Anti-Infectives Exam IV.docx

Exam Date: August 15, 2023 Lectures 19 through 26 Quiz 4 Material- Lectures 91-21 Quiz 5 Material- Lectures 22-25 Antifungal Agents (Echinocandins, Azoles, Polyenes, 5-FC, and Terbinafine): Lecture 19 Fungal cell walls are complex and rigid, including chitin, glucan, mannoproteins, and sterols (prim...

Exam Date: August 15, 2023 Lectures 19 through 26 Quiz 4 Material- Lectures 91-21 Quiz 5 Material- Lectures 22-25 Antifungal Agents (Echinocandins, Azoles, Polyenes, 5-FC, and Terbinafine): Lecture 19 Fungal cell walls are complex and rigid, including chitin, glucan, mannoproteins, and sterols (primarily ergosterol) Fungi are eukaryotic with a discrete nuclear membrane and nucleus containing several chromosomes Fungal Categories Yeasts Unicellular Candida is the most common, also contains cryptococcus Dimorphics Can be mold or yeast “Endemics”- region specific Coccidioides Histoplasma Blastomyces Sporothrix (immunocompromised patients) Molds Multicellular Aspergillus Mucor Rhizopus Scedosporium Tinea Types of Fungal Infections Skin and Soft Tissue: Candida, tinea, other molds Tinea cruris (jock itch), Tinea pedis (foot), Tinea capitis (scalp), Tinea corporis (body), Onychomycosis (Nail beds) Mucus Membrane: Candida (oropharyngeal, vaginal, UTI, etc) Respiratory: Cryptococcus, Blastomyces, Aspergillus Intra-abdominal: Candida CNS: Cryptococcus, Histoplasma Polyene Macrolides: Amphotericin B and Nystatin MOA: bind to ergosterol in the cell wall leading to pore formation and leakage of intracellular contents (most notably, electrolytes including Ca2+, Na+, K+) Low concentrations are more fungal selective than high concentrations (high concentrations will cause mammalian cell toxicity since they also have ergosterol in their cell membranes) Amphotericin B Preparations: Deoxycholate, Liposomal, Lipid Complex, Colloidal Dispersion Nystatin Preparations: oral tablets, oral suspension, vaginal suppositories, topical creams, powder Amphotericin B Spectrum Molds Covered: Aspergillus spp. (except Aspergillus terreus) Partially Covered: Fusarium spp., Scedosporium apiospermum, Mucorales spp. Not covered: Aspergillus terreus, Phaeohyphomycosis spp., Scedosporium prolificans Yeasts Covered: Candida spp. (except lusitaniae and auris), Cryptococcus spp., Saccharomyces spp. Partially Covered: Trichosporon spp. Not Covered: Candida lusitaniae and Candida auris Dimorphics Covered: Blastomyces spp., Histoplasma spp., Coccidioides spp. Partially Covered: None Not Covered: None Amphotericin B Liposomal preparation is the primary product Dosing: IV Only! No dose adjustment for renal or hepatic insufficiency Toxicity: nephrotoxicity (dose limiting, prehydrate prior to administration), hepatic dysfunction, electrolyte wasting (Mg and K+), Hemoglobin/Hematocrit, acute pulmonary toxicity, infusion reactions Nephrotoxicity can be enhanced by tacrolimus/cyclosporine, aminoglycosides, IV contrast, foscarnet, cidofovir, tenofovir disoproxil fumarate This agent is nephrotoxic because it decreases prerenal blood flow leading to a decreased GFR AND it binds to lipid bilayers of the proximal and distal tubules to cause direct toxicity Drug interactions with medications that may deplete Mg or K+ Monitor for signs of infusion reaction- can premedicate with diphenhydramine, acetaminophen Nystatin Dosing: oral suspension, oral tablets, topical cream, ointment, topical powder- all of these are less toxic compared to Amphotericin B because they are not systemically absorbed Toxicity: limited due to minimal systemic absorption, oral formulations can be associated with nausea, vomiting, diarrhea. Potential for hypersensitivity. Spectrum of Activity: Candida spp., Tinea 5-Flucytosine (5-FC) MOA: converted intracellularly from 5-FC to 5-FU via fungal cytosine deaminase, 5-FU is a chemotherapy that prevents fungal DNA/RNA synthesis Only used in combination with other agents given rapid resistance to monotherapy Renal dose adjustments (CrCl < 10-50, extend dosing interval 12-24 hours, CrCl < 10, extend dosing interval 24-48 hours) Spectrum of activity: Candida spp., Cryptococcus neoformans Monitoring: CBC with differential (potential for leukopenia), Nausea, vomiting, serum drug levels Efficacy levels are not well defined Toxicities start to occur around 50-100 mcg/mL Triazole Antifungals: Ketoconazole, Fluconazole, Itraconazole, Voriconazole, Posaconazole, Isavuconazonium (Pro-drug; aka isavuconazole), Topicals (Clotrimazole and Miconazole) MOA: inhibition of fungal 14-alpha demethylase, which blocks ergosterol synthesis and disrupts fungal membrane synthesis Itra & Vori- inhibit the conversion of 24-methylenehydrolanosterol to obtusifoliol Fluc, Itra, and Vori- inhibition of the conversion of 4,14-dimethylzymosterol to zymosterol All triazoles are hepatically metabolized Fluc, Isavu, and Vori are renally excreted Fluc is the most active in the urine Triazole Spectrum of Activity Fluc Itra Vori Posa Isavu Candida albicans + + + + + Candida glabrata +/- +/- + + + Candida krusei - +/- +/- + + Aspergillus fumigatus - + ++ + + Cryptococcus neoformans ++ + + + + Resistant mold Rhizopus Mucor - - - ++ + Fluconazole Dosing: indication based Prophylaxis- IV or PO, once daily Disseminated Candidiasis- IV or PO, loading dose required, then once daily Oropharyngeal Candidiasis- IV or PO, loading dose required, then once daily Reduce maintenance doses by 50% for renal insufficiency Monitoring: hepatotoxicity (liver function tests), and prolonged QTc interval (EKG) Itraconazole (oral) Spectrum of activity: Candida albicans, Cryptococcus neoformans, Aspergillus spp., Histoplasmosis, Blastomycosis, Tinea unguium (nail fungus), Suba-itraconazole Dosing: indication based Capsule dosing is different than suspension dosing Histo/blasto- once daily Aspergillus- TID for 3 days, then once daily Nail fungus- once daily Counseling: take this medication with an acidic beverage when using with drugs that reduce gastric activity (H2 antagonists/PPIs) Adverse