Antimicrobials Flashcards
Antifungals/Antiparasitics/Antivirals
Fungal infections
most commonly superficial involving the skin but if systemic can be severe and life-threatening (often affecting immunocompromised patients)
Amphotericin B MOA
a polyene (produced by Streptomyces nodosus) that is a lipophilic rod-like molecule that disrupts fungal cell wall synthesis by binding to sterols, primarily ergosterol, leading to the formation of pores in the cell membrane resulting in K+ leaking out of the cell and causing death
Amphotericin B spectrum of activity
used to treat severe invasive fungal infections with the widest spectrum of activity of all antifungals
Amphotericin B pharmacokinetics
used IV which has wide tissue distribution with rapid onset of action and is not dependent on the organism’s growth rate, has poor oral absorption and little CSF penetration - narrow therapeutic index
Amphotericin B adverse effects
reversible nephrotoxicity due to a dose-dependent decrease in GFR and vasoconstriction of afferent renal arterioles, infusion-related reactions (fever and rigors), nausea/vomiting, reversible anemia, phlebitis, and renal tubular acidosis with wasting of K+, Mg2+, and HCO3-
Amphotericin B contraindications
use with cyclosporine, tacrolimus, aminoglycosides can exacerbate nephrotoxicity, pre-existing renal insufficiency, intravascular volume depletion - hypotension
Flucytosine (5-FC) MOA
synthetic pyrimidine analog that inhibits thymidylate synthase and incorporates into fungal RNA disrupting nucleic acid and protein synthesis
Flucytosine spectrum of activity
used in combination with amphotericin B (synergistic) to treat systemic mycoses and meningitis caused by cryptococcus and candida species and in combination with itraconazole to treat chromoblastomycosis infections (not used as monotherapy due to high resistance)
Flucytosine resistance mechanism
fungi decrease the level of enzymes that are targeted by flucytosine
Flucytosine pharmacokinetics
has good oral absorption and penetrates CSF, dose adjustment required for renal impairment
Flucytosine adverse effects
most common are GI upset, N/V, and diarrhea, also reversible neutropenia, thrombocytopenia, dose-related bone marrow suppression, reversible hepatic dysfunction,
Ketoconazole MOA
an imidazole that inhibits C-14 alpha-demethylase decreasing synthesis of ergosterol thereby disrupting membrane structure
Ketoconazole spectrum of activity
used topically and orally to treat Candida, Histoplasma, Blastomyces, and Coccidioides infections
Ketoconazole contraindications
use with Amphotericin B and in pregnancy
Ketoconazole pharmacokinetics
requires gastric acid for dissolution and absorption (can’t be used with antacids, H2-histamine blockers, and PPIs), metabolized by CYP450 in the liver - low levels found in urine (cannot treat mycotic UTIs), does not penetrate CSF, inhibits human gonadal and adrenal steroid hormone synthesis
Ketoconazole resistance mechanism
mutations in the C-14 alpha-demethylase gene resulting in decreased binding of the drug and some strains have developed the ability to pump drug out of the cell
Ketoconazole adverse effects
Gi upset most common, hepatitis (monitor LFTs), gynecomastia, decreased libido, menstrual irregularities due to endocrine effect
the Imidazoles
ketoconazole, miconazole, and clotrimazole
the Triazoles
fluconazole, itraconazole, voriconazole, and posaconazole
Fluconazole MOA
a triazole that inhibits the synthesis of cell membranes via inhibition of C-14-alpha-demethylase, a fungal CYP450 enzyme similar to ketoconazole, however, it does not interfere with mammalian CYP450 enzymes involved in the synthesis of steroid hormones
Itraconazole MOA
a triazole that inhibits the synthesis of cell membranes via inhibition of C-14-alpha-demethylase, a fungal CYP450 enzyme similar to ketoconazole, however, it does not interfere with mammalian CYP450 enzymes involved in the synthesis of steroid hormones
Fluconazole spectrum of activity
used to treat Candida, Cryptococcus neoformans, and Coccidiomycosis infections (no activity against aspergillus)
