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1.
PLoS One ; 16(12): e0261849, 2021.
Article in English | MEDLINE | ID: covidwho-1623664

ABSTRACT

BACKGROUND: Tuberculosis (TB) and COVID-19 pandemics are both diseases of public health threat globally. Both diseases are caused by pathogens that infect mainly the respiratory system, and are involved in airborne transmission; they also share some clinical signs and symptoms. We, therefore, took advantage of collected sputum samples at the early stage of COVID-19 outbreak in Ghana to conduct differential diagnoses of long-standing endemic respiratory illness, particularly tuberculosis. METHODOLOGY: Sputum samples collected through the enhanced national surveys from suspected COVID-19 patients and contact tracing cases were analyzed for TB. The sputum samples were processed using Cepheid's GeneXpert MTB/RIF assay in pools of 4 samples to determine the presence of Mycobacterium tuberculosis complex. Positive pools were then decoupled and analyzed individually. Details of positive TB samples were forwarded to the NTP for appropriate case management. RESULTS: Seven-hundred and seventy-four sputum samples were analyzed for Mycobacterium tuberculosis in both suspected COVID-19 cases (679/774, 87.7%) and their contacts (95/774, 12.3%). A total of 111 (14.3%) were diagnosed with SARS CoV-2 infection and six (0.8%) out of the 774 individuals tested positive for pulmonary tuberculosis: five (83.3%) males and one female (16.7%). Drug susceptibility analysis identified 1 (16.7%) rifampicin-resistant tuberculosis case. Out of the six TB positive cases, 2 (33.3%) tested positive for COVID-19 indicating a coinfection. Stratifying by demography, three out of the six (50%) were from the Ayawaso West District. All positive cases received appropriate treatment at the respective sub-district according to the national guidelines. CONCLUSION: Our findings highlight the need for differential diagnosis among COVID-19 suspected cases and regular active TB surveillance in TB endemic settings.


Subject(s)
COVID-19/diagnosis , COVID-19/epidemiology , Coinfection/diagnosis , Coinfection/epidemiology , Mycobacterium tuberculosis/genetics , Pandemics/prevention & control , SARS-CoV-2/genetics , Tuberculosis, Pulmonary/diagnosis , Tuberculosis, Pulmonary/epidemiology , Antibiotics, Antitubercular/pharmacology , COVID-19/prevention & control , COVID-19/virology , Coinfection/virology , Diagnosis, Differential , Drug Resistance, Bacterial/drug effects , Female , Ghana/epidemiology , Humans , Male , Microbial Sensitivity Tests , Mycobacterium tuberculosis/drug effects , Rifampin/pharmacology , Sputum/microbiology , Tuberculosis, Pulmonary/microbiology
2.
PLoS One ; 16(12): e0261442, 2021.
Article in English | MEDLINE | ID: covidwho-1593549

ABSTRACT

A laboratory validation study was conducted to assess the equivalence of Xpert MTB/RIF Ultra testing on the GeneXpert System and the GeneXpert Omni System ('Omni') for tuberculosis and rifampicin resistance. High concordance of the two devices was demonstrated for well-characterized clinical samples as well as control materials, with controls tested on Omni at normal and challenging environmental conditions (i.e. 35°C, 90% relative humidity). Equivalence of the Cts for all probes was also shown. Equivalence was demonstrated for the Omni and GeneXpert devices for tuberculosis and rifampicin resistance detection for a diverse range of clinical specimens and environmental conditions.


Subject(s)
Antibiotics, Antitubercular/pharmacology , Mycobacterium tuberculosis/drug effects , Point-of-Care Testing , Tuberculosis, Multidrug-Resistant/diagnosis , Tuberculosis, Pulmonary/diagnosis , Bacterial Proteins/genetics , DNA-Directed RNA Polymerases/genetics , Drug Resistance, Multiple, Bacterial/genetics , Humans , Microbial Sensitivity Tests , Mycobacterium tuberculosis/genetics , Mycobacterium tuberculosis/isolation & purification , Rifampin/pharmacology , Sputum/microbiology , Tuberculosis, Multidrug-Resistant/drug therapy , Tuberculosis, Pulmonary/drug therapy
3.
Science ; 372(6547): 1169-1175, 2021 06 11.
Article in English | MEDLINE | ID: covidwho-1583231

ABSTRACT

Emergent resistance to all clinical antibiotics calls for the next generation of therapeutics. Here we report an effective antimicrobial strategy targeting the bacterial hydrogen sulfide (H2S)-mediated defense system. We identified cystathionine γ-lyase (CSE) as the primary generator of H2S in two major human pathogens, Staphylococcus aureus and Pseudomonas aeruginosa, and discovered small molecules that inhibit bacterial CSE. These inhibitors potentiate bactericidal antibiotics against both pathogens in vitro and in mouse models of infection. CSE inhibitors also suppress bacterial tolerance, disrupting biofilm formation and substantially reducing the number of persister bacteria that survive antibiotic treatment. Our results establish bacterial H2S as a multifunctional defense factor and CSE as a drug target for versatile antibiotic enhancers.


