No abstract

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 (SpO2)” 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 InformationSupported by professional development funds from SWTJC and CME activities of Subburaj Kannan MDThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

ProCESS, ARISE, ProMISe, PRISM, SSSP‐2, and FEAST are clinical trials exploring the implication of an early resuscitation with intravenous fluids, vasopressors, and blood transfusion (Early Goal Directed Therapy @ EGDT) to reduce mortality as compared with usual care for patients with H3 and S3 showed an overall increase in in‐hospital mortality. In an effort to delineate the underlying mechanism, we have analyzed the hemodynamic factors of NCT01663701. The patient cohort with hypotension had the blood pressure recorded as 95mmHg / 61mmHg (Mean IQR) after 6hr of intravenous fluid administration and SpO2 as 36 (p value<0.03). We have determined the pulse pressure (PP) of 34mmHg indicating the reduced perfusion index (PI) and hypovolemic shock. Our interpretation is that it is hypoxemia (an abnormally low arterial oxygen tension (PAO2) in the blood), escalating hypoxia to dysoxia and/or anoxia? As a result of sustained H3, the SpO2 (peripheral capillary oxygen saturation), as determined an average of 38% which is likely to cause a decrease in PI <50% far below normal PI (95%). Our inference is that such clinical scenario would likely to cause a shift in the hemoglobin ‐ oxygen saturation curve to the left (Ref Figure 41–8 Oxygen‐Hemoglobin Dissociation Curve, p530: Guyton‐Hall Med Phys Elsevier 13ed: 2016) while the Frank – Starling Curve to the left implicit of cardiac output failure with an ensuing endocarditis. It is our interpretation under these conditions; EGDT would unlikely to confer benefit in terms of PI. Our effort to determine the Cardiac Index (CI) was unsuccessful due to the fact that body surface area (BSA) was not available. We have determined the Mean Arterial Pressure (MAP) of 66 mmHg after 2 hr. starting the treatment while 72 mmHg after 6 hr. of intravenous fluid administration indicating an improvement in PI. However, patients with low hemoglobin level (<7g/dl) in sepsis protocol cohort would likely to suffer anemia leading to decrease oxygen delivery to tissues in turn decrease arterial oxygen content. SAPS‐3 (Simplified Acute Physiology Score (SAPS) 52 – 54 indicating the absolute risk of in‐hospital mortality by 15.1% reported in this study probably after the 6hr of intravenous fluid administration (Refer Figure 2 Intensive Care Med. 2005 31(10):1345). 86 patients in the sepsis protocol exhibiting Glasgow Coma Scale (GCS) score 13–15, while eleven patients were in GCS score range of 3–8 indicated that both cohort suffered a trauma possibly with traumatic brain injury (TBI) and meningitis. Based on aforesaid physiological factors, here with we propose that sustained “H3” in patients of sepsis protocol would likely to cause an increase in growth of the anaerobic bacteria leading to Septicemia and/or Bacteremia. With an ensuing septicemia, ARB like P. aeruginosa under hypoxia has been shown to have an increased expression of resistance‐nodulation‐division (RND) family of drug efflux pump genes, conferring AR selection pressure. Taken together, sustained H3 ‐ DIC exacerbate S3 lead ramping up ARG in ARB augmented mortality quotient.Support or Funding InformationSupported by professional development funds from SWTJC and CME activities of Subburaj Kannan MDThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

No abstract

Antibiotic prophylaxis (AP) for an inpatient surgical care unit (SCU) and also intensive care unit (ICU) remains a controversial treatment option. Though in a many instances AP is considered as an invaluable measure to minimize the mortality rate, in other instances AP has been shown to exacerbate the Antibiotic Resistance Pathogen (ARP) induced mortality rate in both SCU and ICU. A rationale is presented to purge the practice of AP in STBI/TBI admitted in ICU to Rout AR Induced Mortality. In a case report where the role of “Colonization Pressure” (CP) (i.e., the proportion of other patients colonized with ARP) analysis indicate, that in an ICU the average expected median time until the acquisition of Vancomycin‐Resistant Enterococci (VRE) ‐ is approximately 19 days when both antibiotic pressure and CP are 25% but 6 days when CP is 75% and antibiotic pressure is 25%. In an another case report, 250 trauma patients in a Surgical Intensive Care Unit (SICU) requiring an one or more surgical modality requiring a stay of 3 days or more received AP by 1 antibiotic (Cefoxitin sodium or ampicillin sodium/sulbactam sodium) for 24 hours (SHORT group or 1 or more antibiotics ( a combination of piperacillin sodium sterile and tazobactam sodium, or the combination of ampicillin, gentamicin sulfate, and metronidazole) prophylaxis administered longer than 24 hours with multiple antibiotics fail to improve morbidity. In a case report focused on patients admitted to the trauma intensive care unit (TICU) from January, 2001 through December, 2004 with blunt, non‐operative traumatic brain injury who is managed solely with an intracranial pressure (ICP) monitor, among those receiving no antibiotics prior to or during ICP monitoring ; and those already receiving antibiotics at the time of ICP monitor insertion were, n = 84. This study concluded that AP does not reduce the CNS infection rate and is associated with more MDR pathogens in any subsequent infectious complications. In a study aimed to determine the role of nosocomial transmission in both deployed hospitals and receiving military medical centers (MEDCENs) eighteen thousand five hundred sixty of 21,272 patients (2005 to 2009) were screened for Multidrug‐resistant organism (MDRO) colonization. Although colonization with Acinetobacter (ACB) declined during the following 5 years, an increase ARP including extended spectrum β‐lactamase (ESBL) ‐producing Enterobacteriaceae were shown to be increasing. However, the risk of ARP selection caused by the antibiotic administration for 48 hours or more, outweighed potential benefits. A study aimed to determine the impact of prolonged use of CNS device for dispensing AP as a factor in inducing the ARP and Clostridium difficile where, patient receiving AP, n = 116, and control group patients had mean APACHE II scores of 17.7 ± 9.2 and 15.1 ± 10.6 with 53.4 and 24.6 % receiving craniotomies. A higher incidence of ARP in patients receiving prolonged AP with a CNS device, but incidence of C. difficile were not significant compared to controls. Taken together, in the absence of Glasgow Coma Scale (GCS) rating upon admission of STBI/TBI patients in ICU, performing culture and sensitivity assay in CSF, implementing prudent antibiotic stewardship and implementing Antibiotic Time Out (ATO) followed by induction of “Trans” state possibly to make suggestions enabling a psychological propensity to sojourn the infectious state would limit the AR induced mortality.Support or Funding InformationSupported by Professional Development funds of SWTJC to Subburaj KannanThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.