HIV-Associated Cryptococcal Meningitis Patients Treated with Amphotericin B Deoxycholate Plus Flucytosine under Routine Care Conditions in a Referral Center in São Paulo, Brazil

Vidal, José E.; Moraes, Camila de Albuquerque; Siqueira, Renata Elisie Barbalho de; Miranda, Nathalya Fernanda Brito; Marcusso, Rosa Maria Nascimento; Boulware, David R.; Oliveira, Augusto César Penalva de

doi:10.1007/s11046-020-00512-2

Cited by 4 publications

(3 citation statements)

References 46 publications

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“…Particularly for cryptococcal meningitis, fungicidal activity is an important property for effective antifungal therapy. Actually, AmB combined with flucytosine is considered the standard fungicidal treatment for cryptococcal meningitis ( WHO, 2018 ), and is associated with improved survival of patients with cryptococcal meningitis compared to treatment with AmB monotherapy ( Molloy et al, 2018 ; Loyse et al, 2019 ; Vidal et al, 2021 ). In vitro experiments also suggest that combinations of natural and/or synthetic compounds with available antifungals can improve the effectiveness of treatments and extend the efficacy of currently used antifungal agents ( Andriani et al, 2021 ; Benelli et al, 2021 ; Iyer et al, 2021 ).…”

Section: Resultsmentioning

confidence: 99%

Synergistic antifungal interaction of N-(butylcarbamothioyl) benzamide and amphotericin B against Cryptococcus neoformans

Andriani

Spoladori²,

Fábris³

et al. 2023

Front. Microbiol.

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IntroductionCryptococcus neoformans is one of the leading causes of invasive fungal infections worldwide. Cryptococcal meningoencephalitis is the main challenge of antifungal therapy due to high morbidity and mortality rates, especially in low- and middle-income countries. This can be partly attributed to the lack of specific diagnosis difficulty accessing treatment, antifungal resistance and antifungal toxicity.MethodsIn the present study, the effect of the synthetic thiourea derivative N-(butylcarbamothioyl) benzamide (BTU-01), alone and combined with amphotericin B (AmB), was evaluated in planktonic and sessile (biofilm) cells of C. neoformans.ResultsBTU-01 alone exhibited a fungistatic activity with minimal inhibitory concentrations (MICs) ranging from 31.25 to 62.5 μg/mL for planktonic cells; and sessile MICs ranging from 125.0 to 1000.0 μg/mL. BTU-01 caused a concentration-dependent inhibitory activity on cryptococcal urease and did not interfere with plasma membrane fluidity. Molecular docking was performed on Canavalia ensiformis urease, and BTU-01 showed relevant interactions with the enzyme. The combination of BTU-01 and AmB exhibited synergistic fungicidal activity against planktonic and sessile cells of C. neoformans. Microscopic analysis of C. neoformans treated with BTU-01, alone or combined with AmB, revealed a reduction in cell and capsule sizes, changes in the morphology of planktonic cells; a significant decrease in the number of cells within the biofilm; and absence of exopolymeric matrix surrounding the sessile cells. Neither hemolytic activity nor cytotoxicity to mammalian cells was detected for BTU-01, alone or combined with AmB, at concentrations that exhibited antifungal activity. BTU-01 also displayed drug-likeness properties.ConclusionThese results indicate the potential of BTU-01, for the development of new strategies for controlling C. neoformans infections.

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Section: Resultsmentioning

confidence: 99%

Synergistic antifungal interaction of N-(butylcarbamothioyl) benzamide and amphotericin B against Cryptococcus neoformans

Andriani

Spoladori²,

Fábris³

et al. 2023

Front. Microbiol.

