Projecting the development of antimicrobial resistance in Neisseria gonorrhoeae from antimicrobial surveillance data: a mathematical modelling study.

BACKGROUND: The World Health Organization recommends changing the first-line antimicrobial treatment for gonorrhoea when ≥ 5% of Neisseria gonorrhoeae cases fail treatment or are resistant. Susceptibility to ceftriaxone, the last remaining treatment option has been decreasing in many countries. We used antimicrobial resistance surveillance data and developed mathematical models to project the time to reach the 5% threshold for resistance to first-line antimicrobials used for N. gonorrhoeae. METHODS: We used data from the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) in England and Wales from 2000-2018 about minimum inhibitory concentrations (MIC) for ciprofloxacin, azithromycin, cefixime and ceftriaxone and antimicrobial treatment in two groups, heterosexual men and women (HMW) and men who have sex with men (MSM). We developed two susceptible-infected-susceptible models to fit these data and produce projections of the proportion of resistance until 2030. The single-step model represents the situation in which a single mutation results in antimicrobial resistance. In the multi-step model, the sequential accumulation of resistance mutations is reflected by changes in the MIC distribution. RESULTS: The single-step model described resistance to ciprofloxacin well. Both single-step and multi-step models could describe azithromycin and cefixime resistance, with projected resistance levels higher with the multi-step than the single step model. For ceftriaxone, with very few observed cases of full resistance, the multi-step model was needed to describe long-term dynamics of resistance. Extrapolating from the observed upward drift in MIC values, the multi-step model projected ≥ 5% resistance to ceftriaxone could be reached by 2030, based on treatment pressure alone. Ceftriaxone resistance was projected to rise to 13.2% (95% credible interval [CrI]: 0.7-44.8%) among HMW and 19.6% (95%CrI: 2.6-54.4%) among MSM by 2030. CONCLUSIONS: New first-line antimicrobials for gonorrhoea treatment are needed. In the meantime, public health authorities should strengthen surveillance for AMR in N. gonorrhoeae and implement strategies for continued antimicrobial stewardship. Our models show the utility of long-term representative surveillance of gonococcal antimicrobial susceptibility data and can be adapted for use in, and for comparison with, other countries.

Biodegradation of COVID19 antibiotic; azithromycin and its impact on soil microbial community in the presence of phenolic waste and with temperature variation.

The increase in using antibiotics, especially Azithromycin have increased steadily since the beginning of COVID19 pandemic. This increase has led to its presence in water systems which consequently led to its presence upon using this water for irrigation. The aim of the present work is to study the impact of irrigation using Azithromycin containing water on soil microbial community and its catabolic activity in the presence of phenolic wastes as compost. Wild berry, red grapes, pomegranate, and spent tea waste were added to soil and the degradation was monitored after 5 and 7 days at ambient and high temperatures. The results obtained show that at 30 °C, soil microbial community collectively was able to degrade Azithromycin, while at 40 °C, addition of spent tea as compost was needed to reach higher degradation. To ensure that the degradation was biotic and depended on degradation by indigenous microflora, a 25 kGy irradiation dose was used to kill the microorganisms in the soil and this was used as negative control. The residual antibiotic was assayed using UV spectroscopy and High Performance Liquid Chromatography (HPLC). Indication of Azithromycin presence was studied using Fourier Transform Infrared Spectroscopy (FTIR) peaks and the same pattern was obtained using the 3 used detection methods, the ability to assign the peaks even in the presence of soil and not to have any overlaps, gives the chance to study this result in depth to prepare IR based sensor for quick sensing of antibiotic in environmental samples.

Local Delivery of Azithromycin Nanoformulation Attenuated Acute Lung Injury in Mice.

