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1.
Pediatr Pulmonol ; 57(7): 1814-1817, 2022 07.
Article in English | MEDLINE | ID: covidwho-1913872

ABSTRACT

This pilot study successfully implemented a standardized protocol for tablet-based ototoxicity screening in pediatric cystic fibrosis (CF) patients exposed to aminoglycosides. Further studies are needed to assess the impact of implementation in a larger number of patients, as well as to determine barriers that may exist at centers with variation in available resources. This method of ototoxicity screening represents an accessible alternative to traditional audiology testing, and given the continued improvements in expected life span for people with CF, it is imperative that patients have regular access to this type of screening to allow for early identification of medication-related toxicities.


Subject(s)
Audiology , Cystic Fibrosis , Ototoxicity , Aminoglycosides/adverse effects , Anti-Bacterial Agents/adverse effects , Child , Cystic Fibrosis/drug therapy , Humans , Pharmacists , Pilot Projects
2.
Lancet Glob Health ; 10(4): e543-e554, 2022 04.
Article in English | MEDLINE | ID: covidwho-1778530

ABSTRACT

BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) is a global health emergency. We aimed to evaluate treatment outcomes among people with MDR-TB in Sierra Leone and investigate social and health factors associated with adverse treatment outcomes. METHODS: This national, retrospective cohort study recruited all people notified with MDR-TB to the Sierra Leone National TB Programme, admitted to Lakka hospital (Lakka, Western Area Rural District, Freetown, Sierra Leone) between April, 2017, and September, 2019. Participants were followed up to May, 2021. People who were eligible but had no social or health data available, or were subsequently found to have been misdiagnosed, were excluded from participation. MDR-TB treatment was with the 2017 WHO-recommended short (9-11 month) or long (18-24 month) aminoglycoside-containing regimens. Multivariable logistic regression models examined associations of programmatic social and health data with WHO-defined adverse treatment outcomes (death, treatment failure, loss to follow-up). FINDINGS: Of 370 notified MDR-TB cases, 365 (99%) were eligible for study participation (five participants were excluded due to lack of social or health data or misdiagnosis). Treatment was started by 341 (93%) of 365 participants (317 received the short regimen, 24 received the long regimen, and 24 received no treatment). Median age was 35 years (IQR 26-45), 263 (72%) of 365 were male and 102 (28%) were female, 71 (19%) were HIV-positive, and 127 (35%) were severely underweight (body-mass index <16·5 kg/m2). Overall, 267 (73%) of 365 participants had treatment success, 95 (26%) had an adverse outcome, and three (1%) were still on treatment in May, 2021. Age 45-64 years (adjusted odds ratio [aOR] 2·4, 95% CI 1·2-5·0), severe underweight (aOR 4·2, 1·9-9·3), untreated HIV (aOR 10, 2·6-40·0), chronic lung disease (aOR 2·0, 1·0-4·2), previously unsuccessful drug-sensitive tuberculosis retreatment (aOR 4·3, 1·0-19), and a long regimen (aOR 6·5, 2·3-18·0) were associated with adverse outcomes. A sensitivity analysis showed that prothionamide resistance (aOR 3·1, 95% CI 1·5-10·0) and aminoglycoside-related complete deafness (aOR 6·6, 1·3-35) were independently associated with adverse outcomes. INTERPRETATION: MDR-TB treatment success in Sierra Leone approached WHO targets and the short regimen was associated with higher success. The social and health factors associated with adverse outcomes in this study suggest a role for integrated tuberculosis, HIV, and non-communicable disease services alongside nutritional and socioeconomic support for people with MDR-TB and emphasise the urgent need to scale up coverage of all-oral aminoglycoside-sparing regimens. FUNDING: Wellcome Trust, Joint Global Health Trials.


