Antivirals & Antifungals PDF

AntiViral AntiFungal Pharm II AntiVirals (HIV and CMV) Diane T. Adamczyk, OD/Copyright © 2024 37 37 AntiViral AntiFungal Diane T. Adamczyk, OD/Copyright © 2024 Pharm II 38 How the viral cycle of HIV works It comes on and attaches to host cell and injects RNA material and converts to DNA (why its cal...

AntiViral AntiFungal Pharm II AntiVirals (HIV and CMV) Diane T. Adamczyk, OD/Copyright © 2024 37 37 AntiViral AntiFungal Diane T. Adamczyk, OD/Copyright © 2024 Pharm II 38 How the viral cycle of HIV works It comes on and attaches to host cell and injects RNA material and converts to DNA (why its called a retrovirus) and incorporates then releases Diagram shows where the various drugs inhibit the duplication of HIV Fusion inhibitors: prevent the virus attaching to host cells NRTI which prevent RNA from becoming DNA NNRTI Protease inhibitors 38 AntiViral AntiFungal Pharm II Antiretroviral Drugs (Examples) Nucleoside Reverse Transcriptase Inhibitors Zidovudine (Retrovir) Protease Inhibitors Nelfinavir (Viracept) Fusion Inhibitor Enfuvirtide (Fuzeon) Various Other Categories Diane T. Adamczyk, OD/Copyright © 2024 39 39 AntiViral AntiFungal Pharm II Antiviral Drugs Zidovudine (Retrovir) Pharmacology Thymidine analog that inhibits HIV replication Cellular enzymes phosphorylate the drug to triphosphate form> inhibits reverse transcriptase and terminates viral DNA elongation Use: Delays progression of HIV infection Decreases mortality rate Reduces risk of opportunistic infection Toxic: bone marrow hypoplasia Diane T. Adamczyk, OD/Copyright © 2024 40 Zidovudine (Retrovir) Thymidine analog that inhibits HIV replication Inhibits reverse transcription and termination DNA elongation Antivirals allows HIV to be not a death sentence bur rather a chronic illness but has sever side effects and in this case it is bone marrow hypoplasia 40 AntiViral AntiFungal Pharm II Antiviral Drugs Ganciclovir (Cytovene) Pharmacology: Nucleoside analog of deoxyguanosine, differs ACV by addition of terminal hydroxy methyl group Use: CMV retinitis in immunocompromised 10-25 Xs as active as A C V in CMV I V infusion Toxicity: bone marrow depression > neutropenia and thrombocytopenia Diane T. Adamczyk, OD/Copyright © 2024 41 Ganciclovir is a nucleoside deoxyguanosine It is used to treat CMV retinitis in the immunocompromised If someone has CMV retinitis this is what you go with b/c it is more active than acyclovir Ganciclovir given by IV infusion But there are risks of bone marrow depression, neutropenia, and thrombocytopenia 41 AntiViral AntiFungal Pharm II Cytomegalovirus retinitis > Viral inflammation of the retina > Ubiquitous DNA virus > Member of the herpes-type viruses > Weakened immune system develop infection so can be reactivated if the following are present: > AIDS, bone marrow transplant, chemo, drugs suppressing immune system, organ transplant > Potential Retinal Detachment Diane T. Adamczyk, OD/Copyright © 2024 42 42 AntiViral AntiFungal Pharm II Antiviral Drugs Foscarnet (Foscavir) Pharm acology Pyrophosphate analog Selectively inhibits viral DNA polymerases and reverse transcriptase (RNA polymerases) Use: C M V retinitis (AIDs) I V infusion Adverse reactions: Fever, GI problems Renal impairment Diane T. Adamczyk, OD/Copyright © 2024 43 So extra care to those with renal impairment or GI problems 43 AntiViral AntiFungal Pharm II AntiVirals: Topical Diane T. Adamczyk, OD/Copyright © 2024 44 44 AntiViral AntiFungal Pharm II Antiviral Drugs Idoxuridine and Vidarabine: No Longer Available > Idoxuridine > N ucleoside analog of thym idine > C linical Use: HSV (cornea) > N o longer available > Vidarabine (Vira-A) > Analog of adenosine > C linical use: HS: Dendritic or geographic epithelial keratitis > O intm ent > N o longer available Diane