Subject(s)
Anti-Bacterial Agents/pharmacology , Cystathionine gamma-Lyase/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Hydrogen Sulfide/metabolism , Pseudomonas aeruginosa/drug effects , Staphylococcus aureus/drug effects , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/metabolism , Biofilms , Crystallography, X-Ray , Cystathionine gamma-Lyase/chemistry , Cystathionine gamma-Lyase/genetics , Cystathionine gamma-Lyase/metabolism , Drug Discovery , Drug Resistance, Bacterial , Drug Synergism , Drug Tolerance , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Mice , Microbial Sensitivity Tests , Models, Molecular , Molecular Docking Simulation , Molecular Structure , Pseudomonas Infections/drug therapy , Pseudomonas Infections/microbiology , Pseudomonas aeruginosa/enzymology , Pseudomonas aeruginosa/genetics , Pseudomonas aeruginosa/growth & development , Small Molecule Libraries/chemistry , Small Molecule Libraries/metabolism , Small Molecule Libraries/pharmacology , Staphylococcal Infections/drug therapy , Staphylococcal Infections/microbiology , Staphylococcus aureus/enzymology , Staphylococcus aureus/genetics , Staphylococcus aureus/growth & development
4.
Biomed Res Int ; 2021: 2347872, 2021.
Article in English | MEDLINE | ID: covidwho-1582891

ABSTRACT

Introduction: Patients with acute respiratory distress syndrome caused by coronavirus disease 2019 (COVID-19) are at risk for superadded infections, especially infections caused by multidrug resistant (MDR) pathogens. Before the COVID-19 pandemic, the prevalence of MDR infections, including infections caused by MDR Klebsiella pneumoniae (K. pneumoniae), was very high in Iran. This study is aimed at assessing the genetic diversity, antimicrobial resistance pattern, and biofilm formation in K. pneumoniae isolates obtained from patients with COVID-19 and ventilator-associated pneumonia (VAP) hospitalized in an intensive care unit (ICU) in Iran. Methods: In this cross-sectional study, seventy K. pneumoniae isolates were obtained from seventy patients with COVID-19 hospitalized in the ICU of Shahid Beheshti hospital, Kashan, Iran, from May to September, 2020. K. pneumoniae was detected through the ureD gene. Antimicrobial susceptibility testing was done using the Kirby-Bauer disc diffusion method, and biofilm was detected using the microtiter plate assay method. Genetic diversity was also analyzed through polymerase chain reaction based on enterobacterial repetitive intergenic consensus (ERIC-PCR). The BioNumerics software (v. 8.0, Applied Maths, Belgium) was used for analyzing the data and drawing dendrogram and minimum spanning tree. Findings. K. pneumoniae isolates had varying levels of resistance to antibiotics meropenem (80.4%), cefepime-aztreonam-piperacillin/tazobactam (70%), tobramycin (61.4%), ciprofloxacin (57.7%), gentamicin (55.7%), and imipenem (50%). Around 77.14% of isolates were MDR, and 42.8% of them formed biofilm. Genetic diversity analysis revealed 28 genotypes (E1-E28) and 74.28% of isolates were grouped into ten clusters (i.e., clusters A-J). Clusters were further categorized into three major clusters, i.e., clusters E, H, and J. Antimicrobial resistance to meropenem, tobramycin, gentamicin, and ciprofloxacin in cluster J was significantly higher than cluster H, denoting significant relationship between ERIC clusters and antimicrobial resistance. However, there was no significant difference among major clusters E, H, and J respecting biofilm formation. Conclusion: K. pneumoniae isolates obtained from patients with COVID-19 have high antimicrobial resistance, and 44.2% of them have genetic similarity and can be clustered in three major clusters. There is a significant difference among clusters respecting antimicrobial resistance.


