Microbiology - Antimicrobials (2) Flashcards

1
Q

Antifungal therapy (189)

A
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2
Q

Amphotericin B

  • Mechanism
  • Clinical use
  • Toxicity
A
  • 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.
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3
Q

Nystatin

  • Mechanism
  • Clinical use
A
  • 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.
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4
Q

Azoles

  • Examples
  • Mechanism
  • Clinical use
  • Toxicity
A
  • 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).
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5
Q

Flucytosine

  • Mechanism
  • Clinical use
  • Toxicity
A
  • 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.
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6
Q

Echinocandins

  • Examples
  • Mechanism
  • Clinical use
  • Toxicity
A
  • 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).
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7
Q

Terbinafine

  • Mechanism
  • Clinical use
  • Toxicity
A
  • 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.
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8
Q

Griseofulvin

  • Mechanism
  • Clinical use
  • Toxicity
A
  • 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.
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9
Q

Antiprotozoan therapy

  • Toxoplasmosis
  • Trypanosoma brucei
  • T. cruzi
  • Leishmaniasis
A
  • Toxoplasmosis
    • Pyrimethamine
  • Trypanosoma brucei
    • Suramin and melarsoprol
  • T. cruzi
    • Nifurtimox
  • Leishmaniasis
    • Sodium stibogluconate
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10
Q

Chloroquine

  • Mechanism
  • Clinical use
  • Toxicity
A
  • 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).
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11
Q

Antihelminthic therapy

A
  • Mebendazole, pyrantel pamoate, ivermectin, diethylcarbamazine, praziquantel
  • Immobilize helminths.
  • Use praziquantel against flukes (trematodes) such as Schistosoma.
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12
Q

Antiviral therapy (191)

A
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13
Q

Zanamivir, oseltamivir

  • Mechanism
  • Clinical use
A
  • Mechanism
    • Inhibit influenza neuraminidase –> decrease the release of progeny virus.
  • Clinical use
    • Treatment and prevention of both influenza A and B.
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14
Q

Ribavirin

  • Mechanism
  • Clinical use
  • Toxicity
A
  • Mechanism
    • Inhibits synthesis of guanine nucleotides by competitively inhibiting inosine monophosphate dehydrogenase.
  • Clinical use
    • RSV, chronic hepatitis C.
  • Toxicity
    • Hemolytic anemia.
    • Severe teratogen.
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15
Q

Acyclovir, famciclovir, valacyclovir

  • Mechanism
  • Clinical use
  • Toxicity
  • Mechanism of resistance
A
  • 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.
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16
Q

Ganciclovir

  • Mechanism
  • Clinical use
  • Toxicity
  • Mechanism of resistance
A
  • 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.
17
Q

Foscarnet

  • Mechanism
  • Clinical use
  • Toxicity
  • Mechanism of resistance
A
  • 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.
18
Q

Cidofovir

  • Mechanism
  • Clinical use
  • Toxicity
A
  • 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).
19
Q

HIV therapy

A
  • 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
20
Q

HIV therapy:
Protease inhibitors

  • Examples
  • Mechanism
  • Toxicity
A
  • 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).
21
Q

HIV therapy:
NRTIs

  • Examples
  • Mechanism
  • Toxicity
A
  • 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).
22
Q

HIV therapy:
NNRTIs

  • Examples
  • Mechanism
  • Toxicity
A
  • 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.
23
Q

HIV therapy:
Integrase inhibitors

  • Examples
  • Mechanism
  • Toxicity
A
  • Examples
    • Raltegravir
  • Mechanism
    • Inhibits HIV genome integration into host cell chromosome by reversibly inhibiting HIV integrase.
  • Toxicity
    • Hypercholesterolemia.
24
Q

HIV therapy:
Fusion inhibitors

  • Examples
  • Mechanism
  • Toxicity
A
  • 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.
25
Q

Interferons

  • Mechanism
  • Clinical use
  • Toxicity
A
  • 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.
26
Q

Antibiotics to avoid in pregnancy & their adverse effects

A
  • 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”