Antifungal Agents

Educational Objectives

The goal of this program is to improve management of fungal infections. After hearing and assimilating this program, the clinician will be better able to:

1. Recognize the effects of food on the absorption of various azole antifungals.
2. Select appropriate azoles for fungal treatment in patients at risk for hepatotoxicity and arrhythmias.
3. Weigh benefits vs risks associated with use of trimethoprim-sulfamethoxazole.

Summary

Background: polyenes — amphotericin B is a very broad-spectrum agent effective against most yeasts, molds, some species of Aspergillus, and dimorphic fungi; azoles — fluconazole is active against yeasts, has variable activity against different Candida species, and has no activity against molds; posaconazole and isavuconazole may have expanded activity against yeasts and molds; echinocandins — have excellent activity against yeasts and modest activity against molds; not typically used for dimorphic fungal infections

Azoles

Available agents

Fluconazole: does not interact with food or antacids; a liquid suspension is available for feeding tube administration

Voriconazole: available in tablets and liquid suspension; food reduces its absorption, so it is usually taken ≥1 hr after meals or tube feeds, but this is not an absolute contraindication; antacids do not affect voriconazole levels, but proton pump inhibitors (PPIs) increase levels

Itraconazole: various formulations are not easily interchangeable; classic capsules — treat invasive fungal infections; food and acid gastric pH significantly increase gastric absorption; super bioavailable (SUBA) capsules — have enhanced absorption with food; PPIs enhance serum levels; capsules cannot be crushed or opened; liquid solution — absorption significantly reduced by food; causes significant diarrhea

Posaconazole: liquid solution — absorption is highly dependent on food; a high-fat meal improves absorption; tablets — excellent bioavailability; much less dependent on food absorption

Isavuconazole: available in capsules

Adverse effects

Renal toxicity: IV posaconazole and IV voriconazole are solubilized through a cyclodextrin complex which is renally eliminated; some concern exists for retention and toxicity in patients with renal dysfunction; the package insert of IV voriconazole suggests avoidance in patients with CrCl <50 mL/min; however, observational studies have suggested the effect may not be large, and effects may be delayed; consider switching patients to an oral formulation when feasible

Inhibition of metabolic enzymes: azoles can inhibit the primary drug-metabolizing enzyme CYP3A4 and may interact with, eg, tacrolimus (levels increase); fluconazole has a more modest effect than posaconazole and isavuconazole; rifampin and phenytoin may lower the levels of antifungal drugs; voriconazole levels increase in patients taking PPIs, which inhibit CYP2C9

Hepatotoxicity: azoles may cause biochemical liver injury and elevate levels of aspartate transaminase (AST) and alanine transaminase (ALT) in 5% to 20% of patients; however, liver dysfunction-induced drug discontinuation is relatively rare; guidance from the Food and Drug Administration (FDA) suggests AST and ALT elevations are concerning if isolated and transient levels are >8 times the upper limit of normal, or sustained levels are >5 times the upper limit of normal, other body systems are involved, or the patient is symptomatic; transient elevations are not necessarily a reason for drug discontinuation; studies suggest a washout period is not necessary when switching to another azole

Cardiac adverse effects: include QTc interval prolongation and (rarely) torsade de pointes; the FDA Spontaneous Reporting System revealed significant risk for torsade de pointes with posaconazole, voriconazole, and fluconazole; risk with newer azoles is more concerning; risk is increased in patients with prolonged azole therapy, baseline prolonged QTc interval, dialysis, and pre-existing cardiovascular disease; monitoring is recommended; isavuconazole does not significantly prolong the QTc interval, and Mellinghoff (2018) reported modest shortening; compared with voriconazole, Maertens et al (2015) demonstrated reduced arrhythmogenic potential with isavuconazole

Voriconazole: visual disturbances — reported by ≈30% of patients taking voriconazole in clinical trials; include, eg, halos around lights, blurred vision; transient; typically peak ≥30 min after administration; completely reversible on drug discontinuation, and patients tend to acclimate over time; visual and auditory hallucinations — occur in ≤5% of patients in clinical trials; persistent during the course of therapy but completely reversible on drug discontinuation; effects are related to dosing and peak concentration; consider reducing the dose of voriconazole, slowing the IV infusion rate, or switching to oral therapy; phototoxicity — sunburn-type phototoxicity is common (2%-10%); preventable with sun protection; immunocompromised patients on long-term therapy may develop actinic keratosis and squamous cell carcinoma; counsel patients about sun protection, especially with long-term therapy or patients who underwent organ transplantation; consider using newer azoles for long-term therapy; fluorine accumulation — long-term therapy, especially in patients with renal failure, may lead to skeletal fluorosis, manifesting as, eg, myalgias, pain, elevated alkaline phosphatase; reversible on drug discontinuation but takes time to wash out

