key: cord-0823084-46us3wzl authors: Firth, Anton; Prathapan, Praveen title: Azithromycin: The First Broad-spectrum Therapeutic date: 2020-08-19 journal: Eur J Med Chem DOI: 10.1016/j.ejmech.2020.112739 sha: 100e5c3d40a9e4dc1d15c356221493c262d4d6cb doc_id: 823084 cord_uid: 46us3wzl The Strategic Plan for Biodefense Research by the U.S. Department of Health and Human Services demarcates the need for drugs which target multiple types of pathogens to prepare for infectious threats. Azithromycin is one such broad-spectrum therapeutic that is both included in the University of Oxford’s RECOVERY and excluded from the World Health Organization’s SOLIDARITY trials. Here we review azithromycin’s broad antibiotic, antimalarial, antiviral pharmacology and contextualise it against a broader history as the most repositioned therapeutic of the macrolide class; we further evaluate azithromycin’s clinical and socio-economic propriety for respiratory pandemics and delineate a model for its combinatorial mechanism of action against COVID-19 pneumonia. The pandemic has led to the emergence of drug repositioning as a short-term strategy 52 to yield a treatment for COVID-19. Such a strategy offers certain advantages over de 53 novo drug discovery, the most important of which is the reduced risk of failure, as 54 large-scale and long-term clinical trials have erstwhile established the safety of these 55 drugs for public medical use. The timeframe for drug development is also 56 significantly reduced as preclinical safety assessments, global pharmaceutical 57 manufacturing, and distribution to front-line medical workers have been completed 58 (REF. 1 ). Considered together, these factors also contribute to the markedly reduced 59 cost of drug repositioning relative to de novo drug development. Indeed, introducing a 60 novel therapeutic to market is estimated to cost $2-3 billion compared to $300 million 61 for an average repositioned drug 2 . In the context of a pandemic, such advantages are 62 critical and, at the time of writing, there is no FDA-approved therapeutic candidate 63 against COVID-19. 64 65 Azithromycin is an antibiotic. Since its discovery, it has been FDA-approved for 66 respiratory tract infections such as pneumonia, genitourinary infections such as 67 chlamydia, and enteric infections such as typhoid, and has also been extensively 68 compounds that consist of a 14-, 15-, or 16-membered macrocyclic lactone ring to 103 which one or more deoxy sugars may be attached. Macrolides are bacteriostatic, a 104 property achieved by reversible binding to the P site on the 50S subunit of the 105 bacterial ribosome. Erythromycin, the first macrolide discovered, was widely used as 106 a substitute for penicillin for patients with a penicillin-resistant illness or allergy. 107 Azithromycin, a derivative of erythromycin, was designed to be more easily absorbed 108 with fewer side-effects, and exhibits bacteriostatic activity against both Gram-positive 109 and Gram-negative bacteria including Bordetella pertussis and Legionella species. 110 The 1970s saw the establishment of macrolides as an effective strategy for 112 inflammatory diseases. In the decades since, azithromycin in particular has been used 113 as an antibiotic for chlamydia, malaria, pneumonia, and trachoma. Today, cumulative 114 in vitro studies perpetually establish a broad-spectrum pharmacological profile for 115 azithromycin ( Fig. 1) Azithromycin is regularly administered around the world. In the USA, it was 137 prescribed over 12 million times in 2017 alone and today is commercially available as 138 250-, 500-, and 600-mg immediate-release tablets, 2-g microsphere extended-release 139 powder, oral suspension (100-200 mg/5 mL), and intravenous preparation (lypholised 140 500 mg/10 mL vial) 26 . Due to its extensive clinical application over the years, 141 historical data of azithromycin, including dosage measurements for bacterial, 142 malarial, and viral diseases, patient-to-patient treatment histories, and even clinical 143 safety comparisons with erythromycin, can be mined and leveraged to inform and There is a perpetual need for a short-term treatment for the current pandemic. 