Antifungal Agents in Fungal Infections of the Lung

INTRODUCTION

• Murray & Nadel's Textbook of Respiratory Medicine, Ch. 57

CLASSIFICATION OF ANTIFUNGAL AGENTS

1. Polyenes
2. Azoles
3. Echinocandins
4. Flucytosine (5-FC)
5. Terbinafine (allylamines)

1. POLYENES - AMPHOTERICIN B

Mechanism of Action

Formulations

• Amphotericin B deoxycholate (conventional AmB, Fungizone) - IV only
• Liposomal Amphotericin B (L-AmB / AmBisome) - lipid formulation
• Amphotericin B Lipid Complex (ABLC / Abelcet) - lipid formulation

Spectrum of Activity

• Aspergillus (including most species; reduced activity in A. terreus, A. ustus)
• Candida (including C. auris resistance emerging)
• Cryptococcus
• Endemic fungi (Histoplasma, Blastomyces, Coccidioides, Paracoccidioides)
• Mucorales (mucormycosis)
• Non-Aspergillus hyaline molds

Major Adverse Effects

• Nephrotoxicity (most common and clinically significant) - reduced with pre- and post-hydration with 500 mL normal saline, and nearly eliminated with lipid formulations
• Electrolyte imbalances - hypokalemia, hypomagnesemia
• Normocytic normochromic anemia
• Infusion-related reactions - fever, chills, nausea, vomiting (can be reduced with acetaminophen premedication and prehydration)

Clinical Applications in Pulmonary Disease

• Fishman's Pulmonary Diseases and Disorders, Ch. 133

2. AZOLES

(a) Fluconazole

• Spectrum: Candida (not C. krusei - intrinsically resistant; variable in C. glabrata; high resistance in C. auris), Cryptococcus, Coccidioides
• Forms: IV, oral
• TDM: Not routinely recommended; dose adjustment needed for renal impairment
• Side effects: Alopecia (prolonged use), GI effects, hepatotoxicity, QT prolongation, exfoliative skin disorders
• Drug interactions: Moderate CYP2C9 and CYP3A4 inhibitor - interacts with many co-medications
• Use in lung: First-line for mild-to-moderate pulmonary cryptococcosis (400 mg/day for minimum 6-12 months); maintenance therapy after induction treatment of cryptococcal meningitis; coccidioidomycosis
• Murray & Nadel, Table 57.1

(b) Itraconazole

• Spectrum: Aspergillus, Candida (including C. krusei, C. glabrata, C. tropicalis), Cryptococcus, dematiaceous molds, endemic mycoses (including paracoccidioidomycosis, histoplasmosis, blastomycosis), Sporothrix, Talaromyces marneffei
• Forms: PO capsule, tablet, solution; no IV formulation available
• TDM: Recommended for systemic infections. Target trough ≥1.0 μg/mL by HPLC (or ≥3.0 μg/mL by bioassay) measured after ≥2 weeks of therapy. The solution gives ~30% higher concentrations than capsules.
• Important: Capsules require an acidic gastric environment - administer with food or carbonated beverages; avoid proton pump inhibitors
• Side effects: GI, hepatotoxicity, QT prolongation, peripheral edema, headache, hearing loss, CHF (avoid in patients with ventricular dysfunction), rare adrenal insufficiency
• Drug interactions: Potent CYP3A4 inhibitor and CYP3A4 substrate; hepatic enzyme inducers like rifampin markedly reduce itraconazole levels
• Use in lung: Highly effective in mild-to-moderate PDH and chronic pulmonary histoplasmosis; step-down therapy after AmB induction in histoplasmosis; primary treatment for pulmonary blastomycosis (mild-moderate)
• Fishman's Pulmonary Diseases and Disorders, Ch. 133

(c) Voriconazole

• Spectrum: Aspergillus (first-line), Candida, Cryptococcus, Fusarium, Scedosporium, dematiaceous molds, endemic mycoses
• Forms: IV, oral
• TDM: Recommended; target trough 1-5.5 μg/mL; non-linear (saturable) pharmacokinetics with significant inter-patient variability
• Side effects: Visual disturbances (photopsia), photosensitivity/phototoxicity (risk of squamous cell carcinoma with long-term use), neurotoxicity (hallucinations), hepatotoxicity, QT prolongation, periostitis (with prolonged use), elevated fluoride levels
• Drug interactions: Potent CYP2C19, CYP2C9, CYP3A4 inhibitor; extensive interactions; contraindicated with rifampin, carbamazepine, long-acting barbiturates
• Use in lung: First-line treatment for invasive pulmonary aspergillosis (IPA) - based on landmark randomized trial showing superiority over conventional AmB (52.8% vs 31.6% response); also used for fusariosis, scedosporiosis
• Murray & Nadel, Table 57.1

