dose animals (mean=2.5 x103 cells/uL and 2.1 x103 cells/uL, respectively). Fibrinogen increased in both low-dose animals consistent with an acute phase reactant while both high-dose animals showed evidence of coagulopathy with stable to decreasing fibrinogen and increased partial thromboplastin time.
Conclusion: Physiological and immunological parameters suggest a stepwise increase in disease severity associated with Klebsiella pneumoniae dose. Our non-human primate model closely matches human sepsis progression and care, providing a unique opportunity to study the molecular pathogenesis and potential therapeutics using a clinically relevant and emerging antibiotic resistant pathogen.