This document discusses different classes of antimicrobial drugs, including their mechanisms of action, spectra of activity, and ophthalmic uses. It covers cell wall synthesis inhibitors like penicillins, cephalosporins, glycopeptides, and carbapenems. It also discusses inhibitors of cytoplasmic membranes, bacterial DNA synthesis, and protein synthesis, including fluoroquinolones, aminoglycosides, tetracyclines, and macrolides. For each class, examples are given and their mechanisms, spectra, pharmacology profiles, indications, and adverse effects are summarized.

1. Chemotherapy

2. Outline
• Introduction
• Antibacterial
• Antifungal
• Antiviral
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3. Chemotherapy

4. Cont…

6. Antimicrobial Chemotherapy
• The broad classification of antimicrobial is as
– Antibacterial
– Antifungal
– Antiviral and
– Antiparasitic
• Classification of an antibiotic is based on:
– The class and spectrum of microorganisms it kills
– The biochemical pathway it interferes
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7. Antibacterial drugs
• The antibiotics are classified on the basis of the following:
• Chemical structure
– (sulfonamides,
– diamino pyrimidines,
– quinolones,
– β-lactam antibiotics, tetracyclines, nitrobenzene derivatives, macrolides,
lincosamides, glycopeptides, oxazolidinones, polypeptides, nitrofuran derivatives,
nitroimidazoles, azoles, and nicotinic acid derivatives)
• Mechanism of action
– Inhibit cell wall synthesis,
– Disrupt cell membrane,
– Inhibit protein synthesis,
– Inhibit DNA topoisomerase, interfere with DNA function or synthesis, and interfere
with intermediary metabolism)

8. Cont…
• Spectrum of activity
– narrow spectrum and broad spectrum
• Type of action (bacteriostatic and bactericidal),
• origin (from bacteria, actinomycetes, and fungi)

9. Cont….
• The choice of an antibacterial is based on considerations of
– pharmacodynamic,
– pharmacokinetic, and
– bacteriological characteristics,
– risk of selecting resistantmutants, and
– cost.

10. Cell wall synthesis inhibitors
• It is the important cellular structure by which selective toxicity is
achieved.
– With -lactam ring
• Penicillin, Cephalosporin, Monobactams, Carbapenems
– With out -lactam ring
• Vancomycin ,Cyclocerine
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11. Cont…
 Beta-lactam antibiotics
• The inhibit D-alanyl-D-alanine-transpeptidase which essential for
cross linkage of peptidoglycan layer of bacterial cell wall
The bacteria is unable to synthesize a stable cell wall and the it will be lysed
• The group includes
• Penicillin,
• Cephalosporins and
• Carbapenems
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12. Cont…
 Penicillin
• Natural - Penicillin G and V are highly active against
Gram +ve & -ve cocci
But, they are hydrolysed by penicillinase
• The penicillinase-resistant penicillin :
Methicillin, Nafcillin, oxacillin, cloxacillin
Choose for S. aureus and S. epidermidis
• Extended-spectrum penicillin
Ampicillin & amoxicillin
Are effective against gram-ve microorganisms :- H. influenzae, E. coli
and Proteus mirabilis
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13. Cont….
Cephalosporins
• Are β-lactam antibiotics having the same action as penicillins, But
more resistant to certain β-lactamases
• Classified as 1st ,2nd .3rd , 4th & 5th generation, based on their
Bacterial susceptibility patterns and
Resistance to β-lactamases
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14. Cont…
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15. Cont…
Glycopeptides
• Vancomycin and Teicoplanin
• MOA
– Bind to D-alanyl-D-alanine in the growing bacterial cell wall→
inhibits the Transglycosylase,
– Preventing further elongation of peptidoglycan and cross-linking.
• Teicoplanin is two- to fourfold more active than vancomycin
against most Gram-positive cocci
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16. Cont….
• Spectrum of activity
– Aerobic and anaerobic Gram-positive organisms, including
• MSSA and MRSA,
• Streptococci, Enterococci, Corynebacterium spp., Bacillus spp., Listeria
monocytogenes, Clostridium spp.
• Resistance of vancomycin is seen in
– Enterococcus faecalis, E. faecium, and
– Coagulase-ve staphylococci
• Pharmacology
– Parenteral use is limited to IV administration, b/c
• Poorly absorbed after oral administration
• IM administration is extremely painful
– Are eliminated from the body by glomerular filtration
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17. Cont…
• Ophthalmic indications
– Topical, subconjunctival and intravitreal administration For:-
• Infectious corneal ulcers
• Endophthalmitis by G +ve organisms
• Adverse reaction
– Subconjunctival injections may cause conjunctival necrosis and
sloughing.
– Topical administration has also been shown to retard epithelial wound
healing in rabbits
– Ototoxicity, nephrotoxicity
– Rapid infusion causes tingling and flushing of the face, neck, and
thorax ----Redman syndrome
– Hemorrhagic occlusive retinal vasculitis
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18. Cytoplasmic Membrane Inhibitors
• Polymyxin B
• Colistin and
• gramicidin are the antibiotics known to impair the bacterial
cytoplasmic membrane.

