Characterisation of Ferritin-Lymphocyte Ratio in COVID-19.

The ferritin-lymphocyte ratio (FLR) is a novel inflammatory biomarker for the assessment of acute COVID-19 patients. However, the prognostic value of FLR for predicting adverse clinical outcomes in COVID-19 remains unclear, which hinders its clinical translation. We characterised the prognostic value of FLR in COVID-19 patients, as compared to established inflammatory markers.

Low CRB-65 Scores Effectively Rule out Adverse Clinical Outcomes in COVID-19 Irrespective of Chest Radiographic Abnormalities.

CRB-65 (onfusion; espiratory rate ≥ 30/min; lood pressure ≤ 90/60 mmHg; age ≥ years) is a risk score for prognosticating patients with COVID-19 pneumonia. However, a significant proportion of COVID-19 patients have normal chest X-rays (CXRs). The influence of CXR abnormalities on the prognostic value of CRB-65 is unknown, limiting its wider applicability.

Effective prognostic and clinical risk stratification in COVID-19 using multimodality biomarkers.

In acute coronavirus disease 19 (COVID-19) patients, effective clinical risk stratification has important implications on treatment and therapeutic resource distribution. This article reviews the evidence behind a wide range of biomarkers with prognostic value in COVID-19. Patient characteristics and co-morbidities, such as cardiovascular and respiratory diseases, are associated with increased mortality risk.

Normal high-sensitivity cardiac troponin for ruling-out inpatient mortality in acute COVID-19.

Introduction: Assessment of inpatient mortality risk in COVID-19 patients is important for guiding clinical decision-making. High sensitivity cardiac troponin T (hs-cTnT) is a biomarker of cardiac injury associated with a worse prognosis in COVID-19. We explored how hs-cTnT could potentially be used in clinical practice for ruling in and ruling out mortality in COVID-19.

The Efficacy of Using Combination Therapy against Multi-Drug and Extensively Drug-Resistant in Clinical Settings.

Unlabelled: is a Gram-negative bacterium which is capable of developing a high level of antibiotic resistance. It has been placed on the WHO's critical priority pathogen list and it is commonly found in ventilator-associated pneumonia infections, blood stream infections and other largely hospital-acquired illnesses. These infections are difficult to effectively treat due to their increasing antibiotic resistance and as such patients are often treated with antibiotic combination regimens.

Zidovudine enhances activity of carbapenems against NDM-1-producing Enterobacteriaceae.

Objectives: To investigate the efficacy of zidovudine in combination with carbapenems against NDM-1-producing Enterobacteriaceae.

Methods: MICs were determined using the broth microdilution method. The combinatory effects of zidovudine and carbapenems were examined using the chequerboard method and time-kill analysis.

A model-based analysis identifies differences in phenotypic resistance between in vitro and in vivo: implications for translational medicine within tuberculosis.

Proper characterization of drug effects on Mycobacterium tuberculosis relies on the characterization of phenotypically resistant bacteria to correctly establish exposure-response relationships. The aim of this work was to evaluate the potential difference in phenotypic resistance in in vitro compared to murine in vivo models using CFU data alone or CFU together with most probable number (MPN) data following resuscitation with culture supernatant. Predictions of in vitro and in vivo phenotypic resistance i.

Translational Model-Informed Approach for Selection of Tuberculosis Drug Combination Regimens in Early Clinical Development.

The development of optimal treatment regimens in tuberculosis (TB) remains challenging due to the need of combination therapy and possibility of pharmacodynamic (PD) interactions. Preclinical information about PD interactions needs to be used more optimally when designing early bactericidal activity (EBA) studies. In this work, we developed a translational approach which can allow for forward translation to predict efficacy of drug combination in EBA studies using the Multistate Tuberculosis Pharmacometric (MTP) and the General Pharmacodynamic Interaction (GPDI) models informed by in vitro static time-kill data.

Effect of Different Media on the Bactericidal Activity of Colistin and on the Synergistic Combination With Azidothymidine Against Positive Colistin-Resistant .