T. Adamczyk, OD/Copyright © 2024 45 They have been replaced by better drugs but older studies have used these drugs so be aware of them Idoxuridine and vidarabine (ointment) 45 AntiViral AntiFungal Pharm II Antiviral Drugs Trifluridine 1% Ophthalmic Solution > Pharmacology Analog of thymidine Inhibitor of thymidine synthetase Inhibits DNA synthesis in virus infected and normal host cells Incorporated into viral and host DNA, producing faulty DNA No replication of the virus > Clinical Use: HSV keratitis (historically drug of choice) Diane T. Adamczyk, OD/Copyright © 2024 46 What we have is trifluridine and it is toxic to the cornea It goes down to the epithelial It inhibits the DNA synthesis of the viral infected host cells Trifluridine is a topical drug so not used systemically b/c of its ability to use host cells and into the viral replication Used topically Used for HSV keratitis à used to be the drug of choice but no longer is 46 AntiViral AntiFungal Pharm II Antiviral Drugs Trifluridine 1% Ophthalmic Solution > Side effects: > Corneal epithelial defects à very toxic to the cornea! But kills the virus > Transient burning, sting > Hyperemia, chemosis > Delayed wound healing Diane T. Adamczyk, OD/Copyright © 2024 47 Used to be the drug of choice but now there are other drugs with less side effects Significant corneal epithelial defects 47 AntiViral AntiFungal Pharm II > Dosage: Antiviral Drugs Trifluridine 1% Diane T. Adamczyk, OD/Copyright © 2024 > Q2H (max daily dose: 9 drops), until reepithelization > Then 1 drop Q4H x 7 days > Toxic to cornea 48 Trifluridine needs to be used with great frequency à used every 2 hours so 9 drops! So until the dendrites reepithelialize and then taper to 1 drop every 4 hours for 7 days So goes after the simplex manifestations but needs to be used with real great frequency 48 AntiViral AntiFungal Pharm II Zirgan 0.15% (Ganciclovir Ophthalmic Gel) Pharmacology Guanosine derivative Inhibits DNA replication of HSV Transformed by viral and cellular kinases to ganciclovir triphosphate This inhibits synthesis of viral DNA by > Competitive inhibition of viral DNA-polymerase > Incorporation into viral DNA resulting in termination of DNA and replication Diane T. Adamczyk, OD/Copyright © 2024 49 Now there is zirgan which is ganciclovir gel It is analogous to what happens with acyclovir so goes after the two mechanisms 49 AntiViral AntiFungal Pharm II Zirgan 0.15% (Ganciclovir Ophthalmic Gel) > Indication: acute herpetic keratitis (dendritic ulcers) > Adverse rx: blurred vision (60%), eye irritation (20%), SPK (5%), hyperemia (5%) Diane T. Adamczyk, OD/Copyright © 2024 50 It’s a gel so can cause blurred vision 5% SPK is not much especially in comparison to trifluridine 50 AntiViral AntiFungal Pharm II Zirgan 0.15% (Ganciclovir Ophthalmic Gel) > 5 x day (approx q3H), > then TIDx7 days Diane T. Adamczyk, OD/Copyright © 2024 51 Not have to take as often as trifluridine but still goes after the epithelial dendrites 51 AntiViral AntiFungal Pharm II Avaclyr (acyclovir ophthalmic ointment) 3% Treatment: acute herpetic keratitis Ointment 5x/day until healed, then tid x 7 days NOT available US Diane T. Adamczyk, OD/Copyright © 2024 52 Available in the rest of the world but not in the US it is a great drug to use for epithelial or acute herpes keratitis It is an ointment used 5x a day but not available in the US 52 AntiViral AntiFungal Pharm II Herpes Simplex Studies HSV epithelial keratitis: No benefit to add oral ACV to trifluridine to prevent development of herpes stromal keratitis or iritis HSV stromal keratitis: No benefit to add oral ACV with topical steroids and trifluridine HSV recurrent eye disease Prophylactic oral ACV decreases Diane T. Adamczyk, OD/Copyright © 2024 53 We don’t like epithelial disease but the