1. Principals of anti viralPrincipals of anti viral
and anti fungal therapyand anti fungal therapy
when and wherewhen and where
Dr.saurabh joshiDr.saurabh joshi
Guide Dr.sunil raoGuide Dr.sunil rao

2. Introduction –Introduction –
Antimycotic drugsAntimycotic drugs
 Used to treat two types of fungal infection:Used to treat two types of fungal infection:
– Superficial fungal infections - skin or mucous membraneSuperficial fungal infections - skin or mucous membrane
– Systemic fungal infections - lungs or central nervousSystemic fungal infections - lungs or central nervous
systemsystem
 Fungi causing mycosis live as commensally or are
present in the environment.
 Earlier superficial infections were uncommon and
systemic rather rare.
 Recently there is increase in local as well as
systemic fungal infections.
 Reason for this is opportunistic infections

3. Opportunistic infectionsOpportunistic infections
 Immuno-suppression due to
- Cancer chemotherapy
- AIDS
– Corticosteroid overuse
 Indiscriminate use of broad spectrum
antibiotics

4. Fungal infections
 Superficial
– Skin
– Hair
– Nails
– Mucous membrane
 Deep
– Tissues (muscle &
connective tissue)
– Organs

5. Types of fungal infections - MycosesTypes of fungal infections - Mycoses
 Superficial mycosesSuperficial mycoses
– Affect the skin, hair and nails – ringworm/tinea orAffect the skin, hair and nails – ringworm/tinea or
onychomycosisonychomycosis
 Subcutaneous mycoses (tropical)Subcutaneous mycoses (tropical)
– Affect the muscle and connective tissue immediatelyAffect the muscle and connective tissue immediately
below the skinbelow the skin
 Systemic (invasive) mycosesSystemic (invasive) mycoses
– Involve the internal organsInvolve the internal organs
 Allergic mycosesAllergic mycoses
– Affect lungs or sinusesAffect lungs or sinuses
– Patients may have chronic asthma, cystic fibrosis or sinusitisPatients may have chronic asthma, cystic fibrosis or sinusitis

6. MOST COMMON FUNGALMOST COMMON FUNGAL
PATHOGENSPATHOGENS
 DermatophytesDermatophytes –– Microsporum,Microsporum,
Epidermophyton and TrichophytonEpidermophyton and Trichophyton
 CandidaCandida –– C.C. albicans, C. glabrata, C.albicans, C. glabrata, C.
tropicalistropicalis
 AspergillusAspergillus
 CryptococcusCryptococcus
 RhizopusRhizopus

7. Causative fungiCausative fungi
 Superficial infections by
– Dermatophytes (ring worms): athlete`s foot or tinea
pedis, jock itch or tinea cruris, tinea capitis etc.
– Candida:Candida: oral thrush, vaginitis and diaper candidiasis
etc.
 Deep infections are
– Candidiasis: Chronic mucocutaneous candidiasis,
systemic candidiasis etc.
– Aspergillosis: broncho-pulmonary aspergillosis
– Coccidiomycosis: pulmonary and disseminated
(complications – pneumonia)
– Histoplasmosis:Histoplasmosis: H. capsulatum (common in HIV)H. capsulatum (common in HIV)

8.  TRETMENTTRETMENT
 SUPERFICIAL FUNGUS ARE TRAEATEDSUPERFICIAL FUNGUS ARE TRAEATED
BY TOPICAL ANTIFUNGALSBY TOPICAL ANTIFUNGALS
 DOC IS ORAL GRESIOFULVINDOC IS ORAL GRESIOFULVIN

9. SYSTEMIC FUNGUS
S.NO. DISEASES DOC
1 INVASIVE CANDIDIASIS AMPHOTERICIN B
FLUCONAZOLE,
CASPOFUNGIN
2 INVASIVE ASPERGILLOSIS VORICONAZOLE,
AMPHOTERICIN B
3 BLASTOMYCOSIS AMPHOTERICIN B .
ITRACONAZOLE
4. COCCIDIOMYCOSIS
RAPIDLY PROGREESIVE
INDOLENT
MENINGIAL
AMPHOTERICIN B
ITRACONAZOLE
FLUCONAZOLE
5 CRYPTOCOCCUS
NON AIDS
AIDS
AMPHOTERICIN B
FLUCONAZOLE