effects: hepatotoxicity, ventricular dysfunction, hypersensitivity, nausea, headache, breast tenderness, gynecomastia Contraindicated in patients with CHF (causes worsening of CHF or pulmonary edema) Second Generation Triazoles: Voriconazole, Posaconazole, Isavuconazole Voriconazole Spectrum of activity: Candida spp. (including some that are resistant to Fluc), Aspergillus spp. (drug of choice for invasive disease), resistant mold including Scedosporium and Fusarium, some activity against other molds (Mucorales, Rhizopus) Dosing: Indication-based, IV or Oral (all azoles have high bioavailability) Hepatic dose adjustments (Child-Pugh A/B, dose reduce by 50%) Monitoring/ADRs: hepatotoxicity (liver function testing), QTc prolongation (EKG), vision (altered color sensing, blurred vision), CNS (hallucinations, agitation, anxiety, delirium), optic neuritis (reversible), hypersensitivity (rash and phototoxicity), periostitis (bone pain and shin splints), trough monitoring for toxicity Posaconazole Spectrum of activity: Candida spp. (including some Fluc resistant), Aspergillus spp., and Resistant molds including Mucor, Rhizopus, Scedosporium, Fusarium Dosing: available as IV, PO extended release, and PO suspension Suspension has erratic absorption Consider alternative dosing in patients with weight extremes Monitoring: hepatic toxicity (liver function tests), prolonged QTc (EKG), hypersensitivity reaction (rash, phototoxicity), therapeutic drug monitoring via the trough Isavuconazonium/Isavuconazole Spectrum of activity: Candida spp. (including some fluconazole resistant), Aspergillus spp., Resistant molds (including Mucor, Scedosporium, Fusarium) Dosing: Isavuconazole is more potent than Isavuconazonium IV : PO = 1:1 Requires a loading dose No dose adjustments in renal or hepatic insufficiency Monitor using peak concentrations, not trough Side effects: GI, peripheral edema, fatigue, chest pain, injection site reaction, hypokalemia/hypomagnesemia, back pain, headache, psychiatric, renal failure, SOB/respiratory failure, rash, hypotension, shortening of the QTc interval* Investigational Triazoles: Ravuconazole, Albaconazole Drug Interactions- Triazoles -Azole CYP3A4 CYP2C9 CYP2C19 CYP2D6 PGP Keto +++ + + + - Isavu ++ - - - - Itra +++ - - - + Vori +++ + + - - Posa ++ - - - + Fluc + + + - - Itraconazole also interacts with H2 antagonists (famotidine, ranitidine), PPIs (omeprazole, pantoprazole), Mg/Al/Ca ant-acid (space out dosing or drink with an acidic beverage) All azoles also interact with drugs that prolong the QTc interval- except Isavuconazole Effects on broad classes: benzodiazepines, calcium channel blockers, cyclosporine, dasatinib and other TK inhibitors, Statins, Omeprazole (Vori only), Phenytoin (Vori only), Sirolimus, Sulfonylureas, Tacrolimus, Vinca alkaloids, Warfarin (Vori and Posa) Inhibitors (increase levels of azoles and cause toxicity): HIV protease inhibitors, Pharmacokinetic booster (Cobicistat) Inducers (decrease levels of azoles leading to treatment failure): Rifamycins (rifabutin is the worst), Carbamazepine, Phenobarbital, Efavirenz, Nevirapine, and Rilpivirine Imidazole antifungals- Ketoconazole MOA: alters the permeability of the fungal cell wall by inhibiting biosynthesis of phospholipids for cell membrane, blocks cytochrome P450 which causes toxic build up of hydrogen peroxide within the cell Spectrum of activity: Yeast Endemic Mold Dermatophytes Candida albicans Blastomycosis Tinea capitis Candida glabrata Histoplasmosis Tinea corporis Candida krusei Coccidiomycosis Tinea pedis Cryptococcus neoformans Paracoccidioidomycosis Tinea unguium Clinical Recommendations NOT RECOMMENDED Oral Salvage ONLY Topical ONLY Dosing: oral, topical cream, shampoo Only indicated orally as an alternative to the treatment of endemic molds Can be used topically for nail fungus or seborrheic dermatitis Adverse effects & Monitoring: hepatic toxicity (liver function tests), hypertension, orthostasis (BP), QTc prolongation (EKG), adrenal insufficiency (hyponatremia, hyperkalemia, and hypercalcemia), endocrine (gynecomastia, hypogonadism), hypersensitivity, headache, dizziness, paresthesia, fatigue, GI effects FDA put out a warning about severe liver injuries, adrenal gland problems, and harmful drug interactions Echinocandins: Caspofungin, Micafungin, Anidulafungin, and Rezafungin MOA: binds to (1,3)-B-D-glucan synthase, preventing cell wall synthesis, which ultimately leads to cell lysis Dosing: IV only, no renal excretion, some hepatic metabolism (Caspo and Mica) Micafungin does not require a loading dose Rezafungin is dosed weekly due to its incredibly long half-life Dose adjustment: Caspo down to 35 mg for hepatic impairment. No other hepatic or renal dose adjustments Adverse effects: Phlebitis, abnormal liver function tests Reza can cause tremors and hypokalemia Drug interactions Caspo: rifampin, efavirenz, phenytoin, carbamazepine, tacrolimus (decreased tacrolimus levels), cyclosporine (increased Caspo levels) Mica: sirolimus and nifedipine (can cause increased levels of these two drugs) Anidula: cyclosporine (increased Anidula levels) Rezafungin: none Echinocandins Spectrum of Activity Fungi Anidulafungin Caspofungin Micafungin Rezafungin Candida albicans + + + + Candida glabrata + + + + Candida krusei + + + + Candida parapsilosis +/- +/- +/- +/- Aspergillus fumigatus - +/- - - Cryptococcus neoformans - - - - Resistant molds: Rhizopus and Mucor - - - - Endemic fungi: Blastomycosis and Histoplasmosis - - - - Miscellaneous antifungals: Terbinafine and Griseofulvin Terbinafine MOA: inhibits fungal squalene epoxidase to decrease sterol formation Indicated for superficial fungal infections (topical), oral use for onychomycosis ADEs: cholestatic hepatitis Do not use orally for patients with chronic or active liver disease Griseofulvin MOA: inhibition of fungal mitosis, causes the production of defective DNA which cannot replicate Indicated for the treatment of ringworm infections of the hair, skin, and nails Drug interactions