Fluconazole pharmacokinetics
available orally and IV and not dependent on gastric acid for absorption, has good CSF penetration, requires dose adjustment for renal impairment
Fluconazole adverse effects
nausea, vomiting, rashes, alopecia, rare hepatitis, teratogenic
Fluconazole contraindications
in pregnancy (teratogenic)
Itraconazole MOA
a triazole that inhibits the synthesis of cell membranes via fungal CYP450 inhibition similar to ketoconazole, however, it does not interfere with mammalian CYP450 enzymes involved in the synthesis of steroid hormones
Itraconazole spectrum of activity
broad spectrum of activity and is the drug of choice for the treatment of histoplasmosis, blastomycosis, Coccidioidomycosis, and sporotrichosis infections
Itraconazole pharmacokinetics
has good oral bioavailability but requires gastric acid for absorption (no IV formulation available), metabolized in the liver, does not require dose adjustment for renal impairment, does not penetrate CSF well
Itraconazole adverse effects
nausea, vomiting, rash, headache, hypertension, hypokalemia, edema, rare hepatitis, alopecia with chronic therapy, teratogenic
Itraconazole contraindications
in pregnancy (teratogenic), in patients with CHF or history of CHF
Caspofungin MOA
an echinocandins that inhibits B(1,3)-D-glucan synthase which is an enzyme involved in fungal wall synthesis
Caspofungin spectrum of activity
used to treat Candida glabrata infections and azole-resistant Candida esophagitis, used second line to treat invasive aspergillus infections (not active against Zygomycetes and Cryptococcus neoformans), has poor CNS penetration
Caspofungin adverse effects
generally well tolerated, only thing is histamine infusion reaction which can be pretreated with diphenhydramine
Caspofungin drug interactions
use with cyclosporine, tacrolimus, and rifampin
DOC for treatment for invasive aspergillus infections
Voriconazole
Nystatin MOA
a polyene that binds to ergosterol and disrupts fungal cell wall synthesis leading to the formation of pores in the cell membrane resulting in K+ leaking out of the cell and causing death
Nystatin clinical indications
used topically (powder, cream, ointment) or as an oral suspension to treat fungal skin/vaginal/mouth infections
Nystatin pharmacokinetics
too toxic for systemic use (never used IV), not absorbed from the GI tract
Griseofulvin MOA
inhibits mitosis by interfering with microtubules
Griseofulvin clinical indications
used to treat dermatophytic nail infections due to accumulation in keratin-containing tissues - treatment may be required for 6-12 months
Griseofulvin drug interactions
induces CYP450 and increases the rate of metabolism of other drugs including warfarin
Itraconazole drug interactions
warfarin, statins, and phenytoin
Ketoconazole drug interactions
cyclosporine, phenytoin, tolbutamide, warfarin, and rifampin
Terbinafine MOA
inhibits cell wall synthesis by inhibiting fungal squalene epoxidase decreasing the synthesis of ergosterol
Terbinafine clinical indications
DOC for treatment of onychomycosis and dermatophytic infections due to accumulation in skin, nails, and fat
Terbinafine contraindications
in nursing mothers due to accumulation in breast milk
Terbinafine adverse effects
hepatotoxicity - needs LFTs at baseline
DOC for the treatment of Coccidioidomycosis
Fluconazole or Itraconazole, if severe/disseminated then Amphotericin B
DOC for the treatment of Histoplasmosis
Itraconazole
DOC for the treatment of Blastomycosis
Itraconazole
DOC for the treatment of Aspergillus
1st line = Voriconazole, then Posaconazole, then Caspofungin, and then Amphotericin B
DOC for the treatment of Zygomycetes
1st line = Posaconazole, then Amphotericin B
Metronidazole MOA
contains a nitro group that serves as an electron acceptor and forms toxic metabolites that disrupt DNA helical structure leading to cell death when activated by anaerobes
Metronidazole spectrum of activity
active against amebiasis, giardiasis, trichomoniasis, and anaerobic bacteria, considered tissue agent and co-administered with luminal agent Paromomycin
Metronidazole pharmacokinetics