19. Polymyxins
Polymyxins are a group of related cyclic basic polypeptides
originally derived from Bacillus polymyxa
– Interact with the phospholipids in cell mm
– Increases the cell permeability
– Disrupts osmotic integrity
– Leakage of intracellular constituents
– Cell death
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20. Cont…
• Ophthalmic indications
– Polymyxin B is generally used in combination for Gram-
negative coverage.
• Combinations
– With trimethoprim, bacitracin, or neomycin are available
– With steroid are available for more persistent ocular infections such
as staphylococcal blepharitis.
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21. Bacterial DNA Synthesis Inhibitors
Fluoroquinolones
• Are bactericidal agents that act by inhibiting DNA replication
• Their targets are enzymes involved in DNA synthesis
– Topoisomerase II (DNA gyrase) and
– Topoisomerase IV
• DNA gyrase exists only in plant and bacterial cells,
– Low toxicity in humans

22. Cont…
• First generation
– Cinoxacin And Nalidixic Acid
– did not achieve systemic antibacterial levels & were useful
only in lower UTI
• Second generation
– Increased Gram –ve activity, Gram +ve
– Ciprofloxacin is the most potent against P. aeruginosa.
– Ciprofloxacin, Ofloxacin, Norfloxacin, Pefloxacin, Enoxacin,
Lomefloxacin
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23. Cont…
• Third generation
– Levofloxacin, Sparfloxacin, Gatifloxacin
– broad Gram-negative coverage, but less Pseudomonas
coverage
• Fourth generation
– Includes Moxifloxacin, Gemifloxacin, Trovafloxacin
– Have activity against anaerobes and retain activity against
Pseudomonas species

24. Cont…
• The available topical agents include
– Ciprofloxacin , Ofloxacin , Gatifloxacin (0.3%)
– Levofloxacin (0.5% , 1.5%)
– Moxifloxacin (0.5%) – is with out preservatives
• Have broad spectrum of activity against some gram positives ,
most gram –ve bacteria and anaerobe’s
• Used in treatment of conjunctivitis & corneal ulcers caused by
– S. aureus, S. epidermidis, Streptococcus pneumoniae &
– P. aeruginosa
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25. Cont…
 Pharmacology
• After oral administration, concentrations in serum peak after 1–2h.
• Half-lives of fluoroquinolones range from 3.5h in ciprofloxacin - 20hrs
• Penetrate well into the aqueous humor after topical application.
• Oral or IV administration, widely distributed
• Anatacids ↓ oral bioavailability
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26. Cont…
– 1st & 2nd group quinolones: mainly renal elimination
– 3rd & 4th group quinolones:
• Moxifloxacin: hepatic elimination
• Gemifloxacin: is metabolized to a limited extent by the liver, it is
excreted into the feces & urine
• Gatifloxacin : mainly renal elimination