Antimicrobial susceptibility testing (AST) performed according to defined guidelines is important to identify resistance and to predict the clinical success or failure of specific antibiotic therapy. However, these guidelines do not cover all physiological conditions that can have a tremendous impact on resistance. In this study, we tested the susceptibility of thirteen positive strains against colistin, one of the last resort antibiotics for treating multi-drug resistant pathogens, in media recommended for ASTs as well as - physiologically more relevant - in human serum and artificial urine (AU).

Antibiotic combination therapy against resistant bacterial infections: synergy, rejuvenation and resistance reduction.

: Anti-Microbial Resistance (AMR) is a pandemic which threatens modern medicine. There is a lack of effective drug treatment due to the slow pace, high cost and low achievable sales prices of new antibiotic monotherapies. New hope comes in the shape of antibiotic combination therapy, which although used by mother nature, is under-explored and could provide the solution to AMR.

Modulation of allergic inflammation in the lung by a peptide derived from Mycobacteria tuberculosis chaperonin 60.1.

Background: We have previously demonstrated that Mycobacteria tuberculosis chaperonin 60.1 inhibits leucocyte diapedesis and bronchial hyperresponsiveness in a murine model of allergic lung inflammation.

Methods: In the present study, we have investigated the effect of a shorter peptide sequence derived from Cpn 60.

Urinary bactericidal activity of colistin and azidothymidine combinations against mcr-1-positive colistin-resistant Escherichia coli.

A phase 1 clinical study was performed to assess the pharmacokinetics and safety of intravenous (i.v.) administration of colistin methanesulfonate (CMS) and azidothymidine (AZT) alone and in combination.

Synergistic activity of colistin with azidothymidine against colistin-resistant Klebsiella pneumoniae clinical isolates collected from inpatients in Greek hospitals.

Background: New antibiotics are urgently needed to treat multi-drug resistant infections; however, production of novel antibiotics is diminishing. Synergistic combination drug therapy to enhance the activity of available antibiotics may improve management of patients with resistant infections.

Methods: Colistin-resistant Klebsiella pneumoniae isolates were collected from inpatients in 10 Greek hospitals and used to study combination activity of colistin plus azidothymidine.

Bedaquiline kills persistent Mycobacterium tuberculosis with no disease relapse: an in vivo model of a potential cure.

Objectives: Non-replicating persistent Mycobacterium tuberculosis is difficult to kill since the organisms become undetectable using our conventional diagnostic methods and tolerant to anti-TB drugs. Resuscitation-promoting factors (RPFs) have been used to 'wake up' non-replicating persisters, making them easy to detect. Bedaquiline is a novel bactericidal and sterilizing anti-TB drug with the potential to eradicate RPF-dependent persistent M.

Azidothymidine Produces Synergistic Activity in Combination with Colistin against Antibiotic-Resistant .

Bacterial infections remain a leading killer worldwide, which is worsened by the continuous emergence of antibiotic resistance. In particular, antibiotic-resistant are prevalent and extremely difficult to treat. Repurposing existing drugs and improving the therapeutic potential of existing antibiotics represent an attractive novel strategy.

Serum bactericidal activity of colistin and azidothymidine combinations against mcr-1-positive colistin-resistant Escherichia coli.

To examine the serum bactericidal activity of colistin sulphate (CS) and azidothymidine (AZT) combinations, time-kill curves were performed in native and heat-inactivated human serum with five colistin-resistant and four colistin-susceptible Gram-negative strains. Serum samples were spiked according to median and minimum plasma peak concentrations measured in a phase 1 clinical study in which seven healthy subjects received three (q12h) 1-h intravenous infusions of 4, 2 and 2 MIU colistin methanesulfonate (CMS) co-administered with 200, 100 and 100 mg AZT, respectively. This trial was performed to assess pharmacokinetics and safety of CMS/AZT combination therapy.