Humanity has suffered from the coronavirus disease 2019 (COVID-19) pandemic over the past two years, which has left behind millions of deaths. Azithromycin (AZ), an antibiotic used for the treatment of several bacterial infections, has shown antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as well as against the dengue, Zika, Ebola, and influenza viruses. Additionally, AZ has shown beneficial effects in non-infective diseases such as cystic fibrosis and bronchiectasis. However, the systemic use of AZ in several diseases showed low efficacy and potential cardiac toxicity. The application of nanotechnology to formulate a lung delivery system of AZ could prove to be one of the solutions to overcome these drawbacks. Therefore, we aimed to evaluate the attenuation of acute lung injury in mice via the local delivery of an AZ nanoformulation. The hot emulsification-ultrasonication method was used to prepare nanostructured lipid carrier of AZ (AZ-NLC) pulmonary delivery systems. The developed formulation was evaluated and characterized in vitro and in vivo. The efficacy of the prepared formulation was tested in the bleomycin (BLM) -mice model for acute lung injury. AZ-NLC was given by the intratracheal (IT) route for 6 days at a dose of about one-eighth oral dose of AZ suspension. Samples of lung tissues were taken at the end of the experiment for immunological and histological assessments. AZ-NLC showed an average particle size of 453 nm, polydispersity index of 0.228 ± 0.07, zeta potential of -30 ± 0.21 mV, and a sustained release pattern after the initial 50% drug release within the first 2 h. BLM successfully induced a marked increase in pro-inflammatory markers and also induced histological changes in pulmonary tissues. All these alterations were significantly reversed by the concomitant administration of AZ-NLC (IT). Pulmonary delivery of AZ-NLC offered delivery of the drug locally to lung tissues. Its attenuation of lung tissue inflammation and histological injury induced by bleomycin was likely through the downregulation of the p53 gene and the modulation of Bcl-2 expression. This novel strategy could eventually improve the effectiveness and diminish the adverse drug reactions of AZ. Lung delivery could be a promising treatment for acute lung injury regardless of its cause. However, further work is needed to explore the stability of the formulation, its pharmacokinetics, and its safety.

Environmentally azithromycin pharmaceutical wastewater management and synergetic biocompatible approaches of loaded azithromycin@hematite nanoparticles.

Pharmaceutical wastewater contamination via azithromycin antibiotic and the continuous emergence of some strains of bacteria, cancer, and the Covid-19 virus. Azithromycin wastewater treatment using the biosynthesized Hematite nanoparticles (α-HNPs) and the biocompatible activities of the resulted nanosystem were reported. Biofabrication of α-HNPs using Echinacea purpurea liquid extract as a previously reported approach was implemented. An evaluation of the adsorption technique via the biofabricated α-HNPs for the removal of the Azr drug contaminant from the pharmaceutical wastewater was conducted. Adsorption isotherm, kinetics, and thermodynamic parameters of the Azr on the α-HNPs surface have been investigated as a batch mode of equilibrium experiments. Antibacterial, anticancer, and antiviral activities were conducted as Azr@α-HNPs. The optimum conditions for the adsorption study were conducted as solution pH = 10, 150 mg dose of α-HNPs, and Azr concentration 400 mg/L at 293 K. The most fitted isothermal model was described according to the Langmuir model at adsorption capacity 114.05 mg/g in a pseudo-second-order kinetic mechanistic at R2 0.9999. Thermodynamic study manifested that the adsorption behavior is a spontaneous endothermic chemisorption process. Subsequently, studying the biocompatible applications of the Azr@α-HNPs. Azr@α-HNPs antibacterial activity revealed a synergistic effect in the case of Gram-positive more than Gram-negative bacteria. IC50 of Azr@α-HNPs cytotoxicity against MCF7, HepG2, and HCT116 cell lines was investigated and it was found to be 78.1, 81.7, and 93.4 µg/mL respectively. As the first investigation of the antiviral use of Azr@α-HNPs against SARS-CoV-2, it was achieved a safety therapeutic index equal to 25.4 revealing a promising antiviral activity. An admirable impact of the use of the biosynthesized α-HNPs and its removal nanosystem product Azr@α-HNPs was manifested and it may be used soon as a platform of the drug delivery nanosystem for the biomedical applications.

Mechanism of action, resistance, synergism, and clinical implications of azithromycin.