Posaconazole: reportedly causes dose-related pseudohyperaldosteronism, manifesting as hypertension, hypokalemia, and metabolic acidosis; posaconazole specifically inhibits minor drug-metabolizing enzymes which metabolize steroids and mineralocorticoids; a linear relationship exists between serum posaconazole levels, increased blood pressure, and reduced serum K levels; these effects were not reported with the oral solution, but were reported with oral tablets; adverse effects are reported at serum levels >2 mg/L

Therapeutic drug monitoring (TDM): consider TDM for voriconazole and itraconazole; consider TDM for patients on long-term treatment with posaconazole; TDM is usually not required for isavuconazole or fluconazole; Park et al (2012) demonstrated reduced adverse events and improved treatment response following routine TDM for voriconazole, compared with standard dosing; Veringa et al (2023) did not demonstrate improved treatment outcome with TDM vs standard dosing for voriconazole

Amphotericin B

Dosing: typical dosing for aspergillosis is 5 mg/kg/day liposomal amphotericin B (L-AMB); the AmBiLoad trial (Cornely et al [2007]) reported greater toxicity with no improved survival rates with 10 mg/kg/day L-AMB; 3 mg/kg/day is prescribed for candidiasis and cryptococcal meningitis; Jarvis et al (2022) reported noninferiority of single-dose L-AMB in combination with other antifungal drugs for treatment of cryptococcal meningitis, compared with standard dosing of L-AMB; Pasqualotto et al (2023) found similar results with a similar approach in patients with histoplasmosis; dosing of L-AMB is calculated with adjusted (nonadipose) body weight in patients with obesity

Adverse effects: nephrotoxicity — develops in 15% to 30% of patients over a few days to 1 wk; generally reversible; toxicity is increased with other nephrotoxic agents; 3 mg/kg/day L-AMB may result in ≤2-fold increase in serum Cr; sodium loading (prehydration with normal saline) can reduce amphotericin–induced nephrotoxicity; Llanos et al (1991) reported a protective effect of saline loading against nephrotoxicity (evidenced by lower serum Cr), compared with use of dextrose, though increased the need for K supplementation; administer 500 mL normal saline before, or sometimes after, drug administration, though data regarding this are not robust; avoid saline in patients with fluid overload; hypokalemia — consider monitoring K and Mg; consider K supplementation in patients on long-term amphotericin B; infusion reactions — somewhat attenuated with L-AMB; include fever and chills; hydrocortisone and diphenhydramine can attenuate these symptoms; other effects — significant anemia, thrombocytopenia, and hepatotoxicity are possible

Trimethoprim/Sulfamethoxazole (TMP-SMX)

Use indications: recommendations to treat pneumocystis with TMP-SMX are not based on robust evidence; most trials involved men with human immunodeficiency virus, though transplant patients are currently more often infected; patients with AIDS and Pneumocystis carinii showed significant improvement when treated with TMP-SMX vs trimetrexate-leucovorin (Sattler et al [1994]) or atovaquone (Hughes et al [1993]), though TMP-SMX was more often discontinued secondary to drug-induced toxicity

Adverse effects: trimethoprim — causes an increase in serum Cr levels without a reduction in glomerular filtration rate because of inhibition of tubular secretion of Cr; TMP is an amiloride (a K-sparing diuretic); the rise in serum Cr is modest, and clinicians should not over-react to modest Cr elevations in patients with high-dose TMP/SMX; blood urea nitrogen or urine output do not change; patients with renal failure are at increased risk for dose-related hyperkalemia; higher doses can cause dose-related bone marrow suppression, though this is not usually reported in patients treated for urinary tract infections or receiving prophylaxis for pneumocystis; sulfamethoxazole — may cause idiosyncratic agranulocytosis

Dose modification: Tritle et al (2021) found no difference in mortality and significantly less adverse effects with doses of <15 mg/kg/day vs conventional dosing (15-20 mg/kg/day)

Echinocandins

Use indications: seem to be drugs of choice as initial therapy for candidemia; compared with azoles, echinocandins offer broader coverage and superior efficacy; however, echinocandins are only available in IV formulation and are expensive

Efficacy and dosing: Vazquez et al (2014) noted similar efficacy with switching hospitalized patients from IV anidulafungin after 5 days of treatment to oral fluconazole or voriconazole, compared with continuing treatment with IV anidulafungin; higher doses of azoles are required for susceptible dose-dependent cultures of Candida glabrata; once-weekly micafungin may soon be approved by the FDA; ibrexafungerp (oral administration) is currently approved only for vulvovaginal candidiasis

