Clinical pharmacology and therapeutics of antifungal agents Flashcards by Meghan Collins

Most common fungal pathogen

Candida (yeast)

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Candida facts

-Part of the normal flora in the human GI tract
-Increased mortality if empiric antifungal tx is delayed by 12H

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RF for invasive candidiasis

-Prolonged ICU stay
-Central venous catheter
-Prolonged tx with broad spectrum antibacterial agents
-Receipt of parenteral nutrition
-Recent surgery (esp abdominal)
-Hemodialysis
-DM
-TPN (big risk bc it has fat in it!)

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Aspergillus

-Mold that is ubiquitous in the environment
-Primarily causes disease in immunocompromised hosts (neutropenia)
-Pulmonary system is the most common infection (it can occur anywhere though)
-Definitive diagnosis requires positive culture from a sterile site
-VERY difficult to tx

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Endemic fungi

-May cause disseminated disease via a primary pulmonary infection
-May cause disease in normal host–>higher risk pts with suppressed cell-mediated immunity (HIV/AIDS, high-dose CCS, TNF-alpha inhibitor, transplant)

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Common endemic fungi

-Histoplasma capsulatum: midwestern states along Ohio and Mississippi river valleys

-Blastomyces spp: Southeastern and Midwestern states along Ohio and Mississippi river valleys & Great Lakes region

-Coccidioides spp: southwestern US

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Cryptococcus

-2 common spp based on location: Cryptococcus neoformans (in US) & cryptococcus gattii
-Encapsulated yeast that primarily impacts the CNS and respiratory tract
-More common in pts who are infected with HIV, who have received organ transplants, or high dose CCS
-Cryptococcal meningitis may occur

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Amphotericin B
-MOA

Broadest spectrum
-Binds ergosterol and gets inserted into fungal cytoplasmic membrane –> disruption of membrane –> leakage of cell components –> cell death

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Amphotericin B is commonly used as initial agent in _________ fungal infections such as Histoplasmosis/Blastomyces and cryptococcal meningitis

Systemic invasive

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Amphotericin B is first line agent for _____

Cryptococcus
Blastomyces
Histoplasma
Mucor

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Usual dose of deoxycholate

0.5-1 mg/kg/day
*Usually Q4-6H, but less ADR with continuous infusion

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Usual dose for Liposomal

3-5 mg/kg/day over 2 hours

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Usual does for lipid complex

5 mg/kg/day over 2.5 mg/kg/hr
***Based on IBW or adjusted BW

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ADR with amphotericin B

NEPHROTOXICITY: dose dependent
*Causes increase in SCr and BUN
*May be permanent (do not give > 2 weeks)
*Infuse over 4-6H at a minimum
*Can adjust dose if this occurs; it is not adjusted for renal dysfunction

Electrolyte abnormality: Hypokalemia and hypomagnesemia

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Flucytosine
-______ bioavailability
-______ into the CSF
-Can do ___ to adjust dose to prevent toxicity
-_______% excreted unchanged in the urine

Great bioavailability (>90%)

Penetrates (~75% in serum)
*Main use is combo tx with AmphoB for Cryptococcal meningitis

TDM

85-95%
*Removed by HD and PD
*3-5H half-life
*Renally dose adjusted

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Flucytosine is the drug of choice for ______

Cryptococcus

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ADR of flucytosine

HEMATOLOGIC: bone marrow suppression (bc converted to 5-FU)

GI: have pt take WF

Monitor: CBC, platelets, SCr, and BUN bc may be nephrotoxic

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Fluconazole (Diflucan)
-Bioavailability: > ______ %
-______ CSF concentration
-Excreted ______ in the urine
-Dosing based on _____

Bioavailability > 90% (independent of gastric pH so no food restrictions)

Decent CSF concentration

Excreted unchanged in the urine (dose reduce in renal insufficiency; removed by HD)

Dosing based on TOTAL body weight

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Fluconazole is first line for ______
-If C. albicans, give _____
-If C. glabrata, give ____

Invasive candidiasis (Candidemia)

-If C. albicans, give 800 mg LD, then 400 mg QD

-If C. glabrata, give 800 mg QD (loading dose 1200-1600 mg) dependent on susceptibility

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Fluconazole ADR

HA
Nausea
Anorexia
QTc PROLONGATION!!!!!! (higher dose = higher risk)
Elevation in hepatic transaminases
Adrenal insufficiency

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Itraconazole facts
-Predominantly metabolized by ______
-Active metabolite: ______
-Clearance ____ with higher doses due to saturable hepatic metabolism
-Good absorption after PO administration–dependent on _____
**Capsules are better absorbed ____
**Oral solution better absorbed ____

CYP450 3A4 isoenzyme (inhibitor) = lots of DDI

Hydroxyitraconazole

decreases

gastric pH
**WF (OJ or Coke)
**Fasting state (not impacted by gastric pH)

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Itraconazole dosing in Histoplasmosis & blastomycosis

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200 mg PO TID x 3 days, then 200 mg PO BID

Itraconazole is first line agent for ____

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Histoplasmosis and blastomycosis

Itraconazole ADR

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-Hepatotoxicity
-CHF (BOXED WARNING) –> C/I IN PTS WITH CHF OR HX OF CHF
-QTc prolongation

