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`Argentum Pharm. LLC V. Alcon Research, Ltd.
`Case IPR2017-01053
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`ALCON 2|26
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`uuuuuuuuuuuuuuuuuuuuuuuuuu
`
`Developments in
`Ophthalmology
`
`Vol. 33
`
`Series Editor
`
`W BehrenS—Baumann Magdeburg
`
`KARGER
`
`

`

`tttttttttttttttttttttttttt
`
`Antiseptic Prophylaxis
`and Therapy in
`Ocular Infections
`
`Principles, Clinical Practice and Infection Control
`
`Volume Editors
`
`A. Kramer Greifswald
`W Behrens-Baumann ‘Magdeburg
`
`27 figures and 68 tables, 2002
`
`Basel - Freiburg - Paris - LondOn -New York -
`'
`‘
`‘
`‘
`'
`‘
`-'
`'
`KARC E R New Delhi ~ Bangkok , Singapore ' Tokyo ' Sydney
`
`

`

`tel-oIII-oolullllloloonoer
`
`Developments in Ophthalmology
`
`Library of Congress Cataloging-in~Publication Data
`
`Antiseptic prophylaxis and therapy in ocular infections : principles, clinical practiceand
`infection control 1 volume editors, A. Kramer, W. Behrens-Baumann.
`p. ; em. — (Developments in ophthalmology ; v. 33)
`Includes bibliographical references and indexes.
`ISBN 3805573162 (hard cover : alk. paper)
`1. Ophthalmic drugs. 2. Antiseptics. 3. Eye-Infections. I. Kramer, Axel.
`Behrens-Baumann, Wolfgang [II Series.
`[DNLM: 1. Eye Infections—drug therapy. 2. Anti—lufectivc Agents. Local-therapeutic
`use. 3. Antibiotic Prophylaxis. WW 166 A633 2002]
`R5994 A55 2002
`617.7'061—dc21
`
`ll.
`
`2002019343
`
`Bibliographic Indioes. This publication is listed in bibliographic services, including Current Contents”
`and Index Medicus.
`
`Drug Dosage. The authors and the publisher have exerted every effort to ensure that drug selection and
`dosage set forth in this text are in accord with current recommendations and practice at the time of publication.
`However, in view of ongoing research, changes in government regulations, and the constant flow of information
`relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any
`change in indications and dosage and for added warnings and precautions. This is particularly important when
`the recommended agent is a new andlor infrequently employed drug.
`
`All rights reserved. No part of this publication may be translated into other languages, reproduced or
`utilized in any form or by any means electronic or mechanical, including photocopying, recording, microcopying,
`or by any information storage and retrieval system, without permission in writing from the publisher.
`
`0 Copyright 2002 by S. Karger AG, 20. Box, Cit-4009 Basel (Switzerland)
`wwwltargencom
`Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel
`ISBN 3—8055—73 16—2
`
`

`

`Ilene-eooueoeoouI-uIna...-
`
`Contents
`
`
`.39‘0
`e
`
`' C)
`3:
`
`
`SE? 1 0 2002
`LU
`=5, CENTER LIBRARY
`
`
`
` \“’
`
`ListofContributors .... ..... ......... VIII
`
`Foreword.....................”......” ....... ...“...Xlll
`
`SJIsenberg
`
`Preface XV
`A. Kramer, W Behrens-Baumann
`
`Fundamentals and Aims
`
`1
`
`2
`
`3
`
`Microbial Colonization of the Eye as Target for Antiseptics .....
`A. Kramer, W Behrens-Baumann
`
`The Eye and Coniunctiva asTarget of Entry for Infectious Agents:
`Prevention by Protection and by Antiseptic Prophylaxis. .
`. . .
`. . .
`L. Gfirtler
`
`2
`
`9
`
`Antisepsis versus Antimicrobial Chemotherapy and
`Indications for Eye Antisepsis ..............................
`A. Kramer, W Behrens-Baumann
`
`14
`
`4
`
`Requirements Concerning Antiseptics for Periorbital, Orbital and
`lntraorbitalApplication . ...... 28
`4.1 Antimicrobial Efficiency ..........................' ...............
`28
`A. Kramer. {-1—}? Werner
`
`4.2
`
`Local Tolerance................................................
`
`32
`
`G. Geerling .l Baaiz, D. Harder; G. Miller: K. Reimer, I? Rudolph, A. Kramer
`
`4.3
`
`Systemic Tolerance of Antiseptics Used in Ophthalmology .............
`W Siegmund, T. Giessmann
`
`57
`
`