BACKGROUND: Azithromycin (AZM), sold under the name Zithromax, is classified as a macrolide. It has many benefits due to its immunomodulatory, anti-inflammatory, and antibacterial effects. This review aims to study different clinical and biochemisterial aspects and properties of this drug which has a priority based on literature published worldwide. METHODS: Several databases including Web of Science, Google Scholar, PubMed, and Scopus were searched to obtain the relevant studies. RESULTS: AZM mechanism of action including the inhibition of bacterial protein synthesis, inhibition of proinflammatory cytokine production, inhibition of neutrophil infestation, and macrophage polarization alteration, gives it the ability to act against a wide range of microorganisms. Resistant organisms are spreading and being developed because of the irrational use of the drug in the case of dose and duration. AZM shows synergistic effects with other drugs against a variety of organisms. This macrolide is considered a valuable antimicrobial agent because of its use as a treatment for a vast range of diseases such as asthma, bronchiolitis, COPD, cystic fibrosis, enteric infections, STIs, and periodontal infections. CONCLUSIONS: Our study shows an increasing global prevalence of AZM resistance. Thus, synergistic combinations are recommended to treat different pathogens. Moreover, continuous monitoring of AZM resistance by registry centers and the development of more rapid diagnostic assays are urgently needed.

Comparative Computational Analysis of Dirithromycin and Azithromycin in Search for a Potent Drug against COVID-19 caused by SARS-CoV-2: Evidence from molecular docking and dynamic simulation.

Due to the emergency and uncontrolled situation caused by the COVID-19 pandemic that arising in the entire world, it is necessary to choose available drugs that can inhibit or prevent the disease. Therefore, the repurposing of the commercial antibiotic, dirithromycin has been screened for the first time against fifteen receptors and compared to the azithromycin using a molecular docking approach to identify possible SARS-CoV-2 inhibitors. Our docking results showed that dirithromycin fit significantly in the Furin catalytic pocket having the lowest binding score (-9.9 Kcal/mol) with respect to azithromycin (-9.4 Kcal/mol) and can interact and block both Asp154 and Ser368 residues by Van der Walls interaction as well as bound to His194 and Ser368 residues via hydrogen bonds. Good results were also obtained with the Tmprss-2 receptor. A Molecular Dynamic simulation was assessed to confirm this interaction. Additionally, detailed receptor-ligand interactions with SARS-CoV-2 and pro-inflammatory mediators were investigated suggesting more target information with interesting results. The findings of this study are very efficient and provide a basis for the development of dirithromycin for clinical trial applications to be efficient in treating SARS-CoV-2 infections.

Beneficial ex vivo immunomodulatory and clinical effects of clarithromycin in COVID-19.

INTRODUCTION: Macrolide antibiotics have immunomodulatory properties which may be beneficial in viral infections. However, the precise effects of macrolides on T cell responses to COVID, differences between different macrolides, and synergistic effects with other antibiotics have not been explored. METHODS: We investigated the effect of antibiotics (amoxicillin, azithromycin, clarithromycin, and combined amoxicillin with clarithromycin) on lymphocyte intracellular cytokine levels and monocyte phagocytosis in healthy volunteer PBMCs stimulated ex vivo with SARS-CoV-2 S1+2 spike protein. A retrospective cohort study was performed on intensive care COVID-19 patients. RESULTS: Co-incubation of clarithromycin with spike protein-stimulated healthy volunteer PBMCs ex vivo resulted in an increase in CD8+ (p = 0.004) and CD4+ (p = 0.007) IL-2, with a decrease in CD8+ (p = 0.032) and CD4+ (p = 0.007) IL-10. The addition of amoxicillin to clarithromycin resulted in an increase in CD8+ IL-6 (p = 0.010), decrease in CD8+ (p = 0.014) and CD4+ (p = 0.022) TNF-alpha, and decrease in CD8+ IFN-alpha (p = 0.038). Amoxicillin alone had no effect on CD4+ or CD8+ cytokines. Co-incubation of azithromycin resulted in increased CD8+ (p = 0.007) and CD4+ (p = 0.011) IL-2. There were no effects on monocyte phagocytosis. 102 COVID-19 ICU patients received antibiotics on hospital admission; 62 (61%) received clarithromycin. Clarithromycin use was associated with reduction in mortality on univariate analysis (p = 0.023), but not following adjustment for confounders (HR = 0.540; p = 0.076). CONCLUSIONS: Clarithromycin has immunomodulatory properties over and above azithromycin. Amoxicillin in addition to clarithromycin is associated with synergistic ex vivo immunomodulatory properties. The potential benefit of clarithromycin in critically ill patients with COVID-19 and other viral pneumonitis merits further exploration.

