Cost‐effectiveness of amphotericin B formulations in the treatment of systemic fungal infections

Borba, Helena Hiemisch Lobo; Steimbach, Laiza Maria; Riveros, Bruno Salgado; Tonin, Fernanda S.; Ferreira, Vinicíus Lins; Bagatim, Bruna Aline de Queiros; Balan, Gisele; Pontarolo, Roberto; Wiens, Astrid

doi:10.1111/myc.12801

Cited by 30 publications

(24 citation statements)

References 21 publications

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“…Conventional formulations are usually affordable but include significant side effects. The most effective and least toxic formulation is liposomal AmB, which can generate costs of up to US$100,000 per patient in different parts of the globe, including developing countries [28].…”

Section: Systemic Mycoses Are Neglected Diseasesmentioning

confidence: 99%

Fungal diseases as neglected pathogens: A wake-up call to public health officials

2020

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Fungal diseases: A real threat to public healthHuman fungal diseases differ fundamentally from other infections in diverse ways. As eukaryotic pathogens, fungi share many similarities with their host cells, which impairs the development of antifungal compounds. Fungal tropism is highly variable, as pathogens infect a wide range of cell types. A single fungal pathogen can infect multiple tissues in the same patient (depending on the host's immunological status) and can undergo morphogenic shifts during infection. Fungi are still underappreciated as major pathogens by both the public and public health officials. Diseases caused by protozoa, bacteria, and viruses have been recognized as important public health issues for centuries. For instance, syphilis, influenza, and Chagas disease have been documented for over 100 years [1], while invasive mycoses were only widely acknowledged as medically important pathogens in the 1980s [2]. Viral diseases of major population impact (such as smallpox, influenza and-more recentlydengue, Zika, Chikungunya, and coronavirus) have affected millions of people with significant effects on human health in developed, developing, and less developed nations [3,4]. These conditions have boosted the generation of knowledge, which has led to the eradication of smallpox [5], the wide availability of effective vaccines [6], and the development of diagnostic and preventive tools against influenza [7] and, more recently, Zika [8]. Bacterial diseases have profoundly impacted human health at different times in history, and although the phenomenon of antimicrobial resistance is a matter of extreme concern, there are several effective tools for the prevention, treatment, and diagnosis of bacterial infections [9]. Human parasitosis have been recognized to negatively impact public health in different parts of the globe for decades, which has stimulated the ongoing development of vaccines, new drugs, and diagnostic tests for malaria, sleeping sickness, leishmaniasis, filariasis, and Chagas disease [10]. Fungal infections, however, are part of a different scenario. These diseases, for most of recorded history as well as the majority of the last century, have been rare or had a low impact on human health.The increase in the number of immunocompromised patients, some of whom are highly susceptible to fungal infections, has totally changed this picture. The invasive diseases caused by fungi, the so-called systemic mycoses, profoundly impact human health. Moreover, the Global Action Fund for Fungal Infections (GAFFI) also highlights the devastating impact of focal fungal diseases in individuals who often have intact immune systems. GAFFI estimates that more than 1 million eyes go blind each year due to fungal keratitis [11]. Nearly one billion people have skin mycoses, which makes this disease only slightly less common on the planet than headaches and dental caries. Fungal spores contribute to significant reactive airway diseases in over 10 million individuals. In total, the GAFFI estimates that over 300 mi...

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Section: Systemic Mycoses Are Neglected Diseasesmentioning

confidence: 99%

Fungal diseases as neglected pathogens: A wake-up call to public health officials

2020

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“…However, due to the high cost of the lipid formulations, in resource-limited settings that rely only on the conventional AmB formulation for the treatment of systemic fungal infections, extemporaneous fat emulsions have been alternatively prepared by mixing AmB-DOC with Intralipid ® 20%, a low-cost commercial water-in-oil (O/W) emulsion for parenteral nutrition containing 20% (w/v) soybean oil [130,131]. AmB-DOC in Intralipid ® (AmB-IL) has shown antifungal efficacy in vitro [132] and in vivo in experimental animal models of systemic candidiasis [133,134] and aspergillosis [135], similar to that of the conventional formulation in dextrose but decreased nephrotoxicity and infusion-related side effects.…”