27. Cont…
• Ciprofloxacin
– Inhibit 90% of common bacterial corneal pathogens
– Has a lower minimum inhibitory concentration than aminoglycosides and
cefazolin
– Less toxic to the corneal epithelium than aminoglycosides.
• Levofloxacin
– Is an isomer of ofloxacin and
– Has increased activity against Gram +ves,
– But, less potent against P. aeruginosa & certain Enterobacteriaceae.
• Gatifloxacin and moxifloxacin
– Are the newer agents, target both DNA gyrase and topoisomerase IV
– are more active against atypical Mycobacteria, Streptococcus pneumoniae
, S aureus and Staphylococcus epidermidis
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28. Cont…
• Adverse reaction
• Local
– Transient ocular burning or discomfort.
– Ciprofloxacin -> crystalline corneal deposits
– Foreign-body sensation, photophobia, tearing, dry eye, and eye
pain
– Systemic
– Irreversible cartilage erosions and skeletal abnormalities
• Lowest age for usage
– Topical – 2 year
– Systemic – 12 years
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29. Protein Synthesis Inhibitors
• Aminoglycosides,
• Tetracyclines , and
• Macrolide antibiotics as well as
• The individual drugs like
– clindamycin and
– chloramphenicol inhibit the protein synthesis in bacteria.

30. Cont…
 Aminoglycosides
• Inhibit bacterial protein synthesis by binding irreversibly to the
bacterial 30S ribosomes
• Then become unavailable for translation of mRNA during protein
synthesis, thereby leading to cell death ( bactericidal).
• Aminoglycosides used in ophthalmology are
• Neomycin, Gentamicin, Tobramycin and Amikacin
• Have post antibiotic effect
• Continued suppression of bacterial growth despite the decline of
antimicrobial concentration.
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31. Cont…
• are active primarily against Aerobic Gram-negative bacilli -
– Enterobacter spp,
– P. aeruginosa, and Acinetobacter spp and
– Staphylococcus aureus
• These agents are only moderately active against Haemophilus
spp. and Neisseria spp.
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32. Cont….
 Pharmacology
• AGs are highly polar
• GI absorption is low with oral aminoglycosides.
• After IV administration they are freely distributed in ECS, but do
not penetrate well into the
– CSF,
– vitreous and
– biliary tract
• Half lives of ∼2–3h
• Excreted by glomerular filtration
– Good renal function is an important factor in their safe use
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33. Cont…
• Have been a mainstay in the treatment of ocular infections.
– However, increasing resistance has limited their use in recent
years.
– Gentamicin and tobramycin - 0.3% topical solutions and
ointments.
• Used for the treatment of severe corneal ulcers, caused by
Pseudomonas spp
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34. Cont…
 Adverse events
• Frequent dosing of fortified aminoglycoside preparations
can result in severe corneal epithelial toxicity.
• Pseudomembranous conjunctivitis is common with
fortified topical gentamicin
• Nephrotoxicity(26%) and ototoxicity(2%)
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35. Cont…
 Tetracyclines
• Inhibit protein synthesis by binding to the 30-S ribosomal so of
polypeptide synthesis
• Are bacteriostatic
• Forms of tetracycline available include
– Chlortetracycline (topical),
– Oxytetracycline,
– Doxycycline and Minocycline
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36. Cont…
 Pharmacology
• Doxycycline has the best penetration into the eye than others
• Penetration of oxytetracycline and chlortetracycline improved by the
presence of a corneal defect
 Spectrum of activity
• Active against
• Most Gram-positive organisms, Certain Enterobacteriaceae , Chlamydia
spp, Rickettsia spp, Mycobacterium marinum,… and
• Protozoans such as:- Plasmodium spp. and Entamoeba histolytica
• Not usually effective against P. Aeruginosa, bacteroides species, or group B
streptococci.
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37. Cont…
• Indications
– Prophylaxis for gonococcal ophthalmia neonatorum
– Ocular trachoma
– Against diseases caused by chlamydia, including
• Conjunctivitis, urethritis, cervicitis and pneumonitis
– In treating noninfectious corneal ulceration and acne rosacea
• Adverse events
– Depression of bone growth, Permanent discoloration of the teeth and
– Enamel hypoplasia when given during tooth and skeletal dev’t
• Avoided in children <8 years old and during pregnancy
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38. Cont…
 Macrolides
• Inhibit bacterial RNA-dependent protein synthesis
• Bind reversibly to the 50S ribosomal subunit blocking peptide
chain elongation
• Includes
– Erythromycin
– Clarithromycin
– Azithromycin
• Spectrum of activity
– Gram-positive cocci & bacilli, Neisseria spp., Mycoplasmas,
Chlamydiae and Propionibacterium acnes
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39. Cont…
• Erythromycin
• Binds to subunit 50S of bacterial ribosomes and interferes with
proteinsynthesis.
• The drug is bacteriostatic against gram- positive cocci such as
• Streptococcus pyogenes and S pneumoniae,
• gram- positive bacilli such as
• C diphtheriae and
• Listeria monocytogenes, and
• a few gram- negative organisms such as
• N gonorrhea and C trachomatis.
• In sufficient dosing, it may be bactericidal against susceptible organisms.
• Drug re sistance to erythromycin is rising and is as high as 40% among
Streptococcus isolates.

