PTx IV Test 3: Invasive Fungal Infections – Flashcards
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What are the MOA's of anti fungal therapies?
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-Inhibitors of the fungal cell membrane such as polyenes (amp B) and azole antifungals -Inhibitors of DNA (5-flucytosine) -Inhibitors of cell wall synthesis (echinocandins)
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How are anti fungal therapies used?
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-Generally uses one or more agents -Depending on severity of infection and patients immune status -Rarely used in combination
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When are IV antifungals switched to PO?
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-IV agent switched to PO once clinical status is improved and therapy is tolerated
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What is the TOC for many fungal infections?
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-Amp B
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What is the anti fungal that is TOC during pregnancy? Why?
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-Amp B -Most azole antifungals are teratogenic
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What are ABLC and ABCD?
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-ACLC=Abelect -ABCD=Amphotec -Both lipid formulations of amp B
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What is Ambisome?
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Liposomal amp B, incorporate into phospholipid bilayer membrane rather than enclosed in aqueous phase
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What is the benefit of ABLC, ABCD, and Ambisome?
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-Larger doses required, but toxicity appears to be much lower
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What is a major ADE with amp B? How can it be improved? What are other ADEs?
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-Nephrotoxicity -Avoid use with other nephrotoxic meds, decrease renal probs with interrupting therapy, decreasing dose, or increasing dosing interval -Electrolyte wasting: hypokalemia, hypomagnesemia
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How is amp B administered?
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IV
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What is 5-flucytosine?
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-Fluoronated pyrimidine analog that penetrates fungal cells and is converter to 5-fluorouracil which interferes with fungal RNA and protein synthesis
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How is 5-fluytosine given?
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-NOT monotherappy b/c resistance rapidly develops
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What are the ADEs of 5-flucytosine?
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-Assocaited with bone marrow suppression leading to blood dycrasias (neutropenia, thrombocytopenia, and anemia)
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What is the renal dose adjustment for 5-flucytosine?
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-Decrease dose 50% in patients with a CrCl 25-50 ml/min -Decrease dose 75% in patients with a clearance 13-25 ml/min
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What drugs are echinocandins?
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-Caspofungin, micafungin, andulafungin
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What is the MOA of echinochandins?
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-Inhibit the fungal enzymes (1,3)beta-D-glucan synthase, an essential component of the cell wall of susceptible filamentous fungi that is absent in mammalian cells.
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How are echinocandins metabolized and eliminated?
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-All display linear kinetics and are degraded in the liver by hydrolysis and N-acetylation. -Degradation products excreted slowly over many days, primarily through the bile.
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What are the renal adjustments for echinocandins?
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-NOT dialyzable (cannot remove by dialysis) -No renal adjustments
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What is the penetration of echinocandins into the CSF?
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minimal, so do not use for fungal infections in the brain
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What are the ADRs of echinocandins?
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-Histamine release causing rash, facial swelling, and itching
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What is the spectrum of itraconazole?
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Broad spectrum of anti fungal activity
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Which azole is itraconazole similar to?
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-Ketoconazole, but greater potency and less CYP mediated SEs
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What is itraconazole dependent on for metabolism?
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low gastric pH for dissolution
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How is itraconazole administered?
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-Give with food to enhance BA of capsules, but decreases BA of solution -Impaired absorption in antacids or H2RA
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How are the pharmacologic features of fluconazole different than other azoles?
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-Rapid, complete absorption following oral admin
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How is fluconazole excreted?
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-Primarily unchanged in urine
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What is the toleration and CNS penetration of fluconazole?
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-Well tolerated -Penetrates CSF
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What is fluconazole inactive against? What is it's susceptibility dose-dependent to?
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-Inactive against molds and C. krusei -Susceptible-dose-dependent against C. glabrata
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What is the dosing for IV and PO fluconazole?
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-Oral an IV doses are the same -PO: 150 mg (yeast infection) or 100mg or 200mg -IVL 200mg, 400mg, 800mg (no 150mg) -Higher dose = more susceptible
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What is the metabolism of voriconazole?