Subject(s)
Biofilms/growth & development , COVID-19/microbiology , Drug Resistance, Multiple, Bacterial/genetics , Genetic Variation/genetics , Klebsiella Infections/microbiology , Klebsiella pneumoniae/genetics , Pneumonia, Ventilator-Associated/microbiology , Anti-Bacterial Agents/pharmacology , Biofilms/drug effects , COVID-19/virology , Cross-Sectional Studies , Humans , Intensive Care Units , Iran , Klebsiella Infections/drug therapy , Klebsiella pneumoniae/drug effects , Microbial Sensitivity Tests/methods , Pandemics/prevention & control , Pneumonia, Ventilator-Associated/virology
5.
ChemMedChem ; 16(22): 3418-3427, 2021 11 19.
Article in English | MEDLINE | ID: covidwho-1525425

ABSTRACT

Currently, limited therapeutic options are available for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). We have developed a set of pyrazine-based small molecules. A series of pyrazine conjugates was synthesized by microwave-assisted click chemistry and benzotriazole chemistry. All the synthesized conjugates were screened against the SAR-CoV-2 virus and their cytotoxicity was determined. Computational studies were carried out to validate the biological data. Some of the pyrazine-triazole conjugates (5 d-g) and (S)-N-(1-(benzo[d]thiazol-2-yl)-2-phenylethyl)pyrazine-2-carboxamide 12 i show significant potency against SARS-CoV-2 among the synthesized conjugates. The selectivity index (SI) of potent conjugates indicates significant efficacy compared to the reference drug (Favipiravir).


Subject(s)
Antiviral Agents/pharmacology , Pyrazines/pharmacology , SARS-CoV-2/drug effects , Amides/pharmacology , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/metabolism , Antiviral Agents/toxicity , Chlorocebus aethiops , Coronavirus RNA-Dependent RNA Polymerase/metabolism , Microbial Sensitivity Tests , Molecular Docking Simulation , Molecular Structure , Pyrazines/chemical synthesis , Pyrazines/metabolism , Pyrazines/toxicity , Quantitative Structure-Activity Relationship , Vero Cells
6.
Curr Opin Infect Dis ; 34(6): 718-727, 2021 12 01.
Article in English | MEDLINE | ID: covidwho-1506882

ABSTRACT

PURPOSE OF REVIEW: The COVID-19 pandemic has caused multiple challenges to ICUs, including an increased rate of secondary infections, mostly caused by Gram-negative micro-organisms. Worrying trends of resistance acquisition complicate this picture. We provide a review of the latest evidence to guide management of patients with septic shock because of Gram-negative bacteria. RECENT FINDINGS: New laboratory techniques to detect pathogens and specific resistance patterns from the initial culture are available. Those may assist decreasing the time to adequate antimicrobial therapy and avoid unnecessary broad-spectrum antibiotic overuse. New antimicrobials, including ß-lactam/ß-lactamase inhibitor combinations, such as ceftolozane-tazobactam, imipenem-relebactam or meropenem-vaborbactam and cephalosporins, such as cefiderocol targeted to specific pathogens and resistance patterns are available for use in the clinical setting. Optimization of antibiotic dosing and delivery should follow pharmacokinetic and pharmacodynamic principles and wherever available therapeutic drug monitoring. Management of sepsis has brought capillary refill time back to the spotlight along with more reasoned fluid resuscitation and a moderate approach to timing of dialysis initiation. SUMMARY: Novel rapid diagnostic tests and antimicrobials specifically targeted to Gram-negative pathogens are available and should be used within the principles of antimicrobial stewardship including de-escalation and short duration of antimicrobial therapy.


Subject(s)
COVID-19 , Gram-Negative Bacterial Infections , Shock, Septic , Anti-Bacterial Agents/therapeutic use , Cephalosporins , Diagnostic Tests, Routine , Gram-Negative Bacteria , Gram-Negative Bacterial Infections/diagnosis , Gram-Negative Bacterial Infections/drug therapy , Humans , Microbial Sensitivity Tests , Pandemics , SARS-CoV-2 , Shock, Septic/drug therapy
7.
Chem Commun (Camb) ; 57(93): 12476-12479, 2021 Nov 23.
Article in English | MEDLINE | ID: covidwho-1500757

ABSTRACT

We identified small-molecule enhancers of cellular stress granules by observing molecular crowding of proteins and RNAs in a time-dependent manner. Hit molecules sensitized the IRF3-mediated antiviral mechanism in the presence of poly(I:C) and inhibited the replication of SARS-CoV-2 by inducing stress granule formation. Thus, modulating multimolecular crowding can be a promising strategy against SARS-CoV-2.


Subject(s)
Antiviral Agents/pharmacology , Benzopyrans/pharmacology , Cytoplasmic Granules/drug effects , Pyrazoles/pharmacology , SARS-CoV-2/drug effects , Virus Replication/drug effects , Animals , Antiviral Agents/chemistry , Benzopyrans/chemistry , Cell Line, Tumor , Chlorocebus aethiops , Cytoplasmic Granules/metabolism , Dose-Response Relationship, Drug , Drug Combinations , Humans , Interferon Regulatory Factor-3/metabolism , Lopinavir/pharmacology , Microbial Sensitivity Tests , Molecular Structure , Poly I-C/pharmacology , Pyrazoles/chemistry , Structure-Activity Relationship , Vero Cells
8.
J Clin Microbiol ; 59(9): e0123021, 2021 08 18.
Article in English | MEDLINE | ID: covidwho-1501536

ABSTRACT

The global incidence of mucormycosis has increased in recent years owing to higher numbers of individuals at risk for these infections. The diagnosis and treatment of this aggressive fungal infection are of clinical concern due to differences in species distribution in different geographic areas and susceptibility profiles between different species that are capable of causing highly aggressive infections. The purpose of this study was to evaluate the epidemiology and susceptibility profiles of Mucorales isolates in the United States over a 52-month period. Species identification was performed by combined phenotypic characteristics and DNA sequence analysis, and antifungal susceptibility testing was performed by CLSI M38 broth microdilution for amphotericin B, isavuconazole, itraconazole, and posaconazole. During this time frame, 854 isolates were included, representing 11 different genera and over 26 species, of which Rhizopus (58.6%) was the predominant genus, followed by Mucor (19.6%). The majority of isolates were cultured from the upper and lower respiratory tracts (55%). Amphotericin B demonstrated the most potent in vitro activity, with geometric mean (GM) MICs of ≤0.25 µg/ml against all genera with the exception of Cunninghamella species (GM MIC of 1.30 µg/ml). In head-to-head comparisons, the most active azole was posaconazole, followed by isavuconazole. Differences in azole and amphotericin B susceptibility patterns were observed between the genera with the greatest variability observed with isavuconazole. Awareness of the epidemiology of Mucorales isolates and differences in antifungal susceptibility patterns in the United States may aide clinicians in choosing antifungal treatment regimens. Further studies are warranted to correlate these findings with clinical outcomes.


Subject(s)
Mucorales , Mucormycosis , Amphotericin B/pharmacology , Antifungal Agents/pharmacology , Antifungal Agents/therapeutic use , Fungi , Humans , Itraconazole , Microbial Sensitivity Tests , Mucormycosis/drug therapy , Mucormycosis/epidemiology , United States/epidemiology
9.
Angew Chem Int Ed Engl ; 60(48): 25428-25435, 2021 11 22.
Article in English | MEDLINE | ID: covidwho-1490696

ABSTRACT

The main protease (3CLp) of the SARS-CoV-2, the causative agent for the COVID-19 pandemic, is one of the main targets for drug development. To be active, 3CLp relies on a complex interplay between dimerization, active site flexibility, and allosteric regulation. The deciphering of these mechanisms is a crucial step to enable the search for inhibitors. In this context, using NMR spectroscopy, we studied the conformation of dimeric 3CLp from the SARS-CoV-2 and monitored ligand binding, based on NMR signal assignments. We performed a fragment-based screening that led to the identification of 38 fragment hits. Their binding sites showed three hotspots on 3CLp, two in the substrate binding pocket and one at the dimer interface. F01 is a non-covalent inhibitor of the 3CLp and has antiviral activity in SARS-CoV-2 infected cells. This study sheds light on the complex structure-function relationships of 3CLp and constitutes a strong basis to assist in developing potent 3CLp inhibitors.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Cysteine Proteinase Inhibitors/pharmacology , SARS-CoV-2/drug effects , Small Molecule Libraries/pharmacology , Animals , Antiviral Agents/chemistry , Binding Sites , Chlorocebus aethiops , Coronavirus 3C Proteases/chemistry , Cysteine Proteinase Inhibitors/chemistry , Drug Evaluation, Preclinical , Microbial Sensitivity Tests , Nuclear Magnetic Resonance, Biomolecular , Protein Conformation , Protein Multimerization , SARS-CoV-2/chemistry , Small Molecule Libraries/chemistry , Vero Cells
10.
Mikrobiyol Bul ; 55(4): 648-655, 2021 Oct.
Article in Turkish | MEDLINE | ID: covidwho-1478368