40. Cont…
• Pharmacology
– Erythromycin is available in
• Topical, Parenteral and Oral preparations
• It is rapidly inactivated by stomach acid
– Metabolism
• Erythromycin and clarithromycin are metabolized by the liver and
excreted in the bile
• Azithromycin is excreted unchanged in the bile.
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41. Cont….
• Ophthalmic indications
– The topical erythromycin is used for
• Treatment of Chlamydia trachomatis infections
• Prophylaxis of ophthalmia neonatorum
• Conjunctivitis and staphylococcal blepharitis
• As replacement for tetracyclines
• Adverse events
– Erythromycin is one of the safest antibiotics used.
– Side effects are dose-related
• Abdominal cramps, Nausea, Vomiting and diarrhea
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42. Cont…
• Clarithromycin is more effective against
– Staphylococci, streptococci and M leprae
• Azithromycin is more active against
– H. influenza, N. gonorrhoeae and Chlamydia species
• Both have enhanced activity against
– Mycobacterium avium-intracellulare, Atypical mycobacteria and
– Toxoplasma gondii
– Are more active than erythromycin against chlamydia spp.
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43. Cont…
 Chloramphenicol
• Inhibits protein synthesis by binding reversibly to the 50S
ribosomal subunit preventing aminoacyl transfer RNA
from binding to the ribosome.
• Active against:- Gram-postve and negatve bacteria,
– Chlamydia, Mycoplasmas and
– Rickettsia
• Effective antibiotic for bacterial conjunctivitis
• Bone marrow toxicity is the major complication of
chloramphenicol use
25/10/2010 E.C 43

44. Cont…
Sulfonamides
• They are structural analogues of para-aminobenzoic acid (PABA) and
• competitive antagonists of dihydropteroate synthase for the bacterial
synthesis of folic acid.
• Unlike mammals, bacteria cannot use exogenous folic acid but must
synthesize it from PABA.
• Sulfonamides are bacteriostatic only and are more effective when
administered with trimethoprim or
• pyrimethamine each of which is a potent inhibitor of bacterial
dihydrofolate reductase; together, they block successive steps in the
synthesis of folic acid.

45. Antifungal agents
• The major classes of antifungals used in ophthalmology are
– Polyenes,
– Imidazole
– Pyrimidines
– Echinocandins
• The choice of an antifungal agent depends on
– The primary site of infection,
– The route of administration,
– The organism involved, and
– The sensitivity data available
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46. Cont…
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47. Polyenes
• This class of drugs includes amphotericin B (AMB), natamycin,
and nystatin.
• Nystatin is not used routinely to treat ocular infection due to its
low intraocular penetration, toxicity, and resistance to the
drug.
• However, natamycin and amphotericin B are the most
commonly used drugs in cases of fungal keratitis.