10. SYSTEMIC FUNGUSSYSTEMIC FUNGUS
S.NO DISEASES DOC
6 HISTOPLASMOSIS
PULMONARY
CNS/AIDS
ITRACONAZOLE
AMPHOTIRICIN B
ITRACONAZOLE
7. MUCORMYCOSIS AMPHOTERICIN B
8 SPOROTRICHOSIS
CUTANEOUS
EXTRA CUTANEOUS
ITRACONAZOLE
AMPHOTERICIN B

11. Cell Membrane Active AntifungalCell Membrane Active Antifungal
Cell membrane
1. Polyene antibiotics
- Amphotericin B, lipid formulations
- Nystatin (topical)
2. Azole antifungals
Imidazoles:
• Topical: Clotrimazole, econazole,
miconazole
• Systemic: Ketoconazole
Triazoles: Fluconazole, itraconazole and
voriconazole

12. cellwall acting anti fungals
1.Echinocandins
2.pneumocandins
3.Papulocandins
4.Polyoxins
5.Nikomycins
Nucleic acid synthesis inhibitors
1.5-fluocytosin
Nuclear division inhibitors
Greseofulvin

13. Local azolesLocal azoles
 Very popular local azoles are – Clotrimazole, Econazole
and Miconazole
 (For Tinea, Ring worm, Athlete’s foot, otomycosis, oral,
cutaneous & vaginal candidiasis)
 Mechanism of action is same as that of Ketoconazole i.e.
ergosterol inhibition by inhibiting CYP450
 Clotrimazole is favoured in vaginitis because of long lasting
residual effect and once daily dosing
 Miconazole causes frequently vaginal irritation & pelvic
cramp.
 Available s lotion, cream, powder, vaginal tablet etc.Available s lotion, cream, powder, vaginal tablet etc.

14. AMPHOTERICIN BAMPHOTERICIN B
 Most Toxic antifungalMost Toxic antifungal
 Fungicide at high and static at low conc.Fungicide at high and static at low conc.
 Effective againstEffective against
– Candida albicansCandida albicans
– Histoplasma capsulatumHistoplasma capsulatum
– CryptococcusCryptococcus

15. UsesUses
 Broad spectrum antifungalBroad spectrum antifungal
 Useful forUseful for
1. Candida that causes1. Candida that causes
– oraloral
– vaginalvaginal
– cutaneous candidiasiscutaneous candidiasis
2. Cryptococcus2. Cryptococcus
3. Histoplasma3. Histoplasma
4. Aspergillosis4. Aspergillosis
5. Also effective for Leishmaniasis(Reserve drug for resistant5. Also effective for Leishmaniasis(Reserve drug for resistant
cases of Kala Azar)cases of Kala Azar)

16. ADRsADRs
1.1. Acute reactions -Acute reactions - occurs with each infusionoccurs with each infusion
– Chills, Nausea, Vomiting, Pain, Fever, Aches, DyspnoeaChills, Nausea, Vomiting, Pain, Fever, Aches, Dyspnoea
– So corticosteroids are administered along with the drugSo corticosteroids are administered along with the drug
1.1. ThrombophlebitisThrombophlebitis
2.2. Bone marrow depressionBone marrow depression - Reversible anemia- Reversible anemia
3.3. On intrathecal injectionOn intrathecal injection – Headache, Vomiting,– Headache, Vomiting,
Nerve paralysisNerve paralysis
4.4. Renal toxicity leading toRenal toxicity leading to – Azotemia, Decreased– Azotemia, Decreased
GFR, Acidosis, Hypokalemia, Inability to conc.GFR, Acidosis, Hypokalemia, Inability to conc.
urineurine

17. Newer Amphotericin BNewer Amphotericin B
They are developed to overcomeThey are developed to overcome
1. Side effects1. Side effects
2. To improve tolerability2. To improve tolerability
3. To get the drug at site of action3. To get the drug at site of action
4. To reduce the toxicity i.e.. Less nephrotoxic and minimal4. To reduce the toxicity i.e.. Less nephrotoxic and minimal
anemiaanemia
Formulations are:Formulations are:
1. Amphotericin B lipid complex1. Amphotericin B lipid complex
2. Amphotericin B colloidal dispersion2. Amphotericin B colloidal dispersion
3. Liposomal Amphotericin B3. Liposomal Amphotericin B
(Only drawback of these formulations is less efficacy)(Only drawback of these formulations is less efficacy)