Subject(s)
HIV Infections , Tuberculosis, Multidrug-Resistant , Tuberculosis , Adult , Aminoglycosides , Antitubercular Agents/therapeutic use , Female , HIV Infections/drug therapy , HIV Infections/epidemiology , Humans , Male , Middle Aged , Retrospective Studies , Sierra Leone/epidemiology , Thinness , Treatment Outcome , Tuberculosis/drug therapy , Tuberculosis, Multidrug-Resistant/drug therapy , Tuberculosis, Multidrug-Resistant/epidemiology
3.
JCI Insight ; 6(21)2021 11 08.
Article in English | MEDLINE | ID: covidwho-1506181

ABSTRACT

COVID-19 is caused by SARS-CoV-2 (SC2) and is more prevalent and severe in elderly and patients with comorbid diseases (CM). Because chitinase 3-like-1 (CHI3L1) is induced during aging and CM, the relationships between CHI3L1 and SC2 were investigated. Here, we demonstrate that CHI3L1 is a potent stimulator of the SC2 receptor angiotensin converting enzyme 2 (ACE2) and viral spike protein priming proteases (SPP), that ACE2 and SPP are induced during aging, and that anti-CHI3L1, kasugamycin, and inhibitors of phosphorylation abrogate these ACE2- and SPP-inductive events. Human studies also demonstrate that the levels of circulating CHI3L1 are increased in the elderly and patients with CM, where they correlate with COVID-19 severity. These studies demonstrate that CHI3L1 is a potent stimulator of ACE2 and SPP, that this induction is a major mechanism contributing to the effects of aging during SC2 infection, and that CHI3L1 co-opts the CHI3L1 axis to augment SC2 infection. CHI3L1 plays a critical role in the pathogenesis of and is an attractive therapeutic target in COVID-19.


Subject(s)
Aging , COVID-19/metabolism , Chitinase-3-Like Protein 1/metabolism , Aging/drug effects , Aminoglycosides/pharmacology , Aminoglycosides/therapeutic use , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/drug therapy , Cell Line, Tumor , Chitinase-3-Like Protein 1/antagonists & inhibitors , HEK293 Cells , Humans , SARS-CoV-2/physiology
4.
J Glob Antimicrob Resist ; 26: 308-316, 2021 09.
Article in English | MEDLINE | ID: covidwho-1313234

ABSTRACT

OBJECTIVES: The aim of this study was to investigate the trends in serotypes and in vitro antimicrobial susceptibility of Streptococcus pneumoniae causing adult invasive pneumococcal disease (IPD) to dalbavancin, telavancin, tedizolid, eravacycline, omadacycline and other comparator antibiotics from 2017-2020 following implementation of the 13-valent pneumococcal conjugate vaccine (PCV-13) and during the COVID-19 (coronavirus disease 2019) pandemic. METHODS: During the study period, 237 S. pneumoniae isolates were collected from non-duplicate patients, covering 15.0% of IPD cases in Taiwan. Antimicrobial susceptibility testing was performed using a Sensititre® system. A latex agglutination method (ImmuLex™ Pneumotest Kit) was used to determine serotypes. RESULTS: Susceptibility rates were high for vancomycin (100%), teicoplanin (100%) and linezolid (100%), followed by ceftaroline (non-meningitis) (98.3%), moxifloxacin (94.9%) and quinupristin/dalfopristin (89.9%). MIC50 and MIC90 values of dalbavancin, telavancin, tedizolid, eravacycline and omadacycline were generally low. Non-vaccine serotype 23A was the leading cause of IPD across the adult age range. Isolates of serotype 15B were slightly fewer than those of PCV-13 serotypes in patients aged ≥65 years. The overall case fatality rate was 15.2% (36/237) but was especially high for non-PCV-13 serotype 15B (21.4%; 3/14). Vaccine coverage was 44.7% for PCV-13 and 49.4% for the 23-valent pneumococcal polysaccharide vaccine (PPSV-23), but was 57% for both PCV-13 and PPSV-23. CONCLUSION: The incidence of IPD was stationary after PCV-13 introduction and only dramatically decreased in the COVID-19 pandemic in 2020. The MIC50 and MIC90 values of dalbavancin, telavancin, tedizolid, eravacycline, omadacycline were generally low for S. pneumoniae causing adult IPD.