48. Cont…
 Amphotericin B
• A polyene used to control serious fungal infections
• Active against Candida, Aspergillus and Cryptococcus
• Is most commonly used in ophthalmology
• Topically for
Keratitis and scleritis,
2.5-10 mg/mL given every 30-60 min for the first 48-72hr
• Intravitreal (5 μg in 0.1 mL - safe and effective in humans)
Endophthalmitis,
• Systemically (0.5- 1mg/kg/d)
Scleritis, dacryocystitis and cellulitis
48

49. Cont…
 Natamycin
• The least toxic , least irritating & the most stable of the polyenes
• Available as a 5% suspension
• Has a broad spectrum of sensitivities, especially to fusarium species
• DOC for filamentous fungi
• Has decreased penetration through an intact epithelium
• Topical therapy
• every 30–60 min for the first 48–72 h, and treatment with tapering over
3–6 weeks depending on the activity of the keratitis
• Significant toxicity with Subconj and IV
• It is indicated for fungal
• Conjunctivitis, Blepharitis and Keratitis
49

50. Cont…
Nystatin
• has been studied experimentally in ophthalmology, and cases
have been reported in which it has been used in external ocular
infections caused by Candida.
• It has been used as a dermatologic ointment, which has a
concentration of 100 000 U/g, and at a frequency of application
every 4–6 h.
• Subconjunctival injections show marked toxicity, and
• experimental intravitreal injection of 0.1 mL of a concentration of
2000 U/mL did not cause a significant reaction and cured an
experimental case of Aspergillus endophthalmitis.

52. Azoles
• Are the largest class of antimycotics
• Mechanisms
– Inhibit enzyme that convert lanosterol → ergosterol (CYP
P450 14 α- demethylase)
• They have a lower affinity for mammalian P450's
• They are divided into two classes:
– imidazoles which were first to be introduced in the market, and
– followed by triazoles
52

53. Cont…
 Imidazoles
• The imidazoles have a broad spectrum of antifungal activity.
• At low concentrations, inhibit formation of ergosterol needed by the cell
membranes.
Miconazole, Econazole, And Ketoconazole
• At higher concentrations, can disrupt lysosomes, causing direct damage
to cell membrane.
Clotrimazole And Miconazole
• Most imidazoles inhibit catalase and cytochrome C peroxidase
intracellulary,
– causing accumulation of H2O2--- leading to cell death
53

54. Cont…
 Ketoconazole
• In ophthalmology,
• Topical and PO ketoconazole has been used clinically and
experimentally for the treatment of keratitis.
• In experimental endophthalmitis, ketoconazole was
effective if started 24 h after injection.
• oral ketoconazole may augment topical natamycin therapy.
54

55. Cont…
 Miconazole
• It is a broad-spectrum antifungal with activity against
Cryptococcus, Fusarium, Aspergillus, Curvularia, Candida, and
Trichophyton.
• It not only acts on the synthesis of ergosterol but also leads to
• Inhibition of peroxidases, resulting in the accumulation of free
radicals in the fungal cytoplasm which leads to cell death.
• Topical use at a dose of 10 mg/ml or a 1 % solution is effective
especially if associated with epithelial scraping.
• Compared to polyenes, MCZ is less effective but provides better
penetration into ocular tissues

56. Cont…
Econazole
• Econazole is primarily used in the treatment of superficial mycosis and
not used routinely for the treatment of ocular infections.
• In a clinical trial, 116 eyes with fungal keratitis were randomized to
either econazole 2 % or natamycin 5 %, and
• it was found that econazole is as efficacious as natamycin for the
treatment of fungal keratitis (Prajna et al. 2010).
• However, the drug is not commercially available for
ocular administration which prevents its ophthalmic use.

