Lee: IFI

Lee: IFI Tuesday, October 29, 2024 11:43 PM Clinical classification Classification Site Infected Example Superficial Outermost skin + hair Malasseziasis (Tinea versicolor) Cutaneous Deep epidermic + nails Dermatophytosis Subcutaneous Dermis + subcutaneous tissue Sporotrichosis Systemic opportunistic Disease of ≥ 1 internal organ Systemic Non-opportunistic Disease of ≥ 1 internal organ Candidiasis Cryptococcosis Aspergillosis Mucormycosis Histoplasmosis Blastomycosis Coccidioidomycosis Treatment of Invasive Mycoses • Prevention or treatment of invasive mycoses can be classified as: ○ Prophylaxis ○ Empirical therapy ○ Secondary prophylaxis or suppression Principal Antifungals used to treat IFI • Azole (aka Triazoles) ○ MOA: reduction of ergosterol synthesis by inhibition of fungal CYP450, greater affinity for fungal ○ Side effects ▪ QTc Prolongation = fluconazole (most azoles EXCEPT isavuconazole) Drug Bioavailability CSF Penetration 70-80% AEs • • • • Pearls Dosing Adjustment Fluconazole (Diflucan) > 90% IV, PO * Food does not affect oral absorption Itraconazole (Sporanox) 55% < 10% PO * Oral solution + capsules are not bioequivalent • Abdominal discomfort • Capsules require fatty meals • ↑ hepatic transaminases • Preferred: Oral Solution (without food) • Rash • Food ↓ absorption of drug • C/I in patients with heart failure • n/a Voriconazole (Vfend) 96% IV,PO 90% • • • • Abdominal discomfort • Oral + IV doses are the same ↑ hepatic transaminases • Visual + auditory hallucinations oiccur in 2-12% of patients • Will disappear despite tx Rash IV: nephrotoxicity • Photosensitivity • Plasma Monitoring NECESSARY • Low levels associated with poor outcome • Variable metabolism • High levels associated with toxicity • Target level ○ Trough: 2-5 µg/mL • Timing ○ Trough after 7 days of therapy • Renal • IV not recommended if CrCl < 50 • Hepatic • Child-Pugh A-B: ↓ maintenance dose 50% • Child-Pugh C: not recommended Posaconzaole (Noxafil) Variable Low * Oral solution + capsules are not bioequivalent • • • • Abdominal discomfort • Oral suspension requires fatty meal or acidic beverage (e.g., ginger ale) • Renal ↑ hepatic transaminases • Preferred: tablets • IV not recommended if CrCl < 50 Rash • Treats mucormycosis • Hepatic IV: nephrotoxicity • None ○ Isavuconazole (Cresemba) 98% IV, PO Low Abdominal discomfort • Oral + IV doses are the same (100% BA) ↑ hepatic transaminases • Renal dose adjustment (decrease dose in renal failure) Rash QTc Prolongation • Abdominal discomfort • IV formulation through in-line filter • ↑ hepatic transaminases • Reduce risk of infusion-related reactions • Rash • Treats mucormycosis Ketoconazole • Renal • ↓ maintenance dose based on CrCl • Hepatic • Clinical judgement n/a • Need acidic environment for absorption • Echinocandins ○ MOA: inhibit the synthesis of beta(1-3) glucan, disruption of fungal cell wall and cell death ○ Elimination: hepatic ○ AEs ▪ ↑ hepatic transaminases ▪ Rash ▪ Infusion-related reactions – histamine release ▪ Phlebitis/Thrombophlebitis Drug Bioavailability Anidulafungin (Eraxis) ○ CSF Penetration IV minimal Urine % of Blood Level: <0.1% Pearls Dosing Adjustment • No hepatic or renal dose adjustments n/a Caspofungin (Cancidas) IV Urine % of Blood Level: 1.4% minimal • Hepatic dose adjustment based on Child-Pugh class • Renal • IV dilution: Saline ONLY • None • Hepatic • Child-Pugh A-B: ↓ maintenance dose 50% • Child-Pugh C: not studied Micafungin (Mycamine) IV Urine % of Blood Level: 0.7% minimal • No hepatic or renal dose adjustment required • Storage-light protection n/a • Polyenes ○ MOA: binds to ergosterol and alters the permeability of the cell by forming pores in the cell membrane, allows the leakage of intracellular ions and macromolecules, leading to cell death ○ Toxicities ▪ Infusion related reactions (fever, rigors, hypotension, N/V) ▪ Nephrotoxicity (+++) ▪ Phlebitis/Thrombophlebitis ▪ Hypokalemia and hypomagnesemia Drug Pearls Amphotericin B Deoxycholate • • • • • • ○ Dosing Adjustment Conventional amphotericin B IV dilution: Dextrose ONLY Nephrotoxicity (80%) Anemia ++++ ↓ K+ (++++) High rate of infusion related toxicity • Renal • ↑ interval based on CrCl • Hepatic • None Amphotericin B Lipid Formulations • Amphotericin B lipid complex – Abelcet • Amphotericin B liposome for injection – Ambisome ○ Important components of Ampho order ▪ Premedication: APAP, antihistamine, meperidine (severe rigors, caution for renal insufficiency – toxic metabolite = normeperidine) ▪ Normal saline hydration ▪ Flush line with D5W before and after infusion (IV dilution: D5W) ▪ Monitor for electrolyte loss • Mg, Na, K • Flucytosine ○ MOA: taken up by fungal cells via the enzyme cytosine permease. Converted intracellularly first to 5FU and then to 5 FdUMP and FUTP, inhibiting DNA and RNA synthesis. Human cells are unable to convert the parent drug to its active metabolites, resulting in selective toxicity ○ Indication: adjunctive tx of systemic fungal infections by susceptible strains of Candida or Cryptococcus ▪ Primarily in combo w/ Ampho B for cryptococcal meningitis ○ BBW: renal toxicity, hepatic + bone marrow toxicity ○ Only available in oral dosage forms ○ Require monitoring serum drug levels Antifungal Spectrum Amphotericin B Echinocandins Azoles • Yeasts + filamentous molds • Yeasts + filamentous molds • Yeasts + most diphormic fungi • LESS active against: • Aspergillus • Candida parapsilosis • Itraconazole • Candida guilliermondii • Voriconazole • • Cryptococcus neoformans • Posaconazole • Isavuconazole • Zygomycetes (Mucor) • Posaconazole • Isavuconazole C. albicans • • • • • • • C. tropicalis Amphotericin B IV Fluconazole IV/PO Itraconazole PO Voriconzaole IV/PO Posa/Isavuconazole IV/PO Caspo/Mica/Anidulafungin IV • • • • • • Cryptococcus neoformans • • • • • Amphotericin B IV Fluconazole IV/PO Itraconazole PO Voriconzaole IV/PO Posa/Isavuconazole IV/PO C. parapsilosis Amphotericin B IV Fluconazole IV/PO Itraconazole PO Voriconzaole IV/PO Posa/Isavuconazole IV/PO Caspo/Mica/Anidulafungin IV • • • • • • Histoplasma capsulatum • • • • • Amphotericin B IV Fluconazole IV/PO Itraconazole PO Voriconzaole IV/PO Posa/Isavuconazole IV/PO Caspo/Mica/Anidulafungin IV C. glabrata • • • • • • Amphotericin B IV Fluconazole IV/PO Itraconazole PO Voriconzaole IV/PO Posa/Isavuconazole IV/PO Caspo/Mica/Anidulafungin IV Blastomyces dermatiditis Amphotericin B IV Fluconazole IV/PO Itraconazole PO Voriconzaole IV/PO Posa/Isavuconazole IV/PO • • • • • Amphotericin B IV Fluconazole IV/PO Itraconazole PO Voriconzaole IV/PO Posa/Isavuconazole IV/PO C. krusei • • • • • Amphotericin B IV Itraconazole PO Voriconzaole IV/PO Posa/Isavuconazole IV/PO Caspo/Mica/Anidulafungin IV Aspergillus spp. • • • • • Fusarium spp. Amphotericin B IV • Amphotericin B IV Itraconazole PO • Voriconzaole IV/PO Voriconzaole IV/PO • Posa/Isavuconazole IV/PO Posa/Isavuconazole IV/PO Caspo/Mica/Anidulafungin IV Zygomyces • Amphotericin B IV • Posa/Isavuconazole IV/PO Invasive Candidiasis • Candidiasis: any infection with candida, including oral thrush • All forms of invasive candidiasis follow an episode of candidemia (“line sepsis”, gut translocation, etc.). ○ The episode of candidemia is not always detected • At times, disease of an organ is the first sign of invasive candidiasis. • Since Candida is a normal skin flora some cultures represent contamination of the specimen. • Candidemia is associated with significant morbidity and mortality. • Common species: C. albicans ○ Non-albicans species: C. glabrata ↑ ○ Candida auris: ↑ mortality Risk Factors Catheter-Related Candidemia (CRC) • Most important and common removable source of Candida spp. in the bloodstream ○ Removal of catheter → ameliorates disease (standard therapy) ▪ Drug therapy still required after