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-Hepatic biotransformation fairly complex including CYP2C19, CYP3A4, and CYP2C9
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Which azole has lots of DI?
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Voriconazole (watch tacrolimus)
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What os the most common ADR with voriconazole?
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visual disturbance (reversible)
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What formulations of voriconazole are available?
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PO and IV
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How does voriconazole affect renal failure?
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-IV formulation in cyclodextrine accumulates and exacerbated renal failure
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Wat is the dosing of voriconazole?
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-6 mg/kg IV q12h on day 1, then 4 mg/kg q12h -PO 200 mg q12h
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When does voriconazole need to be used with caution?
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Hepatic impairment (CYPs)
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What type of transplants is voriconazole used in?
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-Stem cell transplants
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What is posaconazole approved for?
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-Prophylaxis of Candida and Aspergillus in high risk neutropenic patients
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What effects the absorption of posaconazole?
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-Oral suspension has variable absorption -Enhanced with meals or nutritional supplements -Avoid acid suppressing agents
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What is the dose of posaconazole?
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-Dosed 2-3 times daily
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What are ADEs of posaconazole?
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-Prolongation of QTc interval
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What are the DIs with posaconazole?
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-Inhibitor of 3A4 -Substrate and inhibitor of Pgp
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Which azole is good for patients that cannot tolerate other meds?
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Posaconazole
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What are the types of fungal infections?
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-Superficial: skin, nails, vulvovaginal candidiasis, oropharyngeal candidiasis (HIV/AIDs), esophageal candidiasis (HIV/AIDs), oral thrush (neonates, denture wearers, inhaled CSs, immunocompromised) -Invasive: much less common
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What is the outcome of many invasive fungal infections?
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-Disproportionately high rates of mortality -1.5 million people die each year from the 10 most common fungal infections -More than TB and malaria -Likely an underestimate dure to infections going undiagnosed or not reported
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Who do invasive fungal infections most frequently occur in?
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-Immunocompromised hosts: -Organ and bone marrow transplant -Cytotoxic chemo -Indwelling IV catheters -Broad spectrum antibiotics
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What is the most common cause of invasive fungal infections?
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-Candida species
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Where does candida live?
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-Normal inhabitant of mucocutaneous surfaces of human body -Often colonize in female genital tract, GI tract, and skin -Oral candidiasis in newborn - passage through birth canal
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What does candida cause?
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-Infections by overwhelming host defenses and invading sterile areas
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What are the RFs for candida?
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-Neutropenia -DM -Immunodeficiency diseases -High-dose CSs -Immunosuppressants -Antineoplastic agents -Total parenteral nutrition -Antimicrobials -Surgery -Burns
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What is Cryptococcus neoformans? Where is it found? What does it most often cause?
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-Encapsulated yeast, less common than candida -Found in soil or bid excrement -Meningitis in immunocompromised patients
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Who do molds affect? What species is common? Where does it grow? What is infection by mold associated with?
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-Only affects patients with severely suppressed immune system -Aspergillus species = ubiquitous mold (aspergillum fumigates, Aspergillus flavus, aspergillus niger) -Grows in a variety of locations: soil, water, decaying vegetation, moldy hay or straw and organic debris -Associated with big mortality
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When are infections suspect?
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-Signs of infection despite broad-spectrum antibiotic therapy -Especially in immunocompromised patients: Candida or Cryptococcus may be isolated in body fluid (blood or CSF)
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What are the antibody/antigen testing examples for Aspergillus?
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-Histoplasma capsulatum antigen assay -Galactomannan antigen assay -Also CT scan - looking for halo and present signs
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What are yeasts?
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-Small unicellular, thin-walled, ovoid cells that reproduce by budding
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What are the 8 clinically important Candida species?
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C. albicans (50% of species) C. tropaicalis C. parapsilosis (2nd most common infection in neonatal ICU patients) C. krusei C. stellatoides C. guillermondii C. histaniae C. glatrata (more common in adults older than 65)
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What can Candida cause?
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-May cause mucocutaneous or systemic infections -Endocarditis, peritonitis, arthritis, and infections of CNS
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What is the 4th most common cause of blood stream infections?