concern is to make sure the epithelial disease does not become stromal disease b/c that can cause inflammation and scarring so want to prevent this from developing 53 AntiViral AntiFungal Pharm II Herpes Simplex Studies HSV iridocyclitis Add oral ACV with topical steroid and trifluridine, may be beneficial Recurrent HSV Long term oral ACV effective in decreasing recurrence HSV epithelial keratitis Oral ACV may be effective tx - oral acyclovir is an effective tx for HSV epithelial keratitis à oral is just as effective as topical Diane T. Adamczyk, OD/Copyright © 2024 54 54 AntiViral AntiFungal Pharm II Herpes Zoster Studies HZO Oral ACV (800mg 5x) best within 72 hours of rash onset Post herpetic neuralgia (HZO) Contradictory evidence oral ACV decreases Oral valacyclovir may be more effective in decreases Diane T. Adamczyk, OD/Copyright © 2024 55 55 AntiViral AntiFungal Pharm II Zoster Eye Disease Study ZEDS aims to provide scientific evidence on whether suppressive valacyclovir treatment improves outcomes in HZO and should become the standard of care. Diane T. Adamczyk, OD/Copyright © 2024 56 56 AntiViral AntiFungal Pharm II Other Antivirals Diane T. Adamczyk, OD/Copyright © 2024 57 57 AntiViral AntiFungal Pharm II Povidone-Iodine (Betadine) > Pre-operative prep > Periocular surfaces > Irrigation of ocular surface > Cornea, conjunctiva > Broad spectrum antimicrobial action Diane T. Adamczyk, OD/Copyright © 2024 58 58 AntiViral AntiFungal Pharm II Povidone-Iodine 5% Ophthalmic Prep (Betadine) U se with EKC Sting Consider use anesthetic Instill 4-5 drops s/p 1 minute, lavage Corneal stippling NSAID use Diane T. Adamczyk, OD/Copyright © 2024 59 Betadine used for epidemic keratoconjunctivitis Use the ophthalmic version of it and lavaging the eye EKC is very contagious It stings! A LOT à enough stinging that an anesthetic should be used! 59 AntiViral AntiFungal Diane T. Adamczyk, OD/Copyright © 2024 Pharm II 60 Talks about treatment and management of pt Put in a few drops of betadine and then irrigate it 60 AntiViral AntiFungal Pharm II Povidone-Iodine > More than 2 decades of off label use of Povidone-iodine for adenoviral conjunctivitis > Purpose: efficacy of single in office administration of povidone-iodine (PVP-I) and adenoviral conjunctivitis > Conclusion: pilot study suggests single, in office administration of 5%PVP-Imay accelerate reduction in viral load and hasten improvement of clinical signs and symptoms who present within 4 days of symptom onset. > Note: after day 4, viral titers and severity of signs/symptoms decreased markedly in both groups and no differences between groups were detected. Diane T. Adamczyk, OD/Copyright © 2024 61 Looking at efficacy of the iodine and seeing its effect on EKC The time frame is important, the onset then 4 days after that then the viral load decreased when the tx was used So you want to get them before 4 days but after 4 days you wont get an effect 61 AntiViral AntiFungal Pharm II Povidone-Iodine M u co id d isch arge Peak Viral Load Bulbar Redness Bulbar edema Efficay of single administration of 5% povidone-iodine in treatment of adenoviral conjunctivitis. Am J Ophthalmol 2021;231: 28– 38. Diane T. Adamczyk, OD/Copyright © 2024 62 Dotted line is ATs and solid line is povidone-iodine For the viral load, after 4 days then it makes no difference if you use them If used within 4 days then you will reduce amount of redness, tearing, mucous discharge, bulbar edema, taring, etc. But after 4 days the effects of the iodine and the ATs overlap 62 AntiViral AntiFungal Pharm II Anti Fungals Diane T. Adamczyk, OD/Copyright © 2024 63 63 AntiViral AntiFungal Pharm II Antifungal Drugs > Fungi > Yeast (Unicellular organisms) > Candida > M u c o c u ta n e o u s in fe c tio n s of o r a l c a v ity (thrush), G I tra