18. Drug Interactions of Amphotericin BDrug Interactions of Amphotericin B
 With Flucytocin-synergistic actionWith Flucytocin-synergistic action
 Rifampicin and Minocyclin –Rifampicin and Minocyclin –
– Both potentiate Amphotericin BBoth potentiate Amphotericin B
 Vancomycin and Aminoglycoside –Vancomycin and Aminoglycoside –
– Both increase risk of nephrotoxicityBoth increase risk of nephrotoxicity
 Preparation and doses:Preparation and doses:
– 50 – 100 mg four times a day orally50 – 100 mg four times a day orally
– 3% ear drops3% ear drops
– Systemic: 50 mg vial (one vial diluted in 500 ml of 5%Systemic: 50 mg vial (one vial diluted in 500 ml of 5%
glucose and initially 1 mg test dose followed by infusionglucose and initially 1 mg test dose followed by infusion
for 4 – 8 Hrs)for 4 – 8 Hrs)

19. NystatinNystatin
 Similar to Amphotericin B but moreSimilar to Amphotericin B but more toxictoxic thanthan
Amphotericin BAmphotericin B
 Used only for superficial candidiasis ofUsed only for superficial candidiasis of
Skin, Mouth, Vagina, IntestineSkin, Mouth, Vagina, Intestine
 As ointment ,oral tablets & suppositoriesAs ointment ,oral tablets & suppositories
 Available as tablets and ointments (1 to 5 lacs U)Available as tablets and ointments (1 to 5 lacs U)
– also vaginal tablets– also vaginal tablets
 Orally not absorbed but can be used in monilialOrally not absorbed but can be used in monilial
diarrhoeadiarrhoea

20. Other PolyenesOther Polyenes
Hamycin:
 Water soluble
 Absorption from GIT not reliable
 Not used for systemic fungal infections
 Used topically for Aspergillus, Candida, Monilial,
Trichomonas vaginalis infections
Natamycin:
 Broad spectrum
 Used topically for – Keratitis, Monilial infections,
Trichomonas vaginalis

21. Imidazoles and TriazolesImidazoles and Triazoles
Azole antifungals
 Imidazoles:
– Topical: Clotrimazole, econazole, miconazole
– Systemic: Ketoconazole
 Triazoles: Fluconazole, itraconazole and
voriconazole
 Remember that among imidazoles, onlyRemember that among imidazoles, only
ketocanazole is systemic, other 3 are topical onlyketocanazole is systemic, other 3 are topical only
 While, Triazoles are used systemically and largelyWhile, Triazoles are used systemically and largely
replacing ketoconazolereplacing ketoconazole

22. Individual AgentsIndividual Agents
Ketoconazole:Ketoconazole:
 Spectrum: yeasts and moulds - poor absorptionSpectrum: yeasts and moulds - poor absorption
limits its role for severe infections, generally usedlimits its role for severe infections, generally used
in mucosal infections only (dematophytosis)in mucosal infections only (dematophytosis)
 PharmacokineticsPharmacokinetics
– Variable oral absorption, dependent on pH (often givenVariable oral absorption, dependent on pH (often given
with cola or fruit juice)with cola or fruit juice)
– T1/2 = 7-10 hoursT1/2 = 7-10 hours
– Protein binding > 99%Protein binding > 99%
– Hepatic, bile and kidney eliminationHepatic, bile and kidney elimination

23. Ketoconazole – contd.Ketoconazole – contd.
 Adverse effectsAdverse effects
– N&V, worse with higher doses (800 mg/day)N&V, worse with higher doses (800 mg/day)
– Hepatoxicity (2-8%), increase in transaminases,Hepatoxicity (2-8%), increase in transaminases,
hepatitishepatitis
– Dose related inhibition of CYP P450 responsibleDose related inhibition of CYP P450 responsible
for testosterone synthesisfor testosterone synthesis
 Gynecomastia, oligosperma, decreased libidoGynecomastia, oligosperma, decreased libido
– Dose-related inhibition of CYP P450Dose-related inhibition of CYP P450
responsible for adrenal cortisol synthesisresponsible for adrenal cortisol synthesis

