Antifungal Therapy: New and Evolving Therapies

Yasmine Nivoix; Marie-Pierre Ledoux; Raoul Herbrecht

Disclosures

Semin Respir Crit Care Med. 2020;41(1):158-174. 

In This Article

Conventional and Lipid-based Formulations of AmB

AmB is a polyene antifungal agent with a broad range of activity against yeasts and molds. The initial formulation, developed in the 1950s, was DAmB, which was the first antifungal agent available for the treatment of invasive fungal diseases.[1] However, this formulation is associated with several adverse consequences, especially nephrotoxicity. The development of novel, less-toxic lipid-based polyene formulations was attempted during the 1990s to reduce the intrinsic toxicity of AmB.

Three lipid formulations of AmB have since been developed: AmB colloidal dispersion (ABCD), AmB lipid complex (ABLC), and liposomal AmB (LAmB).[7] ABCD production was discontinued in November 2011 and therefore will not be discussed in detail here.[7] ABLC and LAmB differ by their lipid composition and therefore also differ in physical characteristics, pharmacokinetics, and safety and efficacy profile.[7] There is a consensus that there is a reduced, but not absent, level of renal toxicity with lipid formulations of AmB as compared with DAmB. Few well-designed studies have been conducted, and none of them demonstrated superiority in terms of efficacy of any of the lipid preparations over DAmB. Recently, a double-blind randomized study compared a standard dose of 3 mg/kg/day of LAmB with a high loading dose (10 mg/kg/day for 14 days followed by the standard dose) as the primary therapy of invasive filamentous fungal infections. The response rate at the end of randomized therapy and survival at 12 weeks were numerically superior in the standard dose arm, but these differences were not statistically significant.[8] Nephrotoxicity was substantially higher in the loading dose arm, and this should discourage its use in clinical practice for the treatment of aspergillosis.

Mechanism of Action and Antifungal Spectrum

AmB was isolated from Streptomyces nodosus. It has fungistatic and fungicidal activity through binding to the fungal membrane, inducing modifications of membrane permeability; Van der Waals forces led to a stabilization of the AmB and ergosterol interaction, resulting in membrane pores and a higher permeability to protons and monovalent cations (Figure 1). AmB also leads to oxidation with resulting fungal cell damage.

AmB has a wide spectrum of activity including most fungi involved in human pathology: Cryptococcus neoformans, most Candida spp., Aspergillus spp., and agents of mucormycosis.[1,9,10] It is also efficient against some protozoa including Leishmania.[11] Some fungi are resistant to AmB, including Candida lusitaniae, Aspergillus terreus, Trichosporon spp., Geotrichum spp., and Scedosporium spp.[1,9,10]

Clinical Pharmacokinetics

The pharmacokinetics of AmB are complex and only partially investigated in humans.[7,12] AmB strongly binds to plasma proteins (up to 95%) after intravenous (IV) administration. Its plasma half-life ranges from 24 to 48 hours, but its elimination half-life reaches 15 days. Its distribution follows a tricompartment pattern. High AmB concentrations are found in the liver (14–41% of the administered dose), kidneys (0.3–2%), and lungs (1.2–6%). AmB enters cells, notably macrophages, and therefore exerts its activity against phagocytosed fungi. Urinary and biliary elimination are low.

ABLC is rapidly trapped in the reticuloendothelial system, leading to lower plasma maximal concentrations and higher tissue levels in the liver, spleen, bone marrow, and lungs, and a long elimination half-life.[7,13] It is catabolized by macrophage phospholipases and fungal phospholipases, inducing a progressive release of AmB. Renal concentration is reduced compared with DAmB.

LAmB has different pharmacokinetics: compared with conventional or other lipid formulations, it reaches a higher blood trough due to slower clearance by the reticuloendothelial system.[7,13] AmB is released onto fungi after melting of the liposome in the fungal cell membrane. High trough levels of LAmB are found in the liver (13–23% of the delivered dose) and spleen, whereas low concentrations are detected in the lungs and kidney. Less than 1% of the given dose is found in kidneys.