ct > Multicellular fungus > Hyphae, spores Diane T. Adamczyk, OD/Copyright © 2024 64 Candida is a yeast fungus Fungi infections seen in corneal abrasions from a branch 64 AntiViral AntiFungal Pharm II Antifungal Drugs > Fungi (molds and yeasts) > Large and diverse group of microorganisms > 100,000 species (only a few cause human infection) Diane T. Adamczyk, OD/Copyright © 2024 65 Fungal cell Includes molds and yeasts Only a few effect humans and leave us with infections 65 AntiViral AntiFungal Pharm II Netter 1st Ed Diane T. Adamczyk, OD/Copyright © 2024 66 MOA of a variety of different antifungals It can go after the cell membrane or the nuclear division or the synthesis Cell membrane one are usually polyene that ae use don ocular conditions 66 AntiViral AntiFungal Pharm II Antifungal Drugs > Topical: > Polyenes: Natamycin ophthalmic > Systemic: > Polyenes > Amphotericin Bdeoxycholate > Pyrimidines > Flucytosine > Imidazoles > Miconazole > Triazoles > Fluconazole > Itraconazole > Voriconazole Fungal Keratitis Diane T. Adamczyk, OD/Copyright © 2024 67 Only topical ophthalmic out there for fungi tx is natamycin! The systemic antifungals are specially made so fortified and use din conditions like this when things get bad They are fortified and turned into special ophthalmic drops 67 AntiViral AntiFungal Pharm II Antifungal Drugs Amphotericin B > Pharmacology > Polyene > Bind to ergosterol in fungal cell membrane, increasing permeability of membrane > Clinical Use: > Keratomycosis=fungal keratitis > Fungal corneal ulcers > Topical, subconjunctival, systemic Diane T. Adamczyk, OD/Copyright © 2024 68 This goes after the cell membrane and the imbalance that happens Imbalance throws everything off and used for keratomycosis and other fungal corneal ulcers Amphotericin is available systemically Not an ophthalmic version but can be fortified 68 AntiViral AntiFungal Pharm II Antifungal Drugs Nystatin > Pharmacology > Polyene > Bind to ergosterol in fungal cell membrane, increasing permeability of membrane > Clinical Use > Candida infections of the skin, mucous membranes, and intestinal tract > Corneal infections (Candida, Aspergillus) > Oral and topical Diane T. Adamczyk, OD/Copyright © 2024 69 Nystatin also goes at the cell membrane 69 AntiViral AntiFungal Pharm II Antifungal Drugs Natamycin 5% Ophthalmic Suspension (Natacyn) > Only FDA approved drug for topical treatment of ocular fungal infection > Pharmacology > Polyene > Alters permeability of fungal cell membrane > Suspension > Clinical Use: fungal keratitis > Dosage: Q1-2H > Generally non-toxic but can slow healing Diane T. Adamczyk, OD/Copyright © 2024 70 Only ophthalmic suspension that is FDA approved for that use 70 AntiViral AntiFungal Pharm II Antifungal Drugs Voriconazole > Pharmacology Derivative of fluconazole Triazole Alters cell membrane > Off label for fungal corneal ulcer > Oral/IV/Suspension > Effective: aspergillus, candida, fusarium Diane T. Adamczyk, OD/Copyright © 2024 71 Not FDA approved for corneal ulcers but fortified for corneal ulcers 71 AntiViral AntiFungal Pharm II Fungal Keratitis Treatment Diane T. Adamczyk, OD/Copyright © 2024 > Natamycin 5% drops > Amphotericin B drops or fortified voriconazole > Consider oral agents (fluconazole or itraconazole) 72 72 AntiViral AntiFungal Pharm II Other Anti-Infective Diane T. Adamczyk, OD/Copyright © 2024 73 73 AntiViral AntiFungal Pharm II Demodex Mites > Most common ectoparasite found on human skin > Associated with blepharitis > 45% with blepharitis have concomitant Demodex > Demodex blepharitis > Mites inhabit eyelash follicles à they get in and do their thing and causes collarettes > Feed on sebum causing epithelial abrasions, resulting in microscopic epithelial hyperplasia and reactive hyperkeratinization > Digestive enzyme