57. Triazole
• Fluconazole
• wide spectrum of activity against many pathogens
• The treatment of Candida species
• Able to penetrate intact corneal epithelium, due to its lower MW
• Has efficacy in both topical and oral form against Aspergillus
fumigatus --- In animal studies
• Dose
– Adult = 200 mg/day.
– A topical 1% solution in sterile water can be made
– The 2 mg/L aqueous solution for intravenous use can be applied
topically.
57

58. Cont…
• Systemic side effects include
– GI upset, headaches, rash, hepatotoxicity, anaphylaxis and
thrombocytopenia.
• Fluconazole
– Can increase cyclosporine's serum concentration and
decrease the metabolism of warfarin
– Rifampin can increase the metabolism of fluconazole
58

59. Cont…
 Itraconazole
• Is excellent against Aspergillus
• Its spectrum of activity includes
– Candida species,
– Coccidioides and
– Paracoccidioides
– not been very effective against Fusarium.
• Limited use in clinical ophthalmology
• Its oral preparation as an adult dose of 200 mg/day.
• Systemic side effects include:-
– Gastrointestinal upset, hypertriglyceridemia, and hypokalemia
59

60. Pyrimidines
• Are a group of anti metabolites
Flucytosine (5-FC)
• Is a fluorinated pyrimidine that is soluble in water and alcohol
• It inhibits fungal RNA and DNA synthesis
• Is taken orally at 50-150 mg/kg/ day, divided every 6 hrs.
• Topical 1%-- conjunctivitis, blepharitis, canaliculitis, ant stromal
keratitis.
• Mechanism –enters the cytoplasm by action of cytosine permease
Cytosine deaminase
↓
Flucytocine--------- 5-fluorouracil, and then to 5- fluorodeoxyuridylate.
– This last compound inhibits thymidylate synthase, an important enzyme
in DNA synthesis
60

61. Newer agents
• Voriconazole
– derived from fluconazole with activity against fluconazole
resistant fungi.
– Can be used orally and IV.
– Its bioavailability is 96%
• Caspofungin
– Inhibits synthesis of B(1,3)-D-glucan, a component of fungal
cell wall.
– Available parenteral
– Invitro activity against various yeasts and molds
61

64. Antiviral drugs
• Viruses are obligate intracellular parasites that use the
metabolic processes of the invaded host cell.
• Therefore, a major challenge in antiviral therapy has been formulating
antiviral drugs that do not interfere with the normal host-cell
metabolism by causing toxic side effects in the uninfected host cells.
• Theoretically, antiviral drugs may be effective by interacting directly
– with the virus,
– a virus-encoded enzyme or protein,
– a cellular receptor or
– factor required for viral replication or pathogenesis

65. classification

66. Cont…
• Twenty antiviral drugs are currently FDA approved for clinical
use, nine with proven efficacy in ocular viral disease:
• vidarabine (Ara-A, Vira A),
• trifluridine(TFT, F3T, Viroptic),
• acyclovir (ACV, Zovirax),
• famciclovir (FCV,Famvir), and valacyclovir (VCV, Valtrex), and
bromovinyldeoxyuridine (BVDU, Brivudine). Ganciclovir
(DHPG*, Cytovene), foscarnet (PFA, Foscavir), and HPMPC
(Cidovir). All but BVDU are FDA approved

67. CLASSIFICATION OF ANTIVIRAL DRUGS
The viral growth cycle Selective inhibitors
1) Attachment
2) Penetration
-Antiviral antibodies
(gamma globulin)
3) Uncoating -Amantadine, rimantadine
-Interferons
4) Early translation
(early mRNA and protein synthesis)
fomivirsen
5) Transcription
(viral genome replication)
Inhibitors of DNA-polymerase
-Acyclovir -Gancyclovir
-Famcyclovir -Cidofovir
-Vidarabine -Idoxuridine -Trifluridine -
Foscarnet
Inhibitors of RNA-dependent
DNA-polymerase (reverse
transcriptase)
-Zidovudine -Didanosine
-Stavudine -Zalcitabine
-Lamivudine -Foscarnet