Subject(s)
COVID-19 , Streptococcus pneumoniae , Adult , Aminoglycosides , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Drug Resistance, Bacterial , Humans , Lipoglycopeptides , Oxazolidinones , Pandemics , SARS-CoV-2 , Serogroup , Taiwan/epidemiology , Teicoplanin/analogs & derivatives , Teicoplanin/pharmacology , Tetracyclines , Tetrazoles
5.
Ann Clin Microbiol Antimicrob ; 20(1): 37, 2021 May 21.
Article in English | MEDLINE | ID: covidwho-1238722

ABSTRACT

BACKGROUND: Drug repurposing otherwise known as drug repositioning or drug re-profiling is a time-tested approach in drug discovery through which new medical uses are being established for already known drugs. Antibiotics are among the pharmacological agents being investigated for potential anti-SARS-COV-2 activities. The antibiotics are used either to resolve bacterial infections co-existing with COVID-19 infections or exploitation of their potential antiviral activities. Herein, we aimed to review the various antibiotics that have been repositioned for the management of COVID-19. METHODS: This literature review was conducted from a methodical search on PubMed and Web of Science regarding antibiotics used in patients with COVID-19 up to July 5, 2020. RESULTS: Macrolide and specifically azithromycin is the most common antibiotic used in the clinical management of COVID-19. The other antibiotics used in COVID-19 includes teicoplanin, clarithromycin, doxycycline, tetracyclines, levofloxacin, moxifloxacin, ciprofloxacin, and cefuroxime. In patients with COVID-19, antibiotics are used for their immune-modulating, anti-inflammatory, and antiviral properties. The precise antiviral mechanism of most of these antibiotics has not been determined. Moreover, the use of some of these antibiotics against SARS-CoV-2 infection remains highly controversial and not widely accepted. CONCLUSION: The heavy use of antibiotics during the COVID-19 pandemic would likely worsen antibiotic resistance crisis. Consequently, antibiotic stewardship should be strengthened in order to prevent the impacts of COVID-19 on the antibiotic resistance crisis.


Subject(s)
Anti-Bacterial Agents/therapeutic use , COVID-19/drug therapy , Drug Repositioning , SARS-CoV-2 , Aminoglycosides/therapeutic use , Fluoroquinolones/therapeutic use , Glycopeptides/therapeutic use , Humans , Macrolides/therapeutic use
6.
J Infect Public Health ; 14(5): 611-619, 2021 May.
Article in English | MEDLINE | ID: covidwho-1188793

ABSTRACT

BACKGROUND: The emergence and spread of SARS-CoV-2 throughout the world has created an enormous socioeconomic impact. Although there are several promising drug candidates in clinical trials, none is available clinically. Thus, the drug repurposing approach may help to overcome the current pandemic. METHODS: The main protease (Mpro) of SARS-CoV-2 is crucial for cleaving nascent polypeptide chains. Here, FDA-approved antiviral and anti-infection drugs were screened by high-throughput virtual screening (HTVS) followed by re-docking with standard-precision (SP) and extra-precision (XP) molecular docking. The most potent drug's binding was further validated by free energy calculations (Prime/MM-GBSA) and molecular dynamics (MD) simulation. RESULTS: Out of 1397 potential drugs, 157 showed considerable affinity toward Mpro. After HTVS, SP, and XP molecular docking, four high-affinity lead drugs (Iodixanol, Amikacin, Troxerutin, and Rutin) with docking energies -10.629 to -11.776kcal/mol range were identified. Among them, Amikacin exhibited the lowest Prime/MM-GBSA energy (-73.800kcal/mol). It led us to evaluate other aminoglycosides (Neomycin, Paramomycin, Gentamycin, Streptomycin, and Tobramycin) against Mpro. All aminoglycosides were bound to the substrate-binding site of Mpro and interacted with crucial residues. Altogether, Amikacin was found to be the most potent inhibitor of Mpro. MD simulations of the Amikacin-Mpro complex suggested the formation of a complex stabilized by hydrogen bonds, salt bridges, and van der Waals interactions. CONCLUSION: Aminoglycosides may serve as a scaffold to design potent drug molecules against COVID-19. However, further validation by in vitro and in vivo studies is required before using aminoglycosides as an anti-COVID-19 agent.