`

`4.4
`
`4.5
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`10.1
`
`10.2
`
`Pharmacokinetics of Ophthalmic Drugs .......................... .
`H. Tawflk—Schlieper
`
`Formulation Requirements for the Ophthalmic
`Use ofAntiseptics .............................................
`I. Krdmer, M. Haber, A. Duis
`
`Efficacy and Tolerance of Selected Antiseptic SubstancesIn
`RespectofSuitabilityforUseontheEye
`A. Krame): R Rudolph
`
`66
`
`85
`
`117
`
`Importance and Epidemiology of Infectious Eye Diseases . . . . . . 145
`VKlauss, U.C. Schaller, AA. Bialasiewicz
`'
`
`Incidence of Endophthaimitis in Ophthalmic Surgery. ......... 191
`L. Frtech, H.B. Dick
`
`MethiciIlin—Resistant Staphylococcus aureus in Ophthalmology,
`Occurrence, Sanitation Measures and Hygienic Precautions . . . . 199
`JHJI Wagenvoort
`
`Nosocomial Virus Infections of the Eye. . . . . . . . . . . .
`G. Caspari, H. Wizssill
`
`.
`
`. . . . . . . . . 207
`
`
`Clinical Use of Andseptics
`
`Prophylactic Indications for Eye Antiseptics. . . . . . . . . . . . . . . . . . 212
`Pre-, Intra- and Postoperative Antisepsis in Eye Surgery ............... 212
`W Behrens-Baumann, A. Kramer
`
`Prophylaxis against Ophthalmia Neonatorum........................ 223
`A. Kramer, C Aspo'ck, 0. Assadian, H. Below, WBehIens—Baumami, C. Fusch,
`K. Reimer, P Rudolph, P Wutzler
`
`10.3 Measures for Prevention of Infection via Corneal Transplants ........... 233
`E Wilhelm, T. Bredehorn, A. Kramer
`
`11
`11.1
`
`. . . . . . . . . . . 243
`.
`Therapeutic Indications for Local Anti-Infectives .
`Bacterial Infections of the Eye .................................... 243
`AA. Bialasiewicz
`
`11.2 Recommendations for Isolation and Antiseptic Sanitation of
`Patients with MRSA Colonization or Infection ....................... 250
`K.-D. Zastmw, A. Kramer
`
`11.3
`
`Topical Antimycotic Drugs ....................................... 263
`W Behrens-Baumamz
`
`11.4 Viral Ocular Infections: Topical Treatment and Prevention .............. 281
`U. Pleyer
`
`11.5 Anti-infectives against Amebic Keratitis ............................ 297
`W Behrens-Baumann, A. Kramer
`
`Contents
`
`VI
`
`

`

`Supporting Measures for Infection Control
`
`12
`
`Preventive Measurements to Avoid theTransmission of
`
`Relevant Pathogens after Occurrence of Infection . . . . . . . . . . . . 306
`E-A. Pitten. L. Jatzwauck, A. Kramer
`
`13
`
`14
`
`15
`
`16
`
`HandHygiene....... .......
`A. Kramer. M. Exner, M. Rotter
`
`..... . ............ 316
`
`Contact Lens Hygiene ................................... 328
`A. Berke, W Cagnolati
`
`Antimicrobial Efficacy of Contact Lens Care Products and
`Critical Comment on lSOIFDIS 14729 . . . ................... 343
`
`A. Kramen R Rudolph, H-R Werner
`
`Sampling and Transport of Specimens for Microbial Diagnosis of
`Ocular infections ......... . . . .
`.
`. . . . . . , ................... 362
`
`H.—G. Sonnrag
`
`Subject Index ........ . . ........................... . . . . . . 368
`
`Contents
`
`VII
`
`