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Candida
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Which candida species are more resistant to commonly used triazole meds?
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-C. glabrata -C. krusei
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What is the candida breakthrough fungemia in cancer patients?
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C. lusitaniae
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Where is Candida acquired?
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-Generally via GI tract -May enter bloodstream though indwelling catheter
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When should anti fungal prophylaxis be used?
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-Persistenly febrile who do not respond to abx -Patients undergoing hematopoietic stemcell transplantation
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What are the RFs for invasive candidiasis?
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-Colonization (everyone) -Abx use: broad spectrum, 2 or more, abx for at least 10 days -Surgery -Foreign devices -Renal failure and dialysis -Underlying disease/baseline characteristics -ICU -Immunocompromised
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What is the treatment of hematogenous candidiasis guided by?
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-Knowledge of infecting species -Status of patient -Antifungal susceptibility of isolate
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How long is treatment continued for hematogenous candidiasis?
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-2 weeks after last positive blood culture and resolution of s/s of infection
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What is the prophylactic treatment for candidemia in non-neutropenic patients?
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Not recommended except for severely ill/high risk patients
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What is the prophylactic treatment for candidemia in neutropenic patients?
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-Fluconazole IV/PO 400mg qd -Itraconazole solutions 2.5 mg/kg q12 PO -Micafungin 50 mg (1 mg/kg in patients under 50kg) IV daily
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What is the prophylactic treatment for candidemia in solid organ transplant patients?
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-Amp B IV 10-20 mg daily -Liposomal amp B (AmBisome) 1 mg/kg/day -Fluconazole 400 mg orally qd
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What is the empiric anti fungal therapy for candidemia in non-neutropenic patients?
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-No therapy recommended
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When is the initial anti fungal therapy for candidemia given? What is it?
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-Febrile neutropenic patients with prolonged fever despite 4-6 days of empirical antibiotic therapy -Echinocandin or fluconazole (800mg [12 mg/kg] loading dose, then 400 mg [6 mg/kg] daily), add voriconazole if mold coverage desired and continue therapy until resolution of neutropenia
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What is the therapy for documented candidemia in a non-immunocompromised host?
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-Treatment duration 2 weeks after last positive blood culture and resolution of s/s -Remove existing central venous catheter when possible -Fluconazole (LD 800 mg [12mg/kg], then 400 mg [6 mg/kg]) -Echinocandins
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What is the treatment for documented candidemia in a patient with recent azole exposure, moderately severe or severe illness, or who are at high risk of infection due to C. flatboat or C. krusei?
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-Echinocandin -Transitions to fluconazole recommended for patients who are clinically stable or are likely to have isolates susceptible to fluconazole
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What is the treatment for document candidemia in a patient who is less critically illl or no recent abx exposure?
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-Fluconazole
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What is the anti fungal therapy for candidemia caused by C. albicans, C. tropical, or C. parapsilosis?
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1. Fluconazole IV/PO 6 mg/kg/day 2. Echinocandins: capsofungin 70 mg IV LD, then 50 mg IV qd; micafungin 100mg IV qd; anidulafungin 200mg L.D., then 100 mg IV qd 3. Amp B IV 0.7 mg/kg/day + fluconazole IV/PO 800 mg/day
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What is the anti fungal therapy for candidemia caused by C. krusei?
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1. Amp B IV </= 1 mg/kg/day 2. Echinocandins: capsofungin 70 mg IV LD, then 50 mg IV qd; micafungin 100mg IV qd; anidulafungin 200mg L.D., then 100 mg IV qd
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What is the anti fungal therapy for candidemia caused by C. lusitaniae?
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-Fluconazole IV/PO 6 mg/kg/day
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What is the anti fungal therapy for candidemia caused by C. glabrata?
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-Echinocandin -Transition to fluconazole or voriconazole not recommended w/o confirmation of susceptibility
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What causes candiduria? How is it treated?
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-Candida cystitis: follow catheterization or therapy with broad spectrum antimicrobial agents -Hematogenously disseminated renal abscesses -Initial therapy = remove urinary catheter -Therapy in symptomatic pts, neutropenic pats, pts with renal allografts, and those who will undergo urologic manipulation: fluconazole 200 mg/day
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How is aspergillus defined?