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confidence: 99%

Lipid Systems for the Delivery of Amphotericin B in Antifungal Therapy

2020

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Amphotericin B (AmB), a broad-spectrum polyene antibiotic in the clinic for more than fifty years, remains the gold standard in the treatment of life-threatening invasive fungal infections and visceral leishmaniasis. Due to its poor water solubility and membrane permeability, AmB is conventionally formulated with deoxycholate as a micellar suspension for intravenous administration, but severe infusion-related side effects and nephrotoxicity hamper its therapeutic potential. Lipid-based formulations, such as liposomal AmB, have been developed which significantly reduce the toxic side effects of the drug. However, their high cost and the need for parenteral administration limit their widespread use. Therefore, delivery systems that can retain or even enhance antimicrobial efficacy while simultaneously reducing AmB adverse events are an active area of research. Among those, lipid systems have been extensively investigated due to the high affinity of AmB for binding lipids. The development of a safe and cost-effective oral formulation able to improve drug accessibility would be a major breakthrough, and several lipid systems for the oral delivery of AmB are currently under development. This review summarizes recent advances in lipid-based systems for targeted delivery of AmB focusing on non-parenteral nanoparticulate formulations mainly investigated over the last five years and highlighting those that are currently in clinical trials.

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“…It was estimated that the cost to procure one million doses of standard benzimidazoles (500 mg each) would be approximately US$ 20,000, including international transport (37). In comparison to the cost of treating cryptococcosis patients with lipid formulations of amphotericin B (8, 9), these numbers are extraordinarily low. In this context, our results support the development of pharmaceutical preparations of fenbendazole to be tested as alternative anti-cryptococcal agents.…”

Section: Discussionmentioning

confidence: 99%

“…In Malawi, Zambia, Cameroon, and Tanzania, the costs for treating each patient with cryptococcal meningitis includes US $1442 for 2 weeks of oral fluconazole and flucytosine, $1763 for 1 week of amphotericin B and fluconazole, $1861 for 1 week of amphotericin B and flucytosine, $2125 for 2 weeks of amphotericin B and fluconazole, and $2285 for 2 weeks of amphotericin B and flucytosine (7). In Brazil, the therapeutic costs of lipid formulations of amphotericin B can exceed US $100,000 per patient (8). In summary, novel therapeutic protocols for treating the diseases caused by C. neoformans and C. gattii are urgent.…”

Section: Introductionmentioning

confidence: 99%

Fenbendazole controlsin vitrogrowth, virulence potential and animal infection in theCryptococcusmodel

Oliveira

Joffe

Simon

et al. 2020

Preprint

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AbstractThe human diseases caused by the fungal pathogens Cryptococcus neoformans and C. gattii are associated with high indices of mortality, and toxic and/or cost-prohibitive therapeutic protocols. The need for affordable antifungals to combat cryptococcal disease is unquestionable. Previous studies suggested benzimidazoles as promising anti-cryptococcal agents combining low cost and high antifungal efficacy, but their therapeutic potential has not been demonstrated so far. In this study, we investigated the antifungal potential of fenbendazole, the most effective anti-cryptococcal benzimidazole. Fenbendazole was inhibitory against 30 different isolates of C. neoformans and C. gattii at a low concentration. The mechanism of anti-cryptococcal activity of fenbendazole involved microtubule disorganization, as previously described for human parasites. In combination with fenbendazole, the concentrations of the standard antifungal amphotericin B required to control cryptococcal growth were lower than those required when this antifungal was used alone. Fenbendazole was not toxic to mammalian cells. During macrophage infection, the anti-cryptococcal effects of fenbendazole included inhibition of intracellular proliferation rates and reduced phagocytic escape through vomocytosis. Fenbendazole deeply affected the cryptococcal capsule. In a mice model of cryptococcosis, the efficacy of fenbendazole to control animal mortality was similar to that observed for amphotericin B. These results indicate that fenbendazole is a promising candidate for the future development of an efficient and affordable therapeutic tool to combat cryptococcosis.

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Cost‐effectiveness of amphotericin B formulations in the treatment of systemic fungal infections

Cited by 30 publications

References 21 publications

Fungal diseases as neglected pathogens: A wake-up call to public health officials

Fungal diseases as neglected pathogens: A wake-up call to public health officials

Lipid Systems for the Delivery of Amphotericin B in Antifungal Therapy

Fenbendazole controlsin vitrogrowth, virulence potential and animal infection in theCryptococcusmodel

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