DOCSLIB.ORG

Development of New Novel Bacterial Topoisomerase Inhibitors As Promising Antibiotics with a 5-Amino-1,3-Dioxane Linker Moiety DI

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Development of New Novel Bacterial Topoisomerase Inhibitors As Promising Antibiotics with a 5-Amino-1,3-Dioxane Linker Moiety DI Development of New Novel Bacterial Topoisomerase Inhibitors as Promising Antibiotics with a 5-Amino-1,3-dioxane Linker Moiety DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Linsen Li Graduate Program in Pharmaceutical Sciences The Ohio State University 2019 Dissertation Committee: Mark J Mitton-Fry, Ph.D., Advisor Karl A Werbovetz, Ph.D. Mireia Guerau-de-Arellano, Ph.D. James R Fuchs, Ph.D. Copyright by Linsen Li 2019 Abstract Multidrug-resistant bacteria (MDR) have become one of the greatest threats to human beings. Regardless of the mechanism of action involved, resistance has eventually developed after the clinical use of each class of antibiotics. Thus, new antibiotic classes with unprecedented mechanisms of action are in urgent demand. With a distinct mechanism of action, Novel Bacterial Topoisomerase Inhibitors (NBTIs) represent a promising new class of antibiotics. The recent development of NBTIs has been encouraging. Several NBTIs have processed to clinical trials, and one NBTI (Gepotidacin) has successfully completed Phase 2 clinical trials. However, the cardiac toxicity from the inhibition of hERG K+ channels is one of the major challenges in the discovery of NBTIs. In this work, a 5-amino-1,3-dioxane linker moiety was incorporated in new NBTIs to decrease hERG inhibition, which was demonstrated by comparison with several structure- matched pairs with other linker moieties. A variety of NBTIs with a 5-amino-1,3-dioxane linker have been synthesized and evaluated. Many of these newly synthesized NBTIs showed potent antibacterial activity, covering methicillin-resistant Staphylococcus aureus (MRSA) and fluoroquinolone-resistant strains. Some of these new NBTIs displayed dual inhibition against both DNA gyrase and topoisomerase IV of S. aureus, but they targeted DNA gyrase more potently than topoisomerase IV. These new NBTIs presented low toxicity to human cells and minimal inhibition of human topoisomerase IIα. Additionally, several new NBTIs revealed favorable hERG profiles. With promising preclinical ii attributes, some of these NBTIs have the potential to be evaluated in in vivo experiments and can serve as the starting point for further development of new NBTIs. iii Dedication This document is dedicated to my grandparents. iv Acknowledgements It’s like a formality to express thanks to the advisor in the dissertation of each doctoral student. However, I would like to give my sincere appreciation and admiration to my advisor, Dr. Mark Mitton-Fry. I joined the Mitton-Fry research group and became the first student in the lab in the summer of 2016. Then I found this mid-aged man very interesting. Dr. Mitton-Fry is always walking with his fast split steps, enjoying his time in front of his research hood. It’s very easy to tell his brilliant intelligence at most times, but he was even not able to set up an old iPhone, although he tried hard to learn from his young daughter. During the past years, his expertise, cautious and discreet attitude toward research, and passion for work have always inspired me tremendously. I feel very lucky to have Dr. Mitton-Fry as my advisor in my Ph.D. program. I’m grateful to the medicinal chemistry program in the College of Pharmacy for offering me the opportunity to study and work here with many great scholars from the whole world. I’m grateful to Dr. Chenglong Li as my research advisor for my first three years in the program. I learned many useful computational tools for drug discovery and got training in synthetic chemistry in Dr. Chenglong Li’s lab. I’m also grateful to Dr. James Fuchs, Dr. Karl Werbovetz and Dr. Mireia Guerau-de-Arellano for serving as my committee members. They have been always willing to help and have given me lots of beneficial suggestions. I would like to thank Dr. Craig McElroy for assistance with the research instruments. I’m also thankful to all my lab-mates in Dr. Mitton-Fry’s lab and Dr. Chenglong Li’s lab. These interesting people have created a joyful environment in the lab and helped a lot. v I would like to thank all my friends met in the Ohio State University. There are so many fantastic things around campus: the white bass and rainbow trout swimming under harmonious spring breeze, the soccer balls dribbling upon lush green lawn, the snowboard flipping from peak of white mountains, and so on. It was my friends that painted these fantastic things into my memory, which made my Ph.D. program a wonderful journey. I would like to thank my roommates in Nanjing University and intimate friends, Dr. Lichen Liu, Hao Li, Dr. Mufan Li