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-Broadly defined attributed to allergy, colonization, or tissue invasion
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How is aspergillum commonly acquired? How can this be prevented?
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-Inhalation of airborne conidia -Use of high-efficiency particulate air (HEPA) filters in Ors and laminar flow rooms nd removal of immunocompromised patients from hospital renovation sites help prevent infections
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Where are aspergilloma infections in non-immunocompromised patients? What is the therapy?
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-Infection in sinuses as saptophytic colonization ("fungus balls") -Therapy = CSs and surgery
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Where does aspergilloma arise to cause pulmonary aspergillomas? What is the cause? How do they appear?
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-Arise in cavities b/c of TB, histoplasmosis, lung tumors, or radiation fibrosis -Solid round masses
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What is the most common site of invasive aspergillosis?
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-Lungs
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What are the s/s of invasive aspergillosis in an immunocompromised host?
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-Thrombosis -Infarction -Necrosis of tissue and disseminate to other tissues and organs in the body -Survival beyond 2-3 uncommon
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How do patients with invasive aspergillosis present?
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-With classes s/s of acute pulmonary embolus -Pleuritic chest pain -Fever -Hemoptysis -Friction rubs
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What is the diagnostic test used for invasive aspergillosis?
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-Galactomannan levels
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What is the treatment for invasive aspergillosis? What are the mortality rates interrelation to therapy?
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-Amp B (decrease mortality from 90% to 45%) -Mortality in bone marrow transplant patients exceeds 94% regardless of therapy -Voriconazole has emerged as DOC unless untreated -Caspofungin has been FDA approved for salvage therapy
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What is histoplasmosis caused by? Where is it localized in US?
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-Inhalation of dust-borne macromedia of dimorphic H. capsulatum -Ohio and Mississippi River valleys found in nitrogen-enriched soils, particularly those contaminated by avian or bat droppings
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What is the most common manifestation of histoplasmosis in non-immunocompromised patient? What is the treatment?
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- Acute pulmonary histoplasmosis -Asymptomatic or mild-mod disease: 1. Symptoms 4 weeks = intraconazole 200 mg qd x 6-12 wks -Self-limited disease (mod): 1. Amp B 0.3-0.4 mg/kg/day x 2-4 wks 2. Ketoconaole 400 mg PO qd x 3-6 months in patients with severe hypoxia
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What is there treatment for mediastinal granulomas caused by histoplasmosis in non-immunocompromised patients?
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-Most lesions resolve spontaneously -Surgery or anti fungal therapy with amp B or itraconazole
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What is there treatment for modernly severe-severe diffuse pulmonary disease caused by histoplasmosis in non-immunocompromised patients?
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-Lipid amp B followed by itraconazole -Amp B deoxycholate may be used in patients at low risk for nephrotoxicity (no underlying disease or nephrotoxic meds [diuretics and AG]) -Methylprednisolone recommended for patients who develop respiratory complications
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What is there treatment for histoplasma endocarditis caused by histoplasmosis in non-immunocompromised patients?
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-Amp B (lipid formulations may be preferred, due to lower rate of renal toxicity) plus valve replacement -If valve cannot be replaced, lifelong suppression with itraconazole
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What is there treatment for CNS histoplasmosis caused by histoplasmosis in non-immunocompromised patients?
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-Amp B as initial therapy followed by oral azole (fluconazole or voriconazole will cross BBB) for at least 1 year
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What is there treatment for progressive moderately severe to severe histoplasmosis in immunocompromised patients?
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-Liposomal amp B 3 mg/kg/day OR Amp B lipid complex 5 mg/kg/day OR Deoxycholate amp B 0.7-1 mg/kg/day - x 2 weeks followed by itraconazole -Choose based on ADRs
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What is there treatment for progressive mild to moderate histoplasmosis in immunocompromised patients?
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-Itraconazole (200 mg BID for at least 12 months)
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What is there treatment for progressive histoplasmosis in AIDS patients?