SARS-CoV-2 and Prevotella spp.: friend or foe? A systematic literature review.

During this global pandemic of the COVID-19 disease, a lot of information has arisen in the media and online without scientific validation, and among these is the possibility that this disease could be aggravated by a secondary bacterial infection such as Prevotella, as well as the interest or not in using azithromycin, a potentially active antimicrobial agent. The aim of this study was to carry out a systematic literature review, to prove or disprove these allegations by scientific arguments. The search included Medline, PubMed, and Pubtator Central databases for English-language articles published 1999-2021. After removing duplicates, a total of final eligible studies (n=149) were selected. There were more articles showing an increase of Prevotella abundance in the presence of viral infection like that related to Human Immunodeficiency Virus (HIV), Papillomavirus (HPV), Herpesviridae and respiratory virus, highlighting differences according to methodologies and patient groups. The arguments for or against the use of azithromycin are stated in light of the results of the literature, showing the role of intercurrent factors, such as age, drug consumption, the presence of cancer or periodontal diseases. However, clinical trials are lacking to prove the direct link between the presence of Prevotella spp. and a worsening of COVID-19, mainly those using azithromycin alone in this indication.

Antiviral effects of azithromycin: A narrative review.

Viral infections have a great impact on human health. The urgent need to find a cure against different viruses led us to investigations in a vast range of drugs. Azithromycin (AZT), classified as a macrolide, showed various effects on different known viruses such as severe acute respiratory syndrome coronavirus (SARS-CoV), Zika, Ebola, Enterovirus (EVs) and Rhinoviruses (RVs), and Influenza A previously; namely, these viruses, which caused global concerns, are considered as targets for AZT different actions. Due to AZT background in the treatment of known viral infections mentioned above (which is described in this study), in the early stages of COVID-19 (a new zoonotic disease caused by a novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)) development, AZT drew attention to itself due to its antiviral and immunomodulatory effects as a valuable candidate for COVID-19 treatment. AZT usage instructions for treating different viral infections have always been under observation, and COVID-19 is no exception. There are still debates about the use of AZT in COVID-19 treatment. However, eventually, novel researches convinced WHO to announce the discontinuation of AZT use (alone or in combination with hydroxychloroquine) in treating SARS-CoV-2 infection. This research aims to study the structure of all of the viruses mentioned above and the molecular and clinical effects of AZT against the virus.

Arrhythmogenic mechanisms of interleukin-6 combination with hydroxychloroquine and azithromycin in inflammatory diseases.

Inflammatory diseases including COVID-19 are associated with a cytokine storm characterized by high interleukin-6 (IL-6) titers. In particular, while recent studies examined COVID-19 associated arrhythmic risks from cardiac injury and/or from pharmacotherapy such as the combination of azithromycin (AZM) and hydroxychloroquine (HCQ), the role of IL-6 per se in increasing the arrhythmic risk remains poorly understood. The objective is to elucidate the electrophysiological basis of inflammation-associated arrhythmic risk in the presence of AZM and HCQ. IL-6, AZM and HCQ were concomitantly administered to guinea pigs in-vivo and in-vitro. Electrocardiograms, action potentials and ion-currents were analyzed. IL-6 alone or the combination AZM + HCQ induced mild to moderate reduction in heart rate, PR-interval and corrected QT (QTc) in-vivo and in-vitro. Notably, IL-6 alone was more potent than the combination of the two drugs in reducing heart rate, increasing PR-interval and QTc. In addition, the in-vivo or in-vitro combination of IL-6 + AZM + HCQ caused severe bradycardia, conduction abnormalities, QTc prolongation and asystole. These electrocardiographic abnormalities were attenuated in-vivo by tocilizumab (TCZ), a monoclonal antibody against IL-6 receptor, and are due in part to the prolongation of action potential duration and selective inhibition of Na+, Ca2+ and K+ currents. Inflammation confers greater risk for arrhythmia than the drug combination therapy. As such, in the setting of elevated IL-6 during inflammation caution must be taken when co-administering drugs known to predispose to fatal arrhythmias and TCZ could be an important player as a novel anti-arrhythmic agent. Thus, identifying inflammation as a critical culprit is essential for proper management.