475 Repositioning antibiotics that are low-cost, historically safe, and globally distributed 476 is a pragmatic strategy amidst an evolving world health crisis and economic 477 recession; the pharmacological, historical, and socio-economic parameters heretofore 478 used to evaluate azithromycin's repositioning capacity for respiratory pandemics may 479 collectively be applied to similar broad-spectrum therapeutics to culminate an 480 expanding treatment database for forthcoming infectious threats. Azithromycin inhibits fluid-phase endocytosis in vitro. [10] Single-dose azithromycin treats severe cholera in adults. [18] Azithromycin shifts macrophage polarisation towards the M2 phenotype. [9] Azithromycin induces anti-viral responses in bronchial epithelial cells. [8] Azithromycin pretreatment reduces viral replication in cystic fibrosis bronchial epithelial cells. [7] First use of azithromycin prophylaxis for children with primary ciliary dyskinesia. ciprofloxacin (Cp) in J774 macrophages (M^>) Interaction of azithromycin and human phagocytic cells Single-dose 605 azithromycin for the treatment of cholera in adults Azithromycin, a 15-membered macrolide 608 antibiotic, inhibits influenza A(H1N1)pdm09 virus infection by interfering with virus 609 internalization process World Health Organization model list of essential medicines: 21 st list Treatment of Atypical Pneumonia with Azithromycin: 614 Comparison of a 5-Day and a 3-Day Course Macrolides: from in vitro anti-inflammatory and 618 immunomodulatory properties to clinical practice in respiratory diseases Meta-Analysis of the Adverse Effects of Long-622 Term Azithromycin Use in Patients with Chronic Lung Diseases. Antimicrobial 623 Agents and Chemotherapy Hydroxychloroquine and azithromycin as a 625 treatment of COVID-19: results of an open-label non-randomized clinical trial 626 Reply to Gautret et al. 630 2020: A Bayesian reanalysis of the effects of hydroxychloroquine and azithromycin 631 on viral carriage in patients with COVID-19 A Trial of Lopinavir-Ritonavir in Adults Hospitalized with 634 Severe Covid-19 First Case of 2019 Novel Coronavirus in the United 639 Hydroxychloroquine, a less toxic derivative of chloroquine, is 642 effective in inhibiting SARS-CoV-2 infection in vitro Topical azithromycin: new evidence? Lymphopenia predicts disease severity of COVID-19: a descriptive and 647 predictive study Pathological inflammation in patients with COVID-19: a 649 key role for monocytes and macrophages Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute 655 respiratory distress syndrome, and hyperinflammation: a retrospective cohort 656 study Anti-inflammatory effects of antimicrobial agents: an in vivo 658 study The 660 Immunomodulatory Effects of Macrolides-A Systematic Review of the Underlying 661 Azithromycin Suppresses Activation of 663 Nuclear Factor-kappa B and Synthesis of Pro-inflammatory Cytokines in Tracheal 664 Aspirate Cells From Premature Infants COVID-19: consider cytokine storm syndromes and 666 immunosuppression Dysregulation of immune response in patients with COVID-19 in 668 Trials of anti-tumour necrosis factor therapy for COVID-19 Effective treatment of severe COVID-19 patients with tocilizumab Proc. Natl Acad. Sci Host-microorganism interactions in lung diseases The role of short-chain fatty acids, produced by anaerobic bacteria, in the cystic brosis 679 airway The role of bac-teria in the 681 pathogenesis and progression of idiopathic pulmonary brosis Sequencing data (N = 3) shows Wuhan coronavi-rus integration 684 in bacteria (Prevotella mostly) The Wuhan coronavirus has integrated in Prevo-tella, which 688 possibly causes the observed extreme virulence-as sequencing data from 2 di erent 689 studies in China and Hong-Kong shows unequivocally Wuhan outbreak could be caused by the bacteria 692 which is aided by the coronavirus-Prevo-tella is present (sometimes in 693 huge amounts) in patients from two studies in China Beta-lactamase production in Prevo-tella intermedia, Prevotella nigrescens Prevotella pallens genotypes