metabolized in liver and accumulates in patients with severe hepatic disease, excreted in urine
Metronidazole adverse effects
GI upset, metallic taste, seizures, neuropathy, disulfiram effect with alcohol
Griseofulvin contraindication
use with alcohol
Metronidazole contraindications
in pregnancy, breastfeeding, and in recent use with disulfiram
Alternatives to Metronidazole
tinidazole, ornidazole, and nitazoxanide
Trimethoprim-Sulfamethoxazole (TMP-SMX) MOA
combination of TMP-SMX provides sequential and synergistic blockade of folate pathway which leads to the inhibition of thymidine synthesis
TMP-SMX spectrum of activity
active against Cyclospora and Isospora infections
TMP-SMX adverse effects
rash, SJS, kernicterus, hemolysis in G6PD deficiency, bone marrow suppression, anemia, renal impairment, and hepatotoxicity
TMP-SMX contraindications
caution in patients with renal disease, contraindicated in newborns (<2 months) and pregnancy
TMP-SMX drug interactions
warfarin, phenytoin, and methotrexate
Albendazole MOA
binds to microtubules in intestinal and tegmental worms and larvae impairing glucose uptake, leading to glycogen depletion, degeneration of ER and mitochondria, release of lysosomes, and depletion on ATP/energy causing helminth/worm death
Albendazole spectrum of activity
broadly effective against nematode infections (roundworms)
Albendazole adverse effects
headache, elevated LFTs, rarely GI upset and alopecia, and very rarely liver failure, myelosuppression, and seizures, teratogenic
Albendazole contraindication
in pregnancy (teratogenic)
Pyrantel Pamoate MOA
causes the release of acetylcholine and inhibits cholinesterase, acts as a depolarizing neuromuscular blocker, and spastic paralysis and release of helminths
Pyrantel Pamoate spectrum of activity
alternative to albendazole therapy for the treatment of Enterobius vermicularis (pinworms) infections, however, not preferred agent
Pyrantel Pamoate adverse effects
rare headache, dizziness, and GI distress
Praziquantel MOA
increases cell permeability to Ca2+ in schistosomes causing strong contractions and paralysis of helminth musculature which leads to detachment, dislodgement, and death
Praziquantel spectrum of activity
active against cestodes (tapeworms) and trematodes (flukes and Schistosoma)
Praziquantel adverse effects
abdominal pain, dizziness, and drowsiness (CNS side effects such as headache and seizures in patients with cerebral cysticercosis from the death of the parasites)
Praziquantel pharmacokinetics
extensively metabolized by CYP3A4, avoid co-administration with CYP inducers
Ivermectin MOA
binds to and activates glutamate-gated chloride channels in invertebrate nerve and muscle cells causing hyperpolarization and death of the helminth, does not cross the BBB
Ivermectin spectrum of activity
active against strongyloidiasis and onchocerciasis (river blindness) and used topically for treatment of head lice
Ivermectin adverse effects
neurotoxicity (CNS depression, ataxia) from activation of GABA-ergic synapses and some cutaneous effects
Ivermectin contraindications
in pregnancy and meningitis
Oseltamivir MOA
inhibitor of neuraminidase which is an enzyme essential for cleaving the virus from the host cell and allowing the spread of the virus from cell to cell
Oseltamivir spectrum of activity
effective in decreasing Influenza A and B viral load and shortening the course of disease by 1-2 days if administered within 48 hours of symptoms onset, also can be administered prophylactically
Oseltamivir pharmacokinetics
administered orally and is a prodrug that is hydrolyzed in the liver to its active form, required dose adjustment in renal impairment
Oseltamivir adverse effects
most commonly nausea and/or vomiting (recommend taking with food to minimize GI effects)
Patients considered high risk for influenza complications
children < 2 years old or adults > 65 years old, persons with comorbidities or who are immunocompromised, pregnant women, persons morbidly obese, nursing home residents or residents of chronic care facilities
Acyclovir MOA