Possible disulfiram reaction with alcohol Decreased effectiveness of oral contraceptives Decrease in warfarin effectiveness Metabolized via the liver Newest agent- Ibrexafungerp Oral enfumafungin-derived triterpenoid agent MOA: inhibition of (1,3)-B-D-glucan synthase (at a different site than echinocandins) Spectrum of activity: In vitro activity against 271 Candida isolates, retained against many azole-resistant and echinocandin-resistant isolates (including C auris and Aspergillus), no activity against Mucor or Fusarium Dosing: approved for vuvlovaginal candidiasis, oral drug (high fat meal increases absorption) Adverse effects: GI, headache dizziness, fatigue Synergy with vori, isavu, and Ampho-B is being considered for treatment of Aspergillus Drug interactions CYP3A4 substrate Reversible inhibition of CYP2C8 and CYP3A4 Questionable clinical effects of the inhibition Investigational agent- D-Cateslytin Natural peptide derived from chromogranin A Shows in-vitro activity against Candida albicans only Activates neutrophils Currently only available as a topical Investigational agent- APX001A-Fosmanogepix Small molecule N-phosphonooxymethyl prodrug In vitro activity against Candida spp.(including auris), Cryptococcus spp., Aspergillus spp., Scedosporium spp., Fusarium, Mucor, Coccidiomycosis Targets the Gwt1 fungal enzyme, inositol acylase, blocks the glycosylphosphatidylinositol biosynthesis pathway and thus prevents cell wall mannoprotein placement Synergy observed with fluconazole Cytochrome P450 substrate Investigational agent- Olorofim Novel dihydroorotate dehydrogenase enzyme inhibitor that blocks pyrimidine synthesis Oral agent Metabolism via CYP3A4 Spectrum of activity: dimorphic molds (Histoplasma and Coccidiodes spp.), Aspergillus spp., and Scedosporium spp. Not active against yeasts (Candida spp.) or Mucorales group Investigational agent- Opelconazole (inhalation azole) MOA: inhibition of lanosterol 14a-demethylase and the conversion of lanosterol to ergosterol Spectrum of activity: broad activity against yeasts and molds (including C auris, Aspergillus spp., Cryptococcus spp., Rhizopus Bronchospasm after inhalation can occur Inhibitor of CYP3A4 Antiviral Agents: Lectures 20-22 Respiratory viruses- influenza, parainfluenza, coronavirus, Respiratory Syncytial virus, Rhinovirus (Common cold), Adenovirus Influenza Typing (A or B)/city or country of origin/strain number/year (Subtype Hemagglutinin and Neuraminidase) Influenza pandemic: global outbreak of a new influenza A virus that is very different from the current Best protection is vaccination- annually, for everyone 6 months and older Increased risk of complications: immunocompromised, medical comorbidities (asthma, cardiovascular, renal, hepatic, neurologic, hematologic, metabolic disorders, diabetes, BMI > 40), age greater than 50 years or children under 6 years taking ASA, pregnant women, american indians, alaskan indians, healthcare workers, nursing home, LTCF residents Viral life cycle attachment/internalization fusion/uncoating Transcription Replication and viral protein synthesis Budding Release/liberation Target Site definitions: Hemagglutinin- sialic acid receptor-binding molecule, mediates entry of the virus into the cell Neuraminidase enzyme- cleaves the cellular-receptor sialic acid allowing replicated virus to exit, can cleave the sialic acid on the mucin in airway epithelium facilitating airway invasion M2 Porin- allows for transmembrane release of virus across the host cell, aka fusion Influenza Antivirals: Adamantanes (Amantadine, Rimantadine), Neuraminidase Inhibitors (Oseltamivir, Zanamivir, Peramivir), Cap dependent endonuclease inhibitor (Baloxavir) Adamantanes are not used clinically Neuraminidase Inhibitors Oseltamivir- PO Zanamivir- Inhalation Peramivir- IV MOA: Block neuraminidase interfering with the release of replicated influenza virus from infected host cells These have the best efficacy if administered within 12 hours of symptoms Neuraminidase Resistance Mutations causing a histidine to tyrosine substitution (H275Y or R292K for oseltamivir and peramivir) or (S162N and Q223R for zanamivir) Oseltamivir (Tamiflu) Can be used for treatment (BID for 5 days) or for prophylaxis (QD for 10 days) Renally cleared, must dose adjust (100% renal elimination) Increase dose for severely ill or morbidly obese patients Drug interactions: probenecid (inhibition of renal elimination) Safe in pregnancy and lactation per CDC Side effects: GI, CNS (less common), rare side effects (fever hypersensitivity, liver toxicity, more serious GI and CNS effects) High bioavailability, metabolized from pro-drug to active metabolite Zanamivir (Relenza) Can be used for treatment (BID for 5 days) or prophylaxis (QD for 10 days), administer with a bronchodilator prior to use No dose adjustments due to lack of absorption (inhalation) Contraindications: chronic lung disease (asthma, COPD), inability to use an inhaler, hepatic impairment, severe renal impairment, allergy to milk proteins May be preferred over Oseltamivir due to less systemic absorption, safe for Pregnancy and lactation Adverse effects: Common are nasal irritation and caught, uncommon include bronchospasm Low bioavailability, short-half life Peramivir (Rapivab) Used for treatment, IV once daily for 5 days. NOT used for prophylaxis Renal dose adjustments (90% renal clearance) Contraindications: severe hypersensitivity to NIs No known drug interactions Adverse effects: diarrhea, nausea, vomiting, CNS (anxiety, confusion, delirium, depression, insomnia, mood alteration, nightmares, restlessness) Long half-life, no hepatic metabolism Cap endonuclease inhibitor- Baloxavir MOA: intracellular inhibition of Cap-dependent endonuclease (CEN) lends to interruption of viral RNA transcription Dosing: oral, one dose (can be used for prophylaxis or treatment) Contraindications: severe hypersensitivity Drug interactions: do not co-administer with polyvalent cations Adverse effects: diarrhea, nausea, vomiting Administer