Microbiology - Antimicrobials (2)

Question 1

Antifungal therapy (189)

Answer 1

Question 2

Amphotericin B

• Mechanism
• Clinical use
• Toxicity

Answer 2

• Mechanism
  
  • Binds ergosterol (unique to fungi)
  • Forms membrane pores that allow leakage of electrolytes.
  • Amphotericin “tears” holes in the fungal membrane by forming pores.
• Clinical use
  
  • Serious, systemic mycoses.
    
    • Cryptococcus (amphotericin B with/without flucytosine for cryptococcal meningitis), Blastomyces, Coccidioides, Histoplasma, Candida, Mucor.
  • Intrathecally for fungal meningitis.
  • Supplement K+ and Mg2+ because of altered renal tubule permeability.
• Toxicity
  
  • Fever/chills (“shake and bake”), hypotension, nephrotoxicity, arrhythmias, anemia, IV phlebitis (“amphoterrible”).
  • Hydration decreases nephrotoxicity.
  • Liposomal amphotericin decreases toxicity.

Question 3

Nystatin

• Mechanism
• Clinical use

Answer 3

• Mechanism
  
  • Same as amphotericin B.
    
    • Binds ergosterol (unique to fungi)
    • Forms membrane pores that allow leakage of electrolytes.
  • Topical form because too toxic for systemic use.
• Clinical use
  
  • “Swish and swallow” for oral candidiasis (thrush)
  • Topical for diaper rash or vaginal candidiasis.

Question 4

Azoles

• Examples
• Mechanism
• Clinical use
• Toxicity

Answer 4

• Examples
  
  • Fluconazole, ketoconazole, clotrimazole, miconazole, itraconazole, voriconazole.
• Mechanism
  
  • Inhibit fungal sterol (ergosterol) synthesis, by inhibiting the cytochrome P-450 enzyme that converts lanosterol to ergosterol.
• Clinical use
  
  • Local and less serious systemic mycoses.
  • Fluconazole for chronic suppression of cryptococcal meningitis in AIDS patients and candidal infections of all types.
  • Itraconazole for Blastomyces, Coccidioides, Histoplasma.
  • Clotrimazole and miconazole for topical fungal infections.
• Toxicity
  
  • Testosterone synthesis inhibition (gynecomastia, esp. with ketoconazole), liver dysfunction (inhibits cytochrome P-450).

Question 5

Flucytosine

• Mechanism
• Clinical use
• Toxicity

Answer 5

• Mechanism
  
  • Inhibits DNA and RNA biosynthesis by conversion to 5-fluorouracil by cytosine deaminase.
• Clinical use
  
  • Systemic fungal infections (esp. meningitis caused by Cryptococcus) in combination with amphotericin B.
• Toxicity
  
  • Bone marrow suppression.

Question 6

Echinocandins

• Examples
• Mechanism
• Clinical use
• Toxicity

Answer 6

• Examples
  
  • Caspofungin, micafungin, anidulafungin.
• Mechanism
  
  • Inhibits cell wall synthesis by inhibiting synthesis of β-glucan.
• Clinical use
  
  • Invasive aspergillosis, Candida.
• Toxicity
  
  • GI upset, flushing (by histamine release).

Question 7

Terbinafine

• Mechanism
• Clinical use
• Toxicity

Answer 7

• Mechanism
  
  • Inhibits the fungal enzyme squalene epoxidase.
• Clinical use
  
  • Dermatophytoses (especially onychomycosis—fungal infection of finger or toe nails).
• Toxicity
  
  • GI upset, headaches, hepatotoxicity, taste disturbance.

Question 8

Griseofulvin

• Mechanism
• Clinical use
• Toxicity

Answer 8

• Mechanism
  
  • Interferes with microtubule function
  • Disrupts mitosis.
  • Deposits in keratin-containing tissues (e.g., nails).
• Clinical use
  
  • Oral treatment of superficial infections
  • Inhibits growth of dermatophytes (tinea, ringworm).
• Toxicity
  
  • Teratogenic, carcinogenic, confusion, headaches, increases P-450 and warfarin metabolism.

Question 9

Antiprotozoan therapy

• Toxoplasmosis
• Trypanosoma brucei
• T. cruzi
• Leishmaniasis

Answer 9

• Toxoplasmosis
  
  • Pyrimethamine
• Trypanosoma brucei
  
  • Suramin and melarsoprol
• T. cruzi
  
  • Nifurtimox
• Leishmaniasis
  
  • Sodium stibogluconate

Question 10

Chloroquine

• Mechanism
• Clinical use
• Toxicity

Answer 10

• Mechanism
  
  • Blocks detoxification of heme into hemozoin.
  • Heme accumulates and is toxic to plasmodia.
• Clinical use
  
  • Treatment of plasmodial species other than P. falciparum (frequency of resistance in P. falciparum is too high).
  • Resistance due to membrane pump that decreases intracellular concentration of drug.
  • Treat P. falciparum with artemether/lumefantrine or atovaquone/proguanil.
  • For life-threatening malaria, use quinidine in U.S. (quinine elsewhere) or artesunate.
• Toxicity
  
  • Retinopathy
  • Pruritus (especially in dark-skinned individuals).