removal to: • Speed clearance of any local infection • To assist with clearance of undetected foci of hematogenous spread Diagnosis • Gram stain • Cultures (Candida spp. grows easily) • Serologic test ○ β-D glucan assay • Rapid test: PNA-FISH (not widely available) Treatment • Guided by: ○ Knowledge of infecting species ○ Clinical status of patient ○ Antifungal susceptibility (if available) ○ Previous antifungal history • Local conditions should be treated (removing lines, catheters, eliminate urinary obstruction, drain any abscess) • Patients should get ophthalmic examination (10% endophthalmitis) ○ Possible intravitreal Ampho B • IDSA Recommendation ○ Echinocandins preferred initial treatment for invasive bloodstream candidiasis ▪ Efficacy less well-established for deep-tissue candidiasis ▪ Higher failure rates for infections in anatomical sites where penetration is limited • Meninges, eyes, urine ▪ Azoles or lipid amphotericin B may be preferable as initial therapy until diagnosis + culture results available ○ Alternative: Fluconazole ▪ Selected patients • Not critically ill • Unlikely to have fluconazole resistant Candida species • Antifungal Selection Issues ○ Ampho B highly effective + reliable therapy – standard to which others are compared ▪ Useful dose: 0.5-1.0 mg/kg/day ▪ Less toxic lipid forms of Ampho B effective – 3-5 mg/kg/day ▪ Associated with some degree of unavoidable toxicity. ○ Echinocandins + Fluconazole are less toxic alternative therapy effective for management of invasive candidiasis and has more experience Treatment of Candidemia in Non-Neutropenic Patients • Initial therapy: Echinocandin (strong recommendation, high-quality evidence) ○ Within 5-7 days, step down to fluconazole if clinically stable, susceptibility to fluconazole, and have negative repeat B/C following initial antifungal therapy • Alternative: Fluconazole (if not critically ill and unlikely to have resistance) • Recommended testing for azole susceptibility for all candidemia • Amphotericin B - intolerance, limited availability, or resistance to other antifungal agents • C. glabrata = Echinocandin ○ Alternative: higher dose fluconazole or voriconazole • Follow up BCx (blood culture) everyday or every other day until candidemia clears • Duration of therapy: 2 weeks after the last positive BCx or resolution of s/sx (strong, moderate) Treatment of Candidemia in Neutropenic Patients • Initial therapy: Echinocandin (strong, moderate) • Alternative: Liposomal Amphotericin B, fluconazole ○ Voriconazole 400 mg BID x 2, then 200-300 BID when mold coverage is desired ▪ Step down therapy • C. krusei: Echinocandin, liposomal AmB, or voriconazole • Duration of therapy: 2 weeks after the last positive BCx or resolution of s/sx Candidiasis Treatment Scenario Chronic Disseminated (Hepatosplenic) Treatment • Liposomal AmB • Echinocandin, followed by oral fluconazole Suspected Invasive Candidiasis in non-neutropenic patients in ICU • Preferred: Echinocandin • Alternative: fluconazole or liposomal AmB Prophylaxis to prevent invasive candidiasis in ICU • Fluconazole (in high-risk patients) • Alternative: Echinocandin Endocarditis • Liposomal AmB or high-dose echinocandin • Step down to fluconazole Osteomyelitis for 6-12 months • Fluconazole 400 mg QD • Echinocandin x 2 weeks, followed by fluconazole Septic Arthritis • Fluconazole 400 mg QD x 6 weeks • Echinocandin x 2 weeks, followed by fluconazole x 4 weeks CNS • Initial tx: Liposomal AmB 5 mg/kg QD • With or without flucytosine 25 mg/kg QID • Step down to fluconazole 400-800 mg QD • Duration: until s/sx and CSF and radiological abnormalities resolve UTI Asymptomatic candiduria • Removal of catheters • Tx of AFx NOT recommended unless pt has high risk for dissemination (neutropenia or undergo urologic procedures) Symptomatic candiduria • If susceptible to fluconazole: fluconazole PO 200 mg QD x 2 weeks • If