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31

HIV prophylaxis for CD4 < 100

TMP-SMX
- Pneuomcystis jirovecci
- Toxoplasmosis

32

HIV prophylaxis for CD4 < 50

Azithromycin
- Mycobacterium avium complex

33

Treatment of very resistant enterococci

Linezolid (50s inhibitor) and streptogramins (quinupristin/dalfopristin)

34

Amphotericin B

MOA:
- Binds ergosterol (unique in fungi)--> membrane pores--> leak electrolytes

Use: Serious, systemic mycosis:
- Cryptococcus (+/- flucytosine for meningitis)
- Blastomyces
- Coccidioides
- Histoplasma
- Candida
- Mucor

Tox:
- Shake and bake (fever and chills)
- Hypotension
- Nephrotoxicity (supplement K and Mg due to renal tube changes, hydrate)
- Arrhythmias
- Anemia
- Phlebitis

35

Nystatin

MOA:
- Binds ergosterol (unique in fungi)--> membrane pores--> leak electrolytes
- TOPICAL (too toxic for systemic use)

Use:
- Oral candidiasis: swish and swallow
- Diaper rash, vaginal candidiasis

36

Azoles

Fluconazole
Ketoconazole
Clotrimazole
Miconazole
Itraconazole
Voriconazole

MOA:
- Inhibit p450 enzyme converting lanosterol to ergosterol (fungal sterol)

Use:
- Local, less serious mycoses
- Fluconazole= Candidiasis; chronic suppression of cryptococcus in AIDS
- Itraconazole= blastomyces, coccidioides, histoplasma
- Clotrimazole, miconazole for topical fungal

Tox:
- Testosterone synthesis inhibition
- Liver dysfunction (p450): avoid with Warfarin, Cyclosporine, Tacrolimus, phenytoin, INH, rifampin, oral hypoglycemics

37

Flucytosine

MOA: cytosine deaminase converts to 5-FU--> inhibit DNA and RNA biosynthesis

Use:
- Systemic fungal infections (Cryptococcus meningitis) + Ampho B

Tox:
- Bone marrow suppression

38

Capsofungin, Micafungin

MOA: Inhibits Beta-glucan--> blocks cell wall synthesis

Use:
- Invasive aspergillosis
- Candida

Tox:
- GI upset
- flushing

39

Terbafine

MOA:
- Inhibits fungal enzyme squalene epoxidase

Use:
- Dermatophytosis (onchomycosis)

Tox:
- Visual disturbances, abnormal LFTs

40

Griseofulvin

MOA:
- Interferes with microtubule function--> disrupts mitosis (keratin tissue)

Use:
- Oral treatment for superficial infections (dermatophytes)

Tox:
- **Teratogen**, Carcinogen
- Confusion, H/A
- Increased p450, Warfarin metabolism

41

Pyrimethamine

Toxoplasmosis tx

42

Suramin, melarsoprol

Trypanosoma brucei tx

43

Nifurtimox

Trypanosoma cruzi

44

Sodium stibogluconate

Leishmaniasis treatment

45

Chloroquine

MOA:
- Blocks detox of heme--> hemozoin--> heme accumulation toxic to plasmodia

Use:
- Plasmodia EXCEPT falciparum (resistant due to membrane pump decreasing conc)
** treat falciparum with artemether/lumifantrine or atovaquone/proguanil

Tox: retinopathy

46

Helminth tx

Mebendazole
Pyrantel pamoate
Ivermectin
Diethylcarbamazine
Praziquantel

ALL immobilize helminths

47

Praziquantel

Anti-helminthic
Anti-trematode (Schistosoma)

48

Zanamivir, oseltamivir

MOA:
- Inhibit influenza NA--> decreased release of virus

Use:
- Prevent/treat influenza A, B

49

Ribavirin

MOA:
- Inhibit IMP dehydrogenase--> prevent synthesis of guanine nucleotides

Use:
- RSV
- Chronic Hep C

Tox:
- Hemolytic anemia
- **Severe teratogen**

50

Acyclovir

MOA:
1. Viral thymidine kinase monophosphorylates drug--> acyclo GMP
2. Host cell forms triphosphate--> acyclo GTP
3. Inhibits DNA polymerase via chain termination