and Jinping Liu. Regardless of the long distance apart each of us, our daily conversations gave me not only broad insight into chemistry, but also more comprehensive thoughts on the world. Finally, I would like to thank my family. It was their love and selfless support that made the completion of this thesis possible. vi Vita 2008 – 2012………………..B.S. Chemistry, Nanjing University 2012 – 2013………………..Research Assistant, Department of Chemistry, Tsinghua University 2013 – present …………….Graduate Teaching Associate, Graduate Research Associate, Division of Medicinal Chemistry & Pharmacognosy, The Ohio State University Publications Li L, Okumu AA, Nolan S, English A, Vibhute S, Lu Y, Hervert-Thomas K, Seffernick JT, Azap L, Cole SL, Shinabarger D, Koeth LM, Lindert S, Yalowich JC, Wozniak DJ, Mitton-Fry MJ. 1,3-Dioxane-Linked Bacterial Topoisomerase Inhibitors with Enhanced Antibacterial Activity and Reduced hERG Inhibition. ACS Infect Dis 2019, 5, 1115-1128. Li L, Okumu AA, Nolan S, Li Z, Karmahapatra S, English A, Yalowich JC, Wozniak DJ, Mitton- Fry MJ. Synthesis and Anti-staphylococcal Activity of Novel Bacterial Topoisomerase Inhibitors with a 5-Amino-1,3-dioxane Linker Moiety. Bioorg Med Chem Lett 2018, 28, 2477-2480. Webb LM, Amici SA, Jablonski KA, Savardekar H, Panfil AR, Li L, Zhou W, Peine K, Karkhanis V, Bachelder EM, Ainslie KM, Green PL, Li C, Baiocchi RA, Guerau-de-Arellano M. PRMT5-Selective Inhibitors Suppress Inflammatory T Cell Responses and Experimental Autoimmune Encephalomyelitis. J Immunol 2017, 198, 1439-1451. vii Li L, Niu Z, Cai S, Zhi Y, Li H, Rong H, Liu L, Liu L, He W, Li Y. A PdAg bimetallic nanocatalyst for selective reductive amination of nitroarenes. Chem Commun 2013, 49, 6843-6845. Zhang Q, Cai S, Li L, Chen Y, Rong H, Niu Z, Liu J, He W, Li Y. Direct Syntheses of Styryl Ethers from Benzyl Alcohols via Ag Nanoparticle-Catalyzed Tandem Aerobic Oxidation. ACS Catalysis 2013, 3, 1681-1684. Li H, Li L, Li Y. The Electronic Structure and Geometric Structure of Nanoclusters as Catalytic Active Sites. Nanotechnology Reviews 2013, 2, 515-528. Fields of Study Major Field: Pharmacy (Pharmaceutical Sciences) viii Table of Contents Abstract ........................................................................................................................................... ii Dedication ...................................................................................................................................... iv Acknowledgements ......................................................................................................................... v Vita ................................................................................................................................................ vii List of Tables ................................................................................................................................ xiii List of Figures .............................................................................................................................. xiv List of Scheme .............................................................................................................................. xvi Chapter 1. Brief Overview of Antibiotics and Novel Bacterial Topoisomerase Inhibitors ............. 1 1.1 Introduction ........................................................................................................................... 1 1.2 Typical Classes of Antibiotics ............................................................................................... 1 1.2.1 Cell wall antibiotics ............................................................................................................ 2 1.2.1.1 β-lactam antibiotics ..................................................................................................... 3 1.2.1.1 Glycopeptide antibiotics .............................................................................................. 5 1.2.2 Bacterial ribosome antibiotics ............................................................................................ 7 1.2.2.1 Aminoglycoside antibiotics ......................................................................................... 8 1.2.2.2 Macrolide antibiotics ................................................................................................. 10 1.2.2.3 Tetracycline antibiotics ............................................................................................. 11 1.2.2.4 Oxazolidinone antibiotics .......................................................................................... 11 1.2.3 Cell membrane antibiotics ................................................................................................ 12 1.2.4 Folate biosynthesis antibiotics .........................................................................................
