Genesis of Antibiotic Resistance (AR) XLIX: Mechanism(s) of Sepsis‐induced Increase in Mortality Cobblestone Antibiotic Resistance Pandemic (ARP)

NCT01663701 : is a clinical trial with the principle hypothesis that early fluid resuscitation will significantly decrease in‐hospital mortality in patients with severe sepsis and hypotension. Based on the observations from NCT01663701, 209 adults with sepsis and hypotension presenting to an emergency department in Zambia, a 6‐hour sepsis protocol emphasizing administration of intravenous fluids, vasopressors, and blood transfusion significantly increased in‐hospital mortality compared with usual care (48.1% vs 33.0%, respectively)(Verbatim). Here, we present a rationale for the plausible reason for such an outcome of 48.1% mortality in sepsis protocol group as opposed to expected decrease in the mortality rate with a “time zero” of admittance to emergency room (ER) and 28 days. Based on the intake criteria of admission to ER, observations and limitations of this investigation, it is hypothesized that “Colonization Pressure” (CP) of “Persisters (Prs)” is the most ostensible factor for the sepsis and septic shock induced increase in mortality rate from “time zero” of admittance to ER. “Persisters”(Prs) are antibiotic‐sensitive bacterial populations have a small fraction (~10 −6 ) of slow or non‐growing, antibiotic‐tolerant cells”. Stochastic switch of specific toxin‐antitoxin (TA) expression and alarmone (p) ppGpp has been implicated in evolution of AR. Additional contributing factors could be a . Lack of “Antibiogram” for P. aeruginosa, S. aureus , C. difficile ( C. diff ), b . failure to implementation of “Antibiotic Stewardship Program”; c . lack of information on the “CP” data on a daily basis. It is suggested that sustained “low tissue perfusion index (PI)”; “Oxygen Saturation of arterial hemoglobin (SpO 2 )” would hypothetically generate a chronic hypoxic state enabling the emergence of anaerobic gram negative bacilli (GNB)” acquiring antibiotic resistance via multidrug‐resistant (MDR); extensively drug‐resistant (XDR), Gain of function (GOF) mutations and Pandrug‐resistant (PDR) escalating the horizontal gene transfer. Chronic tissue hypoxia would likely to increase the “CP” of GNB due to the sub‐therapeutic drug levels at sites of infection/colonization, drug sequestration in the biofilm matrix, and suboptimal infection control in the setting of outbreaks such as NCT01663701 . Lack of information on utilization antifungals via antifungal stewardship is critical to reduce the morbidity & mortality by limiting emergence of MDR in the Intensive Care Units (ICU). Candida bloodstream infections (BSI) / Candidemia and candidiasis in ( C.albicans, C.glabrata, C.auris with MDR and XDR attributes with higher “CP” indices transmitted via horizontal transmission (~30%) posing serious challenges in caring for chronically ill (HIV patients) in the long term care facilities, ICU, and also across the globe. Taken together, the observed 48% mortality in NCT01663701 is a consequence of solidification of factors beyond the realm of current clinical practices caring for chronically ill infectious diseases patients (ex. HIV) across the globe leading to ARP. Support or Funding Information Supported by professional development funds from SWTJC and CME activities of Subburaj Kannan MD This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .