ABSTRACT
The emergence of carbapenem-resistant, hypervirulent Klebsiella pneumoniae is a new threat to health care. We studied the molecular epidemiology of carbapenem-resistant Klebsiella pneumoniae isolates in Qatar using whole-genome sequence data. We also characterized the prevalence and genetic basis of hypervirulent phenotypes and established the virulence potential using a Galleria mellonella model. Of 100 Klebsiella isolates studied, NDM and OXA-48 were the most common carbapenemases. Core genome single-nucleotide polymorphism (SNP) analysis indicated the presence of diverse sequence types and clonal lineages; isolates belonging to Klebsiella quasipneumoniae subsp. quasipneumoniae sequence type 196 (ST196) and ST1416 may be disseminated among several health care centers. Ten K. pneumoniae isolates carried rmpA and/or truncated rmpA2, and 2 isolates belonged to KL2, indicating low prevalence of classical hypervirulent isolates. Isolates carrying both carbapenem resistance and hypervirulence genes were confined mainly to ST231 and ST383 isolates. One ST383 isolate was further investigated by MinION sequencing, and the assembled genome indicated that blaNDM was located on an IncHI1B-type plasmid (pFQ61_ST383_NDM-5) which coharbored several virulence factors, including the regulator of the mucoid phenotype (rmpA), the regulator of mucoid phenotype 2 (rmpA2), and aerobactin (iucABCD and iutA), likely resulting from recombination events. Comparative genomics indicated that this hybrid plasmid may be present in two additional Qatari ST383 isolates. Carbapenem-resistant, hypervirulent K. pneumoniae ST383 isolates pose an emerging threat to global health due to their simultaneous hypervirulence and multidrug resistance.
Subject(s)
Klebsiella Infections , Klebsiella pneumoniae , Humans , Carbapenems/pharmacology , Qatar/epidemiology , Klebsiella Infections/drug therapy , Klebsiella Infections/epidemiology , Klebsiella , beta-Lactamases/genetics , Plasmids/genetics , Genomics , Anti-Bacterial Agents/pharmacologyABSTRACT
Understanding the relationship of COVID-19 to stroke is important. We compare characteristics of pre-pandemic stroke (PPS), cases in acute COVID infection (CS) and in patients who have recovered from COVID-19 infection (RCS). We interrogated the Qatar stroke database for all stroke admissions between Jan 2020 and Feb 2021 (PPS) to CS and RCS to determine how COVID-19 affected ischemic stroke sub-types, clinical course, and outcomes prior to, during and post-pandemic peak. There were 3264 cases admitted (pre-pandemic: 3111, stroke in COVID-19: 60 and recovered COVID-19 stroke: 93). Patients with CS were significantly younger, had more severe symptoms, fever on presentation, more ICU admissions and poor stroke recovery at discharge when compared to PPS and RCS. Large vessel disease and cardioembolic disease was significantly higher in CS compared to PPS or RCS. There was a significant decline in stroke mimics in CS. Stroke in RCS has characteristics similar to PPS with no evidence of lasting effects of the virus on the short-term. However, CS is a more serious disease and tends to be more severe and have a poor prognosis.
Subject(s)
COVID-19 , Ischemic Stroke , Stroke , COVID-19/epidemiology , Humans , Ischemic Stroke/diagnosis , Ischemic Stroke/epidemiology , Pandemics , Qatar/epidemiology , Stroke/diagnosis , Stroke/epidemiologyABSTRACT
One hundred forty-nine carbapenem-resistant Enterobacterales from clinical samples obtained between April 2014 and November 2017 were subjected to whole genome sequencing and multi-locus sequence typing. Klebsiella pneumoniae (81, 54.4%) and Escherichia coli (38, 25.5%) were the most common species. Genes encoding metallo-ß-lactamases were detected in 68 (45.8%) isolates, and OXA-48-like enzymes in 60 (40.3%). blaNDM-1 (45; 30.2%) and blaOXA-48 (29; 19.5%) were the most frequent. KPC-encoding genes were identified in 5 (3.6%) isolates. Most common sequence types were E. coli ST410 (8; 21.1%) and ST38 (7; 18.4%), and K. pneumoniae ST147 (13; 16%) and ST231 (7; 8.6%).
Subject(s)
Anti-Bacterial Agents/pharmacology , Drug Resistance, Multiple, Bacterial , Enterobacteriaceae Infections/microbiology , Enterobacteriaceae/drug effects , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Enterobacteriaceae/genetics , Enterobacteriaceae Infections/drug therapy , Enterobacteriaceae Infections/epidemiology , Female , Humans , Infant , Male , Middle Aged , Qatar/epidemiology , Young AdultABSTRACT
Patients with COVID-19-associated candidemia (CAC) in an intensive care unit (ICU) were matched 1:2 with those without candidemia, based on ICU admission date and length of stay in ICU being at least equal to that before candidemia in the corresponding case. The incidence rate of CAC was 2.34 per 1000 ICU days. Eighty cases could be matched to appropriate controls. In the multivariate conditional logistic regression analysis, age (P 0.001), and sequential organ failure assessment score (P 0.046) were the only risk factors independently associated with CAC. Tocilizumab and corticosteroids therapy were not independently associated with candidemia. LAY SUMMARY: In COVID-19 patients who need medical care in an intensive care unit, the risk of developing bloodstream Candida infection is higher in older patients and in those who have a more severe critical illness. Treatment with steroids or tocilizumab does not seem to affect the risk of candida bloodstream infection in these patients.
Subject(s)
COVID-19/epidemiology , Candidemia/epidemiology , Adrenal Cortex Hormones/therapeutic use , Adult , Aged , Antibodies, Monoclonal, Humanized/therapeutic use , Female , Humans , Incidence , Intensive Care Units , Male , Middle Aged , Risk FactorsABSTRACT
OBJECTIVES: The presence of COVID-19 infection may increase the risk of thrombotic events including ischemic strokes. Whilst a number of recent reports suggest that COVID-19 associated stroke tends to be severe, there is limited data on the effects of COVID-19 in prospective registries. MATERIAL AND METHODS: To determine how COVID-19 infection may affect cerebrovascular disease, we evaluated the ischemic stroke sub-types, clinical course and outcomes prior to and during the pandemic in Qatar. The Hamad General Hospital (HGH) stroke database was interrogated for stroke admissions during the last 4 months of 2019 and January-May 2020. RESULTS: In Qatar the number of confirmed cases of COVID-19 increased from only 2 in February to 779 in March, 12,628 in April and 45,501 in May. Stroke admissions to HGH declined marginally from an average of 97/month for six pre-COVID months to 72/month in March-May. There were 32 strokes that were positive for COVID-19. When compared to non-COVID-19 stroke during the three months of the pandemic, COVID-19 patients were younger with significantly lower rates of hypertension, diabetes and dyslipidemia. COVID-19 positive patients had more cortical strokes (34.4% vs 5.6%; p = 0.001), severe disease (NIHSS >10: 34.4% vs 16.7%; p = 0.001) prolonged hospitalization and fewer with good recovery (mRS 0-2: 28.1% vs 51.9%; p = 0.001). CONCLUSIONS: When compared to six pre-COVID-19 months, the number of ischemic stroke admissions during the three months of the pandemic declined marginally. COVID-19 positive patients were more likely to have a large cortical stroke with severe symptoms and poor outcome.
Subject(s)
Brain Ischemia/etiology , COVID-19/complications , Stroke/etiology , Adult , Aged , Brain Ischemia/diagnosis , Brain Ischemia/therapy , COVID-19/diagnosis , COVID-19/therapy , Databases, Factual , Female , Humans , Male , Middle Aged , Patient Admission , Prognosis , Qatar , Risk Factors , Severity of Illness Index , Stroke/diagnosis , Stroke/therapy , Time FactorsABSTRACT
Tuberculous mastitis (TBM) is relatively rare disease with an incidence ranging between 0.1 and 4%. Most of the cases are culture negative and often mistaken with chronic benign idiopathic granulomatous mastitis (IGM). It is very crucial to distinguish culture negative TBM from other causes of mastitis as the treatment differs tremendously. We describe here in a young woman originally from India and residing in Qatar; a non endemic area of tuberculosis; for more then fifteen years. She presented with 2 months history of right breast mass, followed by low grade fever, dry cough, headache, erythema nodosum, arthritis, and arthralgia. In view of the origin of the patient, positive family history for tuberculosis and positive quantiferon, the patient was started empirically on anti-tuberculous treatment (ATT). One week later she developed paradoxical reaction to ATT. This case illustrates unusual and rare manifestations of primary TBM and highlights the importance of differentiating and treating culture negative TBM from IGM.