ABSTRACT

Candida auris is a species of fungus that has gained importance in recent years owing to its ability to cause hospital infections and epidemics, resistant to antifungal agents and disinfection processes and frequently misidentified by commercial systems. Hospital outbreaks caused by C.auris have been reported from some countries. It has been determined that C.auris has lower virulence than Candida albicans; however, it is associated with high mortality rates in immunocompromised individuals. An increase in the incidence of invasive fungal infections which can lead to serious complications and death, has been identified in severe coronavirus-2019 (COVID-19) patients or immunocompromised individuals with underlying disease. Studies demonstrated an increase in the frequency of C.auris isolation in COVID-19 patients with candidemia. In this report, the first case of COVID-19 positive C.auris fungemia detected in Turkey was presented. A 71-year-old male patient with a history of myocardial infarction, diabetes mellitus, donation of a single kidney and lobectomy surgery due to lung cancer was hospitalized in the pandemic thoracic surgery service due to the findings consistent with viral pneumonia on thoracic computed tomography. Favipiravir 2 x 600 mg and intravenous dexamethasone 1 x 6 mg therapy was administered. The patient tested positive for SARS-CoV-2 polymerase chain reaction, and severe involvement of the left lung was detected in the following days. Antibiotics were administered, followed by insertion of a right jugular vein catheter and initation of tocilizumab. The patient was transferred to the intensive care unit due to increased respiratory distress. Yeast growth was detected in the patient's hemoculture. The yeast strain could not be identified using API ID 32C (bioMerieux, France) (Sacchromyces kluyveri, Candida sake, unacceptable profile), but was identified as C.auris using the VITEK MALDI TOF MS (bioMerieux, France) (99.9%) system and confirmed by sequencing. The minimum inhibitor concentration values were detected as 3 µg/ml for amphotericin B; > 256 µg/ml for fluconazole; 0.19 µg/ml for voriconazole; 0.19 µg/ml for itraconazole; 0.016 µg/ml for posaconazole; 1 µg/ml for caspofungin and 0.094 µg/ml for anidulafungin by using the antibiotic gradient method. The patient's initial treatment comprised meropenem 3 x 1 g, vancomycin 2 x 1 g, caspofungin 1 x 70 mg, and continued as caspofungine 1 x 50 mg after the loading dose, and vancomycin 1 x 1 g/48 hours from the third day of treatment. The patient died on the ninth day after developing candidemia. The present case is the first case of fungemia caused by C.auris in a COVID-19 positive patient in Turkey, and it emphasizes the need of caution for fungemia due to C.auris in intensive care units in our country which has a high COVID-19 incidence.


Subject(s)
COVID-19 , Candidemia , Fungemia , Aged , Antifungal Agents/pharmacology , Antifungal Agents/therapeutic use , Candida , Candidemia/diagnosis , Candidemia/drug therapy , Candidemia/epidemiology , Fungemia/drug therapy , Humans , Male , Microbial Sensitivity Tests , SARS-CoV-2 , Turkey/epidemiology
11.
Mycopathologia ; 186(6): 883-887, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1474058

ABSTRACT

Candida auris has been reported worldwide, but only in December 2020, the first strain from a COVID-19 patient in Brazil was isolated. Here, we describe the genome sequence of this susceptible C. auris strain and performed variant analysis of the genetic relatedness with strains from other geographic localities.


Subject(s)
COVID-19 , Candidiasis , Nanopores , Antifungal Agents , Brazil , Candida/genetics , Humans , Microbial Sensitivity Tests , SARS-CoV-2
12.
Mem. Inst. Oswaldo Cruz ; 116: e210207, 2021. tab, graf
Article in English | LILACS (Americas) | ID: covidwho-1463351

ABSTRACT

BACKGROUND Treatment of mycoses is often ineffective, usually prolonged, and has some side effects. These facts highlight the importance of discovering new molecules to treat fungal infections. OBJECTIVES To search the Medicines for Malaria Venture COVID Box for drugs with antifungal activity. METHODS Fourteen human pathogenic fungi were tested against the 160 drugs of this collection at 1.0 µM concentration. We evaluated the ability of the drugs to impair fungal growth, their fungicidal nature, and morphological changes caused to cells. FINDINGS Thirty-four molecules (21.25%) presented antifungal activity. Seven are antifungal drugs and one is the agricultural fungicide cycloheximide. The other drugs with antifungal activity included antibiotics (n = 3), antimalarials (n = 4), antivirals (n = 2), antiparasitcs (n = 3), antitumor agents (n = 5), nervous system agents (n = 3), immunosuppressants (n = 3), antivomiting (n = 1), antiasthmatic (n = 1), and a genetic disorder agent (n = 1). Several of these drugs inhibited Histoplasma capsulatum and Paracoccidioides brasiliensis growth (15 and 20, respectively), while Fusarium solani was not affected by the drugs tested. Most drugs were fungistatic, but niclosamide presented fungicidal activity against the three dimorphic fungi tested. Cyclosporine affected morphology of Cryptococcus neoformans. MAIN CONCLUSIONS These drugs represent new alternatives to the development of more accessible and effective therapies to treat human fungal infections.