Serum trough itraconazole concentrations > ____ of combined itraconazole and hydroxyitraconazole is associated with ADR

Posaconazole -Oral suspension: absorption is impacted by ______ -_____ release tablets are the preferred oral formulation -IV formulation contains cyclodextrin (very nephrotoxic) --> avoid if CrCl < _______

Gastric pH Delayed CrCl < 50 ml/min

Posaconazole ADR

QTc prolongation

Posaconazole is effective against ______

Mold and hepatic fungi

Voriconazole -Significantly metabolized via _____ -No dose adjustment needed for ____ admin -Avoid IV voriconazole if CrCl < _____ ml/min due to vehicle -Absorption ____ impacted by H2 antagonists, PPI, or antacids

CYP450 isoenzymes (2C19, 2C9, 3A4) oral <50 ml/min is not (bc not impacted by gastric pH)

Voriconazole clinical use -Dosing should be based on ____ or _____

Invasive aspergillosis -IBW or adjusted body weight

Voriconazole ADR

-Visual disturbances-->hallucinations **** -Elevated LFT -QTc prolongation -Phototoxic skin rxn -Diffuse, painful periostitis

Isavuconazole ADR

-N/V/D -DOES NOT CAUSE QT PROLONGATION (may actually shorten the QT interval)

Isavuconazole DDI

Overall considered to the be azole with the least DI -CYP3A4 and P-gp

Isavuconazole C/I

Patients with familial short QT syndrome b/c isavuconazole shortens the QT interval

Echinocandins MOA

Noncompetitive inhibition of 1,2-Beta-D-glucan --> inhibits glucan synthesis --> fungicidal

Echinocandins are first line for

C. glabrata C. krusei C. lusitaniae C. auris

May add ____ to voriconazole in severe Aspergillus infections

Micafungin

Caspofungin ADR

Histamine-mediated symptoms: rash, facial swelling, pruritis, flushing Fever, phlebitis @ infusion site; N/V; HA Increased liver transaminases, decreased potassium, eosinophilia, increase in urine protein & RBC, decreased Hgb and hematocrit

Micafungin -Give ______ -____dosage adjustment for renal dysfunction -____ metabolized by CYP450 pathways -_____ get into urine, so don't use for urine infection

IV No It is not Does not

Micafungin ADR

Hyperbilirubinemia N/D Eosinophilia Rash, pruritus, urticarial

Ibrexafungerp clinical use

Vulvovaginal candidiasis (VVC) *300 mg (2-150 mg tabs) BID x 1 day

Ibrexafungerp clinical pearl

Verify pregnancy status prior to initiating tx --> C/I in pregnancy ****Use effective contraception during and for 4 days after tx

Oropharyngeal candidiasis (OPC, thrush)

-Infection of the oral mucosa with Candida spp -Most common OI in people living with HIV (PLWH)

Esophageal candidiasis (EC)

Infection of the esophagus with candida spp *Prevalence increased secondary to HIV

Candida albicans is the most common

70-80% of cases of oropharyngeal & esophageal candidiasis

The primary line of host defenses against superficial candida infections is ______

Cell-mediated immunity (mediated by CD4 T cells)

Local RF for oropharyngeal & esophageal candidiasis

-Use of inhaled steroids & antibiotics -Dentures -Xerostomia due to drugs, chemo, HSCT, radiotx -Smoking -Disruption of oral mucosa

Systemic RF for oropharyngeal & esophageal candidiasis

DRUGS (cytotoxic agents, ccs, immunosuppressants after organ transplant, PPIs) -Neonates/elderly -HIV infection/AIDS -DM -Malignancies -Nutritional deficiency

Esophageal candidiasis clinical presentation

-Dysphagia, odynophagia, & retrosternal chest pain -Fever; few-numerous white or beige plaques -Plaques can be hyperemic or edematous -Perform upper GI endoscopy with biopsy if they aren't going away

Treatment for mild oropharyngeal candidiasis

Topical nystatin 100000 units/ml suspension (5 ml swish and swallow QID) x 7-14 days

Treatment for esophageal candidiasis

**SYSTEMIC TX IS ALWAYS REQUIRED** Fluconazole 200-400 mg PO/IV QD x 14-21 d

What is vulvovaginal candidiasis: _____ *Uncomplicated: _____ *Complicated: _____

Infection in women with or without sx who have positive vaginal cultures for candida spp Uncomplicated: sporadic infection that is susceptible to all forms of antifungal tx regardless of tx duration Complicated: recurrent VVC; severe disease; non-candida albicans infection; host factors (DM, immunosuppression, pregnancy) ***Incidence increases after 20 years of age; peak incidence between 30-40 y/o

VVC RF

-Sexually active -Oral-genital contact -Contraceptive agents (spermicide; IUD; high dose pill) -ANTIBIOTIC USE -Post-menopausal taking hormone-replacement tx

VVC tx for uncomplicated

-Cure rates 80-95% with topical or oral azoles -Many topical agents do not require a prescription -Topical preparations can decrease efficacy of latex condoms and diaphragms --> advise to use another form of contraceptive

Clinical pharmacology and therapeutics of antifungal agents Flashcards

(54 cards)