Forecasting Clinical Dose-Response From Preclinical Studies in Tuberculosis Research: Translational Predictions With Rifampicin.

A crucial step for accelerating tuberculosis drug development is bridging the gap between preclinical and clinical trials. In this study, we developed a preclinical model-informed translational approach to predict drug effects across preclinical systems and early clinical trials using the in vitro-based Multistate Tuberculosis Pharmacometric (MTP) model using rifampicin as an example. The MTP model predicted rifampicin biomarker response observed in 1) a hollow-fiber infection model, 2) a murine study to determine pharmacokinetic/pharmacodynamic indices, and 3) several clinical phase IIa early bactericidal activity (EBA) studies.

Moxifloxacin Replacement in Contemporary Tuberculosis Drug Regimens Is Ineffective against Persistent Mycobacterium tuberculosis in the Cornell Mouse Model.

Tuberculosis (TB), which is caused by , remains a leading killer worldwide, and disease control is hampered by the ineffective control of persistent infections. Substitution of moxifloxacin for isoniazid or ethambutol in standard anti-TB regimens reduces the treatment duration and relapse rates in animal studies, and 4-month regimens were not noninferior in clinical trials. Resuscitation-promoting factor (RPF)-dependent bacilli have recently been implicated in persistence.

A Method to Evaluate Persistent Mycobacterium tuberculosis In Vitro and in the Cornell Mouse Model of Tuberculosis.

Persistent Mycobacterium tuberculosis will not grow on solid or liquid media. They will, however, grow in the presence of resuscitation promoting factors (RPF). Here we describe the production of RPF rich culture supernatants, and their use for the stimulation of growth of persisters in vitro as well as in the Cornell model of tuberculosis.

Optimal doses of rifampicin in the standard drug regimen to shorten tuberculosis treatment duration and reduce relapse by eradicating persistent bacteria.

Objectives: Although high-dose rifampicin holds promise for improving tuberculosis disease control by eradication of persistent bacteria, the optimal dose of rifampicin that kills persistent bacteria and shortens the treatment duration is unknown.

Methods: The Cornell mouse model was used to test the efficacy of rifampicin at elevated doses combined with isoniazid and pyrazinamide to kill actively growing and persistent bacilli and to measure relapse rate. Persistent bacteria were evaluated using Mycobacterium tuberculosis culture supernatant containing resuscitation-promoting factors.

Comparing the action of HT61 and chlorhexidine on natural and model Staphylococcus aureus membranes.

HT61 and chlorhexidine (CHX) are both putative membrane-active antimicrobials, which non-specifically target the anionic lipids abundant in bacterial membranes. In model systems, the ability of these antimicrobials to partition into lipid monolayers and increase the permeability of lipid bilayers is dependent upon the presence and proportion of anionic lipids such as phosphatidylglycerol. Despite their apparent similarity in membrane affinity, we have found that HT61 and CHX differ in the extent to which they affect membrane integrity.

Mechanism of Action of a Membrane-Active Quinoline-Based Antimicrobial on Natural and Model Bacterial Membranes.

HT61 is a quinoline-derived antimicrobial, which exhibits bactericidal potency against both multiplying and quiescent methicillin resistant and sensitive Staphylococcus aureus, and has been proposed as an adjunct for other antimicrobials to extend their usefulness in the face of increasing antimicrobial resistance. In this study, we have examined HT61's effect on the permeability of S. aureus membranes and whether this putative activity can be attributed to an interaction with lipid bilayers.

A Novel erm(44) Gene Variant from a Human Staphylococcus saprophyticus Isolate Confers Resistance to Macrolides and Lincosamides but Not Streptogramins.

A novel erm(44) gene variant, erm(44), has been identified by whole-genome sequencing in a Staphylococcus saprophyticus isolate from the skin of a healthy person. It has the particularity to confer resistance to macrolides and lincosamides but not to streptogramin B when expressed in S. aureus The erm(44) gene resides on a 19,400-bp genomic island which contains phage-associated proteins and is integrated into the chromosome of S.