Use:
- HSV: lesions, encephalitis, prophylaxis
- VSV
- Weak EBV activity
- NO CMV activity

**Valacyclovir= better oral bioavailability
** Famciclovir= Herpes zoster

Tox: few

Resistance: mutated viral thymidine kinase

51

Ganciclovir

MOA:
1. Viral kinase--> 5' monophosphate--> GMP
2. Host cell--> triphosphate--> GTP
3. Inhibits viral DNA polymerase

Use:
- CMV (esp. immunocompromised)
** Valganciclovir= better oral bioavailability

Tox:
- Leukopenia, neutropenia, thrombocytopenia, renal (more toxic than acyclovir)

Resistance: Mutated viral DNA pol or no viral kinase

52

Foscarnet

MOA:
- Binds pyrophosphate binding site of viral DNA polymerase--> inhibition (no activation needed)

Use:
- CMV retinitis in immunocompromised
- Ganciclovir failure
- Acyclovir-resistant HSV

Tox: Nephrotoxic

Resistance: DNA polymerase mutation

53

Cidofovir

MOA:
- Inhibits viral DNA polymerase
- No P-tion by viral kinase

Use:
- CMV retinitis in immunocompromised
- Acyclovir-resistant HSV
* long half-life

Tox:
- Nephrotoxic (use probenecid, IV saline to reduce toxicity)

54

HIV therapy principles

2 Nucleoside reverse transcriptase inhibitors (NRTIs) PLUS 1 of following:
- non-nucleoside reverse transcriptase inhibitor (NNRTI)
- protease inhibitor
- integrase inhibitor

55

Protease inhibitors

-navir ("Navir tease a protease")

MOA:
- HIV-1 protease (pol gene)--> cleaves polypeptide product of HIV mRNA
- PI prevents maturation of new viruses
** Ritonavir= boost other drug concentrations by inhibiting CYP450

Tox:
- Hyperglycemia
- Lipodystrophy
- GI intolerance (N/V/D)
- Nephropathy, hematuria (indinavir)

56

Nucleoside Reverse Transcriptase Inhibitors (NRTI)

Tenofovir
Emtricitabine
Abacavir
Lamivudine
Zidovudine
Didanosine
Stavudine

MOA:
- Binds to reverse trascriptase--> terminates DNA chain (missing 3'OH group)
- Requires activation= phosphorylation (except tenofovir)

Zidovudine (ZDV) used for general prophylaxis in pregnancy (reduce fetal transmission)

Tox:
- Bone marrow suppression (reverse with G-CSF and Epo)
- Peripheral neurpoathy
- Lactic acidosis (nucleosides)
- Anemia (ZDV)

57

Tenofovir

Nucleoside Reverse Transcriptase inhibitor (NRTI)
- Nucleotide analog= does NOT require activation
- Binds to reverse trascriptase--> terminates DNA chain (missing 3'OH group)

Tox:
- Bone marrow suppression (reverse with G-CSF and Epo)
- Peripheral neurpoathy
- Lactic acidosis (nucleosides)

58

Non-nucleoside reverse transcriptase inhibitors (NNRTI)

Nevirapine
Efavirenz
Delavirdine

MOA:
- Bind to reverse transcriptase (different site from NRTI)
- Do not require phosphorylation to be activated
- Do no compete with nucleotides

Tox:
- Bone marrow suppression (reverse with G-CSF and Epo)
- Peripheral neurpoathy
- Rash (non-nucleosides)

59

Raltegravir

Integrase inhibitor

MOA:
- Inhibits integrase: blocks HIV genome integration into host cell DNA

Tox:
- Hypercholesterolemia

60

Interferons

MOA:
- Glycoproteins synthesized by virus-infected cells--> block RNA/DNA viral replication

Use:
- IFN alpha= Chronic Hep B, C, Kaposi's
- IFN beta= MS
- IFN gamma= NADPH oxidase deficiency

Tox:
- Neutropenia
- Myopathy