Load more

Recommended publications
  • CLINICAL USE of RIFABUTIN, a RIFAMYCIN-CLASS ANTIBIOTIC, for the TREATMENT of TUBERCULOSIS (A Supplement to the 2008 Revision Of“ Standards for Tuberculosis Care”)
    Kekkaku Vol. 86, No. 1: 43, 2011 43 CLINICAL USE OF RIFABUTIN, A RIFAMYCIN-CLASS ANTIBIOTIC, FOR THE TREATMENT OF TUBERCULOSIS (A supplement to the 2008 revision of“ Standards for tuberculosis care”) August, 2008 The Treatment Committee of the Japanese Society for Tuberculosis The Treatment Committee of the Japanese Society for [Dosage and administration of rifabutin] Tuberculosis published statements on the“ Standards for Rifabutin, 5 mg/kg in body weight/day, maximum 300 mg/ tuberculosis care” in April 2008. Therein we referred to day, once daily. rifampicin as follows“; Use of rifampicin requires attention The dosage of rifabutin can be increased up to the maximum because of the interactions with a number of other drugs. daily dose of 450 mg in cases where decreased rifabutin serum Particularly for HIV-infected patients who need antiviral levels are expected due to anti-HIV drugs such as efavirenz, drugs, the replacement of rifampicin by rifabutin should be and in other cases if necessary. considered”. Rifabutin, belonging to rifamycin-class antibiotics In non-HIV-infected patients, rifabutin can be used for like rifampicin, causes less significant drug-drug interactions intermittent treatment with a regimen of twice or three times a than rifampicin, and can be used in combination with antiviral week, with the same dosage as daily administration. drugs mentioned above. In July 2008, rifabutin was approved as antituberculous drug, and is expected to be added to the drug [Important points for use of rifabutin] price listing in the near future*. Therefore, to the published (1) Rifabutin causes drug interactions due to induction of opinions, we add new statements concerning the use of rifabutin hepatic enzyme though less significantly than rifampicin.
    [Show full text]
  • Folic Acid Antagonists: Antimicrobial and Immunomodulating Mechanisms and Applications
    International Journal of Molecular Sciences Review Folic Acid Antagonists: Antimicrobial and Immunomodulating Mechanisms and Applications Daniel Fernández-Villa 1, Maria Rosa Aguilar 1,2 and Luis Rojo 1,2,* 1 Instituto de Ciencia y Tecnología de Polímeros, Consejo Superior de Investigaciones Científicas, CSIC, 28006 Madrid, Spain; [email protected] (D.F.-V.); [email protected] (M.R.A.) 2 Consorcio Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina, 28029 Madrid, Spain * Correspondence: [email protected]; Tel.: +34-915-622-900 Received: 18 September 2019; Accepted: 7 October 2019; Published: 9 October 2019 Abstract: Bacterial, protozoan and other microbial infections share an accelerated metabolic rate. In order to ensure a proper functioning of cell replication and proteins and nucleic acids synthesis processes, folate metabolism rate is also increased in these cases. For this reason, folic acid antagonists have been used since their discovery to treat different kinds of microbial infections, taking advantage of this metabolic difference when compared with human cells. However, resistances to these compounds have emerged since then and only combined therapies are currently used in clinic. In addition, some of these compounds have been found to have an immunomodulatory behavior that allows clinicians using them as anti-inflammatory or immunosuppressive drugs. Therefore, the aim of this review is to provide an updated state-of-the-art on the use of antifolates as antibacterial and immunomodulating agents in the clinical setting, as well as to present their action mechanisms and currently investigated biomedical applications. Keywords: folic acid antagonists; antifolates; antibiotics; antibacterials; immunomodulation; sulfonamides; antimalarial 1.
    [Show full text]
  • 1057-1064, 1984 the Effect of Pipemidic Acid on The
    Microbiol. Immunol. Vol. 28 (9), 1057-1064, 1984 The Effect of Pipemidic Acid on the Growth of a Stable L-Form of •ôNH•ôStaphylococcus aureus•ôNS•ô Kunihiko YABU,*,1 Hiromi ToMizu,1 and Yayoi KANDA2 1 Department of Biology, Hokuriku University School of Pharmacy, Kanazawa-machi, Kanazawa, Ishikawa ,920-11, and 2Department of Microbiology, Teikyo University School of Medicine, Kaga 2-chome, Ilabashi-ku, Tokyo 173 (Accepted for publication, June 12, 1984) Bacterial L-forms usually display spherical forms in an osmotically protective medium and seem to lack the typical binary fission process of cellular division ob servedin most bacteria (7). Although various modes of replication, such as budding binary fission, and release of elementary bodies from large bodies have been observed by light and electron microscopy (2, 5, 16), little is known about the processes involved in replication of L-forms. In the course of an experiment designed to test the effect of DNA synthesis inhibitors on the growth of a stable L-form of •ôNH•ôStaphylococcus•ôNS•ôaureus which grows in liquid medium, it was found that pipemidic acid, a synthetic antibacterial agent structurally related to nalidixic acid (13), induced a marked morphological altera tionat growth inhibitory concentrations. This study was initiated in an attempt to clarify the mechanism of replication of stable L-forms by analyzing the mor phologicalalteration caused by pipemidic acid. The stable L-form used was isolated as follows. S. •ôNH•ôaureus•ôNS•ôFDA 209P was grown in 10ml of Brain Heart Infusion broth (Difco) at 37C. The culture grown at 5•~105 colony-forming units (CFU) per ml was washed with saline by filtration and suspended in saline containing 100ƒÊg of N-methyl-N'-nitro-N-nitrosoguanidine per nil.
    [Show full text]
  • Crystal Structure and Stability of Gyrase–Fluoroquinolone Cleaved Complexes from Mycobacterium Tuberculosis
    Crystal structure and stability of gyrase–fluoroquinolone cleaved complexes from Mycobacterium tuberculosis Tim R. Blowera,1, Benjamin H. Williamsonb, Robert J. Kernsb, and James M. Bergera,2 aDepartment of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205; and bDivision of Medicinal and Natural Products Chemistry, University of Iowa, Iowa City, IA 52242 This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected in 2013. Contributed by James M. Berger, December 22, 2015 (sent for review October 28, 2015; reviewed by Benjamin Bax and Yuk-Ching Tse-Dinh) Mycobacterium tuberculosis (Mtb) infects one-third of the world’s threatens both first-line and second-line use (11). The wide- population and in 2013 accounted for 1.5 million deaths. Fluoro- spread testing of fluoroquinolones against TB has revealed quinolone antibacterials, which target DNA gyrase, are critical considerable variation in efficacy of different drug variants agents used to halt the progression from multidrug-resistant tu- against Mtb. For example, ciprofloxacin is only marginally active, berculosis to extensively resistant disease; however, fluoroquino- and its early use with Mtb was halted in favor of ofloxacin and lone resistance is emerging and new ways to bypass resistance are levofloxacin (7). These two agents are now proving to be less required. To better explain known differences in fluoroquinolone effective than moxifloxacin and gatifloxacin (7, 10); however, the action, the crystal structures of the WT Mtb DNA gyrase cleavage newest two compounds also exhibit some nonideality. For ex- core and a fluoroquinolone-sensitized mutant were determined in ample, gatifloxacin can elicit side effects such as hypo/hypergly- complex with DNA and five fluoroquinolones.
    [Show full text]
  • A TWO-YEAR RETROSPECTIVE ANALYSIS of ADVERSE DRUG REACTIONS with 5PSQ-031 FLUOROQUINOLONE and QUINOLONE ANTIBIOTICS 24Th Congress Of
    A TWO-YEAR RETROSPECTIVE ANALYSIS OF ADVERSE DRUG REACTIONS WITH 5PSQ-031 FLUOROQUINOLONE AND QUINOLONE ANTIBIOTICS 24th Congress of V. Borsi1, M. Del Lungo2, L. Giovannetti1, M.G. Lai1, M. Parrilli1 1 Azienda USL Toscana Centro, Pharmacovigilance Centre, Florence, Italy 2 Dept. of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), 27-29 March 2019 Section of Pharmacology and Toxicology , University of Florence, Italy BACKGROUND PURPOSE On 9 February 2017, the Pharmacovigilance Risk Assessment Committee (PRAC) initiated a review1 of disabling To review the adverse drugs and potentially long-lasting side effects reported with systemic and inhaled quinolone and fluoroquinolone reactions (ADRs) of antibiotics at the request of the German medicines authority (BfArM) following reports of long-lasting side effects systemic and inhaled in the national safety database and the published literature. fluoroquinolone and quinolone antibiotics that MATERIAL AND METHODS involved peripheral and central nervous system, Retrospective analysis of ADRs reported in our APVD involving ciprofloxacin, flumequine, levofloxacin, tendons, muscles and joints lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, pefloxacin, prulifloxacin, rufloxacin, cinoxacin, nalidixic acid, reported from our pipemidic given systemically (by mouth or injection). The period considered is September 2016 to September Pharmacovigilance 2018. Department (PVD). RESULTS 22 ADRs were reported in our PVD involving fluoroquinolone and quinolone antibiotics in the period considered and that affected peripheral or central nervous system, tendons, muscles and joints. The mean patient age was 67,3 years (range: 17-92 years). 63,7% of the ADRs reported were serious, of which 22,7% caused hospitalization and 4,5% caused persistent/severe disability. 81,8% of the ADRs were reported by a healthcare professional (physician, pharmacist or other) and 18,2% by patient or a non-healthcare professional.
    [Show full text]
  • Maxaquin® Lomefloxacin Hydrochloride Tablets to Reduce The
    Maxaquin® lomefloxacin hydrochloride tablets To reduce the development of drug-resistant bacteria and maintain the effectiveness of Maxaquin and other antibacterial drugs, Maxaquin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. DESCRIPTION Maxaquin (lomefloxacin HCl) is a synthetic broad-spectrum antimicrobial agent for oral administration. Lomefloxacin HCl, a difluoroquinolone, is the monohydrochloride salt of (±)-1-ethyl-6, 8-difluoro-1, 4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3- quinolinecarboxylic acid. Its empirical formula is C17H19F2N3O3·HCl, and its structural formula is: Lomefloxacin HCl is a white to pale yellow powder with a molecular weight of 387.8. It is slightly soluble in water and practically insoluble in alcohol. Lomefloxacin HCl is stable to heat and moisture but is sensitive to light in dilute aqueous solution. Maxaquin is available as a film-coated tablet formulation containing 400 mg of lomefloxacin base, present as the hydrochloride salt. The base content of the hydrochloride salt is 90.6%. The inactive ingredients are carboxymethylcellulose calcium, hydroxypropyl cellulose, hypromellose, lactose, magnesium stearate, polyethylene glycol, polyoxyl 40 stearate, and titanium dioxide. CLINICAL PHARMACOLOGY Pharmacokinetics in healthy volunteers: In 6 fasting healthy male volunteers, approximately 95% to 98% of a single oral dose of lomefloxacin was absorbed. Absorption was rapid following single doses of 200 and 400 mg (Tmax 0.8 to 1.4 hours). Mean
    [Show full text]
  • Antimicrobial Resistance Benchmark 2020 Antimicrobial Resistance Benchmark 2020
    First independent framework for assessing pharmaceutical company action Antimicrobial Resistance Benchmark 2020 Antimicrobial Resistance Benchmark 2020 ACKNOWLEDGEMENTS The Access to Medicine Foundation would like to thank the following people and organisations for their contributions to this report.1 FUNDERS The Antimicrobial Resistance Benchmark research programme is made possible with financial support from UK AID and the Dutch Ministry of Health, Welfare and Sport. Expert Review Committee Research Team Reviewers Hans Hogerzeil - Chair Gabrielle Breugelmans Christine Årdal Gregory Frank Fatema Rafiqi Karen Gallant Nina Grundmann Adrián Alonso Ruiz Hans Hogerzeil Magdalena Kettis Ruth Baron Hitesh Hurkchand Joakim Larsson Dulce Calçada Joakim Larsson Marc Mendelson Moska Hellamand Marc Mendelson Margareth Ndomondo-Sigonda Kevin Outterson Katarina Nedog Sarah Paulin (Observer) Editorial Team Andrew Singer Anna Massey Deirdre Cogan ACCESS TO MEDICINE FOUNDATION Rachel Jones The Access to Medicine Foundation is an independent Emma Ross non-profit organisation based in the Netherlands. It aims to advance access to medicine in low- and middle-income Additional contributors countries by stimulating and guiding the pharmaceutical Thomas Collin-Lefebvre industry to play a greater role in improving access to Alex Kong medicine. Nestor Papanikolaou Address Contact Naritaweg 227-A For more information about this publication, please contact 1043 CB, Amsterdam Jayasree K. Iyer, Executive Director The Netherlands [email protected] +31 (0) 20 215 35 35 www.amrbenchmark.org 1 This acknowledgement is not intended to imply that the individuals and institutions referred to above endorse About the cover: Young woman from the Antimicrobial Resistance Benchmark methodology, Brazil, where 40%-60% of infections are analyses or results.
    [Show full text]
  • Overcoming Fluoroquinolone Resistance: Mechanistic Basis of Non- Quinolone Antibacterials Targeting Type Ii Topoisomerases
    OVERCOMING FLUOROQUINOLONE RESISTANCE: MECHANISTIC BASIS OF NON- QUINOLONE ANTIBACTERIALS TARGETING TYPE II TOPOISOMERASES By Elizabeth Grace Gibson Dissertation Submitted to the Faculty of the Graduate School of Vanderbilt University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY in Pharmacology May 10, 2019 Nashville, Tennessee Approved: Neil Osheroff, Ph.D. Joey Barnett, Ph.D. Wendell S. Akers, Pharm.D., Ph.D. Sean Davies, Ph.D. Benjamin Spiller, Ph.D. Timothy R. Sterling, M.D. DEDICATION To all my family and church family who have supported and encouraged me over all my years in school. To Him who I put all my trust. Commit your way to the Lord, trust also in Him and He shall bring it to pass. Psalm 37:5 ii ACKNOWLEDGEMENTS I want to first thank my Ph.D. advisor, Dr. Neil Osheroff, for allowing me to work in his laboratory. Thank you for all your support and encouragement and just being an overall great mentor. You really know how to bring us up when we need it or give us an ego check when we get a little high and mighty when things are going well. I appreciate your supportiveness to careers outside academia. I also appreciate that you always have our best interest at heart. To Dr. Joe Deweese, my first research mentor and the one who instilled the love of topoisomerase research. Without your guidance I would not be where I am today. Thank you for introducing me to Neil and his laboratory and helping with the transition from research in your lab to his.
    [Show full text]
  • The Total Synthesis of Securinine and Other Methodology Studies
    University of Windsor Scholarship at UWindsor Electronic Theses and Dissertations Theses, Dissertations, and Major Papers 2010 The total synthesis of securinine and other methodology studies Bhartesh Dhudshia University of Windsor Follow this and additional works at: https://scholar.uwindsor.ca/etd Recommended Citation Dhudshia, Bhartesh, "The total synthesis of securinine and other methodology studies" (2010). Electronic Theses and Dissertations. 8275. https://scholar.uwindsor.ca/etd/8275 This online database contains the full-text of PhD dissertations and Masters’ theses of University of Windsor students from 1954 forward. These documents are made available for personal study and research purposes only, in accordance with the Canadian Copyright Act and the Creative Commons license—CC BY-NC-ND (Attribution, Non-Commercial, No Derivative Works). Under this license, works must always be attributed to the copyright holder (original author), cannot be used for any commercial purposes, and may not be altered. Any other use would require the permission of the copyright holder. Students may inquire about withdrawing their dissertation and/or thesis from this database. For additional inquiries, please contact the repository administrator via email ([email protected]) or by telephone at 519-253-3000ext. 3208. The Total Synthesis of Securinine and Other Methodology Studies by Bhartesh Dhudshia A Dissertation Submitted to the Faculty of Graduate Studies through the Department of Chemistry and Biochemistry in Partial Fulfillment of the Requirements
    [Show full text]
  • Eye Infections
    CLINICAL Approach Taking a Look at Common Eye Infections John T. Huang, MD, FRCSC and Peter T. Huang, MD, FRCSC he acutely red eye is often seen first by the primary-care physician. The exact Tcause may be difficult to determine and may cause some concern that a serious ocular condition has been missed. Thorough history and clinical examination will help delineate the final diagnosis. When there are doubts, prompt referral to an oph- thalmologist can prevent serious consequences. Often, the most likely diagnosis of an acutely red eye is acute conjunctivitis. In the first day, an acute bacterial infection may be hard to differentiate from viral, chlamydial and noninfectious conjunctivitis and from episcleritis or scleritis. Below is a review of the most commonly seen forms of eye infections and treat- ments. Failure to improve after three to five days should lead to a re-evaluation of the patient and appropriate referral where necessary. CHRONIC BLEPHARITIS Clinical: Gritty burning sensation, mattering, lid margin swelling and/or scaly, flaky debris, mild hyperemia of conjunctiva; may have acne rosacea or hyperkeratotic dermatitis (Figure 1). Anterior: Staphylococcus aureus (follicles, accessory glands); posterior (meibomian glands). Treatment: • Lid scrubs (baby shampoo, lid-care towellettes, warm compresses). Figure 1. Chronic blepharitis. There may be localized sensitivity to the shampoo or the components of the solution in the towellettes (e.g., benzyl alcohol). • Hygiene is important for the treatment and management of chronic blepharitis. Topical antibiotic-corticosteroid combinations (e.g., tobramycin drops, tobramycin/dexamethasone or sulfacetamide sodium-prednisolone acetate). Usage of these medications is effective in providing symptomatic relief, as the inflammatory component of the problem is more effectively dealt with.
