Linezolid is a synthetic oxazolydinone active against multi-resistant Gram-positive cocci that inhibits proteins synthesis by interacting with the 50S ribosomal subunit. Although linezolid-resistant strains are infrequent, several outbreaks have been recently described, associated with prolonged treatment with the antibiotic. As an alternative to monotherapy, the combination of different antibiotics is a commonly used option to prevent the selection of resistant strains. In this work, we evaluated combinations of linezolid with classic and new aminoglycosides (amikacin, gentamicin and plazomicin), carbapenems (doripenem, imipenem and meropenem) and fosfomycin on several linezolid- and methicillin-resistant strains of Staphylococcus aureus and S. epidermidis, isolated in a hospital intensive care unit in Madrid, Spain. Using checkerboard and time-kill assays, interesting synergistic effects were encountered for the combination of linezolid with imipenem in all the staphylococcal strains, and for linezolid–doripenem in S.epidermidis isolates. The combination of plazomicin seemed to also have a good synergistic or partially synergistic activity against most of the isolates. None of the combinations assayed showed an antagonistic effect.

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.

Antibiotic Stewardship Programs (“ASP”) have been created to promote optimal use of antibiotics in the acute and chronic infectious disease by effective monitoring and implementation of defined daily dose (DDD), days of therapy (DOT), route of administration, and infection clearance rate. An extensive review of “ASP” policies across the globe exhibit lack of continuity in the chain of command and inadequate elements for a successful “ASP”. We have identified that impediments in the current implementation of “ASP” lacks a clear and coherent chain of communication in terms: a. data availability to the “ASP” team (Emergency Room‐Clinical data on AntiBio gram‐ pharmacy director‐charge nurse‐infection control personal ‐intensive care unit ‐ family involvement‐county‐state‐CDC&P epidemiologist); b. Implementation of isolation protocol for patients with infections lasting more than 7days to limit the spread of infection; c. Implementation of effective informed decision making based on mandatory continuing education on “ASP” in home health care, hospice care, dentistry, nurse practitioners, physician assistants, urgent care, and urgent care /emergency (STAT) dispensaries, and physicians in private practice, education on FDA Adverse Event Reporting System(FAERS); d. Patient education on auto medication, poly pharmacy, drug‐drug reaction, sharing of antibiotics, prevailing trends in infection in the community; e. monitor and rule out the cause of the infection by determining Infection vs. contamination vs. colonization‐ false positive, duration antibiotic therapy (7 days/10 days); f. institution need based specific “ASP” review committee/expertise; g. correlation of meat (Red / White) consumption and clearance of infection by an expert dietician/nutritionist are missing elements. Based on our review here with we propose a “DTAS” constituting the following members: pharmacy director, charge nurse, director of nursing (DON), Clinical Infectious Diseases Director (an MD with expertise in interventions strategies on the infectious diseases expertise across the modality as per the health care setting (Ex: Surgery, Transplant medicine, Oncology, and ICU), director of nutrition/dietician, director of clinical laboratory, director of housekeeping operation, local representative of state health and human services, local representative USDA, hospital epidemiologist, local representative of state and national epidemiology and/or local representative of CDC&P, with an expertise on morbidity and mortality rate of infectious disease and vital statistics data, and community liaison with an expertise in patient education with resource supplemented via health district administration (“Bubble Map”). Taken together, implementation of the DTAS to break the Chain of Infection for Mitigation of Antibiotic Resistance Pandemic (ARP) across the globe in both acute and long term care (Hospice, rehabilitation, dialysis centers, outpatient clinics in the developing countries, physicians in private practice), while plausible “ASP” code enforcement just as the law enforcement agencies would be the pivotal first step to mitigate ARP.Support or Funding InformationSupported by Professional Development Funds provided by SWTJC to Subburaj KannanThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.