A escolha do tratamento depende dos locais de envolvimento, do quadro imunológico do paciente e da gravidade da doença. A determinação da gravidade da doença se baseia no julgamento clínico.
O tratamento da meningite criptocócica e de outras formas de criptococose extrapulmonar geralmente é iniciado com uma formulação de anfotericina B em combinação com flucitosina oral.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
Formulações lipídicas ou lipossomais de anfotericina B são preferenciais à anfotericina B desoxicolato, quando disponíveis, porque são eficazes para criptococose e apresentam menor toxicidade.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
[62]Botero Aguirre JP, Restrepo Hamid AM. Amphotericin B deoxycholate versus liposomal amphotericin B: effects on kidney function. Cochrane Database Syst Rev. 2015 Nov 23;(11):CD010481.
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD010481.pub2/full
http://www.ncbi.nlm.nih.gov/pubmed/26595825?tool=bestpractice.com
A anfotericina B desoxicolato está associada a comprometimento renal, acidose tubular renal, hipocalemia, hipomagnesemia e anemia.[63]Meya DB, Williamson PR. Cryptococcal disease in diverse hosts. N Engl J Med. 2024 May 2;390(17):1597-610.
http://www.ncbi.nlm.nih.gov/pubmed/38692293?tool=bestpractice.com
A adição de flucitosina à anfotericina B durante o tratamento agudo pode causar a eliminação mais rápida da criptococose do líquido cefalorraquidiano (LCR).[63]Meya DB, Williamson PR. Cryptococcal disease in diverse hosts. N Engl J Med. 2024 May 2;390(17):1597-610.
http://www.ncbi.nlm.nih.gov/pubmed/38692293?tool=bestpractice.com
O fluconazol é usado para a terapia de manutenção e de consolidação nos pacientes com HIV com meningoencefalite criptocócica, podendo também ser utilizado como monoterapia para os pacientes com formas mais leves de infecção que não envolvam o sistema nervoso central (SNC).[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
[64]Jarvis JN, Dromer F, Harrison TS, et al. Managing cryptococcosis in the immunocompromised host. Curr Opin Infect Dis. 2008 Dec;21(6):596-603.
http://www.ncbi.nlm.nih.gov/pubmed/18978527?tool=bestpractice.com
[65]Lewis JS 2nd, Graybill JR. Fungicidal versus Fungistatic: what's in a word? Expert Opin Pharmacother. 2008 Apr;9(6):927-35.
http://www.ncbi.nlm.nih.gov/pubmed/18377336?tool=bestpractice.com
Os antifúngicos azólicos e a flucitosina devem ser evitados no primeiro trimestre de gestação, em razão do risco de teratogenicidade; eles só devem ser usados durante a gestação se os benefícios superarem os riscos.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
[66]Pursley TJ, Blomquist IK, Abraham J, et al. Fluconazole-induced congenital anomalies in three infants. Clin Infect Dis. 1996 Feb;22(2):336-40.
http://www.ncbi.nlm.nih.gov/pubmed/8838193?tool=bestpractice.com
A consideração do uso de flucitosina deve ser limitada ao terceiro trimestre.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
As mulheres que estiverem em uso de antifúngicos azólicos no período pós-parto não devem amamentar. A maioria dos casos relatados de criptococose durante a gestação foram tratados com anfotericina B, com desfechos favoráveis tanto para a mãe quanto para o bebê.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
[28]Nakamura S, Izumikawa K, Seki M, et al. Pulmonary cryptococcosis in late pregnancy and review of published literature. Mycopathologia. 2009 Mar;167(3):125-31.
http://www.ncbi.nlm.nih.gov/pubmed/18931938?tool=bestpractice.com
Pessoas sem HIV: doença pulmonar focal leve a moderada
Não há estudos randomizados para tratamento da criptococose pulmonar.[35]Chang CC, Harrison TS, Bicanic TA, et al. Global guideline for the diagnosis and management of cryptococcosis: an initiative of the ECMM and ISHAM in cooperation with the ASM. Lancet Infect Dis. 2024 Aug;24(8):e495-512. [Erratum in: Lancet Infect Dis. 2024 Aug;24(8):e485.]