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-Amp B 15-30 mg/kg (lipid) -Itraconazole 200 mg TID x 3 days, then BID x 12 wks followed by lifelong suppressive therapy with itraconazole 200-400 mg PO qd
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What is blastomycosis? How does it present?
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-Systemic fungal infection that primarily infects the lungs -Mimics TB pyogenic bacteria, other fungi, or malignancy -Can disseminate to virtually every other organ in body -Patients present with skin, bone and joint, or genitourinary tract involvement without any evidence of pulmonary disease
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Where is blastomycosis common?
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-SE and souther central states as well as Midwestern state and Canadian provinces -MS and OH river basins
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Who requires anti fungal therapy if infected with blastomycosis?
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-Immunocompetent host, mild, self-limiting disease - may not require treatment -All individuals with moderate to severe pneumonia, disseminated infection, or those who are immunocompromised require anti fungal therapy
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What is the treatment for moderately severe to severe pulmonary blastomycosis?
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-Lipid formulation of amp B (3-5 mg/kg IV daily) or amp B (0.7-1 mg/kg IV daily)x 1-2 wks -Followed by itraconazole 200 mg PO TID x 3 days, then 200 mg BID for a total of 6-12 months
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What is the treatment for mild to moderate pulmonary blastomycosis?
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Itraconazole 200 mg PO TID x 3 days, then 200 mg BID for a total of 6 months
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What is there treatment for CNS disease caused by blastomycosis?
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-Induction: lipid formuation of amp B 5 mg/kg IV daily x 4-6 wks followed by consolidation therapy -Consolidation: fluconazole 800 mg PO daily, itraconazole 200 mg BID or TID PO daily, or voriconazole 200-400ng PO BID for > 12 months and resolution of CSF abnormalities
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What is there treatment for moderately severe to severe disseminated or extra pulmonary disease caused by blastomycosis?
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-Lipid formulation of amp B 3-5 mg/kg IV daily or amp B 0.7-1 mg/kg IV daily x 1-2 weeks -Followed by itraconazole 200 mg orally TID for 3 days, then 200 mg BID x 6-12 months
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What is there treatment for mild to moderate disseminated or extra pulmonary disease caused by blastomycosis?
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-Itraconazole 200 mg PO TID x 3 days, then 200 mg qd or BID x 12 months
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What is the treatment for blastomycosis in an immunocompromised host?
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-Acute disease: Lipid formulation of amp B 3-5 mg/kg IV daily or amp B 0.7-1 mg/kg IV daily x 1-2 weeks -Followed by suppressive therapy: itraconazole 200 mg PO TID x 3 days, then 200 mg BID for at least 12 months -Lifelong suppressive therapy with oral itraconazole may be required in patients whose immunosuppressioncannot be reversed
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What is coccidioidomycosis caused by?
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-Caused by infection with Coccidioides immitis -Fungus found in the SW and western US and parts of Mexico and South America -Areas where there is scant annual rainfall, hot summers, and sandy, alkaline soil -C. immitis grows in soil as mold and become airborne when the soil is disturbed
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What are the RFs for coccidioidomycosis?
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-Race: Filipinos > AA > Native Americans > Hispanics > Asians -Pregnancy esp when infection is acquired or reactivated in the second or third trimester -Compromised cellular immune system: AIDS patients, patiens receiving CSs, immunosuppressive agents, or chemo -Male -Neonates -Patients with B or AB blood types
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What is coccidioidomycosis aka?
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-"Valley fever"
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What are the symptoms of coccidioidomycosis?
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-60% of infected patients have asymptomatic, self-limited infection -40% have non-specific symptoms: fever, cough, HA, sore throat, myalgia, and fatigue; leading to diffuse, mild erythroderma or maculopapular rash; may also have pleuritic chest pain and peripheral eosinophilia
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What is the treatment for chronic pulmonary disseminated coccidioidomycosis infections?
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-Azole antifungals have replaced amp B: fluconazole 400-800 mg/d IV or oral, itraconazole 200-300 mg PO BID or TID as either capsules or solution, ketoconazole 400 mg/d orally -Amp B reserved for patients in respiratory failure or initial therapy in patients with rapidly progressive disease: amp B 0.5-1.5 mg/kg/day IV
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What type of infection is cryptococcus?