Subject(s)
Arthritis, Reactive , Erythema Nodosum , Granulomatous Mastitis , Cough , Erythema Nodosum/diagnosis , Erythema Nodosum/drug therapy , Female , Granulomatous Mastitis/complications , Granulomatous Mastitis/diagnosis , Granulomatous Mastitis/drug therapy , Headache , HumansABSTRACT
Mucor is an angioinvasive fungus that was reported mainly in immunocompromised patients. It usually presents as rhino-orbital, pulmonary, gastrointestinal, and disseminated disease. Isolated renal mucormycosis is an extremely rare infection in immunocompetent patients and is associated with high fatality rate. Early diagnosis, prompt antifungal treatment, and surgery give the patient the best chance for cure and survival. We describe herein a case of renal zygomycosis caused by Apophysomyces elegans (A. elegans) in an immunocompetent host. To the best of our knowledge, this is the first case of renal A. elegans to be reported from Qatar and the Middle East.
Subject(s)
Mucorales , Mucormycosis , Antifungal Agents/therapeutic use , Humans , Male , Mucormycosis/diagnosis , Mucormycosis/drug therapyABSTRACT
BACKGROUND: Cryptococcosis is a major opportunistic invasive mycosis that mostly affects immunocompromised patients. METHODS: This was an observational study of all culture-confirmed cases of cryptococcosis conducted in the State of Qatar from January 2005 to December 2016. Cryptococcus fungi were identified using Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS). RESULTS: Fourteen culture-confirmed cases of cryptococcosis were identified during the study period. Four patients had a Human Immunodeficiency Virus (HIV) infection with low CD4 count and five were receiving immunosuppressant medications. The rest of the patients were apparently immuno-competent. The central nervous system was the most common site of infection (57%) followed by bloodstream infection (36%) and pneumonia (14%). One patient had a cryptococcal scrotal infection. Twelve isolates were Cryptococcus neoformans and 2 were Cryptococcus laurentii. All isolates were within the wild type ECV values to amphotericin B and fluconazole. Only 2 patients with bloodstream infection (HIV negative) died. The rest were cured of the infection. CONCLUSION: Cryptococcosis is a rare fungal disease in the State of Qatar, mostly diagnosed in Asian immigrants. The central nervous system is the most common site of infection. The presence of the fungus in the blood carries a high mortality.
Subject(s)
Cryptococcosis , HIV Infections , Antifungal Agents/therapeutic use , Basidiomycota , Cryptococcosis/diagnosis , Cryptococcosis/drug therapy , Cryptococcosis/epidemiology , HIV Infections/complications , HIV Infections/drug therapy , HIV Infections/epidemiology , Humans , IncidenceABSTRACT
BACKGROUND: There are limited data on Coronavirus Disease 2019 (COVID-19) outcomes at a national level, and none after 60 days of follow up. The aim of this study was to describe national, 60-day all-cause mortality associated with COVID-19, and to identify risk factors associated with admission to an intensive care unit (ICU). METHODS: This was a retrospective cohort study including the first consecutive 5000 patients with COVID-19 in Qatar who completed 60 days of follow up by June 17, 2020. The primary outcome was all-cause mortality at 60 days after COVID-19 diagnosis. In addition, we explored risk factors for admission to ICU. RESULTS: Included patients were diagnosed with COVID-19 between February 28 and April 17, 2020. The majority (4436, 88.7%) were males and the median age was 35 years [interquartile range (IQR) 28-43]. By 60 days after COVID-19 diagnosis, 14 patients (0.28%) had died, 10 (0.2%) were still in hospital, and two (0.04%) were still in ICU. Fatal COVID-19 cases had a median age of 59.5 years (IQR 55.8-68), and were mostly males (13, 92.9%). All included pregnant women (26, 0.5%), children (131, 2.6%), and healthcare workers (135, 2.7%) were alive and not hospitalized at the end of follow up. A total of 1424 patients (28.5%) required hospitalization, out of which 108 (7.6%) were admitted to ICU. Most frequent co-morbidities in hospitalized adults were diabetes (23.2%), and hypertension (20.7%). Multivariable logistic regression showed that older age [adjusted odds ratio (aOR) 1.041, 95% confidence interval (CI) 1.022-1.061 per year increase; P < 0.001], male sex (aOR 4.375, 95% CI 1.964-9.744; P < 0.001), diabetes (aOR 1.698, 95% CI 1.050-2.746; P 0.031), chronic kidney disease (aOR 3.590, 95% CI 1.596-8.079, P 0.002), and higher BMI (aOR 1.067, 95% CI 1.027-1.108 per unit increase; P 0.001), were all independently associated with increased risk of ICU admission. CONCLUSIONS: In a relatively younger national cohort with a low co-morbidity burden, COVID-19 was associated with low all-cause mortality. Independent risk factors for ICU admission included older age, male sex, higher BMI, and co-existing diabetes or chronic kidney disease.