Question 11

Antihelminthic therapy

Answer 11

• Mebendazole, pyrantel pamoate, ivermectin, diethylcarbamazine, praziquantel
• Immobilize helminths.
• Use praziquantel against flukes (trematodes) such as Schistosoma.

Question 12

Antiviral therapy (191)

Answer 12

Question 13

Zanamivir, oseltamivir

• Mechanism
• Clinical use

Answer 13

• Mechanism
  
  • Inhibit influenza neuraminidase –> decrease the release of progeny virus.
• Clinical use
  
  • Treatment and prevention of both influenza A and B.

Question 14

Ribavirin

• Mechanism
• Clinical use
• Toxicity

Answer 14

• Mechanism
  
  • Inhibits synthesis of guanine nucleotides by competitively inhibiting inosine monophosphate dehydrogenase.
• Clinical use
  
  • RSV, chronic hepatitis C.
• Toxicity
  
  • Hemolytic anemia.
  • Severe teratogen.

Question 15

Acyclovir, famciclovir, valacyclovir

• Mechanism
• Clinical use
• Toxicity
• Mechanism of resistance

Answer 15

• Mechanism
  
  • Monophosphorylated by HSV/VZV thymidine kinase and not phosphorylated in uninfected cells –>Ž few adverse effects.
  • Guanosine analog.
  • Triphosphate formed by cellular enzymes.
  • Preferentially inhibits viral DNA polymerase by chain termination.
• Clinical use
  
  • HSV and VZV.
  • Weak activity against EBV.
  • No activity against CMV.
  • Used for HSV-induced mucocutaneous and genital lesions as well as for encephalitis.
  • Prophylaxis in immunocompromised patients.
  • No effect on latent forms of HSV and VZV.
  • Valacyclovir, a prodrug of acyclovir, has better oral bioavailability.
  • For herpes zoster, use a related agent, famciclovir.
• Toxicity
  
  • Obstructive crystalline nephropathy and acute renal failure if not adequately hydrated.
• Mechanism of resistance
  
  • Mutated viral thymidine kinase.

Question 16

Ganciclovir

• Mechanism
• Clinical use
• Toxicity
• Mechanism of resistance

Answer 16

• Mechanism
  
  • 5′-monophosphate formed by a CMV viral kinase.
  • Guanosine analog.
  • Triphosphate formed by cellular kinases.
  • Preferentially inhibits viral DNA polymerase.
• Clinical use
  
  • CMV, especially in immunocompromised patients.
  • Valganciclovir, a prodrug of ganciclovir, has better oral bioavailability.
• Toxicity
  
  • Leukopenia, neutropenia, thrombocytopenia, renal toxicity.
  • More toxic to host enzymes than acyclovir.
• Mechanism of resistance
  
  • Mutated CMV DNA polymerase or lack of viral kinase.

Question 17

Foscarnet

• Mechanism
• Clinical use
• Toxicity
• Mechanism of resistance

Answer 17

• Mechanism
  
  • Viral DNA polymerase inhibitor that binds to the pyrophosphate-binding site of the enzyme.
    
    • Foscarnet = pyrofosphate analog.
  • Does not require activation by viral kinase.
• Clinical use
  
  • CMV retinitis in immunocompromised patients when ganciclovir fails
  • Acyclovir-resistant HSV.
• Toxicity
  
  • Nephrotoxicity.
• Mechanism of resistance
  
  • Mutated DNA polymerase.

Question 18

Cidofovir

• Mechanism
• Clinical use
• Toxicity

Answer 18

• Mechanism
  
  • Preferentially inhibits viral DNA polymerase.
  • Does not require phosphorylation by viral kinase.
• Clinical use
  
  • CMV retinitis in immunocompromised patients
  • Acyclovir-resistant HSV.
  • Long half-life.
• Toxicity
  
  • Nephrotoxicity (coadminister with probenecid and IV saline to decrease toxicity).