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-Noncontagious -Systemic mycotic infection
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What causes cryptococcus?
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-Encapsulated soil yeast Cryptococcus -Particularly found in pigeon droppings
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How is cryptococcus infection acquired?
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-By inhalation of the organism
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Where does primary cryptococcus infection always occur? What does it lead to?
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-Primary infection always occurs in the lungs, although normally a subclinical infection -Leading to meningitis: HA, fever, N/V, mental status changes and neck stiffness
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What is the treatment for cryptococcus in non-immunocompromised that causes meningoencephalitis w/o neurological complications (neg CSF after 2 weeks of therapy)?
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-Induction: Amp B deoxycholate IV 0.7-1 mg/kg/d + flucytosine 100 mg/kg/d PO in four divided doses x 4 weeks -A lipid formulation may be substituted in the second 2 weeks (if kidney problems) -Consolidation: fluconazole 400-800 mg daily x 8 weeks -Maintenance: fluconazole 200 mg orally daily x 6-12 months
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What is the treatment for cryptococcus in non-immunocompromised that causes meningoencephalitis w/ neurological complications (pos CSF after 2 weeks of therapy)?
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-Induction: amp B IV 0.7-1 mg/kg/day + flucytosine 100 mg/kg/day PO in 4 diveded doses x 6 weeks -A lipid formulation may be substituted in the second 4 weeks -Consolidation: fluconazole 40-800 mg PO daily x 8 weeks
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What is the treatment for mild-mod pulmonary disease caused by cryptococcus in non-immunocompromised?
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-Fluconazole 400 mg orally dialy x 6-12 months
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What is the treatment for severe pulmonary disease caused by cryptococcus in non-immunocompromised and immunocompromised?
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-Same as CNS disease x 12 months: -Induction: amp B IV 0.7-1 mg/kg/day + flucytosine 100 mg/kg/day PO in 4 diveded doses x 6 weeks -A lipid formulation may be substituted in the second 4 weeks -Consolidation: fluconazole 40-800 mg PO daily x 8 weeks
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What is the treatment for cryptococcemia caused by cryptococcus in non-immunocompromised and immunocompromised?
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-Same as CNS disease x 12 months: -Induction: amp B IV 0.7-1 mg/kg/day + flucytosine 100 mg/kg/day PO in 4 diveded doses x 6 weeks -A lipid formulation may be substituted in the second 4 weeks -Consolidation: fluconazole 40-800 mg PO daily x 8 weeks
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What is the primary therapy for HIV-infected patients with cryptococcus?
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-Induction: amp B IV 0.7-1 mg/kg/d + flucytosine 100 mg/kg/d PO in four divided doses for >/= 2 weeks (liposomal or lipid complex may be substituted in patients at risk for renal dysfunction) -Consolidation: fluconazole 400 mg (6 mg/kg) PO daily x 8 weeks
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What is the suppressive/maintenance therapy for HIV-infected patients with cryptococcus?
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-Preferred: fluconazole 200 mg PO qd x >/= 1 year -Itraconazole 200 mg PO BID x >/= 1 year -Amp B IV 1 mg/kg weekly x >/= 1 year
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What is the treatment of cryptococcus in transplant patients with mid-mod non-CNS disease or mild-mod symptoms w/o diffuse pulmonary infiltrates?
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-Fluconazole 400 mg (6 mg/kg) PO QD x 6-12 months
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What is the treatment of cryptococcus in transplant patients with CNS disease, moderately severe or severe CNS disease or disseminated disease w/o CNS disease, or severe pulmonary disease w/o evidence of extra pulmonary or disseminated disease?
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-Induction: Liposomal amp B 3-4 mg/kg IV daily or amp B lipid complex 5 mg/kg IV daily + flucytosine 100 mg/kg/day PO in four divided doses x 2 weeks -Consolidation: fluconazole 400-800 mg (6-12 mg/kg) per day orally for 8 weeks -Maintenance: fluconazole 200-400 mg per day PO for 6-12 months