Heterogeneity in susceptibility to hydroxychloroquine of SARS-CoV-2 isolates.

BACKGROUND: Despite the fact that the clinical efficacy of hydroxychloroquine is still controversial, it has been demonstrated in vitro to control SARS-CoV-2 multiplication on Vero E6 cells. In this study, we tested the possibility that some patients with prolonged virus excretion could be infected by less susceptible strains. METHOD: Using a high-content screening method, we screened 30 different selected isolates of SARS-CoV-2 from different patients who received azithromycin ± hydroxychloroquine. We focused on patients with viral persistence, i.e., positive virus detection in a nasopharyngeal sample ≥10 days, and who were tested during two French epidemic waves, late winter-spring of 2020 and the summer of 2020. Dose-response curves in single-molecule assays with hydroxychloroquine were created for isolates with suspected reduced susceptibility. Genome clustering was performed for all isolates. RESULTS: Of 30 tested strains, three were detected as replicating in the presence of azithromycin + hydroxychloroquine, each at 5 µM. The dose-response model showed a decrease in susceptibility of these three strains to hydroxychloroquine. Whole genome sequencing revealed that these three strains are all from the second epidemic wave and two cluster with isolates from Africa. CONCLUSIONS: Reduced susceptibility to hydroxychloroquine was not associated with viral persistence in naso-pharyngeal samples. Rather, it was associated with occurring during the second epidemic wave, which began in the summer and with strains clustering with those with a common genotype in Africa, where hydroxychloroquine was the most widely used.

Hydroxychloroquine and azithromycin used alone or combined are not effective against SARS-CoV-2 ex vivo and in a hamster model.

Drug repositioning has been used extensively since the beginning of the COVID-19 pandemic in an attempt to identify antiviral molecules for use in human therapeutics. Hydroxychloroquine and azithromycin have shown inhibitory activity against SARS-CoV-2 replication in different cell lines. Based on such in vitro data and despite the weakness of preclinical assessment, many clinical trials were set up using these molecules. In the present study, we show that hydroxychloroquine and azithromycin alone or combined does not block SARS-CoV-2 replication in human bronchial airway epithelia. When tested in a Syrian hamster model, hydroxychloroquine and azithromycin administrated alone or combined displayed no significant effect on viral replication, clinical course of the disease and lung impairments, even at high doses. Hydroxychloroquine quantification in lung tissues confirmed strong exposure to the drug, above in vitro inhibitory concentrations. Overall, this study does not support the use of hydroxychloroquine and azithromycin as antiviral drugs for the treatment of SARS-CoV-2 infections.

Nonantimicrobial Actions of Macrolides: Overview and Perspectives for Future Development.