for uncomplicated flu within 48 hours of onset Extremely long half-life, metabolized from a pro-drg to an active metabolite via UGT1A3 and CYP3A4, limited renal excretion Coronavirus Binding of the spike proteins to the ACE2 receptor Fusion and endocytosis Release of viral RNA Synthesis of viral proteins (proteolysis by 3CLpro) RNA replication via RNA-dependent RNA polymerase Immune response Stage I (early infection): intense viral replication, mild symptoms, fever, dry cough, diarrhea, headache, lymphopenia, increased prothrombin time, increase D-dimer and LDH Stage II (Pulmonary phase): shortness of breath, hypoxia, abnormal chest imaging, transaminitis, low normal procalcitonin Stage III (hyperinflammation phase): ARDs, SIRS/Shock, cardiac failure, elevated inflammatory mediators Fusion/Entry inhibition: JAK 1 inhibitor (baricitinib, tofacitinib) Disruption of replication: nucleotide analogue (resdesivir, molnupiravir) and protease inhibitor (nirmatrelvir/ritonavir) Remdesivir: adenosine analog MOA: binds to RNA-dependent RNA polymerase, inhibits viral activity causing premature termination of RNA transcription and thus preventing viral replication In vitro activity against Ebola, MERS, SARS Indicated when the patient is positive on chest x-ray and has a need for O2 support Treatment for mild-moderate: once daily for 2 days Treatment for severe: once daily for 5 days No renal or hepatic dose adjustments Contraindicated: hepatic or renal dysfunction Adverse effects: rash, nephrotoxicity, hepatic toxicity Drug interactions: hepatic enzyme and p-glycoprotein inducers not recommended Inducers: rifamycins, carbamazepine, phenobarbital, efavirenz, nevirapine, rilpivirine Hepatic metabolism, renal excretion is only 5% but can cause severe renal adverse effects Dexamethasone MOA- multiple Binding to Mpro/3Chymotrypsin like pro (viral protease) Inhibition of neutrophil apoptosis/demargination Promotion of anti-inflammatory genes (IL-10) Inhibition of neutrophil apoptosis/demargination Indicated when the patient is positive for chest imaging, need for O2 supplementation Dosing: IV or PO daily for 10 days for TREATMENT (not prophylaxis) No dosing adjustments Contraindications: Current TB, HSV Drug interactions: Moderate CYP3A4 inducer Adverse effects: reactivation of HBV, HSV, TB, dysglycemia, CNS changes Tocilizumab: JAK-1 inhibitor MOA: monoclonal antibody to IL-6 receptor, treats cytokine release syndrome Indicated for patients experiencing a rapid decompensation and oxygen desaturation with elevated markers of inflammation Dosing: once IV, DO NOT re-dose, treatment only (no prophylaxis) No dosage adjustments Contraindications: liver dysfunction, low platelet count, active infection, IBS or GI perforation Drug interactions: Immunosuppressants (steroids) Adverse effects: HSV/VZV reactivation, opportunistic infection, tuberculosis thrombosis, GI perforation, hypersensitivity Baracitinib: JAK-1 inhibitor MOA: inhibit clathrin-mediated endocytosis and thereby inhibit viral entry, modulate hematopoiesis and immune cell function Dosing: PO once daily, treatment ONLY Dosage adjustment: 50% in renal dysfunction Contraindications: severe renal dysfunction Drug interactions: probenecid (decreased clearance), azathioprine and cyclosporine (increase cytopenias) Adverse effects: cytopenias, hepatotoxicity, dyslipidemia, malignancy, HSV/VZV reactivation, opportunistic infections, thrombosis, GI perforation, hypersensitivity Metabolized via CYP3A4, Pgp, BCRP, OAT3, and MATE2-K, 75% renally excreted Paxlovid (Nirmatrelvir with Ritonavir) MOA: protease inhibition with booster (Nirmatrelvir is a 3CLpro/nsp5 protease inhibitor and Ritonavir is a CYP450 enzyme inhibitor) Dosing: BID for 5 days Dosing adjustments: 50% with renal dysfunction Contraindications: severe renal dysfunction Drug interactions: Potent CYP3A4 inhibitor Classes affected- benzodiazepines, antiarrhythmics, statins, narcotics, antiepileptics, immunosuppressants, antibiotics, PDE5 antagonists, antidepressants, calcium channel blockers, oral contraceptives/hormones, direct oral anticoagulants Enzyme inducers (reduce levels of Paxlovid): rifampin, rifabutin, phenytoin, phenobarbital, carbamazepine Enzyme inhibitors (increase levels of Paxlovid): itraconazole, voriconazole, fluconazole, posaconazole, isavuconazole, clarithromycin Adverse effects: GI, myalgias, rebound phenomena Molnupiravair (Lagevrio) MOA: the active metabolite (NHC-TP) works via lethal mutagenesis by interfering with viral RNA-dependent RNA polymerase resulting in an accumulation of errors in the viral genome leading to inhibition of replication Dosing: BID for 5 days No dosing adjustments Contraindications: pregnancy, patient who are of childbearing age (including men) not on barrier contraception No significant drug interactions Adverse effects: teratogenicity, cartilage and bone growth abnormalities in pediatrics, diarrhea, nausea Monoclonal antibodies MOA: bind to the receptor-binding domain of the spike protein, blocking spike protein attachment to the human ACE2 receptor, fusion, entry, and replication Mostly intended for mold-moderate disease to prevent progression and hospitalization Multiple agents have been developed but are no longer used clinically due to viral resistance because COVID will replicate/evolve every few months Investigational agents: Shionogi Protease Inhibitor (S-217622) MOA: 3CLpro protease inhibitor Dosing: 3 tablets on day one, then one tablet PO once daily for 4 days, treatment only (Not indicated for prophylaxis) No dosage adjustments Contraindicated with strong inducers/inhibitors of CYP3A4 Adverse effects are still being studied Investigational agents: Vilobelimab Treatment of severe COVID-19 in patients within 48 hours of mechanical ventilation or extracorporeal membrane oxygenation Dosed once, with the potential for repeat dosing Adverse effects: infusion related reactions (rash, hypotension, hypertension, hypoxia, supraventricular tachycardia), hypersensitivity