Subject(s)
Humans , Pharmaceutical Preparations , Cryptococcus neoformans , COVID-19 , Malaria/drug therapy , Microbial Sensitivity Tests , Drug Repositioning , SARS-CoV-2 , Antifungal Agents/therapeutic use , Antifungal Agents/pharmacology
13.
Ann Med ; 53(1): 1779-1786, 2021 12.
Article in English | MEDLINE | ID: covidwho-1462157

ABSTRACT

BACKGROUND: An unexpected high prevalence of enterococcal bloodstream infection (BSI) has been observed in critically ill patients with COVID-19 in the intensive care unit (ICU). MATERIALS AND METHODS: The primary objective was to describe the characteristics of ICU-acquired enterococcal BSI in critically ill patients with COVID-19. A secondary objective was to exploratorily assess the predictors of 30-day mortality in critically ill COVID-19 patients with ICU-acquired enterococcal BSI. RESULTS: During the study period, 223 patients with COVID-19 were admitted to COVID-19-dedicated ICUs in our centre. Overall, 51 episodes of enterococcal BSI, occurring in 43 patients, were registered. 29 (56.9%) and 22 (43.1%) BSI were caused by Enterococcus faecalis and Enterococcus faecium, respectively. The cumulative incidence of ICU-acquired enterococcal BSI was of 229 episodes per 1000 ICU admissions (95% mid-p confidence interval [CI] 172-298). Most patients received an empirical therapy with at least one agent showing in vitro activity against the blood isolate (38/43, 88%). The crude 30-day mortality was 42% (18/43) and 57% (4/7) in the entire series and in patients with vancomycin-resistant E. faecium BSI, respectively. The sequential organ failure assessment (SOFA) score showed an independent association with increased mortality (odds ratio 1.32 per one-point increase, with 95% confidence interval 1.04-1.66, p = .021). CONCLUSIONS: The cumulative incidence of enterococcal BSI is high in critically ill patients with COVID-19. Our results suggest a crucial role of the severity of the acute clinical conditions, to which both the underlying viral pneumonia and the enterococcal BSI may contribute, in majorly influencing the outcome.KEY MESSAGESThe cumulative incidence of enterococcal BSI is high in critically ill patients with COVID-19.The crude 30-day mortality of enterococcal BSI in critically ill patients with COVID-19 may be higher than 40%.There could be a crucial role of the severity of the acute clinical conditions, to which both the underlying viral pneumonia and the enterococcal BSI may contribute, in majorly influencing the outcome.


Subject(s)
Bacteremia/epidemiology , COVID-19/epidemiology , Cross Infection/epidemiology , Enterococcus faecalis , Enterococcus faecium , Gram-Positive Bacterial Infections/epidemiology , Mortality , Vancomycin-Resistant Enterococci , Aged , Bacteremia/microbiology , Critical Illness , Female , Gram-Positive Bacterial Infections/microbiology , Humans , Intensive Care Units , Male , Microbial Sensitivity Tests , Middle Aged , Organ Dysfunction Scores , Retrospective Studies , SARS-CoV-2
14.
Molecules ; 26(19)2021 Oct 06.
Article in English | MEDLINE | ID: covidwho-1463769

ABSTRACT

Pristine high-density bulk disks of MgB2 with added hexagonal BN (10 wt.%) were prepared using spark plasma sintering. The BN-added samples are machinable by chipping them into desired geometries. Complex shapes of different sizes can also be obtained by the 3D printing of polylactic acid filaments embedded with MgB2 powder particles (10 wt.%). Our present work aims to assess antimicrobial activity quantified as viable cells (CFU/mL) vs. time of sintered and 3D-printed materials. In vitro antimicrobial tests were performed against the bacterial strains Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Staphylococcus aureus ATCC 25923, Enterococcus faecium DSM 13590, and Enterococcus faecalis ATCC 29212; and the yeast strain Candida parapsilosis ATCC 22019. The antimicrobial effects were found to depend on the tested samples and microbes, with E. faecium being the most resistant and E. coli the most susceptible.


Subject(s)
Anti-Infective Agents/pharmacology , Bacteria/drug effects , Boron Compounds/pharmacology , Fungi/drug effects , Magnesium Compounds/pharmacology , Candida parapsilosis/drug effects , Enterococcus faecalis/drug effects , Enterococcus faecium/drug effects , Escherichia coli/drug effects , Microbial Sensitivity Tests , Polyesters/pharmacology , Printing, Three-Dimensional , Pseudomonas aeruginosa/drug effects , Staphylococcus aureus/drug effects
15.
Molecules ; 26(19)2021 Sep 23.
Article in English | MEDLINE | ID: covidwho-1463764

ABSTRACT

Due to their large possibility of the structure modification, alkylammonium gemini surfactants are a rapidly growing class of compounds. They exhibit significant surface, aggregation and antimicrobial properties. Due to the fact that, in order to achieve the desired utility effect, the minimal concentration of compounds are used, they are in line with the principle of greenolution (green evolution) in chemistry. In this study, we present innovative synthesis of the homologous series of gemini surfactants modified at the spacer by the ether group, i.e., 3-oxa-1,5-pentane-bis(N-alkyl-N,N-dimethylammonium bromides). The critical micelle concentrations were determined. The minimal inhibitory concentrations of the synthesized compounds were determined against bacteria Escherichia coli ATCC 10536 and Staphylococcus aureus ATCC 6538; yeast Candida albicans ATCC 10231; and molds Aspergillus niger ATCC 16401 and Penicillium chrysogenum ATCC 60739. We also investigated the relationship between antimicrobial activity and alkyl chain length or the nature of the spacer. The obtained results indicate that the synthesized compounds are effective microbicides with a broad spectrum of biocidal activity.