and in vitro susceptibilities to selected antimicrobial 698 agents E ect of azithromy-cin on Prevotella 700 intermedia lipopolysaccharide-induced produc-tion of interleukin-6 in murine 701 macrophages Imbalanced host response to SARS-CoV-2 drives 703 development of COVID-19 Impaired type I interferon activity and exacerbated inflammatory 705 Heightened innate immune responses in the respiratory tract of 708 COVID-19 patients Dysregulated type I interferon and inflammatory 711 monocyte-macrophage responses cause lethal pneumonia in SARS-CoV-infected 712 mice Dysregulation of type I interferon responses 714 in COVID-19 Functional exhaustion of antiviral lymphocytes in COVID-19 716 patients Combinatorial screening of a 721 panel of FDA-approved drugs identi es several candidates with anti-Ebola activities ICR suckling mouse 724 model of Zika virus infection for disease mode-ling and drug validation 15-membered macrolide antibi-otic virus infection by inter-fering with virus internalization process Role of prophylactic azithromycin to reduce air-way in ammation and mortality in a 732 RSV mouse infection model azithromycin, safe for administration to children, exert antiviral activity against 735 enterovirus A71 in vitro and in vivo In vitro screening of a FDA approved chemical library reveals 737 Azithromycin protects against Zika virus infection by upregulating 740 virus-induced type I and III interferon responses Evaluation of Ebola virus inhibitors for drug repurposing Randomized trial to evaluate azithromycin's e ects on serum and upper airway IL-746 8 levels and recurrent wheezing in infants with respiratory syncytial virus 747 bronchiolitis Pharmacokinetics 749 of azithromycin in lung tissue, bronchial washing, and plasma in patients given 750 multiple oral doses of 500 and 1000 mg daily Azithromycin augments rhinovirus-induced IFNβ via cytosolic MDA5 in 753 experimental models of asthma exacerbation Azithromycin 756 protects against Zika virus infection by upregulat-ing virus-induced type I and III 757 interferon responses Basigin (CD147), a multifunctional transmembrane glycoprotein 760 with various binding partners Basigin is a receptor essential for erythrocyte invasion by Plasmodium 765 falciparum SARS-CoV-2 invades host cells via a 770 novel route: CD147-spike protein Roles of CD147 on T lymphocytes 773 activation and MMP-9 secretion in Systemic Lupus Erythematosus COVID-19 pneumonia: an open-labelled, concurrent controlled add-on clinical trial Macrolides 782 rapidly inhibit red blood cell invasion by the human malaria parasite, Plasmodium 783 falciparum CD147 as a Target for COVID-19 Treatment The macrolide antibiotic 788 azithromycin interacts with lipids and affects membrane organization and fluidity: 789 Studies on langmuir-blodgett monolayers, liposomes and J774 macrophages SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and 794 Is Blocked by a Clinically Proven Protease Inhibitor Targeting the Endocytic Pathway and Autophagy Process as a 796 Novel Therapeutic Strategy in COVID-19 Insights from nanomedicine into chloroquine 799 efficacy against COVID-19 Accumulation, release and subcel-lular localization of azithromycin in 803 phagocytic and non-phago-cytic cells in culture Clarithromycin inhibits type A seasonal influenza virus 805 infection in human airway epithelial cells Suppression of influenza A virus replication in human lung 807 epithelial cells by noncytotoxic concentrations bafilomycin A1 Azithromycin and the risk 810 of cardiovascular death Vos 812 MA: No proarrhythmic properties of the antibiotics Moxifloxacin or Azithromycin in 813 anaesthetized dogs with chronic-AV block Association of treatment with hydroxychlo-roquine or azithromycin with in-hospital 817 mortality in patients with COVID-19 in New York State Serisier DJ. Risks of population antimicrobial resistance associated with chronic 820 macrolide use for inflammatory airway diseases Meta-analysis of the 822 adverse effects of long-term azithromycin use in patients with chronic lung diseases We thank our colleagues at the Department of Biochemistry and Trinity College,