activated by viral thymidine kinase (TK) into acycloGTP (a guanosine analog) which inhibits viral DNA polymerase and terminates viral transcription
Acyclovir spectrum of activity
active against Herpes simplex viruses (HSV) 1 and 2 and Varicella-zoster (VZV) which causes chickenpox and zoster, no activity against CMV or latent Herpes viruses
Acyclovir pharmacokinetics
administered orally or through IV and metabolized by the kidneys, has poor oral bioavailability so requires frequent dosing, requires dose adjustment in renal impairment
Acyclovir adverse effects
generally well tolerated, more side effects with IV administration - most common is GI upset, nephrotoxicity due to IV acyclovir crystallization in renal tubules causing obstruction, and neurotoxicity causing lethargy, confusion, and delirium
Valacyclovir MOA
a valine ester of acyclovir and prodrug that is hydrolyzed by first-pass metabolism in the intestine and liver with a 99% conversion rate to acyclovir, requires less frequent dosing in comparison to acyclovir (but 5x more expensive)
Valacyclovir spectrum of activity
active against Herpes simplex viruses (HSV) 1 and 2 and Varicella-zoster (VZV) which causes chickenpox and zoster, no activity against CMV or latent Herpes viruses
Valacyclovir adverse effects
same adverse effects as acyclovir but headache more common with valacyclovir
Famciclovir MOA
metabolized to penciclovir via phosphorylation by viral thymidine kinase (TK) in infected cells which activates it where it then selectively inhibits viral DNA polymerase by termination of transcription
Famciclovir adverse effects
same as acyclovir
Famciclovir spectrum of activity
same as acyclovir
Acyclovir resistance mechanism
mutation or loss of viral thymidine kinase (TK) which is the first step in the phosphorylation of acyclovir with 6-8% incidence in immunocompromised hosts
Foscarnet MOA
inorganic pyrophosphate analog that directly inhibits DNA polymerase by reversibly blocking the pyrophosphate binding site of viral DNA polymerase (does not require activation by viral TK)
Foscarnet spectrum of activity
active against CMV retinitis and mucocutaneous acyclovir-resistant HSV in immunocompromised patients and VZV infections
Foscarnet pharmacokinetics
available only in IV form and requires dose adjustment for renal impairment
Foscarnet adverse effects
GI upset, electrolyte abnormalities including hypokalemia, hypocalcemia, hypomagnesemia, and hypophosphatemia, also reversible nephrotoxicity worsened by concomitant use of nephrotoxic agents (Amphotericin B, cyclosporine, tacrolimus, and aminoglycosides)
Interferons MOA
host cytokines (proteins) with complex antiviral, immunomodulatory, and anti-proliferative activities thought to induce gene transcription of host cell enzymes that inhibit viral RNA, increase phagocytic activity of macrophages, and increase cytotoxicity of lymphocytes for target cells
Interferons clinical indications
used to treat HBV and HCV as part of a combination but rarely used as first-line choice
Interferons adverse effects
flu-like symptoms shortly after admin, mood disorders, depression, somnolence, confusion, profound fatigue, weight loss, seizures, myelosuppression, rash, cough, myalgia, alopecia, tinnitus, reversible hearing loss, retinopathy, pneumonitis, cardiotoxicity, and autoimmune reaction
Interferons pharmacokinetics
administered IV or subcutaneously, no oral formulation, require dose adjustment with renal disease (if CrCl < 10)
Goals of HBV antiviral treatment
suppression of HBV DNA levels, seroconversion of HBeAg-positive to HBeAg-negative, loss of HBsAg detection, and decrease the risk of liver damage due to necrosis, failure, and hepatocellular carcinoma
Lamivudine MOA
cytosine analog that works to inhibit viral DNA synthesis by inhibiting HBV DNA polymerase, also works against HIV reverse transcriptase
Lamivudine clinical indications
used to treat chronic Hep B infections and may be used in combination with other Hep B antivirals in the treatment of HIV-HBV co-infections, requires HIV testing prior to treatment initiation
Lamivudine pharmacokinetics