`

`4. Proprietary Preparations
`C3 eye drops (Thilo, GER)
`Propionate de sodium eye drops (Chibret, F)
`5. Concentration
`
`25—10% aqueous solutions.
`6. pH, Buffer
`pH of aqueous solutions: 7—8
`The solutions are buffered to pH 7.0—7.3
`7. Tonicity
`Freezing-point depression: 035°C (1% aqueous solution of sodium
`propionate)
`Isoosmotic concentration: 1.47%
`
`Sodium chloride equivalent (E—factor): 0.60
`8. Sterilization, Preservatives
`Sterilization by moist heat (121°C, 15 min) is recommended.
`9. Recommended Storage Conditions
`Airtight containers.
`10. Stability
`2 years at pH 7.1 (FNA).
`ll. Known Incompatibilities
`Fe(lll) salts.
`
`2.10.
`
`Zinc Sulphate
`1. Clinical Aspects
`Zinc sulphate exhibits astringent and weak microbiostatic properties.
`Precipitation of proteins and reaction with zinc-dependent enzymes are the
`primary aspects of activity.
`Zinc sulphate and other zinc salts like zinc borate are used as eye lotions
`or eye drops for the treatment of unspecified inflammation and irritation of
`the conjunctiva. Zinc salts, in combination with vasoconstrictors, are often used
`for the treatment of conjunctivitis angularis caused by Diplobacillus Morax~
`Axenfeld (= Moraxella lacunata) [72].
`Except from occasionally seen chemical conjunctivitis, no significant
`side effects ofzinc sulphate solutions administered to the eye are described [73].
`2. Drug Monographs
`DAB, USP, Ph. Helv., AB—DDR, several other pharmacopoeias.
`
`3. Selected Eye Preparations
`Formulations of ophthalmic preparations are found in several Pharmaco-
`poeias and Drug Codices, i.e. DAC/NRF, FNA, 2. AB DDR, Ph. Nord., BPC,
`
`BP, NF Belg.
`
`4.5
`
`Formulation Requirements for the Ophthalmic Use of Antiseptics
`
`ll 1
`
`

`

`Zinksulfat/lugentmpfen 0. 25% (NRF 15. 9.) (zinc sulphate eye drops 0. 25%)
`
`[74]
`Zinc sulphate ' 7 H20
`Boric acid
`
`0.025 g
`0.178 g
`
`1.0 g
`Thiomersal stock solution 0.02%
`ad 10.0 g
`Water for injection
`Oculoguztae zinci sulfatis 0.25 % (FNA) (zinc sulphate eye drops 0. 25%)
`
`[75]
`0.250 g
`Zinc sulphate
`2 g
`Boric acid
`Phenylmercuric solution 40 mg/l FNA ad 100 ml
`Filtration of the solution through a 1.2-um or less membrane filter
`and sterilization with moist heat (30min, 100°C) in appropriate containers is
`recommended.
`
`Oculoguttae zinci sulfatis 0.25% sine conservans (FNA) (zinc sulphate eye
`drops 0.25% without preservation) [76]
`Zinc sulphate
`0.250 g
`Boric acid
`2 g
`Purified water
`ad 100 ml
`
`Filtration of the solution through a 1.2-um or less membrane filter and
`sterilization with moist heat (15 min, 121°C) in single-dose containers (Redipak®)
`is recommended.
`
`4. Proprietary Preparations
`Zinc sulphate:
`Eye Sed® 0.25% eye drops (Scherer, USA)
`Oftan Zinl<® 0.25% eye drops (Leiras, SF)
`Op-Thal-Zin® eye drops (Alcon, GER)
`Timeuphrasin® N eye drops (Optima, GER)
`Zinco solfato 0.5% eye drops (Ogna, I)
`link DAK 0.35% eye drops (Nycomed, DK)
`Oculosan® N eye drops and rinsing solution (DiSpersa, GER, in combina-
`tion with a vasoconstrictor)
`Zincfrin® eye drops (Alcon, GER, in combination with a vasoconstrictor)
`Other zinc salts:
`
`Ophthopur® eye drops and rinsing solution (Winzer, GER, zinc borate in
`combination with a vasoconstrictor)
`‘Zinc. bor.’ in der Ophthiole (Mann, GER, zinc lactate and boric acid)
`5. Concentration
`
`0.02—0.5% in eye drops (preferred 0.25%).
`0.1% in eye lotions.
`Up to 0.5% in eye ointments.
`
`4
`
`Requirements Concerning Antiseptics Application
`
`112
`
`