Readings

Abuhelwa AY, Foster DJ, Mudge S, et al. Population pharmacokinetic modeling of itraconazole and hydroxyitraconazole for oral SUBA-itraconazole and sporanox capsule formulations in healthy subjects in fed and fasted states. Antimicrob Agents Chemother. 2015;59(9):5681-5696. doi:10.1128/AAC.00973-15; Cornely OA, Maertens J, Bresnik M, et al. Liposomal amphotericin B as initial therapy for invasive mold infection: a randomized trial comparing a high-loading dose regimen with standard dosing (AmBiLoad trial). Clin Infect Dis. 2007;44(10):1289-97. doi:10.1086/514341; Eyler RF, Shvets K. Clinical pharmacology of antibiotics. Clin J Am Soc Nephrol. 2019;14(7):1080-1090. doi:10.2215/CJN.08140718; Hughes W, Leoung G, Kramer F, et al. Comparison of atovaquone (566C80) with trimethoprim-sulfamethoxazole to treat Pneumocystis carinii pneumonia in patients with AIDS. N Engl J Med. 1993;328(21):1521-7. doi:10.1056/NEJM199305273282103; Jarvis JN, Lawrence DS, Meya DB, et al. Single-dose liposomal amphotericin B treatment for cryptococcal meningitis. N Engl J Med. 2022;386(12):1109-1120. doi:10.1056/NEJMoa2111904; Kuriakose K, Nesbitt WJ, Greene M, et al. Posaconazole-induced pseudohyperaldosteronism. Antimicrob Agents Chemother. 2018;62(5):e02130-17. doi:10.1128/AAC.02130-17; Llanos A, Cieza J, Bernardo J, et al. Effect of salt supplementation on amphotericin B nephrotoxicity. Kidney Int. 1991;40(2):302-308. doi:10.1038/ki.1991.214; Maertens JA, Raad II, Marr KA, et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial. Lancet. 2016;387(10020):760-9. doi:10.1016/S0140-6736(15)01159-9; Mellinghoff SC, Bassetti M, Dörfel D, et al. Isavuconazole shortens the QTc interval. Mycoses. 2018;61(4):256-260. doi:10.1111/myc.12731; Park WB, Kim NH, Kim KH, et al. The effect of therapeutic drug monitoring on safety and efficacy of voriconazole in invasive fungal infections: a randomized controlled trial. Clin Infect Dis. 2012 Oct;55(8):1080-7. doi:10.1093/cid/cis599; Pasqualotto AC, Lana DD, Godoy CSM, et al. Single high dose of liposomal amphotericin B in human immunodeficiency virus/AIDS-related disseminated histoplasmosis: a randomized trial. Clin Infect Dis. 2023;77(8):1126-1132. doi:10.1093/cid/ciad313; Sattler FR, Frame P, Davis R, et al. Trimetrexate with leucovorin versus trimethoprim-sulfamethoxazole for moderate to severe episodes of Pneumocystis carinii pneumonia in patients with AIDS: a prospective, controlled multicenter investigation of the AIDS Clinical Trials Group Protocol 029/031. J Infect Dis. 1994;170(1):165-72. doi:10.1093/infdis/170.1.165; Treem WR, Palmer M, Lonjon-Domanec I, et al. Consensus Guidelines: best practices for detection, assessment and management of suspected acute drug-induced liver injury during clinical trials in adults with chronic viral hepatitis and adults with cirrhosis secondary to hepatitis B, C and nonalcoholic steatohepatitis. Drug Saf. 2021;44(2):133–165. doi:10.1007/s40264-020-01014-2; Tritle BJ, Hejazi AA, Timbrook TT. The effectiveness and safety of low dose trimethoprim-sulfamethoxazole for the treatment of pneumocystis pneumonia: a systematic review and meta-analysis. Transpl Infect Dis. 2021;23(6):e13737. doi:10.1111/tid.13737; Vazquez J, Reboli AC, Pappas PG, et al. Evaluation of an early step-down strategy from intravenous anidulafungin to oral azole therapy for the treatment of candidemia and other forms of invasive candidiasis: results from an open-label trial. BMC Infect Dis. 2014;14:97. doi:10.1186/1471-2334-14-97; Veringa A, Brüggemann RJ, Span LFR, et al. Therapeutic drug monitoring-guided treatment versus standard dosing of voriconazole for invasive aspergillosis in haematological patients: a multicentre, prospective, cluster randomised, crossover clinical trial. Int J Antimicrob Agents. 2023;61(2):106711. doi:10.1016/j.ijantimicag.2023.106711.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose. Dr. MacDougall presented information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. MacDougall was recorded at the Infectious Diseases in Clinical Practice: Update on Inpatient and Outpatient Infectious Diseases, held February 19-24, 2023, on Kauai, HI, and presented by the University of California, San Francisco, School of Medicine. For information on future CME activities from this presenter, please visit https://meded.ucsf.edu/continuing-education. Audio Digest thanks the speakers and presenters for their cooperation in the production of this program.

CME/CE INFO

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The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 1.75 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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Lecture ID:

IM711501

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.