Editing Cryptococcus neoformans (section)

==Treatment==
[[Image:Cryptococcosis of lung in patient with AIDS. Mucicarmine stain 962 lores.jpg|thumb|right|250px|''C. neoformans'' seen in the lung of a patient with AIDS. Mucicarmine stain is used in this case, staining the inner capsule of the organism red.]]
Cryptococcosis that does not affect the central nervous system can be treated with [[fluconazole]] alone.

It was recommended in 2000 that cryptococcal meningitis be treated for two weeks with intravenous [[amphotericin B]] 0.7–1.0&nbsp;mg/kg per day and oral [[flucytosine]] 100&nbsp;mg/kg per day (or [[intravenous]] flucytosine 75&nbsp;mg/kg per day{{Citation needed|date=November 2024}}day if the patient is unable to swallow), followed by oral fluconazole 400–800&nbsp;mg daily for ten weeks<ref name=":0">{{cite journal |last1=Melhem |first1=Marcia |last2=Júnior |first2=Diniz |last3=Takahashi |first3=Juliana |last4=Macioni |first4=Milena |last5=Oliveira |first5=Lidiane |last6=Siufi de Araújo |first6=Lisandra |last7=Fava |first7=Wellington |last8=Bonfietti |first8=Lucas |last9=Paniago |first9=Anamaria |last10=Venturini |first10=James |last11=Espinel-Ingroff |first11=Ana |display-authors= |date=29 January 2024 |title=Antifungal Resistance in Cryptococcal Infections |journal=Pathogens |volume=13 |issue=2 |pages=128 |doi=10.3390/pathogens13020128 |doi-access=free |pmid=38392866 |pmc=10891860 }}</ref> and then 200&nbsp;mg daily for at least one year and until the patient's [[CD4]] count is above 200 cells/mcl.<ref>{{cite journal | title=Discontinuation of secondary prophylaxis for cryptococcal meningitis in HIV-infected patients responding to highly active antiretroviral therapy | journal=AIDS | volume=14 | issue=16 | year=2000 | pages=2615–26 |vauthors=Martínez E, García-Viejo MA, Marcos MA |pmid=11101078 | doi=10.1097/00002030-200011100-00029 |display-authors=etal| doi-access=free }}</ref><ref name=":2">{{cite journal |last1=Diehl |first1=Camila |last2=Pinzan |first2=Camila |last3=Alves de Castro |first3=Patrícia |last4=Delbaje |first4=Endrews |last5=García Carnero |first5=Laura |last6=Sánchez-León |first6=Eddy |last7=Bhalla |first7=Kabir |last8=Kronstad |first8=James |last9=Kim |first9=Dong-gyu |last10=Doering |first10=Tamara |last11=Alkhazraji |first11=Sondus |last12=Misha |first12=Nagendra |last13=Idrahin |first13=Ashraf |last14=Yoshimura |first14=Mami |last15=Goldman |first15=Gustavo |display-authors= |date=25 June 2024 |title=Brilacidin, a novel antifungal agent against Cryptococcus neoformans |journal=mBio |volume=15 |issue=2 |pages=e01031-24 |doi=10.1128/mbio.01031-24 |pmid=38916308 |pmc=11253610 }}</ref>  [[Flucytosine]] is a generic, off-patent medicine, but the cost of two weeks of flucytosine therapy is about [[US$]]10,000,{{Citation needed|date=November 2024|reason=Also, when?}} so that flucytosine has been unavailable in low- and middle-income countries. In 1970, flucytosine was available in Africa.<ref>{{cite journal |vauthors=Mpairwe Y, Patel KM | year = 1970 | title = Cryptococcal meningitis in Mulago Hospital, Kampala | journal = East Afr Med J. | volume = 47 | issue = 8| pages = 445–7 | pmid = 5479794 }}</ref>  A dose of 200&nbsp;mg/kg per day of flucytosine is associated with more side effects but is not more effective.{{Citation needed|date=November 2024}}