Macrolides are among the most widely prescribed broad spectrum antibacterials, particularly for respiratory infections. It is now recognized that these drugs, in particular azithromycin, also exert time-dependent immunomodulatory actions that contribute to their therapeutic benefit in both infectious and other chronic inflammatory diseases. Their increased chronic use in airway inflammation and, more recently, of azithromycin in COVID-19, however, has led to a rise in bacterial resistance. An additional crucial aspect of chronic airway inflammation, such as chronic obstructive pulmonary disease, as well as other inflammatory disorders, is the loss of epithelial barrier protection against pathogens and pollutants. In recent years, azithromycin has been shown with time to enhance the barrier properties of airway epithelial cells, an action that makes an important contribution to its therapeutic efficacy. In this article, we review the background and evidence for various immunomodulatory and time-dependent actions of macrolides on inflammatory processes and on the epithelium and highlight novel nonantibacterial macrolides that are being studied for immunomodulatory and barrier-strengthening properties to circumvent the risk of bacterial resistance that occurs with macrolide antibacterials. We also briefly review the clinical effects of macrolides in respiratory and other inflammatory diseases associated with epithelial injury and propose that the beneficial epithelial effects of nonantibacterial azithromycin derivatives in chronic inflammation, even given prophylactically, are likely to gain increasing attention in the future. SIGNIFICANCE STATEMENT: Based on its immunomodulatory properties and ability to enhance the protective role of the lung epithelium against pathogens, azithromycin has proven superior to other macrolides in treating chronic respiratory inflammation. A nonantibiotic azithromycin derivative is likely to offer prophylactic benefits against inflammation and epithelial damage of differing causes while preserving the use of macrolides as antibiotics.

COVID-19: potential therapeutics for pediatric patients.

The global spread of COVID-19 has imparted significant economic, medical, and social burdens. Like adults, children are affected by this pandemic. However, milder clinical symptoms are often experienced by them. Only a minimal proportion of the affected patients may develop severe and complicated COVID-19. Supportive treatment is recommended in all patients. Antiviral and immunomodulatory medications are spared for hospitalized children with respiratory distress or severe to critical disease. Up till now, remdesivir is the only USFDA-approved anti-COVID-19 medication indicated in the majority of symptomatic patients with moderate to severe disease. Dexamethasone is solely recommended in patients with respiratory distress maintained on oxygen or ventilatory support. The use of these medications in pediatric patients is founded on evidence deriving from adult studies. No randomized controlled trials (RCTs) involving pediatric COVID-19 patients have assessed these medications' efficacy and safety, among others. Similarly, three novel monoclonal anti-SARS-CoV-2 spike protein antibodies, bamlanivimab, casirivimab and imdevimab, have been recently authorized by the USFDA. Nonetheless, their efficacy has not been demonstrated by multiple RCTs. In this review, we aim to dissect the various potential therapeutics used in children with COVID-19. We aspire to provide a comprehensive review of the available evidence and display the mechanisms of action and the pharmacokinetic properties of the studied therapeutics. Our review offers an efficient and practical guide for treating children with COVID-19.

Hydroxychloroquine (HCQ) decreases the benefit of anti-PD-1 immune checkpoint blockade in tumor immunotherapy.

Immunotherapy using checkpoint blockade (ICB) with antibodies such as anti-PD-1 has revolutionised the treatment of many cancers. Despite its use to treat COVID-19 patients and autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis, the effect of hydroxychloroquine (HCQ) on cancer immunotherapy has not been examined. In this study, remarkably, we find that HCQ alone, or in combination with azithromycin (AZ), at doses used to treat patients, decreased the therapeutic benefit of anti-PD-1 in cancer immunotherapy. No deleterious effect was seen on untreated tumors. Mechanistically, HCQ and HCQ/AZ inhibited PD-L1 expression on tumor cells, while specifically targeting the anti-PD-1 induced increase in progenitor CD8+CD44+PD-1+TCF1+ tumor infiltrating T cells (TILs) and the generation of CD8+CD44+PD-1+ effectors. Surprisingly, it also impaired the appearance of a subset of terminally exhausted CD8+ TILs. No effect was seen on the presence of CD4+ T cells, FoxP3+ regulatory T cells (Tregs), thymic subsets, B cells, antibody production, myeloid cells, or the vasculature of mice. This study indicates for the first time that HCQ and HCQ/AZ negatively impact the ability of anti-PD-1 checkpoint blockade to promote tumor rejection.

SARS-CoV-2 proteins and anti-COVID-19 drugs induce lytic reactivation of an oncogenic virus.