24. Ketoconazole – contd.Ketoconazole – contd.
Drug Interaction:Drug Interaction:
 Potent inhibitor of cytochrome P450 3A4Potent inhibitor of cytochrome P450 3A4
– Rifampin and phenytoin decrease ketoconazole levelsRifampin and phenytoin decrease ketoconazole levels
– Ketoconazole increases cyclosporin, waKetoconazole increases cyclosporin, warrfarin, astemizole,farin, astemizole,
corticosteroid, and theophylline levelscorticosteroid, and theophylline levels
– Many of these drug interactions are severeMany of these drug interactions are severe
 Drugs that increase gastric pH will decrease blood levels ofDrugs that increase gastric pH will decrease blood levels of
ketoconazoleketoconazole
– Antacids, omeprazole, H2 blockersAntacids, omeprazole, H2 blockers
 Doses:Doses:
– Serious infections 800 mg/day POSerious infections 800 mg/day PO
– Other: 200-400 mg/day POOther: 200-400 mg/day PO

25. Fluconazole - KineticsFluconazole - Kinetics
 Available as both IV and POAvailable as both IV and PO
– Bioavailibility > 90%Bioavailibility > 90%
 PharmacokineticsPharmacokinetics
– t 1/2 = ~24 hourst 1/2 = ~24 hours
– Protein binding < 12%Protein binding < 12%
– Vd 0.85 L/kg (widely distributed)Vd 0.85 L/kg (widely distributed)
– >90% excreted unchanged through the kidney>90% excreted unchanged through the kidney
 DosingDosing
1.1. Mucosal candidiasisMucosal candidiasis
 100-200 mg/day (150 mg tablet vulvovaginal candidiasis)100-200 mg/day (150 mg tablet vulvovaginal candidiasis)
1.1. Systemic fungal infectionsSystemic fungal infections
 400-800 mg q24h400-800 mg q24h
 >> 800 mg q24h in unstable patient, S-DD isolate, or if non-800 mg q24h in unstable patient, S-DD isolate, or if non-albicansalbicans spp.spp.
(except(except C. kruseiC. krusei))
1.1. Maintenance for cryptococcal meningitisMaintenance for cryptococcal meningitis
 400 mg q24h400 mg q24h

26. Fluconazole - ADRsFluconazole - ADRs
 N&V, rash:N&V, rash:
– More likely with high doses and in AIDS patientsMore likely with high doses and in AIDS patients
– Asymptomatic increase in LFTs (7%)Asymptomatic increase in LFTs (7%)
 Drug interactions:Drug interactions:
– May increase phenytoin, cyclosporin, rifabutin,May increase phenytoin, cyclosporin, rifabutin,
warfarin, and zidovudine concentrationswarfarin, and zidovudine concentrations
– Rifampin reduced fluconazole levels to halfRifampin reduced fluconazole levels to half
(even though FLU is not a major substrate)(even though FLU is not a major substrate)

27. ItraconazoleItraconazole
Some Features:Some Features:
 Newer orally active triazoleNewer orally active triazole
 Broader spectrun than KTZ and FCZ –Broader spectrun than KTZ and FCZ –
includes moulds like aspergillusincludes moulds like aspergillus
 Fungistatic action but very effective inFungistatic action but very effective in
immunocompromizrd patientsimmunocompromizrd patients
 Steroid hormone synthesis inhibition isSteroid hormone synthesis inhibition is
absent and no serious hepatotoxicityabsent and no serious hepatotoxicity

28. Heterocyclic Nitrofurans -Heterocyclic Nitrofurans -
GriseofulvinGriseofulvin
 Used for superficial fungal infections byUsed for superficial fungal infections by
dermatophytesdermatophytes
 Derived from Penicillium griseofulvum butDerived from Penicillium griseofulvum but
no antibacterial activityno antibacterial activity
 Effective against most dermatophytes, butEffective against most dermatophytes, but
not against candida causing deep mycosisnot against candida causing deep mycosis
 Dermatophytes actively concentrate it –Dermatophytes actively concentrate it –
accounts for selective toxicity against themaccounts for selective toxicity against them
 Taken up by newly formed keratinTaken up by newly formed keratin