fluconazole resistant C. glabrata: AmB deoxycholate 0.3-0.6 mg/kg QD x 1-7 days ○ Alternative: Flucytosine PO mg/kg QID for 7-10 days • C. krusei: AmB deoxycholate • Remove Catheter • AmB deoxycholate bladder irrigation Aspergillosis • Mold • Common pathogen: Aspergillus fumigatus • Invasive Aspergillosis (IA) ○ 2nd most common IFI • Affects immunocompromised patients ○ Highest risk ▪ Acute myeloid leukemia (AML) ▪ Allogeneic HSCT (hematopoietic stem cell transplant) • Invasive Pulmonary Aspergillosis (IPA) ○ S/sx: mimics acute pulmonary embolus (fever, pleuritic chest pain) ○ Diagnosis ▪ Galactomannan (GM) ○ Mortality ~94% in BMT recipients ○ High risk patients ▪ Prolonged severe neutropenia ○ ○ Start antifungal therapy in any of these conditions: • Persistent fever or progressive sinusitis unresponsive to antimicrobial therapy • Presence of characteristic radiographic findings • Orbital or cavernous sinus disease or acute vascular event associated with fever • Isolation of Aspergillus spp. from nasal or respiratory secretion (Galactomannan) ○ Treatment • Therapy ↓ mortality 90% → 45% • Preferred: Voriconazole 6mg/kg Q12H x1 day, 4mg/kg Q12H IV • Response rate: 52-69% • TDM (therapeutic drug monitoring) at steady states • Duration of therapy: minimum 6-12 weeks • Alternative: Combo therapy (consider in refractory disease) • Azole + Echinocandin OR • Azole + L-AMB or ABLC OR • Echinocandin + L-AMB or ABLC • Survival beyond 2-3 week uncommon without treatment ○ Monitoring • Biomarkers to assess patient response to therapy • Serial monitoring of serum GM (hematologic malignancy, HSCT) • Prophylaxis/Empiric Tx of Invasive Aspergillosis ○ Prophylaxis of IA • During prolonged neutropenia for those who are at high risk for IA (strong, high) • Posaconazole (strong, high) • Voriconazole (strong, moderate) • Itraconazole (strong, moderate), but limited by absorption and tolerability ○ Empiric Treatment • High-risk patient with prolonged neutropenia who remain persistently febrile despite broad-spectrum antibiotic therapy • Voriconazole Histoplasmosis • Aka North American Histoplasmosis • Common in Ohio and Mississippi river valleys • No treatment Blastomycosis • Blastomyces dermatitidis: Dimorphic fungus that infects primarily the lungs ○ Inhalation → yeast → lungs • Chicago Disease • Treat all clinical presentations ○ CNS Blastomycosis: Liposomal AmB Coccidioidomycosis • Coccidioides immitis dimorphic fungus ○ Initial infection via inhalation of the spores ○ transform into spherical cells called "spherules" • Endemic region ○ lower Sonoran zone (California to Texas) ○ San Joaquin Valley fever, Valley fever • Diagnosis ○ Positive skin test ○ IgM antibody peaks at 2-3 weeks ○ Histologic exam of tissue with silver staining shows large endosporulated spherules • Treatment ○ Primary pulmonary disease • Mild-moderate (treat 3-12 months) • Fluconazole • Itraconazole • Severe or disseminated • AmB, then fluconazole or itraconazole (at least a year) ○ Coccidioidal Meningitis (treat definitely) • Primary tx: Fluconazole PO/IV 400-1200 mg/day Cryptococcosis • • • • • Yeast: Cryptococcus neoformans Found in pigeon droppings worldwide Opportunistic infection as it affects mainly immunosuppressed individuals Well-known for causing meningitis in AIDS patients Treatment Non-meningeal – Non-AIDS ○ Summary • • • • Meningitis – Non-AIDS HIV+/AIDS Fluconazole (+/- flucytosine) • AmB + Flucytosine • AmB + Flucytosine Itraconazole • AmB • Then lifelong suppression (Maintenance Therapy) Posaconazole • Liposomal AmB • 1st-line: Fluconazole More severe • AmB Lipid Complex • 2nd-line: AmB, itraconazole • Step down to fluconazole • Minimum of 12 months of antifungal therapy • AmB + Flucytosine ○ AmB • Refractory ○ Liposomal AmB • Intraventricular or intrathecal AmB ○ AmB Lipid Complex • Recurrent or Progressive • Step down to fluconazole • Lifelong azole maintenance