and debris can provoke inflammatory response > Collarettes are pathognomonic > May result in: tear film disruption, MGD, lid erythema, lash loss or misalignment, peripheral corneal vascularization, others Diane T. Adamczyk, OD/Copyright © 2024 74 Almost everyone has demodex Ectoparasite so lives on tops of things so gets into our lids and lashes not our GI system It is associated with blepharitis Can cause lid margin erythema They feed on the sebum and cause keratinization and chews up the material inside the follicles and spits it out and causes all these problems The digestive enzymes and the debris causes problems Can cause issues on the corneal like vascularization 74 AntiViral AntiFungal Pharm II Demodex Mites > Life cycle of Demodex mite is 14-18 days (egg to larval to adult stage) > Demodex folliculorum: found in clusters around root of lashes and lash follicles > Results in anterior blepharitis > Demodex brevis: resides solitarily in sebaceous and Meibomian gland > Results in posterior blepharitis, meibomian gland dysfunction, recurrent chalazia Diane T. Adamczyk, OD/Copyright © 2024 75 75 AntiViral AntiFungal Pharm II Teatree oil (Cliradex) > Use: eradicate mites and reduce ocular surface inflammation > Anti-inflammatory, antimicrobial, antifungal and acaricidal (mites) effects > Tea tree oil (TTO): active ingredient terpinen-4-ol (4terpineol) > A natural essential oil steam distilled from the leaf of Melaleuca alternifolia > Aboriginal medicine in Australia for wounds and cutaneous infection Diane T. Adamczyk, OD/Copyright © 2024 76 Tea tree oil is used and goes after the mites It is a natural essential oil 76 AntiViral AntiFungal Pharm II Teatree oil (Cliradex) Antimicrobial effects and mechanism ispoorly understood. Findings indicate that TTO penetrate bacterial and fungal cell wall and cytoplasmic membrane Possibly compromise cytoplasmic membrane leading to cell death Diane T. Adamczyk, OD/Copyright © 2024 77 77 AntiViral AntiFungal Pharm II Teatree oil (Cliradex) > Tx: > Mild to moderate symptoms: QD x 6-8 weeks > Moderate to severe symptoms: BID x 6-8 weeks > Note: 6 weeks covers 2 life cycles of Demodex > Maintenance: once a day Diane T. Adamczyk, OD/Copyright © 2024 78 You don’t know where in the life cycle you are catching the demodex so if you do it for 6 weeks you know you are covering at least 2 life cycles 78 AntiViral AntiFungal Pharm II Teatree oil (Cliradex) > Cliradex light: everyday ocular hygiene > Used for blepharitis and to maintain clean/healthy ocular environment > Cliradex towelettes: use for Demodex and severe ocular irritation > Use on lid and surrounding ocular area > Cosmetic product, therefore does not require FDA approval > Purchase on line or through doctor Diane T. Adamczyk, OD/Copyright © 2024 79 79 AntiViral AntiFungal Pharm II TransVisSciTech 2013 Vol. 2 No. 7 Article 2 Diane T. Adamczyk, OD/Copyright © 2024 80 80 AntiViral AntiFungal Diane T. Adamczyk, OD/Copyright © 2024 Pharm II 81 New FDA approved, goes after the bug 81 AntiViral AntiFungal Pharm II XDEMVY (lotilaner ophthalmic solution) 0.25% Ectoparasiticide (anti-parasitic) indicated for treatment of Demodex blepharitis Is a member of the isooxazoline family of compounds Mechanism: is a gamma-aminobutyric acid (GABA)gated chloride channel inhibitor selective for mites Inhibition of GABA chloride channels causes paralytic action in target organism leading to its death Does not inhibitor mammalian channels Dosage: BIDfor 6 weeks ADR: stinging and burning Diane T. Adamczyk, OD/Copyright © 2024 82 Inhibiting GABA channels kills the mites but does not effect the mammals they are on! 82 AntiViral AntiFungal Pharm II XDEMVY (lotilaner) PI 2023 Diane T. Adamczyk, OD/Copyright © 2024 83 You can see that the xtemvy worked well in both studies 83