29. Griseofulvin - MOAGriseofulvin - MOA
 Interferes with mitosis – results inInterferes with mitosis – results in
multinucleated and stuntedmultinucleated and stunted hyphaehyphae
((In most fungi, hyphae are the main mode of vegetative growth, and areIn most fungi, hyphae are the main mode of vegetative growth, and are
collectively called a mycelium yeasts are unicellular fungi that do notcollectively called a mycelium yeasts are unicellular fungi that do not
grow as hyphae)grow as hyphae)
 Abnormal metaphase configurations leadingAbnormal metaphase configurations leading
to failure of daughter nuclei to fall apartto failure of daughter nuclei to fall apart
(Colchicine and vinca alkloids also mitotic inhibitors but they cause(Colchicine and vinca alkloids also mitotic inhibitors but they cause arrestarrest
of mitosis)of mitosis)
 Disorientation of polymerized microtubulesDisorientation of polymerized microtubules

30. Griseofulvin - ADRsGriseofulvin - ADRs
 Safe with mild side effectsSafe with mild side effects
1. GIT upsets1. GIT upsets
2. CNS symptoms2. CNS symptoms
3. Hepatotoxicity3. Hepatotoxicity
4. Leucopenia4. Leucopenia
5. Photosensitivity5. Photosensitivity
6. Allergy etc.6. Allergy etc.
 Microsomal enzyme inducerMicrosomal enzyme inducer
 Causes decrease in activity of anticoagulantsCauses decrease in activity of anticoagulants
 Cause intolerance to alcoholCause intolerance to alcohol
 Phenobarbitone reduces its oral absorption so failure ofPhenobarbitone reduces its oral absorption so failure of
therapytherapy

31. FlucytosinFlucytosin
 Fluorinated pyrimidine related to flurouracilFluorinated pyrimidine related to flurouracil
 Restricted spectrum of activity.Restricted spectrum of activity.
 Acquired Resistance due to > result of monotherapyAcquired Resistance due to > result of monotherapy
 Due to:Due to:
1) Decreased uptake (permease activity)1) Decreased uptake (permease activity)
2) Altered 5-FC metabolism (cytosine deaminase or UMP2) Altered 5-FC metabolism (cytosine deaminase or UMP
pyrophosphorylase activity)pyrophosphorylase activity)
Kinetics:Kinetics:
 Orally absorbedOrally absorbed
 Widely distributed even in CSFWidely distributed even in CSF
 Exc. in urine.Exc. in urine.
 Converted in fungal cell to 5-FU which is antimetabolite.Converted in fungal cell to 5-FU which is antimetabolite.
 Mammalian cells remain unaffected except few bone marrow cellsMammalian cells remain unaffected except few bone marrow cells

32. FlucytosinFlucytosin
Monotherapy : NeverMonotherapy : Never
 CandidiasisCandidiasis
 CryptococcosisCryptococcosis
 ?Aspergillosis?Aspergillosis
} In combination with amphotericin B or
fluconazole.
Doses:
1. Vaginal candidiasis: 200 mg OD for 3 days
2. Dermatophytosis; 100-200 mg OD for 7-15 days
3. Onychomycosis: 200 mg per day for 3 months
ADRs: 1.Mild BM depression
2. Loss of hair
3. Dose should be decreased in the presence of renal impairment

33. TerbinafineTerbinafine
 Belongs to a newer allylamine class of antifungalsBelongs to a newer allylamine class of antifungals
 Given both orally & locallyGiven both orally & locally
 Lipophillic so widely distributedLipophillic so widely distributed
 Fungicidal in contrast to azoles (fungistatic)Fungicidal in contrast to azoles (fungistatic)
 Acts by non-competitive inhibition ofActs by non-competitive inhibition of “squalene epoxidase”“squalene epoxidase”
(early step enzyme in ergosterol synthesis accumulation of(early step enzyme in ergosterol synthesis accumulation of
squalene in fungal cells – cidal effectsqualene in fungal cells – cidal effect
 Used for dermatophytes & candidaUsed for dermatophytes & candida
 Dose is 250mg OD for 2-6 wksDose is 250mg OD for 2-6 wks
 Locally 1% ointmentLocally 1% ointment.

34. Terbinafine – contd.Terbinafine – contd.
ADRsADRs
 With oralWith oral
– GIT upsetGIT upset
– Hepatic dysfunctionHepatic dysfunction
– RashRash
– Taste disturbanceTaste disturbance
– No interaction with CYP450No interaction with CYP450
 Preparations and doses:Preparations and doses:
– 1% cream 125/250 mg tablets etc.1% cream 125/250 mg tablets etc.
– Tinea pedis: 250 mg OD for 2-6 weeksTinea pedis: 250 mg OD for 2-6 weeks
– Onychmycosis: 3-12 months (alternative to fluconazole)Onychmycosis: 3-12 months (alternative to fluconazole)
• On local application -On local application -
ddryness, Erythemaryness, Erythema,, Rash,Rash,
itching etc.itching etc.