`

`6. pH, Bufi‘er
`Aqueous solutions of zinc sulphate are acidic: 5% zinc sulphate = pH
`4.4-5.6, 1% zinc sulphate = pH 4, 0.2% zinc sulphate a pH approx 5.5.
`The pH may cause irritation to the eye. However, elevated pH Values or initiating
`for zinc sulphate solutions is inappropriate due to loss of activity and increased
`irritation risk. At higher pH values, precipitation of zinc hydroxide may occur.
`Eye drops containing other zinc salts, e.g. zinc acetate, may be buffered
`to higher pH values using boric acid buffers or boric acid acetate buffers [73].
`7. Tonicity
`Freezing-point depression: 006°C (1% solution of zinc sulphate)
`Isoosmotic concentration: 7.65%
`
`Recommended excipient to achieve isotonicity: boric acid (At 028°C;
`E-factor 0.48), sodium chloride (At 058°C; E-factor 0.90)
`Sodium chloride equivalent (E—factor): 0.16 (0.5% solution)
`8. Sterilization, Preservatives
`The unbuffered zinc sulphate solution (pH 5) can be sterilized by moist heat
`(121°C, 15 min, or 100°C, 30 min). Zinc sulphate solutions buffered to higher pH
`values should be sterilized by filtration because heating may cause precipitation.
`Thiomersal, phenylmercury salts and benzalkonium chloride are recom-
`mended as additional preservatives.
`9. Recommended Storage Cenditions
`Protected from light in hermetic non—metallic containers.
`10. Stability
`Zinksulfat Augentropfen 0.25% (NRF 15.9.) are labelled to be used within
`6 weeks after preparation [74].
`Oculoguttae zinei sulfatis 0.25% (FNA): stable for 2 years (pH 4.5) [75].
`Oculoguttae zinci sulfatis 0.25% sine conservans (FNA): stable for 1 year,
`should be used within 1 week of opening [76].
`Collyrium Zinci Sulfatis 0.25% (FNA): stable for 2 years (pH 7.6) [77].
`ll. Known Incompatibilities
`Alkaline agents, lead salts, proteins, silver protein, tannins, borax, phos-
`phates, calcium salts, earth metal hydroxides and carbonates, chlorhexidine,
`cetylpyridinium chloride, methylcellulose (10% zinc sulphate).
`Non-resistant glass and rubber stoppers may also be incompatible with zinc
`salts.
`
`References
`
`l
`
`2
`
`1997:1163 Eye Preparations; in European Pharmacopoeia, ed 3. Strasbourg, Council of Europe, 1997,
`pp 1761—1763.
`Van Ooteghem M: Wissrige Augenpriiparatc, Viskositiit; in Dolder R, Skinner PS (eds): Ophthalmika.
`Stuttgart, Wisacnschafiliche Verlagsgesellschaft mbl-l, 1990, pp 393-407.
`
`4.5
`
`Formulation Requirements for the Ophthalmic Use ofAntiseptics
`
`113
`
`

`

`Dolder R: Wissrigc Augcnpriiparate, Die Angleichung des pH-Wertes; in Bolder R, Skinner FS (eds):
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`10
`
`11
`
`l3
`
`14
`
`1.5
`
`16
`
`17
`
`18
`19
`
`2O
`
`21
`22
`23
`
`24
`
`25
`26
`
`27
`
`28
`
`Requirements Concerning Antiseptics Application
`
`114
`
`

`

`29
`
`30
`
`31
`32
`
`33
`
`34
`
`35
`36
`
`37
`
`38
`
`39
`
`40
`
`4]
`
`42
`
`43
`
`45
`46
`
`47
`
`4s
`
`49
`
`so
`
`51
`
`$2
`
`53
`
`54
`
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