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“…Cryptococcal-related mortality is highest during the first 12 weeks following diagnosis 34,39,40 . Ten-week mortality under routine care conditions ranges from 19-50% in low-and middleincome countries (LMICs), to less than 20% in high-income countries 8,[41][42][43][44][45] . Prognosis in clinical trials conducted in LMICs has improved in the past years (10-week mortality of 24-36%) 12,13 .…”

Section: [H2] Hiv-associated Cryptococcal Meningitismentioning

confidence: 99%

Cryptococcal meningitis

Tugume,

Ssebambulidde,

Kasibante

et al. 2023

Nat Rev Dis Primers

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Cryptococcus neoformans and Cryptococcus gattii species complexes cause meningoencephalitis with high fatality rates and considerable morbidity, particularly in persons with deficient T cell mediated immunity, most commonly affecting people living with HIV. Whereas the global incidence of HIV-associated cryptococcal meningitis (HIV-CM) has decreased over the past decade, cryptococcosis still accounts for one in five AIDSrelated deaths globally due to the persistent burden of advanced HIV disease. Moreover, mortality remains high (~50%) in low resource settings. The armamentarium to decrease cryptococcosis-associated mortality is expanding: cryptococcal antigen (CrAg) screening in the serum and pre-emptive azole therapy for cryptococcal antigenemia are well established, whereas enhanced pre-emptive combination treatment regimens to improve survival of persons with cryptococcal antigenemia are under trials. Short course ( 7 days) amphotericin-based regimens combined with flucytosine are currently the preferred options for induction therapy of cryptococcal meningitis. Whether short course induction regimens improve long term morbidity such as depression, reduced neurocognitive performance and physical disability among survivors is subject to further study. Here, we discuss underlying immunology, changing epidemiology, and updates on management of cryptococcal meningitis with emphasis on HIV-associated disease.

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“…The drug is efficient for the treatment of cryptococcosis when combined with amphotericin B 39,40 . However, its use as a single antifungal agent is discouraged owing to its significant adverse effects, in particular, hepatotoxicity, myelotoxicity, and resistance when used in monotherapy, thereby compromising therapeutic success 8,[41][42][43] .…”

Section: Conventional Therapymentioning

confidence: 99%

Searching for new antifungals for the treatment of cryptococcosis

Sousa

Almeida

Frickmann

et al. 2023

Rev. Soc. Bras. Med. Trop.

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There is a consensus that the antifungal repertoire for the treatment of cryptococcal infections is limited. Standard treatment involves the administration of an antifungal drug derived from natural sources (i.e., amphotericin B) and two other drugs developed synthetically (i.e., flucytosine and fluconazole). Despite treatment, the mortality rates associated with fungal cryptococcosis are high. Amphotericin B and flucytosine are toxic, require intravenous administration, and are usually unavailable in low-income countries because of their high cost. However, fluconazole is cost-effective, widely available, and harmless with regard to its side effects. However, fluconazole is a fungistatic agent that has contributed considerably to the increase in fungal resistance and frequent relapses in patients with cryptococcal meningitis. Therefore, there is an unquestionable need to identify new alternatives or adjuvants to conventional drugs for the treatment of cryptococcosis. A potential antifungal agent should be able to kill cryptococci and "bypass" the virulence mechanism of the yeast. Furthermore, it should have fungicidal action, low toxicity, high selectivity, easily penetrate the central nervous system, and widely available.In this review, we describe cryptococcosis, its conventional therapy, and failures arising from the use of drugs traditionally considered to be the reference standard. Additionally, we present the approaches used for the discovery of new drugs to counteract cryptococcosis, ranging from the conventional screening of natural products to the inclusion of structural modifications to optimize anticryptococcal activity, as well as drug repositioning and combined therapies.

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HIV-Associated Cryptococcal Meningitis Patients Treated with Amphotericin B Deoxycholate Plus Flucytosine under Routine Care Conditions in a Referral Center in São Paulo, Brazil

Cited by 4 publications

References 46 publications

Synergistic antifungal interaction of N-(butylcarbamothioyl) benzamide and amphotericin B against Cryptococcus neoformans

Synergistic antifungal interaction of N-(butylcarbamothioyl) benzamide and amphotericin B against Cryptococcus neoformans

Cryptococcal meningitis

Searching for new antifungals for the treatment of cryptococcosis

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