35.  DRUGS FOR NON - HIV VIRALDRUGS FOR NON - HIV VIRAL
INFECTIONSINFECTIONS

37. Possible Sites of ActionPossible Sites of Action
 Viral attachmentViral attachment
 Cell entryCell entry
 TranscriptionTranscription
 TranslationTranslation
 Viral assemblyViral assembly

38. Drugs for HSV and VZVDrugs for HSV and VZV
 Oral AgentsOral Agents
– AcyclovirAcyclovir
– ValacyclovirValacyclovir
– FamciclovirFamciclovir
 OphthalmicOphthalmic
– TrifluridineTrifluridine
 Topical AgentsTopical Agents
– AcyclovirAcyclovir
– DocosanolDocosanol
– PenciclovirPenciclovir

39. AcyclovirAcyclovir
 Guanosine analogGuanosine analog
 Topical, oral, and intravenous formulationsTopical, oral, and intravenous formulations
 Spectrum: Herpes simplex 1 and 2,Spectrum: Herpes simplex 1 and 2,
varicella-zoster virus, possibly the Epstein-varicella-zoster virus, possibly the Epstein-
Barr VirusBarr Virus
 Treatment of choice for visceral,Treatment of choice for visceral,
disseminated, or central nervous systemdisseminated, or central nervous system
involvementinvolvement

40. Acyclovir Adverse effectsAcyclovir Adverse effects
 PhlebitisPhlebitis
 Reversible renal toxicityReversible renal toxicity
– Crystalization in the renalCrystalization in the renal
tubulestubules
 Neurological symptomsNeurological symptoms
– Encephalopathic changesEncephalopathic changes
such as somnolence,such as somnolence,
hallucinations, confusionhallucinations, confusion
comacoma
 GI symptomsGI symptoms
 HeadacheHeadache
 TTP/HUSTTP/HUS
 PhotosensitivityPhotosensitivity
 AnemiaAnemia

41. ValacyclovirValacyclovir
 Available orally onlyAvailable orally only
 Spectrum: similar to acyclovirSpectrum: similar to acyclovir
 Adverse effects: headache, nausea,Adverse effects: headache, nausea,
weakness, dizziness, confusionweakness, dizziness, confusion

42. FamciclovirFamciclovir
 Cyclic guanine analogCyclic guanine analog
 Available orally onlyAvailable orally only
 Spectrum: HSV 1 and 2, VZV, to a lesserSpectrum: HSV 1 and 2, VZV, to a lesser
extent, EBV, in vitro activity to HBVextent, EBV, in vitro activity to HBV
 Adverse effects: headache, GI, abnormalAdverse effects: headache, GI, abnormal
LFT’sLFT’s

43. Other Topicals for HSVOther Topicals for HSV
 Orolabial herpesOrolabial herpes
– Penciclovir (Denavir® 1% cream)Penciclovir (Denavir® 1% cream)
 Topical guanine analog similar to acyclovirTopical guanine analog similar to acyclovir
 Apply every 2 hours while awakeApply every 2 hours while awake
– Docosanol (Abreva® OTC)Docosanol (Abreva® OTC)
 Active against a broad range of lipid-envelop virusesActive against a broad range of lipid-envelop viruses
 MOA: interferes with viral fusion to host cellMOA: interferes with viral fusion to host cell
 Apply 5X per day until healing (up to 10 days)Apply 5X per day until healing (up to 10 days)
– Shortens healing time by 0.7 daysShortens healing time by 0.7 days
 HSV KeratoconjuctivitisHSV Keratoconjuctivitis
– Trifluridine (Viroptic® 1% ophthalmic)Trifluridine (Viroptic® 1% ophthalmic)
 1 drop q2h (max 9 drops/day)1 drop q2h (max 9 drops/day)
 Active against acyclovir resistant strainsActive against acyclovir resistant strains
 Also active against vaccinia virus and smallpoxAlso active against vaccinia virus and smallpox

44. Anti-CMV AgentsAnti-CMV Agents
 GanciclovirGanciclovir
 ValganciclovirValganciclovir
 FoscarnetFoscarnet
 CidofovirCidofovir