https://www.idsociety.org/globalassets/idsa/practice-guidelines/diagnosis-and-management-of-crypto/global-guideline-for-the-diagnosis-and-management-of-cryptococcosis-an-initiative-of-the-ecmm-and-isham-in-cooperation-with-the-asm.pdf
http://www.ncbi.nlm.nih.gov/pubmed/38346436?tool=bestpractice.com
As opções de tratamento são baseadas em diretrizes globais e dos EUA.[35]Chang CC, Harrison TS, Bicanic TA, et al. Global guideline for the diagnosis and management of cryptococcosis: an initiative of the ECMM and ISHAM in cooperation with the ASM. Lancet Infect Dis. 2024 Aug;24(8):e495-512. [Erratum in: Lancet Infect Dis. 2024 Aug;24(8):e485.]
https://www.idsociety.org/globalassets/idsa/practice-guidelines/diagnosis-and-management-of-crypto/global-guideline-for-the-diagnosis-and-management-of-cryptococcosis-an-initiative-of-the-ecmm-and-isham-in-cooperation-with-the-asm.pdf
http://www.ncbi.nlm.nih.gov/pubmed/38346436?tool=bestpractice.com
[60]Limper AH, Knox KS, Sarosi GA, et al; American Thoracic Society Fungal Working Group. An official American Thoracic Society statement: treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med. 2011 Jan 1;183(1):96-128.
https://www.atsjournals.org/doi/10.1164/rccm.2008-740ST
http://www.ncbi.nlm.nih.gov/pubmed/21193785?tool=bestpractice.com
[67]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322.
https://academic.oup.com/cid/article/50/3/291/392360
http://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com
O fluconazol oral é o tratamento antifúngico de primeira escolha para doença pulmonar focal leve a moderada causada por Cryptococcus neoformans, e criptococomas pequenos e únicos causados por Cryptococcus variante gattii.[35]Chang CC, Harrison TS, Bicanic TA, et al. Global guideline for the diagnosis and management of cryptococcosis: an initiative of the ECMM and ISHAM in cooperation with the ASM. Lancet Infect Dis. 2024 Aug;24(8):e495-512. [Erratum in: Lancet Infect Dis. 2024 Aug;24(8):e485.]
https://www.idsociety.org/globalassets/idsa/practice-guidelines/diagnosis-and-management-of-crypto/global-guideline-for-the-diagnosis-and-management-of-cryptococcosis-an-initiative-of-the-ecmm-and-isham-in-cooperation-with-the-asm.pdf
http://www.ncbi.nlm.nih.gov/pubmed/38346436?tool=bestpractice.com
[60]Limper AH, Knox KS, Sarosi GA, et al; American Thoracic Society Fungal Working Group. An official American Thoracic Society statement: treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med. 2011 Jan 1;183(1):96-128.
https://www.atsjournals.org/doi/10.1164/rccm.2008-740ST
http://www.ncbi.nlm.nih.gov/pubmed/21193785?tool=bestpractice.com
[67]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322.
https://academic.oup.com/cid/article/50/3/291/392360
http://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com
A duração da terapia é normalmente de 6 a 12 meses e é orientada pela resolução dos sintomas.[35]Chang CC, Harrison TS, Bicanic TA, et al. Global guideline for the diagnosis and management of cryptococcosis: an initiative of the ECMM and ISHAM in cooperation with the ASM. Lancet Infect Dis. 2024 Aug;24(8):e495-512. [Erratum in: Lancet Infect Dis. 2024 Aug;24(8):e485.]
https://www.idsociety.org/globalassets/idsa/practice-guidelines/diagnosis-and-management-of-crypto/global-guideline-for-the-diagnosis-and-management-of-cryptococcosis-an-initiative-of-the-ecmm-and-isham-in-cooperation-with-the-asm.pdf
http://www.ncbi.nlm.nih.gov/pubmed/38346436?tool=bestpractice.com
[60]Limper AH, Knox KS, Sarosi GA, et al; American Thoracic Society Fungal Working Group. An official American Thoracic Society statement: treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med. 2011 Jan 1;183(1):96-128.
https://www.atsjournals.org/doi/10.1164/rccm.2008-740ST
http://www.ncbi.nlm.nih.gov/pubmed/21193785?tool=bestpractice.com
[67]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322.