Dosage and Adjustments

Due to its poor tolerance, the use of AmB is no longer justified except if lipid formulations or other alternatives are not available.[3,14] The recommended dose of AmB ranges from 0.7 to 1 mg/kg/day (Table 2).[7] Close monitoring of serum creatinine, potassium, and magnesium levels is mandatory. The risk of renal failure is higher in the case of previous renal failure, dehydration, or concomitant use of diuretics or other nephrotoxic agents.

Lipid formulations of AmB have better renal tolerance.[7,13] The recommended dose of liposomal AmB in the treatment of yeasts and Aspergillus spp. is 3 to 5 mg/kg/day. The recommended dose for ABLC is 3 to 5 mg/kg/day. In the case of renal failure during the use of lipid formulations of AmB, the dosage can be transiently reduced by half, or infusions can be spaced farther apart than once daily.

DAmB, ABLC, and LAmB have also been administered through aerosols, mostly for primary or secondary prophylaxis of invasive fungal infections in leukemic patients or in hematopoietic stem cell or lung transplant recipients.[4,15–18] Effective concentrations of aerosolized AmB have been obtained in epithelial lining fluid.[19] Limited data are available on the use of nebulized AmB for the treatment of established fungal infection; this has usually been employed in combination with systemic voriconazole for tracheobronchial aspergillosis in lung transplant patients.[4]

Drug–Drug Interactions

AmB shows no interaction with cytochrome P450 (CYP) and hence has no drug interactions through that mechanism, but its side effects can be worsened by a concomitant use of medication with similar toxicities.[7] Caution must be used when administering the following medicines with AmB or its lipid formulations:

  • Hypokalemia-inducing medications: hypokalemia induced by AmB can be exacerbated and may lead to cardiac dysrhythmia (notably torsade de pointes), particularly in the context of digoxin use. Agents that may contribute to hypokalemia include diuretics, laxatives, glucocorticoids, and tetracosactid.

  • Torsade de pointes-inducing medications: QT-prolonging and bradycardia-inducing medicines must be avoided while treating with AmB.

  • Nephrotoxic medications: iodic contrast agents, aminoglycosides, platinum salts, high-dose methotrexate, some antimicrobials such as pentamidine, foscarnet, and antiviral "ciclovirs," and certain anti-rejection drugs such as cyclosporine and tacrolimus can worsen renal function. If such use cannot be avoided, careful monitoring of renal function is mandatory.

  • Zidovudine: its use with AmB can lead to synergistic bone marrow toxicity and should prompt more frequent blood count monitoring.

Tolerability

Infusion-related reactions are described in 70 to 90% of patients receiving DAmB.[7] They comprise fever and shivers, headaches, nausea, vomiting and diarrhea, bronchospasm, hypotension, and cardiac dysrhythmia. Some of these side effects may be related to a release of prostaglandins and cytokines. Among immediate side effects, chemical phlebitis, thrombophlebitis, and allergic reactions should also be mentioned. The early intolerance reactions can be reduced by a slower pace of infusion, compliance with advised dilution, and premedication with acetaminophen. Steroids can also prevent infusion reactions but should generally be avoided in the setting of an invasive fungal infection.

Nephrotoxicity is the predominant limiting factor for the use of DAmB. It is observed in 24 to 80% of patients. It is dose-dependent and usually reversible. DAmB leads to a tubulopathy as well as glomerular impairment in late stages. Tubulopathy manifests as electrolyte disorders such as hypokalemia, sometimes extremely severe and decreased alkaline reserve, and hypomagnesemia. As noted earlier, the concomitant use of other nephrotoxic drugs increases the risk of toxicity. Prevention of electrolyte disorders and appropriate sodium intake (hydration by 500–1,000 mL of saline solution) may reduce the renal toxicity of DAmB.

ABCD infusions are associated with immediate adverse events in similar frequency and intensity as DAmB.[7,13,20] ABLC also has similar immediate side effects but with a lower frequency. LAmB-treated patients present with less fever and shivers and less renal toxicity, and need less premedication than DAmB-treated patients. A prospective, double-blind study comparing LAmB and ABLC demonstrated better tolerability of LAmB.[21] The nephrotoxicity is reduced for these three lipid formulations compared with DAmB.[1,7,13]

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