Subject(s)
Coronavirus Infections/diagnosis , Pneumonia, Viral/diagnosis , Adolescent , Adult , Aged , Betacoronavirus , COVID-19 , Child , Cohort Studies , Coronavirus Infections/epidemiology , Female , Hospitalization , Humans , Intensive Care Units , Logistic Models , Male , Middle Aged , Odds Ratio , Pandemics , Pneumonia, Viral/epidemiology , Pregnancy , Pregnancy Complications, Infectious , Qatar/epidemiology , Retrospective Studies , Risk Factors , SARS-CoV-2 , Young AdultABSTRACT
In the era of the diseasomes and interactome networks, linking genetics with phenotypic traits in Turner syndrome should be studied thoroughly. As a part of this stratagem, mosaicism of both X and Y chromosome which is a common finding in TS and an evaluation of congenital heart diseases in the different situations of mosaic TS types, can be helpful in the identification of disturbed sex chromosomes, genes and signaling pathway actors. Here we report the case of a mosaic TS associated to four left-sided CHD, including BAV, COA, aortic aneurysms and dissections at an early age. The mosaicism included two cell lines, well-defined at the cytogenetic and molecular levels: a cell line which is monosomic for Xp and Xq genes (45,X) and another which is trisomic for pseudoautosomal genes that are present on the X and Y chromosomes and escape X inactivation: 45,X[8]/46,X,idic(Y)(pterâq11.2::q11.2âpter)[42]. This case generates two hypotheses about the contribution of genes linked to the sex chromosomes and the signaling pathways involving these genes, in left-sided heart diseases. The first hypothesis suggests the interaction between X chromosome and autosomal genes or loci of aortic development, possibly dose-dependent, and which could be in the framework of TGF-ß-SMAD signaling pathways. The second implies that left-sided congenital heart lesions involve sex chromosomes loci. The reduced dosage of X chromosome gene(s), escaping X inactivation during development, contributes to this type of CHD. Regarding our case, these X chromosome genes may have homologues at the Y chromosome, but the process of inactivation of the centromeres of the isodicentric Y spreads to the concerned Y chromosome genes. Therefore, this case emerges as an invitation to consider the mosaics of Turner syndrome and to study their phenotypes in correlation with their genotypes to discover the underlying developmental and genetic mechanisms, especially the ones related to sex chromosomes.
Subject(s)
Heart Defects, Congenital/genetics , Mosaicism , Sex Chromosome Aberrations , Turner Syndrome/genetics , Adolescent , Aortic Coarctation/genetics , Aortic Valve/abnormalities , Aortic Valve/metabolism , Bicuspid Aortic Valve Disease , Chromosome Banding , Chromosomes, Human, X/genetics , Chromosomes, Human, Y/genetics , Female , Heart Defects, Congenital/complications , Heart Valve Diseases/genetics , Heart Valve Diseases/metabolism , Humans , In Situ Hybridization, Fluorescence , Karyotyping , Turner Syndrome/complicationsABSTRACT
BACKGROUND: To report a case of bilateral acute angle closure-glaucoma following the use of subcutaneous Tramadol. CASE PRESENTATION: A 42-year-old healthy man with unremarkable past medical and ocular history, was admitted to the Orthopedic Department for surgical treatment of a bilateral open fracture of the femur following a road accident. Three hoursafterTramadolsubcutaneous injection, the patient complained of a bilateral acute painful visual loss with persistent vomiting. An ocular examination showed bilateral acute angle-closure-glaucoma. The patient was treated with topical anti-glaucoma therapy and intravenous Mannitol 20%.After resolution of ocular hypertension attack, NdYag laser peripheral iridotomy was performed on both eyes. After a follow-up period of 7 days visual acuity improved to 20/20 in both eyes and intraocular pressure returned to normal levels. CONCLUSIONS: This case highlights the risk of developing bilateral acute angle-closure glaucoma after Tramadol administration.