reactions, infection complications (due to immune modulation, bacterial pneumonia, Aspergillus infection, HSV infection), pulmonary embolism, LFT increases, thrombocytopenia, deep vein thrombosis Agents not currently recommended for the treatment of COVID-19: ribavirin, interferon beta-1b, zinc, vitamin c, vitamin d, ivermectin COVID-19 vaccines Pfizer-BioNTech: Bivalent booster, 30 mcg/0.3 mL Moderna: Bivalent booter, 100 mcg/0.5 mL Respiratory Syncytial Virus Primary infection is a typically asymptomatic Mild URTI or LRTI (bronchitis, pneumonia, otitis media) Risk factors for severe infection: preterm birth, congenital heart disease, low birth weight, congenital or acquired immunodeficiency, interstitial lung disease, neuromuscular disease, liver disease, adults over 65 with a compromised immune system 50% of the patients are infected within their first year of life (2-6 months are the highest risk), reinfection can occur Mortality is the highest in children under 2 years, higher mortality in developing countries Palivizumab MOA: monoclonal antibody targeted to interact with RSV F-protein to prevent serious LTRIs in infants and young children at high risk (premature infants born under 35 weeks or children under 2 years with bronchopulmonary dysplasia) IM injection, once a month for 5 months, start at the beginning of the RSV season No dosing adjustments Contraindication: severe hypersensitivity No known drug interactions Adverse effects: cardiac (dysrhythmia), injection site reactions, GI, thrombocytopenia, increase liver enzymes, dyspnea, urticaria, cyanosis, fever New: motavizumab can be used for prophylaxis Half-life is 22 days Ribavirin Spectrum of activity: RSV, adenovirus, Hepatitis C, Hemorrhagic viruses, Influenza, Parainfluenza Dosing: Inhalation or given Orally, twice daily MOA: synthetic nucleoside analog consisting of D-ribose attached to a 1,2,4 triazole carboxamide, alters nucleotide pools and normal messenger RNA Dose adjustments: dose adjust for renal impairment, leukopenia, thrombocytopenia, or anemia Contraindications: low platelets, low hemoglobin, low white cell counts, pregnancy, allergy Drug interactions: abacavir and zidovudine (causes lactic acidosis), azathioprine or other myelosuppressives (causes neutropenia) Adverse effects: fatal teratogenicity, hypothyroidism, pancreatitis, hematologic (thrombocytopenia, anemia, leukopenia), increased liver enzymes, hypersensitivity, ophthalmic (decreased vision, vision loss, retinopathy), Psychiatric (severe depression, homicidal ideation), respiratory (dyspnea, pneumonitis, pulmonary hypertension) Half-life is 298 hours RSV novel agents: neutralizing monoclonal antibody MK-1654, presatovir, reservoir, sisunatovir, JNJ-43718678, EDP-938 RSV Vaccine Abrysvotm (Pfizer) and Arexvy (GSK) Pfizer seems to have better efficacy Herpesviruses Major Family: Human herpesviridae, branches into subfamilies alphaviridae and betaviridae Alphaviridae Simplexvirus = HSV-1 (oral and labial) and HSV-2 (genital) Varicellavirus = VZV (Chicken-pox) Betaviridiae = Cytomegalovirus = CMV HSV-2 can have a risk of encephalitis/hepatitis (very rare) 18 month mortality of HSV encephalitis = 28% Patients who are immunocompromised have the highest risk Bimodal distribution: patient usually get the primary infection when they are under 20 years old and the virus is then reactivated when they are over 40 years of age Varicella Zoster Virus Presents as either Primary Varicella (Chicken Pox) or Herpes Zoster (reactivation) 1 in 3 people will develop this during their lifetime 96 deaths annually, usually elderly or immunocompromised patients Herpes Virus Therapy (Val)Acyclovir = acyclovir Famciclovir = penciclovir (val)acyclovir: converted to acyclovir and L-valine MOA: nucleoside analog of guanosine, taken up by viral infected cells and inhibits viral DNA synthesis The drug is a pro-drug and requires Thymidine kinase to activate the drug Bioavailability is low, mostly renally excreted, minor hepatic metabolism ADEs: phlebitis due to high pH, nephrotoxicity (rapid infusion, dehydration) To combat these effects, adequate dilute the product, use a slower infusion, in line filter, prehydrate the patient Resistance mechanisms: Thymidine kinase alterations is the primary mechanism, DNA polymerase mutations can also occur but that is rare CMV and VZV resistance is more common than HSV Resistance is higher is immunocompromised patients If the patient fails to respond to 4-5 days of therapy, consider the patient resistant and switch them to Foscarnet. If foscarnet fails, switch them again to Cidofovir Foscarnet MOA: non-nucleoside pyrophosphate analog, inhibits DNA polymerase (viral specific) and reverse transcriptase (viral specific) Not dependent on thymidine kinase because it does not have to be phosphorylated Spectrum of activity: HSV-1 and 2, HHV-6, VZV, EBV, CMV Only available IV, no hepatic metabolism, majority is renally excreted ADEs: nephrotoxicity (33%), nausea, vomiting, headache, seizures, Electrolyte deficiencies, numbness and paresthesia (brin)Cidofovir MOA: nucleotide analogue of cytosine, inhibition of viral DNA synthesis via inhibition of DNA polymerase Spectrum of activity: resistant HSV, CMV, HHV6, BKV, Adenovirus, Ebola, and anthrax Given with probenecid and IV fluids in order to prevent nephrotoxicity and dehydration Cidofovir has no bioavailability- Brincidofovir has 100% bioavailability (it is the prodrug of cidofovir) Both are excreted 100% renally ADEs: nephrotoxicity, proteinuria, neutropenia, cardiac arrest, QTc prolongation, ventricular tachycardia Cytomegalovirus (CMV) Most common viral infection in infants born in the US, 1 in 5 infants with congenital CMV will develop permanent disability Many pregnant women will be infected with CMV and pass it on to their infant Can cause pneumonia, gastroenteritis, hepatitis, retinitis, encephalitis, bone marrow suppression Viral Kinases UL97- Phosphorylates viral proteins involved in viral DNA synthesis, nuclear lamina disruption