(d) Posaconazole

• Spectrum: Aspergillus, Candida (including azole-resistant species), Mucorales, endemic fungi, dematiaceous molds - broadest spectrum of azoles
• Forms: IV, oral suspension, delayed-release tablet; tablet provides superior bioavailability
• TDM: Recommended; target trough ≥0.7 μg/mL for prophylaxis; ≥1.0 μg/mL for treatment
• Side effects: QT prolongation, GI, hepatotoxicity; fewer visual side effects than voriconazole
• Drug interactions: CYP3A4 inhibitor; PPIs reduce absorption of oral suspension; rifampin markedly reduces levels
• Use in lung: Salvage therapy for mucormycosis (70% success in 24 patients in open-label trial; 61% in 91-patient retrospective review); antifungal prophylaxis in high-risk patients (stem cell transplant, leukemia); important limitation is poor oral absorption of suspension especially in mucositis, requiring TDM
• Fishman's Pulmonary Diseases and Disorders, Ch. 131

(e) Isavuconazole

• Spectrum: Aspergillus, Candida, Mucorales, Fusarium, dematiaceous molds; variable activity across Mucorales species
• Forms: IV, oral (near-perfect bioavailability; IV and PO considered interchangeable)
• TDM: Generally not required; may be considered in selected patients
• Side effects: Generally well tolerated; QTc shortening (opposite of other azoles - relevant consideration); hepatotoxicity; GI
• Drug interactions: Moderate CYP3A4 inhibitor
• Use in lung: FDA-approved for both invasive aspergillosis and mucormycosis (first-line). Non-inferiority was shown vs. voriconazole for aspergillosis (SECURE trial). An open-label study for mucormycosis showed outcomes similar to historical AmB controls; breakthrough mucormycosis during isavuconazole prophylaxis has been reported
• Murray & Nadel, Table 57.1

3. ECHINOCANDINS

Mechanism

Spectrum

• Active against Candida (including most azole-resistant species) and Aspergillus
• Not active against Cryptococcus, Mucorales, Fusarium, Scedosporium, or endemic fungi
• Although Cryptococcus produces small amounts of (1-3)-β-D-glucan, echinocandins are not active against C. neoformans in vitro and should not be used for cryptococcosis
• Murray & Nadel, Ch. 57

TDM

Adverse Effects

Drug Interactions

Clinical Applications

• Invasive pulmonary candidiasis - first-line or salvage depending on species and prior azole exposure
• Invasive pulmonary aspergillosis - salvage therapy or combination with voriconazole in refractory disease
• Prophylaxis in high-risk immunocompromised patients

4. FLUCYTOSINE (5-Fluorocytosine, 5-FC)

Mechanism

Spectrum

TDM

Adverse Effects

Clinical Use

• Always used in combination - never monotherapy (resistance emerges rapidly with monotherapy)
• Cryptococcal meningitis/severe cryptococcosis: Combined with AmB during induction phase (AmB + 5-FC for 2 weeks, then consolidation with fluconazole). In resource-limited settings, 2 weeks of high-dose fluconazole (1200 mg/day) combined with 5-FC has shown comparable efficacy to AmB + 5-FC
• Candida endocarditis and CNS candidiasis: Combined with AmB
• Murray & Nadel, Ch. 57

5. TERBINAFINE

Mechanism

Spectrum

Clinical Use in Lung Disease

• Severe or refractory mold infections: Lomentospora, Fusarium, hyaline and dematiaceous molds
• It offers a complementary mechanism to azoles and polyenes, making combination regimens attractive for difficult-to-treat mold infections
• Murray & Nadel, Ch. 57

PRACTICAL PRINCIPLES FOR CLINICAL USE

ANTIFUNGAL RESISTANCE - KEY POINTS

• C. neoformans fluconazole resistance is a growing concern: MIC90 has increased from 8 to 32 μg/mL in recent decades; 31% of isolates from Uganda had MIC ≥16 μg/mL. This is attributed to both clinical use and agricultural azole fungicide use.
• C. auris demonstrates multi-drug resistance and is resistant to all three major classes in some strains.
• Breakthrough mucormycosis has been reported during isavuconazole and posaconazole prophylaxis, and activity varies across Mucorales species.
• Voriconazole MICs for Histoplasma are higher than itraconazole, and outcomes of histoplasmosis treated with voriconazole show higher mortality than with itraconazole.
• Echinocandins should not be used for Cryptococcus, Mucorales, Fusarium, or Scedosporium infections.
• Fishman's Pulmonary Diseases and Disorders, Ch. 132

SUMMARY