Subject(s)
COVID-19 , Drug Repositioning , Aminoglycosides , Antiviral Agents/pharmacology , Humans , Molecular Docking Simulation , Peptide Hydrolases , Protease Inhibitors/pharmacology , SARS-CoV-2
8.
Virus Res ; 288: 198102, 2020 10 15.
Article in English | MEDLINE | ID: covidwho-1003124

ABSTRACT

Coronavirus disease 2019 (COVID-19) is an infectious disease, caused by a newly emerged highly pathogenic virus called novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Targeting the main protease (Mpro, 3CLpro) of SARS-CoV-2 is an appealing approach for drug development because this enzyme plays a significant role in the viral replication and transcription. The available crystal structures of SARS-CoV-2 Mpro determined in the presence of different ligands and inhibitor-like compounds provide a platform for the quick development of selective inhibitors of SARS-CoV-2 Mpro. In this study, we utilized the structural information of co-crystallized SARS-CoV-2 Mpro for the structure-guided drug discovery of high-affinity inhibitors from the PubChem database. The screened compounds were selected on the basis of their physicochemical properties, drug-likeliness, and strength of affinity to the SARS-CoV-2 Mpro. Finally, we have identified 6-Deaminosinefungin (PubChem ID: 10428963) and UNII-O9H5KY11SV (PubChem ID: 71481120) as potential inhibitors of SARS-CoV-2 Mpro which may be further exploited in drug development to address SARS-CoV-2 pathogenesis. Both compounds are structural analogs of known antivirals, having considerable protease inhibitory potential with improved pharmacological properties. All-atom molecular dynamics simulations suggested SARS-CoV-2 Mpro in complex with these compounds is stable during the simulation period with minimal structural changes. This work provides enough evidence for further implementation of the identified compounds in the development of effective therapeutics of COVID-19.


Subject(s)
Aminoglycosides/chemistry , Antiviral Agents/chemistry , Betacoronavirus/chemistry , Protease Inhibitors/chemistry , Pyrrolidines/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Aminoglycosides/metabolism , Antiviral Agents/metabolism , Betacoronavirus/enzymology , COVID-19 , Catalytic Domain , Coronavirus 3C Proteases , Coronavirus Infections/drug therapy , Cysteine Endopeptidases/chemistry , Cysteine Endopeptidases/genetics , Cysteine Endopeptidases/metabolism , Drug Discovery , Gene Expression , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Pandemics , Pneumonia, Viral/drug therapy , Protease Inhibitors/metabolism , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , Pyrrolidines/metabolism , SARS-CoV-2 , Substrate Specificity , Sulfonic Acids , Thermodynamics , User-Computer Interface , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolism
9.
Med Hypotheses ; 144: 109984, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-592505

ABSTRACT

In the current COVID-19 pandemic, prioritizing the immunity enhancers is equally important to anti-virals. Defensins are the forgotten molecules that enhance the innate immunity against various microbes. Although macrolides like azithromycin and clarithromycin etc., have been reported to act against respiratory infections but they lack the ability of immunity enhancement through defensins. The aminoglycosides were proved to have defensin mediated antiviral activity, that could enhance the immunity. So, Consideration of aminoglycosides can be a double edge sword viz., against respiratory infection as well as Immunity enhancer (along with anti-virals) for COVID-19 regimen.


Subject(s)
Aminoglycosides/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Defensins/genetics , Drug Repositioning , Immunity, Innate/drug effects , Immunologic Factors/therapeutic use , Macrolides/therapeutic use , Aminoglycosides/pharmacology , Antiviral Agents/pharmacology , COVID-19/epidemiology , COVID-19/immunology , Codon, Nonsense/drug effects , Defensins/biosynthesis , Defensins/physiology , Humans , Immunologic Factors/pharmacology , Models, Genetic , Pandemics , SARS-CoV-2/physiology , Transcription, Genetic/drug effects , Virus Internalization
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