Subject(s)
Analgesics, Opioid/adverse effects , Glaucoma, Angle-Closure/chemically induced , Tramadol/adverse effects , Adult , Analgesics, Opioid/administration & dosage , Humans , Injections, Subcutaneous , Intraocular Pressure , Male , Tramadol/administration & dosageABSTRACT
OBJECTIVES: To evaluate the safety and efficacy of switching from intravenous (IV) to oral antimicrobial therapy in patients with Enterobacterales bacteraemia, after completion of 3-5 days of microbiologically active IV therapy. METHODS: A multicentre, open-label, randomized trial of adults with monomicrobial Enterobacterales bacteraemia caused by a strain susceptible to ≥1 oral beta-lactam, quinolone, or trimethoprim/sulfamethoxazole. Inclusion criteria included completion of 3-5 days of microbiologically active IV therapy, being afebrile and haemodynamically stable for ≥48 hours, and absence of an uncontrolled source of infection. Pregnancy, endocarditis, and neurological infections were exclusion criteria. Randomization, stratified by urinary source of bacteraemia, was to continue IV (IV Group) or to switch to oral therapy (Oral Group). Agents and duration of therapy were determined by the treating physicians. The primary endpoint was treatment failure, defined as death, need for additional antimicrobial therapy, microbiological relapse, or infection-related re-admission within 90 days. Non-inferiority threshold was set at 10% in the 95% CI for the difference in the proportion with treatment failure between the Oral and IV Groups in the modified intention-to-treat population. The protocol was registered at ClinicalTrials.gov (NCT04146922). RESULTS: In the modified intention-to-treat population, treatment failure occurred in 21 of 82 (25.6%) in the IV Group, and 18 of 83 (21.7%) in the Oral Group (risk difference -3.7%, 95% CI -16.6% to 9.2%). The proportions of subjects with any adverse events (AE), serious AE, or AE leading to treatment discontinuation were comparable. DISCUSSION: In patients with Enterobacterales bacteraemia, oral switch, after initial IV antimicrobial therapy, clinical stability, and source control, is non-inferior to continuing IV therapy.
Subject(s)
Bacteremia , Quinolones , Adult , Humans , Anti-Bacterial Agents/adverse effects , Bacteremia/drug therapy , Bacteremia/microbiology , Treatment Failure , Administration, Intravenous , Treatment OutcomeABSTRACT
Candida glabrata is a commensal yeast of the gastrointestinal tract and skin of humans. However, it causes opportunistic infections in immunocompromised patients, and is the second most common Candida pathogen causing bloodstream infections. Although there are many studies on the epidemiology of C. glabrata infections, the fine- and large-scale geographical nature of C. glabrata remain incompletely understood. Here we investigated both the fine- and large-scale population structure of C. glabrata through genome sequencing of 80 clinical isolates obtained from six tertiary hospitals in Qatar and by comparing with global collections. Our fine-scale analyses revealed high genetic diversity within the Qatari population of C. glabrata and identified signatures of recombination, inbreeding and clonal expansion within and between hospitals, including evidence for nosocomial transmission among coronavirus disease 2019 (COVID-19) patients. In addition to signatures of recombination at the population level, both MATa and MATα alleles were detected in most hospitals, indicating the potential for sexual reproduction in clinical environments. Comparisons with global samples showed that the Qatari C. glabrata population was very similar to those from other parts of the world, consistent with the significant role of recent anthropogenic activities in shaping its population structure. Genome-wide association studies identified both known and novel genomic variants associated with reduced susceptibilities to fluconazole, 5-flucytosine and echinocandins. Together, our genomic analyses revealed the diversity, transmission patterns and antifungal drug resistance mechanisms of C. glabrata in Qatar as well as the relationships between Qatari isolates and those from other parts of the world.