A single high dose of liposomal amphotericin B with 14 days of flucytosine and fluconazole is recommended by the newest WHO guideline for cryptococcal meningitis.<ref>{{cite web | url=https://www.who.int/news/item/20-04-2022-rapid-advice-new-guidelines-for-simpler-safer-treatment-for-cryptococcal-disease-in-plhiv | title=New guidelines from WHO recommend a simpler, safer treatment for cryptococcal disease in people living with HIV }}</ref> A new study found that brain glucose can trigger amphotericin B (AmB) tolerance of ''C. neoformans'' during meningitis which means it needs longer treatment time to kill the fungal cells. The study found that the brain glucose induced AmB tolerance of ''C. neoformans'' via glucose repression activator Mig1. Mig1 inhibits the production of ergosterol, the target of AmB, and promotes the production of inositol phosphoryl ceramide (IPC), which competes with AmB for ergosterol to limit AmB efficacy in mouse brain and human CSF. Strikingly, Results of this study indicated that IPC synthase inhibitor aureobasidin A (AbA) can enhance the anti-cryptococcal activity of AmB. AbA+AmB AmB had an even better therapeutic effect in a mouse model of cryptococcal meningitis than AmB+flucytosine which may bring new hope for the treatment of Cryptococcal meningitis.<ref name=chen/>

In Africa, oral fluconazole at a rate of 200&nbsp;mg daily is often used. However, this does not result in cure, because it merely suppresses the fungus and does not kill it; viable fungus can continue to be grown from [[cerebrospinal fluid]] of patients not having taken fluconazole for many months. An increased dose of 400&nbsp;mg daily does not improve outcomes,<ref>{{cite journal | title=Outcome of AIDS-associated cryptococcal meningitis initially treated with 200 mg/day or 400 mg/day of fluconazole |author1=CF Schaars |author2=Meintjes GA |author3=Morroni C | journal=BMC Infect Dis | year=2006 | volume=6 | pages=118 | doi=10.1186/1471-2334-6-118 | pmid=16846523 | pmc=1540428 |display-authors=etal|hdl=11427/14193 |doi-access=free }}</ref> but prospective studies from [[Uganda]] and Malawi reported that higher doses of 1200&nbsp;mg per day have more fungicidal activity.<ref>{{cite journal |vauthors=Longley N, Muzoora C, Taseera K, Mwesigye J, Rwebembera J, Chakera A, Wall E, Andia I, Jaffar S, Harrison TS | year = 2008 | title = Dose response effect of high-dose fluconazole for HIV-associated cryptococcal meningitis in southwestern Uganda | journal = Clin Infect Dis | volume = 47 | issue = 12| pages = 1556–61 | doi = 10.1086/593194 | pmid=18990067| doi-access = free }}</ref> The outcomes with fluconazole monotherapy have 30% worse survival than amphotericin-based therapies, in a recent systematic review.<ref>{{cite journal |vauthors=Rajasingham R, Rolfes MA, Birkenkamp KE, Meya DB, Boulware DR | year = 2012 | title = Cryptococcal meningitis treatment strategies in resource-limited settings: a cost-effectiveness analysis | journal = PLOS Med | volume = 9 | issue = 9| page = e1001316 | doi = 10.1371/journal.pmed.1001316 | pmid = 23055838 | pmc=3463510 | doi-access = free }}</ref>

The current treatment options for cryptococcosis are not optimal for treatment.<ref name=":0" /> AmB is highly toxic to humans, and both fluconazole and flucytosine have been shown to cause development of drug resistanse in ''C. neoformans''. A recent study from 2024 suggested brilacidin as an alternative treatment option.<ref name=":2" /> Brilacidin was shown to be non-toxic and it caused no drug resistance development in ''C. neoformans'', while still being efficient at causing fungal mortality. Brilacidin enhances permiability of the cell wall and membrane by binding to ergosterol and disrupting its distribution. It also affects the cell wall integrity pathway and disrupts calsium metabolism. Through these methods it not only causes cell mortality on its own, but also enables more effective use of other antifungal agents such as AmB against ''C. neoformans.''