68. 6) Late translation
(late mRNA an protein synthesis)
-Ribavirin
-Interferons
7) Posttranslational
modifications
(proteolytic cleavage)
Protease inhibitors
-Saquinavir -Indinavir
-Ritonavir
8) Assembly
(packaging of viral nucleic acids)
-Interferons
-Rifampin
9) Release
(virion is released from cell)
-Antiviral antibodies
-Cytotoxic T lymphocytes

69. The major sites of antiviral drug action.

70. Cont…
• Depending on roote of admnistration
• Topical or
• Systemic

71. Idoxuridine
• It was the first topical antiviral to be used for the treatment of
herpetic epithelial keratitis .
• However, it was later replaced by its thymidine analogue,
trifluridine
• Mechanism of Action IDU
– owes its antiviral activity to the conversion into a triphosphate form, which
mimics thymidine triphosphate and
– becomes incorporated into viral DNA which results in faulty transcription of
viral proteins and inhibition of viral replication.

72. Trifluridine
• like IDU, is a thymidine analogue which is far more potent and has
less ocular and systemic toxicity.
• Mechanism of Action
– Trifluridine, like IDU, gets converted into a triphosphate
form and gets incorporated into the viral DNA leading to inhibition of
transcriptionand viral protein synthesis.
– Though it also gets incorporated into the host DNA, however, viral DNA
polymerase utilizes trifluridine triphosphate more efficiently than does
host cell DNA polymerase.
– Hence, it has a more selective antiviral activity with lower ocular toxicity
as compared to IDU

73. Cont…
• Indication
– Trifluridine is active in vitro and in vivo against HSV-1, HSV-2 and
vaccinia and in vitro against CMV and some strains ofadenovirus.
– It is more potent than IDU against HSV.
– It is available as a 1 % solution. Though its penetration is better
than IDU, however, it is not very efficient in iridocyclitis or
stromal keratitis.
– The recommended dosage is one drop every 2 h until healing is
complete.
– This is followed by one drop every 4 h for 7 days to prevent
reactivation of disease

74. Vidarabine
• Vidarabine was the second agent approved for the topical
treatment of herpetic epithelial keratitis.
• It was also the first antiviral agent approved for systemic use;
however, recently it has been replaced with acyclovir.

75. Cont…
• Mechanism of Action
• Vidarabine is obtained from fermentation cultures of Streptomyces
antibioticus.
• It is a purine nucleoside analogue that resembles deoxyadenosine.
• It gets converted into its triphosphate form which gets
incorporated into the viral DNA.
• Unlike IDU, trifluridine, or acyclovir, vidarabine does not require viral
thymidine kinase for its phosphorylation.
• Therefore, it might be expected to have high activity against thymidine kinase-
deficient mutants of HSV

76. Acyclovir
• Acyclovir is a synthetic purine nucleoside analog derived
from guanine.
• It is a highly potent antiviral agent.
• Acyclovir interferes with DNA synthesis, thus inhibiting virus
replication.
• It can be administered both topically and systemically.
• In the topical form it is used as a 3% ointment.

77. Cont…
• Mechanism of Action
• It is an acyclic analogue of guanosine which is activated by
viral thymidine kinase and becomes a potent inhibitor of viral
DNA polymerase.
• It gets converted into the triphosphate form and is found in
HSV-infected cells in a concentration which is 40–100 times
higher than uninfected cells.
• It has a greater affinity of viral DNA polymerase as compared to
cellular DNA polymerase.

