**2. Lipid formulations of Amphotericin B**

The burden of invasive fungal infections has grown in the last years, leading to higher morbidity and mortality, especially among immunosuppressed individuals. Amphotericin B deoxycholate (AmBD) (**Figure 1**) is still regarded as one of the most important antifungals of the last 60 years and has been the foundation to treat these infections, showing efficient fungicidal activity against candidiasis, cryptococcosis, aspergillosis, histoplasmosis, blastomycosis, coccidioidomycosis, zygomycosis, sporotrichosis, fusariosis, and phaeohyphomycosis [29, 30].

Nonetheless, given the adverse effects in 50–90% of cases, efforts were made to reformulate the first amphotericin B formulation (Fungizone®) with equivalent efficacy yet reduced toxicity.

The commercially available formulations for this effect are Albelcet® (lipid complex), Amphotec® / Amphocil® (colloidal dispersion), and AmBisome® (liposomal formulation) [27, 29]. On account of their superior safety profiles and higher drug therapeutic index, these lipid-based preparations can nowadays be regarded as worthy substitutes for AmBD. Currently, they are first-line therapy for numerous invasive fungal infections in routine medical practice and clinical investigation, for instance, for disseminated histoplasmosis and AIDS, *Candida* meningitis, or endophthalmitis [27, 31–33].

Even in pregnancy, the lipid formulations of AmB are the cornerstone treatment of any invasive fungal infection and deemed as safe. On the contrary, azoles present complications in view of their teratogenicity, embryotoxicity, and of transplacental infection transmission to the fetus, consequently being contraindicated in this group. Their use during pregnancy should be restricted to superficial infections [14, 34].

Currently, only AmBisome® has been evaluated in the treatment of disseminated histoplasmosis [2, 31]. Besides, some case reports have also stressed its clinical efficacy in the rare primary cutaneous form of the disease in immunocompetent patients [9–11].

AmBisome® received its FDA approval in 1997 and is formed of small spherical unilamellar liposomes with a size inferior to 100 nm, where AmB is encapsulated. L-Amb is represented in **Figure 2**. Hydrogenated soy phosphatidylcholine, cholesterol, and phosphatidylglycerol are composition elements of these liposomes [30].

#### **Figure 1.**

*Chemical structure of amphotericin B (C71H112NNaO21). Drawn using ChemDraw Professional 22.0 from PerkinElmer Informatics, Inc.*

#### **Figure 2.**

*Schematic representation of liposomal amphotericin B. Parts of the figure were drawn by using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License. (https://creativecommons.org/licenses/by/3.0/).*

In a 2002 multicenter randomized, double-blind, prospective clinical trial, with 81 participants, intravenous infusion doses of 3.0 mg/kg of body weight liposomal amphotericin B (L-AmB) and 0.7 mg/kg of AmBD were compared. The purpose was to evaluate both their safety and efficacy for induction therapy of moderate to severe disseminated Histoplasmosis in patients with AIDS [24]. A higher treatment response of 88% was achieved for L-AmB counter to 64% for AmBD, as well as lower mortality rates (2% vs. 13%). Furthermore, nephrotoxicity (assessed through an increase in serum creatinine level) was reported for 9% of patients treated with L-AmB, in opposition to 37% for AmBD, along with fewer infusion-related side effects (25% vs. 63%). Taking all these trial findings into account, L-AmB has clearly revealed to be an upgraded choice to the first standardized treatment AmBD, therefore modifications on therapy recommendations were undertaken after this study. Despite being more costly, L-AmB's attractiveness lies in its less toxic profile, superior efficacy, and improved survival rates for moderate-to-severe invasive histoplasmosis [24, 31].

Nevertheless, clearance rates of fungemia and *H. capsulatum* antigen from serum and urine were alike with the two treatments. For this reason, 2 weeks after the beginning, induction therapy was replaced by itraconazole, for another 10 weeks of consolidation therapy [24, 35].

With the goal of clearly proving the benefits of L-AmB as the initial treatment of moderate-to-severe histoplasmosis, another study was carried out. It comprised two separate closed clinical trials and aimed to compare the clearance of fungal burden (correlated with survival) in patients with disseminated histoplasmosis treated with L-AmB (n = 51) versus itraconazole (n = 59). The clinical response rates were similar: 86% for L-AmB and 85% for itraconazole group. However, after 2 weeks of treatment, fungemia, antigenemia, and antigenuria cleared more rapidly with L-AmB than with

*Is Micro and Nanotechnology Helping Us Fight Histoplasmosis? DOI: http://dx.doi.org/10.5772/intechopen.110544*

itraconazole. This quicker fungemia clearance justifies the use of L-AmB, in opposition to itraconazole, as the initial treatment of moderate-to-severe histoplasmosis [35].

To address the issue of continuously high morbidity and mortality rates brought about by fungal infections, a preclinical study comparing different prophylactic agents was conducted (AmBisome® and Fungizone®). A single high dose of AmBisome® was able to deliver sufficient concentrations of AmB in tissue in immunocompetent and immunosuppressed murine while keeping a safety standard. It effectively inhibited the growth of *Candida albicans* in the kidneys and prevented the growth of *H. capsulatum* in the spleen of mice [36].