45. Foscarnet – Mechanism of ActionFoscarnet – Mechanism of Action
 Trisodium phosphonoformate hexahydrateTrisodium phosphonoformate hexahydrate
– Inorganic pyrophosphate analogInorganic pyrophosphate analog
 Does not require thymidine kinaseDoes not require thymidine kinase
– Works on HSV strains deficient of this enzymeWorks on HSV strains deficient of this enzyme
 Selective inhibition at the pyrophosphate bindingSelective inhibition at the pyrophosphate binding
site on virus-specific DNA polymerasesite on virus-specific DNA polymerase
– Noncompetetive inhibitorNoncompetetive inhibitor
– Does not affect cellular DNA polymeraseDoes not affect cellular DNA polymerase
 Resistance by alterations to viral DNA polymeraseResistance by alterations to viral DNA polymerase
– Not caused by thymidine kinase alterationsNot caused by thymidine kinase alterations
– Does not cause cross resistance to ganciclovir or cidofovirDoes not cause cross resistance to ganciclovir or cidofovir

46. FoscarnetFoscarnet
 Intravenous only – controlled infusionsIntravenous only – controlled infusions
 Spectrum: CMV including ganciclovir resistant strains,Spectrum: CMV including ganciclovir resistant strains,
acyclovir resistant HSV or VZV, EBV, Influenza A and B,acyclovir resistant HSV or VZV, EBV, Influenza A and B,
HBV, and HIVHBV, and HIV
 Adverse effects: renal dysfunction (common, can requireAdverse effects: renal dysfunction (common, can require
dialysis), NV, anemia, CNS disturbances, electrolytedialysis), NV, anemia, CNS disturbances, electrolyte
abnormalities, seizures, arrhythmias, neutropeniasabnormalities, seizures, arrhythmias, neutropenias
 Reduction of renal failureReduction of renal failure
– Saline loading (adequate hydration)Saline loading (adequate hydration)
– Appropriate renal dosing adjustmentsAppropriate renal dosing adjustments
– Avoidance of concurrent nephrotoxic medicationsAvoidance of concurrent nephrotoxic medications

47. CidofovirCidofovir
 Available intravenous onlyAvailable intravenous only
 Spectrum: CMV including acyclovir and foscarnetSpectrum: CMV including acyclovir and foscarnet
resistant strains, HSV 1 and 2, VZV, EBV, HHV-6,resistant strains, HSV 1 and 2, VZV, EBV, HHV-6,
HHV-8HHV-8
– Also has activity against DNA viruses: papilloma virus,Also has activity against DNA viruses: papilloma virus,
polyomavirus, poxvirus, and adenoviruspolyomavirus, poxvirus, and adenovirus
 Must be avoided in preexisting renal impairmentMust be avoided in preexisting renal impairment
 Adverse effects: nephrotoxicity (dose-limiting),Adverse effects: nephrotoxicity (dose-limiting),
neutropenia, metabolic acidosisneutropenia, metabolic acidosis
 Must be given with adequate hydration and POMust be given with adequate hydration and PO
probenecid---see labeled dosing directionsprobenecid---see labeled dosing directions

48. Hepatitis B AgentsHepatitis B Agents
 Interferon alfa-2b/-n3/-2aInterferon alfa-2b/-n3/-2a
 Peginterferon alfa-2a/-2bPeginterferon alfa-2a/-2b
 EntecavirEntecavir
 AdefovirAdefovir
 TelbivudineTelbivudine
 Lamivudine/ EmtricitabineLamivudine/ Emtricitabine
 TenofovirTenofovir

49. InterferonsInterferons
 Discovered in 1957 for their antiviral effectsDiscovered in 1957 for their antiviral effects
– GlycoproteinsGlycoproteins
– Interferes with viral growthInterferes with viral growth
– Responsible for complex antiviral, immunomodulating, andResponsible for complex antiviral, immunomodulating, and
antiproliferative effectsantiproliferative effects
 Three classes (Three classes (αα,, ββ, and, and γγ))
– Each distinctEach distinct
– Different producer cells, inducers, and biologic effectsDifferent producer cells, inducers, and biologic effects
– INF-INF-αα and –and –ββ are produced by nearly all cells in repsonse toare produced by nearly all cells in repsonse to
invasioninvasion
– Only INF-Only INF-αα has been approved for viral treatmenthas been approved for viral treatment
– INF-INF- γγ only produced by T cells and NK cellsonly produced by T cells and NK cells