78. Cont….
• Acyclovir triphosphate inhibits virus growth in 3 ways:
– It can function as a competitive inhibitor of DNA polymerases, with viral
DNA polymerases being significantly more susceptible to acyclovir
triphosphate than are human DNA polymerases.
– It can be a DNA chain terminator.
– It can produce irreversible binding between viral DNA polymerase and
the interrupted chain, causing permanent inactivation.
78

79. Cont…
Spectrum of activity:
• Antiviral activity against HSV types 1 and 2 (HSV-1 and HSV-2),
VZV, EBV and CMV.
• Topical use of acyclovir ointment is well tolerated.
• Systemic side effects of oral acyclovir include:-
– Nausea, vomiting, and headache.
– Other adverse reactions: diarrhea, dizziness, anorexia, fatigue, edema,
skin rash, leg pain, medication taste, and sore throat.
79

80. Cont…
• 3% acyclovir may be superior to other antiviral agents with
regards
– To corneal penetration and
– In the treatment of deep herpetic keratitis and uveitis.
• However, acyclovir topical treatment did not significantly
reduce the incidence of stromal keratitis that developed with
herpes simplex epithelial keratitis.
80

81. Cont…
• For ocular HSV,
– Oral ACV 400 mg 5id is equivalent to topical ACV in treating epithelial
keratitis, with 90% of patients’ ulcers healing in a mean of 5 days.(in
89% of patients on PO and in 97% on Topical)
• PO acyclovir ocular indication
– In patients with HSV keratitis
• as an adjunct to topical antivirals in patients with atopic disease or in
immunosuppressed patients
• Pediatric patients
• Those unable to tolerate topical medication and good RFT
– For preventing recurrence of herpetic disease
– HZO
81

82. Cont…
• For HZO ACV 800 mg PO 5id for 7–10 days,
• Induces significant resolution of rash, pain, new vesicles and
viral shedding,
• Lower incidence and severity of acute and late dendritiform
keratopathy, scleritis, episcleritis, iritis,
• The incidence but not severity of stromal keratitis
82

83. Cont…
• Resistance
• There are three mechanisms by which the virus can become
resistant to acyclovir therapy.
• The most common mutation is loss of synthesis of viral
thymidine kinase so that acyclovir is not phosphorylated to its
active form .
• A second type of mutation induces thymidine kinase with
altered substrate specificity that phosphorylates thymidine but
not acyclovir.
• 3rd , a mutation of the viral DNA polymerase gene induces
altered DNA polymerase that is not sensitive to inhibition by
acyclovir triphosphate.

84. Cont…

87. Rational Use of Antibiotics
• Antibacterials should be used to only certain definite indications
• Indications for antibacterial therapy
– Definitive therapy
• Narrow spectrum,
• Least toxic and
• Less expensive drug
– Empirical therapy
• To critical cases
• Drugs that cover the most probable infective agent
– Prophylactic therapy
• To susceptible patients
• Narrow spectrum and specific drugs are used
87

88. Cont…
• Factors that should be considered while prescribing an
antibacterial agent:
• Site & Severity of infection
• Source of infection
• Host factors
• Drug related factors
88

89. …cont.
• Host factors
– Age
• Infants: CAF is contraindicated
– Not metabolized → ↑concentration blocks electron
transport
• Below the age of 8 years:
– TTCs are CI → discolor the teeth
• Below the age of 12 years:
– Fluoroquinolones are contraindicated
• Elderly: In the elderly
– Drug elimination is slower → dose adjustments
89

90. Cont…
– Pregnancy:
• TTCs, quinolones, erythromycin and clarithromycin are
CI in all T/Ms
– In lactating mothers
• Tetracyclines, sulfa and quinolones are CI
– Renal failure:
• Tetracyclines , aminoglycosides, cephalosporins &
fluoroquinolones are CI
90

91. Drug Resistance
• If the maximal level of antibiotic that can be tolerated by the host does
not halt the growth bacteria
• Mechanisms
A. Genetic alterations leading to drug resistance
• DNA undergoes spontaneous mutation
B. Altered expression of proteins
• Modification of target sites
– Alterations in penicillin-binding proteins
• Decreased accumulation
– ↓ed uptake or increased efflux of an antibiotic
• Enzymatic inactivation
91