UL54- Viral DNA replication UL56- Cleavage and packaging of viral genome (Val)Ganicyclovir MOA: UL97 and UL54 targeted nucleoside analogue of guanosine, inhibition of DNA polymerase 10x more active against CMV than ACY Dosing: Ganciclovir is IV and PO (poor bioavailability) and Valganicyclovir is the prodrug of Ganicyclovir, so it is available orally (improved bioavailability) Organ transplant patients receive prophylaxis depending on the risks Patients with active disease or viral loads will require treatment for at least 2 weeks Renally cleared (95%)- dose reduce for renal insufficiency Spectrum of activity: cytomegalovirus and acyclovir resistant viruses (HSV) ADEs: neutropenia, thrombocytopenia, lactic acidosis, N/V, hypersensitivity, seizures, stroke, encephalopathy Letermovir MOA: 3,4 dihydroquinazoline, inhibition of CMV DNA terminase that is responsible for DNA cleavage Spectrum of activity: CMV only High bioavailability- can be given PO or IV Hepatic metabolism (UGT1A1, OATP1B1)- not recommended in severe renal impairment Not recommended in renal impairment because hydroxypropyl betadex will accumulate (inactive ingredient) ADEs: no statistical difference between placebo and letermovir for any side effects Drug interactions Induces 2C9 (decreased levels of voriconazole, warfarin, and phenytoin) Substrate of OATP1B1 (affected by cyclosporine- dose reduce by 50%, rifampin- do not use in conjunction) Inhibits 3A4 (increased levels of amiodarone, glyburide, rosiglitazone, and atorvastatin) Maribavir MOA: inhibition of UL97 kinase, multimodal inhibition of CMV DNA replication and nuclear egress of viral capsids High bioavailability, only available orally (two tablets twice daily) Metabolism via CYP3A4 Inducers may decrease levels and inhibitors may increase levels Majority is renally excreted ADEs: GI, hematologic (decreased hemoglobin, platelet count, and neutrophils), infection, fatigue, taste disorder, increased SCr CMV drug resistance UL97 mutation- renders ganciclovir useless Active drugs: cidofovir, foscarnet, letermovir, and maribavir UL54 Mutation- broad spectrum mutation, Foscarnet may or may not be active Active drugs: letermovir and maribavir Summary of CMV Drugs Ganicyclovir Foscarnet Cidofovir Letermovir Maribavir Use 1st line 2nd line Salvage Prophylaxis Salvage Mechanism Guanosine analogue, incorporates into viral DNA and causes chain termination Pyrophosphate analogue, inhibits UL54 Nucleotide analog, incorporates into viral DNA and causes chain termination Inhibits UL56- disrupts cleavage and packaging of viral genome Inhibition of UL97 kinase, inhibition of DNA replication and encapsulation PK Poor oral bioavailability- valganciclovir is better IV only IV only, poor CNS penetration IV = PO Moderate drug interactions PO only Moderate drug interactions ADEs Bone marrow suppression Nephrotoxicity Electrolyte imbalances Nephrotoxicity (coadministered with probenecid) Neutropenia GI upset Thrombocytopenia Peripheral edema Taste disturbance GI effects Resistance UL97 UL54 UL54 UL54 UL56 gene mutation UL97 (but different than ganciclovir) Adenovirus Primary infection is usually mild Usually occurs with solid organ transplant (typically present 2-3 months after transplant) Can occur with HSCT (allogeneic): hemorrhagic cystitis/nephropathy, disseminated infection Antiviral therapy for ADV: Intravenous Cidofovir Administer with probenecid to decrease nephrotoxicity Adenovirus does not encode thymidine kinases (acyclovir, ganciclovir, and foscarnet will not be able to be activated) Oral Ribavirin for ADV Primarily in vitro data, only effective for a small portion of adenovirus subtypes and myelosuppression limits utility in the clinic BK Virus Asymptomatic, latent infection Can be reactivated in immunocompromised patients: high rates of hemorrhagic cystitis/nephropathy Treatment- Primary goal is to reduce immunosuppression Leflunomide (weak) Fluoroquinolones (weak) Cidofovir* drug of choice despite toxicity IV Immunoglobulin Cidofovir Low dose: given to patients who underwent a renal transplant, given without probenecid because we want the drug to accumulate in the kidneys May not be a high enough dose to inhibit viral replication Cidofovir high dose: Majority is given with probenecid, given to HSCT patients Causes lots of renal toxicity, but administration with probenecid may limit the therapeutic effect in renal tubular cells Intravesicular Cidofovir ADEs: intense burning pain that limits dwell time No treatment related renal failure observed Hepatitis A An RNA virus that is transmitted fecally, orally, or sexually Risks come from Endemic travel, MSM, and Daycare Causes mild jaundice, 4-10x ULN LFTs, no cirrhosis- symptoms occur in 50% of patients Self-limiting, symptomatic treatment Prevention with the HepA vaccine Hepatitis B Infectious process Viral attachment to hepatocytes and intracellular uptake Viral DNA integration into human DNA Expression of HBsAg, HBcAg, and HLA Class I on the surface of the hepatocyte Recognition with CD8 and CD4 cytotoxic T cells Increased synthesis of cytokines Hepatocellular destruction Can be chronic, treated with chronic antivirals Prevention with the HepB vaccine Antiviral Treatment Treatment Clinical Use Long-term Oral HBV treatment Potency (higher = better) Resistance barrier (higher = better) Tenofovir Entecavir Rapid activity, most effective agents (even with ranitidine resistance) Relatively safe Clinical experience Toxicities (renal, bone complications with tenofovir) Resistance (high with lamivudine, low with entecavir, none with tenofovir) Cost Pill burden Tenofovir: Mod-high Entecavir: High Tenofovir: High Entecavir: Mod-high Lamivudine (3TC) Relative safety but with more resistance High Low IFN-alpha Unacceptable safety profile ? ? Adefovir More resistance and nephrotoxicity Low High Nucleoside Analog Therapy: Lamivudine MOA: inhibits HBV DNA polymerase ADRs: headache, fatigue, anemia, nausea, neuropathy, increased LFTs, pancreatitis, mitochondrial toxicity, lactic acidosis* Renal dosage adjustments required No drug interactions Dosing: oral, once daily Nucleoside Analog Therapy: Adefovir MOA: inhibits HBV DNA polymerase ADRs: nephrotoxicity*, hypophosphatemia, lactic acidosis, weight loss, elevated LFTs, GI, decreased carnitine levels*, asthenia Renal dose adjustment required Dosing: oral, once daily Special instructions: can co administer with L-carnitine Nucleoside Analog Therapy: EVT (Baraclude) MOA: guanosine analog, inhibition of HBV DNA Polymerase ADRs: lactic acidosis, nausea, headache, dizziness, fatigue, myopathy Dosage: renal dose adjustments required, oral once daily No significant drug interactions Nucleoside Analog Therapy: Emtricitabine FTC Chemically related to lamivudine (resistance to lamivudine = resistance to emtricitabine) MOA: inhibits HBV DNA polymerase ADRs: lactic acidosis, hyperpigmentation of the palms and soles, liver damage, pancreatitis, mitochondrial toxicity, rash, headache, dizziness, fatigue Dosing: oral, once daily Renal dose adjustment required No significant drug interactions Nucleoside Analog Therapy: Tenofovir (TDF or TAF) MOA: inhibits HBV DNA polymerase ADRs: nephrotoxicity, hypophosphatemia, lactic acidosis, elevated LFTs, GI, asthenia, osteoporosis Dosing TDF requires a higher dose (due to higher plasma concentrations of the drug) and more renal adjustment TAF requires a lower dose (due to higher hepatocyte concentrations of the drug) and less renal adjustment. TAF = prodrug of tenofovir Drug interactions: Pgp inhibitors and inducers Interferon therapy: PEG Interferon alfa 2a MOA: stimulates HLA Class I protein (immune enhancer for increased viral recognition) ADRs: GI (anorexia, nausea, diarrhea), hepatic (increases in liver enzymes), fatigue, fever, myalgia, weight loss, hair loss, hypersensitivity, CNS (concentration difficulties, anxiety, depression, suicidal ideation, seizures, hearing loss), hematologic (thrombocytopenia, myelosupression, hemolytic, anemia), endocrine (glucose intolerance, thyroid dysfunction) Dosing: SQ administration, once weekly Not recommended in any renal insufficiency Interactions: other immunosuppression (increased myelosuppression) Greatest benefit to this therapy is lack of resistance HBV Resistance to Nucleoside Reverse Transcriptase Inhibitors Amino acid mutations confer resistance Decrease in susceptibility is determined by the drug and the number of mutations Lamivudine loses activity with a single mutation called YMDD Entecavir and Tenofovir resistance is uncommon Treatment algorithm for resistance Lamivudine resistance Switch to tenofovir (TDF or TAF) Entecavir resistance Switch to tenofovir (TDF or TAF) TDF/TAF resistance Lamivudine Naive = Switch to Entecavir Lamivudine Resistant = Add Entecavir Multidrug resistance Switch to Entecavir + (TDF or TAF) combination Hepatitis C- RNA Virus Viral entry Uncoating and translation Viral replication Viral assembly and release Hep C is a chronic disease that is associated with worsened outcomes and is one of the leading causes of liver transplantation It is often asymptomatic in early infection but can progress over time to irreversible damage Goals of therapy: reduce morbidity (hepatitis, cirrhosis, hepatocellular CA, transplant) and virologic control (undetectable viral load after 12 weeks of therapy) IFN MOA: Engage receptors on surface of the hepatocyte Initiate intracellular signal transduction that prompts the transcription of multiple interferon stimulated genes ISGs encode proteins that interfere with nucleic acid and protein synthesis Interferon was replaced with Peginterferon alpha 2a/2b Advantages: once weekly versus three times weekly, lower incidence and severity of side effects Peginterferon alfa 2a Indicated for use in combination with ribavirin for all genotypes Can add ribavirin + protease inhibitor for GT1 Once weekly SQ dosing, duration is dependent on genotype Peginterferon alfa 2b Indicated for use in combination with ribavirin for all genotypes Can add ribavirin + protease inhibitor for GT1 Once weekly SQ dosing, duration dependent on genotype Contraindications to peginterferon 2a/2b: autoimmune hepatitis, hepatic decompensation (Child-pugh score > 6), neonates/infants, known hypersensitivity, neutropenia or thrombocytopenia, major depressive disorder, end stage renal disease If the neutrophils/platelets are moderately low = reduce dose If the neutrophils/platelets are severely low = discontinue treatment Depression Management Mild: no dose modification, evaluate weekly Moderate: reduce dose, evaluate once weekly in person Severe: discontinue permanently, immediate consultation, psychiatric therapy as necessary Renal dose adjustments when CrCl < 30 or hemodialysis Ribavirin MOA: purine nucleoside analog, affects immune clearance, inhibition of IMPDH, inhibition of HCV RNA-dependent RNA polymerase, RNA mutagenesis Indicated in combination with other agents for all genotypes Dosing is either a fixed dose or weigh based, oral therapy taken BID ADEs: fatal teratogenicity, hypothyroidism, pancreatitis, thrombocytopenia, anemia, leukopenia, increased liver enzymes, hypersensitivity (rash, SJS, angioedema), ophthalmic (vision loss, retinopathy), psychiatric (severe depression, homicidal ideation), respiratory (dyspnea, pneumonitis, pulmonary hypertension, sarcoidosis) Dose adjustments in renal impairment, leukopenia, thrombocytopenia, and anemia Moderate to Low hemoglobin (no cardiac history): reduce dose Severely low hemoglobin (cardiac history or no cardiac history): discontinue Decreased hemoglobin in the past 2 weeks (cardiac history): decrease dose Low hemoglobin after 4 weeks of dose reductions (cardiac history): discontinue Decreased hemoglobin in the past 2 weeks (no cardiac history): do nothing Low platelets: discontinue Low WBCs: discontinue Contraindications: low platelets, low hemoglobin, low white count, pregnancy, allergy Drug interactions abacavir and zidovudine (increased lactic acidosis), azathioprine and other immunosuppressants (increased neutropenia) Direct Acting Antivirals: Staple of Therapy for Hepatitis C Ribavirin: works on all structural domains NS3/4A Protease Inhibitors: targets NS3 Includes: Grazoprevir, Voxilaprevir, Glecaprevir NS5A Replication Complex Inhibitors: Targets NS5A Includes: Elbasvir, Ledipasvir, Velpatasvir NS5B NUC inhibitors: Targets NS5B Includes: Sofosbuvir NS34A Protease Inhibitors- “evirs” MOA: inhibition of initial cleavage of HCV polyprotein through attachment at this site First generation drugs caused serious rashes Includes: Grazoprevir, Voxilaprevir, and Glecaprevir Glecaprevir ADRs: none PO once daily No renal dose adjustment Drug interactions: Substrate of UGT and Pgp transport Grazoprevir ADRs: LFT increases, hepatic dysfunction No renal dose adjustment, avoid in liver dysfunction Drug interactions: affected by strong inducers/inhibitors of OATP1B1/1B3, CYP3A4, and Pgp Voxilaprevir ADRs: none No renal dose adjustment Drug interactions: substrate and inhibitor of PgP and OATP1B1/1B3. Also a CYP3A4 substrate. NS5A Replication Complex Inhibitors- “asvirs” MOA: inhibition of initial cleavage of HCV polyprotein through attachment at this site Includes: Ledipasvir, Elbasvir, Velpatasvir Elbasvir ADRs: none No renal dose adjustment, avoid in liver impairment Drug interactions: CYP3A4 substrate Ledipasvir ADRs: none NO USE in patients with CrCl < 30 Drug interactions: Amiodarone (with sofosbuvir- CONTRAINDICATED), antacids, H2 blockers and PPIs NS5B RNA Polymerase Inhibitors Includes: Sofosbuvir ADRs: fatigue, headache, nausea, rash, hematologic Renal dose adjustment with CrCl < 30 Drug interactions: CYP3A4 (avoid amiodarone and other strong inducers) Overview of Drug Interactions Metabolism Inhibition Transporter dependence Glecaprevir 3A4 Inhibition of PGP, BCRP, and OATP1B1/1B3 PGP, BCRP, and OATP1B1/1B3 Grazoprevir 3A4 Inhibits BCRP OATP1B1/1B3 and PGP Voxilaprevir 3A4 Inhibits BCRP PGP, BCRP, OATP1B1/1B3 Ledipasvir None Inhibits CYP3A4, UGT, PGP, BCRP PGP and BCRP Elbasvir 3A4 Inhibits BCRP, PGP PGP Velpatasvir 3A4, 2B6, 2C8 Inhibits BCRP PGP, BCRP, OATP1B1/1B3 Pibrentasvir None Inhibits PGP, BCRP, OATP1B1/1B3 PGP and BCRP Sofosbuvir Cathepsin None PGP and BCRP Acid suppression: Ledipasvir (doses of omeprazole under 20 mg are okay), velpatasvir (coadministration of PPIs not recommended, separate if absolutely necessary) Concomitant Medication Sofosbuvir Ledipasvir Grazoprevir Elbasvir Velpatasvir Glecaprevir Pibrentasvir Acid reducers X X Amiodarone X X X Anticonvulsants X X X Digoxin X X Glucocorticoids X PDE5i X Rifamycins X X X X X Statins X X X OATP1B inhibitors: rifampin, atazanavir, darunavir, cyclosporine CYP3A4 Inducers: phenytoin, carbamazepine, efavirenz Hepatitis C Resistance Considerations Most patients will fail treatments due to emergent resistance-associated substitutions NS5A mutations will persist longer than PI resistance More likely to develop resistance: NS5A, NS5B Genotypes with higher resistance: GT1b (compared to lower in GT1a) HIV: Human Immunodeficiency Virus Treated with cART (combination antiretroviral therapy) NRTIs/NtRTIs: abacavir, emtricitabine*, lamivudine*, tenofovir*, zidovudine NNRTIs: efavirenz, nevirapine, etravirine, rilpivirine*, doravirine Protease inhibitors: Atazanavir, Darunavir*, Lopinavir, Rionavir Fusion inhibitors: Enfuvirtide Integrase inhibitors: Raltegravir, Dolutegravir*, elvitegravir, bictegravir*, cabotegravir* Biologic: ibalizumab Booster: cobicistat Entry inhibitor: Maraviroc Gp120 attachment inhibitor: fostemsavir Capsid inhibitor: lencapavir NRTIs Spectrum of activity: HIV1 and HIV2 MOA: inhibit HIV RNA dependent DNA polymerase (reverse transcriptase) to inhibit viral replication ADEs Nausea, vomiting, diarrhea All Lactic acidosis all Lipodystrophy AZT, 3TC, abacavir Hypersensitivity abacavir Renal failure tenofovir Hyperpigmentation emtricitabine Anemia zidovudine Leukopenia lamivudine Mitochondrial toxicity: caused by inhibition of mitochondrial DNA polymerase, results in impaired mitochondrial enzyme synthesis and impaired ATP production Causes myopathy, neuropathy, hepatic steatosis, pancreatitis, peripheral lipoatrophy Early signs include nausea, abdominal pain, weight loss, tachycardia, hyperventilation, weakness Late signs are hepatic failure and encephalopathy Can have 50% mortality Highest risk: prolonged duration of therapy, female patients, obese patients, pregnant patients Older NRTIs (zidovudine and lamivudine) are associated with more dyslipidemia than newer (tenofovir and emtricitabine) Lipoatrophy-fat redistribution: occurs with zidovudine, older age, higher triglycerides, CD4 < 200 Abacavir: within 6 weeks (hypersensitivity, fever, rash fatigue, GI, increased LFTs, and leukopenia) Later can cause cardiovascular disease Causes increased inflammatory markers in the blood (IL-6 and hsCRP) Causes increased LDL and TG in the blood Currently there is conflicting information on whether there is an association Presence of the HLA-B*5701 correlates with susceptibility to hypersensitivity Do not rechallenge or give this medication if the patient is HLA-B*5701 positive Not renally cleared, so can be administered to patients with CKD High viral load (> 100,000) may lead to treatment failure Drug interactions: alcohol (no dose adjustment), methadone (may need to increase methadone dose) Tenofovir (TDF versus TAF) Nephrotoxicity (moreso with TDF, switching to TAF will result in recovery of kidney function) and Fanconi syndrome Will lead to osteoporosis (moreso with TDF, switching to TAF can result in regain of bone density) TAF has a higher incidence of weight gain TDF is recommended NRTI in pregnancy Drug interactions: atazanavir (may need increased atazanavir dose) All NRTIs except abacavir are eliminated renally NRTI Resistance M184V: most common mutation Lamivudine and Emtrivitabine resistance, but confers increased activity with tenofovir and ZDV K65R: bad, confers resistance to most, except zidovudine Medicinal Chemistry: Lectures 23-26