50. Hepatitis C AgentsHepatitis C Agents
 RibavirinRibavirin
 Pegylated interferonPegylated interferon

51. RibavirinRibavirin
 Available orally and via inhalationAvailable orally and via inhalation
– Intravenous and intraventricular availableIntravenous and intraventricular available
through the CDCthrough the CDC
 Spectrum: RNA and DNA viruses includingSpectrum: RNA and DNA viruses including
influenza A and B, mumps, measles,influenza A and B, mumps, measles,
parainfluenza, HSV, togavirus, bunyavirus,parainfluenza, HSV, togavirus, bunyavirus,
adenovirus, coxsackievirus, RSV, Hepatitisadenovirus, coxsackievirus, RSV, Hepatitis
A, B and CA, B and C
– Data also available for hemorrhagic fever,Data also available for hemorrhagic fever,
Lassa fever, and Hantaan virusLassa fever, and Hantaan virus

52. Influenza AgentsInfluenza Agents
 OseltamivirOseltamivir
 ZanamivirZanamivir
 AmantadineAmantadine
 RimantadineRimantadine

53. OseltamivirOseltamivir
 Oral neuraminidase inhibitorOral neuraminidase inhibitor
– Cleaves terminal sialic acid residues onCleaves terminal sialic acid residues on
glycoconjugates and destroys receptorsglycoconjugates and destroys receptors
– Newly formed virions adhere to cell surface andNewly formed virions adhere to cell surface and
limit spreadlimit spread
 Spectrum: Infuenza A and B in both childrenSpectrum: Infuenza A and B in both children
and adults, avian influenza, H5N1 diseaseand adults, avian influenza, H5N1 disease
 Adverse effects: NV, headacheAdverse effects: NV, headache

54. ZanamivirZanamivir
 Neuraminidase inhibitorNeuraminidase inhibitor
 Given via inhalationGiven via inhalation
 Spectrum: Uncomplicated influenza A andSpectrum: Uncomplicated influenza A and
B, some strains of avian influenza, possiblyB, some strains of avian influenza, possibly
effective for H5N1effective for H5N1
 Adverse effects: nasal and throatAdverse effects: nasal and throat
discomfort, bronchospasmdiscomfort, bronchospasm

55. AmantadineAmantadine
RamanitidineRamanitidine
 MOA: Prevents the release of viral nucleicMOA: Prevents the release of viral nucleic
acid into host cellacid into host cell
 Spectrum: Influenza A, however resistanceSpectrum: Influenza A, however resistance
is frequentis frequent
 Adverse effects: Seizures, anticholinergic,Adverse effects: Seizures, anticholinergic,
CNS, edema, blurry visionCNS, edema, blurry vision
 Not currently recommended in the USNot currently recommended in the US

56. Papillomavirus OptionsPapillomavirus Options
 ImiquimodImiquimod
 PodofiloxPodofilox
 Trichloroacetic AcidTrichloroacetic Acid
 PodophyllinPodophyllin
 CryotherapyCryotherapy

57. ImiquimodImiquimod
 Imidazoquinoline compoundImidazoquinoline compound
 ImmunomodulatorImmunomodulator
– Activates immune cells (monocytes, macrophages, NK cells)Activates immune cells (monocytes, macrophages, NK cells)
 Produces antiviral cytokines (IFN-Produces antiviral cytokines (IFN-αα, TNF-, TNF-αα, and various interleukins, and various interleukins
 Indirectly activates APC’s including Langerhan’s cells and T-helperIndirectly activates APC’s including Langerhan’s cells and T-helper
cellscells
 Topical treatmentTopical treatment
– 5% cream 3X per week (for 8 hours) for 16 weeks5% cream 3X per week (for 8 hours) for 16 weeks
– Can be used as adjunctive therapy with laser or surgical txCan be used as adjunctive therapy with laser or surgical tx
 Spectrum: External and perianal genital warts by HPVSpectrum: External and perianal genital warts by HPV
 Adverse effects:Adverse effects:
– Site reactions (pain, erythema, scarring, and pruritis)Site reactions (pain, erythema, scarring, and pruritis)
– No systemic reactions reportedNo systemic reactions reported

58.  THANKSTHANKS