    [Show full text]
  • Rifabutin (Mycobutin) Reference Number: HIM.PA.12 Effective Date: 09.04.18 Last Review Date: 11.19 Revision Log Line of Business: HIM
    Clinical Policy: Rifabutin (Mycobutin) Reference Number: HIM.PA.12 Effective Date: 09.04.18 Last Review Date: 11.19 Revision Log Line of Business: HIM See Important Reminder at the end of this policy for important regulatory and legal information. Description Rifabutin (Mycobutin®) is a derivative of rifamycin, an antimycobacterial agent. FDA Approved Indication(s) Mycobutin is indicated for the prevention of disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection. Policy/Criteria Provider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria. It is the policy of health plans affiliated with Centene Corporation® that Mycobutin is medically necessary when the following criteria are met: I. Initial Approval Criteria A. Mycobacterium avium Complex Prophylaxis (must meet all): 1. Prescribed by or in consultation with an HIV or infectious disease specialist; 2. Age ≥ 18 years; 3. Failure of azithromycin or clarithromycin, unless contraindicated or clinically significant adverse effects are experienced; 4. Dose does not exceed 300 mg per day. Approval duration: 12 months B. Tuberculosis (must meet all): 1. Diagnosis of tuberculosis infection; 2. Prescribed by or in consultation with an HIV or infectious disease specialist; 3. Documentation of current treatment with protease inhibitors or non-nucleoside reverse transcriptase inhibitors (NNRTIs) for the treatment of HIV infection; 4. Age ≥ 18 years; 5. Dose does not exceed 5 mg/kg per day. Approval duration: 12 months C. Other diagnoses/indications 1. Refer to the off-label use policy for the relevant line of business if diagnosis is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized): HIM.PHAR.21 for health insurance marketplace.
    [Show full text]
  • Resistance Pattern of Coagulase Positive Staphylococcus Aureus Clinical Isolates from Asir Region, Kingdom of Saudi Arabia
    Journal of Microbiology and Antimicrobials Vol. 3(4), pp. 102-108, April 2011 Available online http://www.academicjournals.org/JMA ISSN 2141-2308 ©2011 Academic Journals Full Length Research Paper Resistance pattern of coagulase positive Staphylococcus aureus clinical isolates from Asir region, Kingdom of Saudi Arabia Mohamed E. Hamid Department of Microbiology, College of Medicine, King Khalid University, P. O. Box 641, Abha, Kingdom of Saudi Arabia. E-mail: [email protected]. Accepted 6 April, 2011 The objectives of this study were to determine the prevalence of methicillin resistant coagulase positive Staphlococcus aureus (MRSA) infections in two major hospitals in Asir region, Kingdom of Saudi Arabia and to compare it with the community-acquired infections. Two hundreds and ten coagulase positive S. aureus recovered from 9831 specimens from various infections at Asir Central Hospital and Abha General Hospital, KSA (Kingdom of Saudi Arabia), were tested against 44 commonly used antibacterial agents. One hundred of the isolates were from hospital-acquired infections, 100 from community-acquired infections and 10 isolates were collected from the hospital environment. All isolates were found resistant to aztreonam, colistin, mecillinam, metronidazole, polymyxin B and nalidixic acid but were sensitive to vancomycin, nitrofurantoin and novobiocin. Various levels of resistant were recorded for the remaining antibiotics. High resistance to antimicrobial agents was detected among hospital acquired infections compared to community acquired infections (p<0.01). The resistance rates of S. aureus to antimicrobial agents among hospital acquired infections isolates were significantly higher (p<0.05) than community acquired infections. This implies that hospital environment is a strong risk factor for the prevalence of MRSA in the hospitalized patients, visitors, and hospital staff with potential risk of spreading to the community.
    [Show full text]