Subject(s)
Anti-Infective Agents/pharmacology , Quaternary Ammonium Compounds/pharmacology , Surface-Active Agents/pharmacology , Anti-Infective Agents/chemistry , Aspergillus niger/drug effects , Candida albicans/drug effects , Escherichia coli/drug effects , Green Chemistry Technology , Micelles , Microbial Sensitivity Tests , Molecular Structure , Penicillium chrysogenum/drug effects , Quaternary Ammonium Compounds/chemistry , Staphylococcus aureus/drug effects , Surface-Active Agents/chemistry
17.
Molecules ; 25(8)2020 Apr 18.
Article in English | MEDLINE | ID: covidwho-1450861

ABSTRACT

(1) Background: Viral respiratory infections cause life-threatening diseases in millions of people worldwide every year. Human coronavirus and several picornaviruses are responsible for worldwide epidemic outbreaks, thus representing a heavy burden to their hosts. In the absence of specific treatments for human viral infections, natural products offer an alternative in terms of innovative drug therapies. (2) Methods: We analyzed the antiviral properties of the leaves and stem bark of the mulberry tree (Morus spp.). We compared the antiviral activity of Morus spp. on enveloped and nonenveloped viral pathogens, such as human coronavirus (HCoV 229E) and different members of the Picornaviridae family-human poliovirus 1, human parechovirus 1 and 3, and human echovirus 11. The antiviral activity of 12 water and water-alcohol plant extracts of the leaves and stem bark of three different species of mulberry-Morus alba var. alba, Morus alba var. rosa, and Morus rubra-were evaluated. We also evaluated the antiviral activities of kuwanon G against HCoV-229E. (3) Results: Our results showed that several extracts reduced the viral titer and cytopathogenic effects (CPE). Leaves' water-alcohol extracts exhibited maximum antiviral activity on human coronavirus, while stem bark and leaves' water and water-alcohol extracts were the most effective on picornaviruses. (4) Conclusions: The analysis of the antiviral activities of Morus spp. offer promising applications in antiviral strategies.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus/drug effects , Morus/chemistry , Plant Extracts/pharmacology , Respiratory Tract Infections/drug therapy , Antiviral Agents/therapeutic use , Cell Line , Cytopathogenic Effect, Viral/drug effects , Flavonoids/pharmacology , Humans , Mass Spectrometry , Microbial Sensitivity Tests , Picornaviridae/drug effects , Plant Bark/chemistry , Plant Extracts/therapeutic use , Plant Leaves/chemistry
18.
J Antimicrob Chemother ; 76(10): 2538-2545, 2021 09 15.
Article in English | MEDLINE | ID: covidwho-1447597

ABSTRACT

OBJECTIVES: To assess the spread of New Delhi metallo-ß-lactamase-1 (NDM-1)-producing Klebsiella pneumoniae ST147 organisms in Poland since an introduction from Tunisia in March 2015, including their phylogenetic position in the global population of the high-risk clone. METHODS: Out of 8925 unique NDM-positive K. pneumoniae isolates identified in Poland from April 2015 till December 2019, 126 isolates, including the Tunisian imports, were related by PFGE and blaNDM gene-carrying Tn125 transposon derivatives. Forty-seven representative isolates were sequenced by Illumina MiSeq. The phylogeny, resistome, virulome and plasmid replicons were analysed and compared with the international ST147 strains. Plasmids of six isolates were studied by the MinION sequencing. RESULTS: A high homogeneity of the 47 isolates was observed, with minor variations in their resistomes and plasmid replicon profiles. However, the detailed SNP comparison discerned a strict outbreak cluster of 40 isolates. All of the organisms were grouped within the ST147 phylogenetic international lineage, and four NDM-1 producers from Tunisia, Egypt and France were the closest relatives of the Polish isolates. Yersiniabactin genes (YbST280 type) were located within the ICEKpn12-like element in most of the outbreak isolates, characterized by O2v1 and KL64 antigen loci. The blaNDM-1 genes were located in double-replicon IncFIIK2+IncFIBK plasmids. CONCLUSIONS: The continuous spread of K. pneumoniae ST147 NDM-1 in Poland since 2015, largely in the Warsaw area, is demonstrated by this genomic analysis. The isolates showed a high degree of homogeneity, and close relatedness to organisms spreading in the Mediterranean region.