Question 19

HIV therapy

Answer 19

• Highly active antiretroviral therapy (HAART):
  
  • Initiated when patients present with AIDS-defining illness, low CD4 cell counts (< 500 cells/mm3), or high viral load.
  • Regimen consists of 3 drugs to prevent resistance:
    
    • 2 nucleoside reverse transcriptase inhibitors (NRTIs) +
    • 1 non-nucleoside reverse transcriptase inhibitor (NNRTI) OR 1 protease inhibitor OR 1 integrase inhibitor

Question 20

HIV therapy:
Protease inhibitors

• Examples
• Mechanism
• Toxicity

Answer 20

• Examples
  
  • Atazanavir
  • Darunavir
  • Fosamprenavir
  • Indinavir
  • Lopinavir
  • Ritonavir
  • Saquinavir
  • All protease inhibitors end in -navir
    
    • Navir (never) tease a protease
• Mechanism
  
  • Assembly of virions depends on HIV-1 protease (pol gene), which cleaves the polypeptide products of HIV mRNA into their functional parts.
    
    • Thus, protease inhibitors prevent maturation of new viruses.
  • Ritonavir can “boost” other drug concentrations by inhibiting cytochrome P-450.
• Toxicity
  
  • Hyperglycemia, GI intolerance (nausea, diarrhea), lipodystrophy.
  • Nephropathy, hematuria (indinavir).

Question 21

HIV therapy:
NRTIs

• Examples
• Mechanism
• Toxicity

Answer 21

• Examples
  
  • Abacavir (ABC)
  • Didanosine (ddI)
  • Emtricitabine (FTC)
  • Lamivudine (3TC)
  • Stavudine (d4T)
  • Tenofovir (TDF)
  • Zidovudine (ZDV, formerly AZT)
• Mechanism
  
  • Competitively inhibit nucleotide binding to reverse transcriptase and terminate the DNA chain (lack a 3′ OH group).
    
    • Tenofovir is a nucleoTide; the others are nucleosides and need to be phosphorylated to be active.
  • ZDV is used for general prophylaxis and during pregnancy to decrease risk of fetal transmission.
  • Ha_ve you dined_ (vudine) with my nuclear (nucleosides) family?
• Toxicity
  
  • Bone marrow suppression (can be reversed with granulocyte colony-stimulating factor [G-CSF] and erythropoietin), peripheral neuropathy, lactic acidosis (nucleosides), rash (non-nucleosides), anemia (ZDV), pancreatitis (didanosine).

Question 22

HIV therapy:
NNRTIs

• Examples
• Mechanism
• Toxicity

Answer 22

• Examples
  
  • Efavirenz
  • Nevirapine
  • Delavirdine
• Mechanism
  
  • Bind to reverse transcriptase at site different from NRTIs.
  • Do not require phosphorylation to be active or compete with nucleotides.
• Toxicity
  
  • Rash and hepatotoxicity are common to all NNRTIs.
  • Vivid dreams and CNS symptoms are common with efavirenz.
  • Delavirdine and efavirenz are contraindicated in pregnancy.

Question 23

HIV therapy:
Integrase inhibitors

• Examples
• Mechanism
• Toxicity

Answer 23

• Examples
  
  • Raltegravir
• Mechanism
  
  • Inhibits HIV genome integration into host cell chromosome by reversibly inhibiting HIV integrase.
• Toxicity
  
  • Hypercholesterolemia.

Question 24

HIV therapy:
Fusion inhibitors

• Examples
• Mechanism
• Toxicity

Answer 24

• Examples
  
  • Enfuvirtide
  • Maraviroc
• Mechanism
  
  • E: Binds gp41, inhibiting viral entry.
  • M: Binds CCR-5 on surface of T cells/monocytes, inhibiting interaction with gp120.
• Toxicity
  
  • Skin reaction at injection sites.

Question 25

Interferons

• Mechanism
• Clinical use
• Toxicity

Answer 25

• Mechanism
  
  • Glycoproteins normally synthesized by virus-infected cells, exhibiting a wide range of antiviral and antitumoral properties.
• Clinical use
  
  • IFN-α: chronic hepatitis B and C, Kaposi sarcoma, hairy cell leukemia, condyloma acuminatum, renal cell carcinoma, malignant melanoma.
  • IFN-β: multiple sclerosis.
  • IFN-γ: chronic granulomatous disease.
• Toxicity
  
  • Neutropenia, myopathy.

Question 26

Antibiotics to avoid in pregnancy & their adverse effects

Answer 26

• SAFe Children Take Really Good Care.
• Sulfonamides
  
  • Kernicterus
• Aminoglycosides
  
  • Ototoxicity
• Fluoroquinolones
  
  • Cartilage damage
• Clarithromycin
  
  • Embryotoxic
• Tetracyclines
  
  • Discolored teeth, inhibition of bone growth
• Ribavirin (antiviral)
  
  • Teratogenic
• Griseofulvin (antifungal)
  
  • Teratogenic
• Chloramphenicol
  
  • “Gray baby”