An outbreak of the novel coronavirus SARS-CoV-2, the causative agent of Coronavirus Disease-2019 (COVID-19), a respiratory disease, has infected almost one hundred million people since the end of 2019, killed over two million, and caused worldwide social and economic disruption. Because the mechanisms of SARS-CoV-2 infection of host cells and its pathogenesis remain largely unclear, there are currently no antiviral drugs with proven efficacy. Besides severe respiratory and systematic symptoms, several comorbidities increase risk of fatal disease outcome. Therefore, it is required to investigate the impacts of COVID-19 on pre-existing diseases of patients, such as cancer and other infectious diseases. In the current study, we report that SARS-CoV-2 encoded proteins and some currently used anti-COVID-19 drugs are able to induce lytic reactivation of Kaposi's sarcoma-associated herpesvirus (KSHV), one of major human oncogenic viruses, through manipulation of intracellular signaling pathways. Our data indicate that those KSHV + patients especially in endemic areas exposure to COVID-19 or undergoing the treatment may have increased risks to develop virus-associated cancers, even after they have fully recovered from COVID-19.

COVID-19 Drugs Chloroquine and Hydroxychloroquine, but Not Azithromycin and Remdesivir, Block hERG Potassium Channels.

Drug-induced long QT syndrome (LQTS) is an established cardiac side effect of a wide range of medications and represents a significant concern for drug safety. The rapidly and slowly activating delayed rectifier K+ currents, mediated by channels encoded by the human ether-a-go-go-related gene (hERG) and KCNQ1 + KCNE1, respectively, are two main currents responsible for ventricular repolarization. The common cause for drugs to induce LQTS is through impairing the hERG channel. For the recent emergence of COVID-19, caused by severe acute respiratory syndrome coronavirus 2, several drugs have been investigated as potential therapies; however, there are concerns about their QT prolongation risk. Here, we studied the effects of chloroquine, hydroxychloroquine, azithromycin, and remdesivir on hERG channels. Our results showed that although chloroquine acutely blocked hERG current (IhERG), with an IC50 of 3.0 µM, hydroxychloroquine acutely blocked IhERG 8-fold less potently, with an IC50 of 23.4 µM. Azithromycin and remdesivir did not acutely affect IhERG When these drugs were added at 10 µM to the cell culture medium for 24 hours, remdesivir increased IhERG by 2-fold, which was associated with an increased mature hERG channel expression. In addition, these four drugs did not acutely or chronically affect KCNQ1 + KCNE1 channels. Our data provide insight into COVID-19 drug-associated LQTS and cardiac safety concerns. SIGNIFICANCE STATEMENT: This work demonstrates that, among off-label potential COVID-19 treatment drugs chloroquine, hydroxychloroquine, azithromycin, and remdesivir, the former two drugs block hERG potassium channels, whereas the latter two drugs do not. All four drugs do not affect KCNQ1 + KCNE1. As hERG and KCNQ1 + KCNE1 are two main K+ channels responsible for ventricular repolarization, and most drugs that induce long QT syndrome (LQTS) do so by impairing hERG channels, these data provide insight into COVID-19 drug-associated LQTS and cardiac safety concerns.

Azithromycin: Immunomodulatory and antiviral properties for SARS-CoV-2 infection.

Azithromycin, a member of the macrolide family of antibiotics, is commonly used to treat respiratory bacterial infections. Nevertheless, multiple pharmacological effects of the drug have been revealed in several investigations. Conceivably, the immunomodulatory properties of azithromycin are among its critical features, leading to its application in treating inflammatory diseases, such as asthma and chronic obstructive pulmonary disease (COPD). Additionally, azithromycin may directly inhibit viral load as well as its replication, or it could demonstrate indirect inhibitory impacts that might be associated with the expression of antiviral genes. Currently, coronavirus disease 2019 (COVID-19) is an extra urgent issue affecting the entire world, and it is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Acute respiratory distress syndrome (ARDS), which is associated with hyper inflammation due to cytokine release, is among the leading causes of death in COVID-19 patients with critical conditions. The present paper aims to review the immunomodulatory and antiviral properties of azithromycin as well as its potential clinical applications in the management of COVID-19 patients.