Subject(s)
Candida glabrata , Cross Infection , Humans , Candida glabrata/genetics , Cross Infection/epidemiology , Genome-Wide Association Study , Metagenomics , Genomics , Recombination, GeneticABSTRACT
OBJECTIVE: This study investigated the association between Coronavirus Disease 2019 mRNA vaccination and stroke in Qatar. METHODS: Between December 1, 2020, and April 11, 2023, a matched case-control study was conducted to investigate the association between 3036 acute stroke cases and 3036 controls drawn from the entire population of Qatar. RESULTS: The adjusted odds ratio (aOR) for vaccination among cases compared to controls was 0.87 (95% CI: 0.75-1.00). The aOR was 0.74 (95% CI: 0.45-1.23) for a single vaccine dose, 0.87 (95% CI: 0.73-1.04) for primary-series vaccination (two doses), and 0.91 (95% CI: 0.66-1.25) for booster vaccination (three or more doses). The aOR was 0.87 (95% CI: 0.72-1.04) for BNT162b2 and 0.86 (95% CI: 0.67-1.11) for mRNA-1273. Subgroup analyses, considering different durations since vaccination, also demonstrated no association. Subgroup analyses based on nationality, age, number of coexisting conditions, or prior infection status yielded similar results. Subgroup analysis, stratified by stroke type, suggested an association between vaccination and cerebral venous sinus thrombosis (aOR of 2.50 [95% CI: 0.97-6.44]), but it did not reach statistical significance. CONCLUSION: There was no evidence of an increased risk of stroke following vaccination, both in the short term and in the long term, extending beyond a year after receiving the vaccine.
Subject(s)
COVID-19 Vaccines , COVID-19 , SARS-CoV-2 , Stroke , Vaccination , Humans , Qatar/epidemiology , Case-Control Studies , Male , Female , Middle Aged , COVID-19/prevention & control , COVID-19/epidemiology , Stroke/epidemiology , Aged , Adult , Vaccination/adverse effects , COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/administration & dosage , BNT162 Vaccine/administration & dosage , Odds Ratio , 2019-nCoV Vaccine mRNA-1273 , Risk FactorsABSTRACT
Health care workers (HCWs) may be at a variable risk of SARS-CoV2 infection. Regardless of their involvement in providing direct clinical treatment, most of the prior research had included all HCWs. Understanding infection rates, risk factors and outcomes among different subgroups of HCWs is crucial. From February 28, 2020 to January 1, 2022, we conducted a retrospective analysis encompassing all full-time non-clinical staff (NCS) subcontracted with Hamad Medical Corporation (HMC) facilities. To determine current or previous SARS-CoV2 infection, all personnel underwent RT-PCR and/or serology testing. To identify the demographic factors linked to the risk of infection, we utilized Cox-Hazard regression analysis. Herein 3158/6231 (50.7%) subcontracted NCS tested positive for SARS-CoV-2 by RT-PCR or serology during the research period. The median age was 30 years (IQR 25,35), 69.8% of the population were males, 82.4% were from South Asia, 86.6% did not have any concomitant conditions. 6032 (96.8%) of the population lived in shared housing, while 4749 (76.2%) had low to median levels of education. While infection (PCR positive with or without seropositive results) was independently predicted by male gender, working in the catering, laundry, and security sectors and being intermediate (7-12 years of education), lower (0-6 years of education), higher (exposure to confirmed case), and having symptoms. Male gender, working in the security sectors and being intermediate (7-12 years of education) were independently associated with accidently detected cases (PCR negative and seropositive). 299 (4.8%) required hospitalization, of them 3 cases were severe pneumonia and one required ICU admission without mechanical ventilation, with no deaths reported. In conclusion Infection rates among NCS are high. The majority are asymptomatic and may contribute to ongoing illness spread in the public or in healthcare facilities. During a pandemic, routine screening of this population is crucial and may aid in containing the spread of infection.
ABSTRACT
It has been more than four years since the first report of SARS-CoV-2, and humankind has experienced a pandemic with an unprecedented impact. Moreover, the new variants have made the situation even worse. Among viral enzymes, the SARS-CoV-2 main protease (Mpro) has been deemed a promising drug target vs. COVID-19. Indeed, Mpro is a pivotal enzyme for viral replication, and it is highly conserved within coronaviruses. It showed a high extent of conservation of the protease residues essential to the enzymatic activity, emphasizing its potential as a drug target to develop wide-spectrum antiviral agents effective not only vs. SARS-CoV-2 variants but also against other coronaviruses. Even though the FDA-approved drug nirmatrelvir, a Mpro inhibitor, has boosted the antiviral therapy for the treatment of COVID-19, the drug shows several drawbacks that hinder its clinical application. Herein, we report the synthesis of new thiazolidine-4-one derivatives endowed with inhibitory potencies in the micromolar range against SARS-CoV-2 Mpro. In silico studies shed light on the key structural requirements responsible for binding to highly conserved enzymatic residues, showing that the thiazolidinone core acts as a mimetic of the Gln amino acid of the natural substrate and the central role of the nitro-substituted aromatic portion in establishing π-π stacking interactions with the catalytic His-41 residue.