has good oral bioavailability and requires dose adjustment in renal impairment (if CrCl < 50)
Lamivudine adverse effects
generally well tolerated, can cause headache, dizziness, pancreatitis, and rarely lactic acidosis and severe hepatomegaly
Entecavir MOA
phosphorylated to guanosine triphosphate (GTP) and competitively inhibits HBV DNA polymerase
Entecavir clinical indications
used to treat chronic Hep B infections and weakly active against HIV (not recommended for use in HIV-HBV co-infections without a fully suppressive anti-HIV regimen as it may cause resistance to lamivudine), also not preferred for lamivudine-resistant HBV strains
Entecavir pharmacokinetics
requires dose adjustment in renal impairment (CrCl < 50)
Entecavir adverse effects
may cause increased ALT levels, mild GI upset, mild hyperglycemia, headache, and rarely lactic acidosis and hepatomegaly
Tenofovir MOA
inhibits replication of HBV by inhibiting HBV DNA polymerase, also works against HIV reverse transcriptase
Tenofovir clinical indications
used to treat chronic Hep B infections and may be used in patients who have had prior treatment or developed drug resistance, preferred if there is lamivudine resistance, HIV testing required prior to treatment initiation
Tenofovir pharmacokinetics
2 formulations are available: tenofovir disoproxil fumarate and tenofovir alafenamide (associated with less renal and bone toxicity), dose adjustment is required in renal impairment (CrCl < 50)
Tenofovir adverse effects
GI upset, rash, hypercholesterolemia, decreased bone mineral density, and rarely lactic acidosis and hepatomegaly
Black Box Warning for anti-hep B therapy discontinuation
severe acute exacerbations of hepatitis have been reported in hepatitis B virus-infected patients who have discontinued anti-hep B therapy (must monitor liver function closely for several months in patients who discontinue therapy to avoid this)
Goal of chronic HCV treatment
eradicate the virus where the response to therapy is measured by looking at the sustained virologic response (SVR) which is determined by measuring HCV RNA (quantitative assay) and eradication = undetectable RNA levels after 12 weeks of therapy
Ribavirin MOA
inhibits guanine nucleotide synthesis thereby inhibiting viral transcription and RNA replication
Ribavirin clinical indications
used for the treatment of Hep C (oral administration in combo with interferon) and also may be used for the treatment of severe pediatric RSV infections (aerosol)
Ribavirin adverse effects
hemolytic anemia
Ledipasvir MOA
direct-acting antiviral that inhibits NS5A protein which plays a role in both Hep C viral replication and viral assembly
Ledipasvir pharmacokinetics
administered orally in combination with other direct-acting antivirals and also available in combination treatment with sofosbuvir, increased gastric pH levels may decrease absorption
Ledipasvir adverse effects
generally well tolerated, expensive
Sofosbuvir MOA
direct-acting antiviral that inhibits NS5B protein which plays a role in both Hep C viral replication and viral assembly
Sofosbuvir pharmacokinetics
administered orally in combination with ledipasvir and/or protease inhibitors, expensive
Sofosbuvir adverse effects
generally well tolerated but may cause fatigue, headache, and insomnia, if used with amiodarone can cause symptomatic bradycardia and a fatal cardiac arrest
Sofosbuvir contraindications/drug interactions
use with rifampin, rifapentine, carbamazepine, phenytoin, phenobarbital, oxcarbazepine, and tipranavir/ritonavir (used for HIV)
Ledipasvir-Sofosbuvir clinical indications
administered orally as a single combination tablet with or without ribavirin for treatment of hepatitis C depending on the patient
Ledipasvir-Sofosbuvir adverse effects
generally well tolerated but can cause fatigue, headache, and insomnia
Ledipasvir-Sofosbuvir contraindications
avoid in patients with severe renal impairment (CrCl < 30) and coadministration with amiodarone due to symptomatic bradycardia and fatal cardiac arrest
Ledipasvir-Sofosbuvir drug interactions
potential drug interactions due to the presence of Sofosbuvir