Subject(s)
Klebsiella Infections , Klebsiella pneumoniae , Anti-Bacterial Agents , Humans , Klebsiella Infections/epidemiology , Klebsiella pneumoniae/genetics , Microbial Sensitivity Tests , Phylogeny , Plasmids/genetics , Poland/epidemiology , beta-Lactamases/genetics
19.
Eur J Med Chem ; 221: 113494, 2021 Oct 05.
Article in English | MEDLINE | ID: covidwho-1446590

ABSTRACT

In the search for new anti-influenza virus (IV) compounds, we have identified the 1,2,4-triazolo[1,5-a]pyrimidine (TZP) as a very suitable scaffold to obtain compounds able to disrupt IV RNA-dependent RNA polymerase (RdRP) PA-PB1 subunits heterodimerization. In this work, in order to acquire further SAR insights for this class of compounds and identify more potent derivatives, we designed and synthesized additional series of analogues to investigate the role of the substituents around the TZP core. To this aim, we developed four facile and efficient one-step procedures for the synthesis of 5-phenyl-, 6-phenyl- and 7-phenyl-2-amino-[1,2,4]triazolo[1,5-a]pyrimidines, and 2-amino-5-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-ol. Two analogues having the ethyl carboxylate moiety at the C-2 position of the TZP were also prepared in good yields. Then, the scaffolds herein synthesized and two previous scaffolds were functionalized and evaluated for their anti-IAV activity, leading to the identification of compound 22 that showed both anti-PA-PB1 (IC50 = 19.5 µM) and anti-IAV activity (EC50 = 16 µM) at non-toxic concentrations, thus resulting among the most active TZP derivatives reported to date by us. A selection of the synthesized compounds, along with a set of in-house available analogues, was also tested against SARS-CoV-2. The most promising compound 49 from this series displayed an EC50 value of 34.47 µM, highlighting the potential of the TPZ scaffold in the search for anti-CoV agents.


Subject(s)
Antiviral Agents/pharmacology , Protein Multimerization/drug effects , Pyrimidines/pharmacology , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Triazoles/pharmacology , Viral Proteins/antagonists & inhibitors , Animals , Antiviral Agents/chemical synthesis , Chlorocebus aethiops , Dogs , Drug Design , HEK293 Cells , Humans , Influenza A virus/drug effects , Madin Darby Canine Kidney Cells , Microbial Sensitivity Tests , Pyrimidines/chemical synthesis , SARS-CoV-2/drug effects , Triazoles/chemical synthesis , Vero Cells
20.
J Am Chem Soc ; 143(40): 16777-16785, 2021 10 13.
Article in English | MEDLINE | ID: covidwho-1442692

ABSTRACT

The most recent global health crisis caused by the SARS-CoV-2 outbreak and the alarming use of chemical warfare agents highlight the necessity to produce efficient protective clothing and masks against biohazard and chemical threats. However, the development of a multifunctional protective textile is still behind to supply adequate protection for the public. To tackle this challenge, we designed multifunctional and regenerable N-chlorine based biocidal and detoxifying textiles using a robust zirconium metal-organic framework (MOF), UiO-66-NH2, as a chlorine carrier which can be easily coated on textile fibers. A chlorine bleaching converted the amine groups located on the MOF linker to active N-chlorine structures. The fibrous composite exhibited rapid biocidal activity against both Gram-negative bacteria (E. coli) and Gram-positive bacteria (S. aureus) with up to a 7 log reduction within 5 min for each strain as well as a 5 log reduction of SARS-CoV-2 within 15 min. Moreover, the active chlorine loaded MOF/fiber composite selectively and rapidly degraded sulfur mustard and its chemical simulant 2-chloroethyl ethyl sulfide (CEES) with half-lives less than 3 minutes. The versatile MOF-based fibrous composite designed here has the potential to serve as protective cloth against both biological and chemical threats.


Subject(s)
Anti-Bacterial Agents/pharmacology , Antiviral Agents/pharmacology , Chemical Warfare Agents/chemistry , Chlorine/pharmacology , Metal-Organic Frameworks/pharmacology , Protective Clothing , Animals , Anti-Bacterial Agents/chemical synthesis , Antiviral Agents/chemical synthesis , Cell Line , Chlorine/chemistry , Escherichia coli/drug effects , Halogenation , Humans , Metal-Organic Frameworks/chemical synthesis , Microbial Sensitivity Tests , Mustard Gas/analogs & derivatives , Mustard Gas/chemistry , Oxidation-Reduction , SARS-CoV-2/drug effects , Staphylococcus aureus/drug effects , Textiles , Zirconium/chemistry
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