ABSTRACT
OBJECTIVES: During the COVID-19 pandemic in Qatar, many patients who were severely ill were colonized and infected by Candida auris, an invasive multidrug-resistant yeast pathogen that spreads through nosocomial transmission within healthcare facilities. Here, we investigated the molecular epidemiology of these C. auris isolates and the mechanisms associated with antifungal drug resistance. METHODS: Whole genomes of 76 clinical C. auris isolates, including 65 from patients with COVID-19 collected from March 2020 to June 2021, from nine major hospitals were sequenced on Illumina NextSeq. Single nucleotide polymorphisms were used to determine their epidemiological patterns and mechanisms for antifungal resistance. The data were compared with those published prior to the COVID-19 pandemic from 2018 to 2020 in Qatar. RESULTS: Genomic analysis revealed low genetic variability among the isolates from patients with and without COVID-19, confirming a clonal outbreak and ongoing dissemination of C. auris among various healthcare facilities. Based on antifungal susceptibility profiles, more than 70% (22/28) of isolates were resistant to both fluconazole and amphotericin B. Variant analysis revealed the presence of multi-antifungal resistant isolates with prominent amino acid substitutions: Y132F in ERG11 and V704L in CDR1 linked to reduced azole susceptibility and the emergence of echinocandin resistance samples bearing mutations in FKS1 in comparison with pre-COVID-19 pandemic samples. One sample (CAS109) was resistant to three classes of antifungal drugs with a unique premature stop codon in ERG3 and novel mutations in CDR2, which may be associated with elevated amphotericin B and azole resistance. DISCUSSION: Candida auris isolates from patients with COVID-19 and from most patient samples without COVID-19 in Qatar were highly clonal. The data demonstrated the emergence of multidrug-resistant strains that carry novel mutations linked to enhanced resistance to azoles, echinocandins, and amphotericin B. Understanding the epidemiology and drug resistance will inform the infection control strategy and drug therapy.
Subject(s)
COVID-19 , Candidiasis , Humans , Antifungal Agents/pharmacology , Antifungal Agents/therapeutic use , Candida auris , Amphotericin B/therapeutic use , Pandemics , Qatar/epidemiology , Candidiasis/microbiology , Candida , COVID-19/epidemiology , Echinocandins/therapeutic use , Azoles/therapeutic use , Drug Resistance, Fungal/genetics , Microbial Sensitivity TestsABSTRACT
Introduction: The BNT162b2 mRNA-based vaccine has shown high efficacy in preventing COVID-19 infection but there are limited data on the types and persistence of the humoral and T cell responses to such a vaccine. Methods: Here, we dissect the vaccine-induced humoral and cellular responses in a cohort of six healthy recipients of two doses of this vaccine. Results and discussion: Overall, there was heterogeneity in the spike-specific humoral and cellular responses among vaccinated individuals. Interestingly, we demonstrated that anti-spike antibody levels detected by a novel simple automated assay (Jess) were strongly correlated (r=0.863, P<0.0001) with neutralizing activity; thus, providing a potential surrogate for neutralizing cell-based assays. The spike-specific T cell response was measured with a newly modified T-spot assay in which the high-homology peptide-sequences cross-reactive with other coronaviruses were removed. This response was induced in 4/6 participants after the first dose, and all six participants after the second dose, and remained detectable in 4/6 participants five months post-vaccination. We have also shown for the first time, that BNT162b2 vaccine enhanced T cell responses also against known human common viruses. In addition, we demonstrated the efficacy of a rapid ex-vivo T cell expansion protocol for spike-specific T cell expansion to be potentially used for adoptive-cell therapy in severe COVID-19, immunocompromised individuals, and other high-risk groups. There was a 9 to 13.7-fold increase in the number of expanded T cells with a significant increase of anti-spike specific response showing higher frequencies of both activation and cytotoxic markers. Interestingly, effector memory T cells were dominant in all four participants' CD8+ expanded memory T cells; CD4+ T cells were dominated by effector memory in 2/4 participants and by central memory in the remaining two participants. Moreover, we found that high frequencies of CD4+ terminally differentiated memory T cells were associated with a greater reduction of spike-specific activated CD4+ T cells. Finally, we showed that participants who had a CD4+ central memory T cell dominance expressed a high CD69 activation marker in the CD4+ activated T cells.