https://academic.oup.com/cid/article/50/3/291/392360
http://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com
O acompanhamento por 1 ano é recomendado porque a criptococose pulmonar pode se disseminar.[60]Limper AH, Knox KS, Sarosi GA, et al; American Thoracic Society Fungal Working Group. An official American Thoracic Society statement: treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med. 2011 Jan 1;183(1):96-128.
https://www.atsjournals.org/doi/10.1164/rccm.2008-740ST
http://www.ncbi.nlm.nih.gov/pubmed/21193785?tool=bestpractice.com
O fluconazol é recomendado tanto para receptores não transplantados quanto para receptores de transplante.[67]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322.
https://academic.oup.com/cid/article/50/3/291/392360
http://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com
Se o fluconazol não for uma opção, itraconazol, voriconazol ou posaconazol por via oral podem ser administrados por 6 a 12 meses.[60]Limper AH, Knox KS, Sarosi GA, et al; American Thoracic Society Fungal Working Group. An official American Thoracic Society statement: treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med. 2011 Jan 1;183(1):96-128.
https://www.atsjournals.org/doi/10.1164/rccm.2008-740ST
http://www.ncbi.nlm.nih.gov/pubmed/21193785?tool=bestpractice.com
[67]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322.
https://academic.oup.com/cid/article/50/3/291/392360
http://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com
Se a terapia com antifúngico azólico for contraindicada (por exemplo, gestação), discuta as opções de tratamento com um especialista em doenças infecciosas. Em gestantes sem evidência de doença do SNC ou infecção disseminada e sem sintomas significativos, pode-se considerar o monitoramento cuidadoso e o adiamento da terapia antifúngica até depois da gestação.[67]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322.
https://academic.oup.com/cid/article/50/3/291/392360
http://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com
Geralmente, o fluconazol é bem tolerado. Os efeitos adversos mais comuns são náuseas, dor abdominal e rash cutâneo. Embora tenha sido relatada uma resistência do C neoformans ao fluconazol, ela é rara em alguns países, como nos EUA, e os testes de suscetibilidade não são rotineiramente recomendados, a menos que haja recidiva ou falha do tratamento.[64]Jarvis JN, Dromer F, Harrison TS, et al. Managing cryptococcosis in the immunocompromised host. Curr Opin Infect Dis. 2008 Dec;21(6):596-603.
http://www.ncbi.nlm.nih.gov/pubmed/18978527?tool=bestpractice.com
[67]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322.
https://academic.oup.com/cid/article/50/3/291/392360
http://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com
[68]Brandt ME, Pfaller MA, Hajjeh RA, et al; Cryptococcal Disease Active Surveillance Group. Trends in antifungal drug susceptibility of Cryptococcus neoformans isolates in the United States: 1992 to 1994 and 1996 to 1998. Antimicrob Agents Chemother. 2001 Nov;45(11):3065-9.
https://journals.asm.org/doi/10.1128/aac.45.11.3065-3069.2001
http://www.ncbi.nlm.nih.gov/pubmed/11600357?tool=bestpractice.com
Pacientes imunossuprimidos com criptococose pulmonar devem ser submetidos a uma punção lombar para descartar doença assintomática do SNC. A punção lombar deve ser considerada para pacientes imunocompetentes.[67]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322.
https://academic.oup.com/cid/article/50/3/291/392360
http://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com
Considere a cirurgia se os sintomas não responderem à terapia antifúngica. A cirurgia pode auxiliar no diagnóstico de anormalidades radiográficas persistentes.[67]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322.
https://academic.oup.com/cid/article/50/3/291/392360
http://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com
Pessoas sem HIV: receptor de transplante de órgãos sólidos com doença do SNC ou doença pulmonar grave ou doença disseminada
O tratamento de indução é realizado com anfotericina B lipossomal ou complexo lipídico de anfotericina B associado a flucitosina por pelo menos 2 semanas.[67]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322.
https://academic.oup.com/cid/article/50/3/291/392360
http://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com
A anfotericina B desoxicolato não é recomendada como terapia de primeira linha devido à maior frequência de comprometimento renal em receptores de transplante e ao risco associado de nefrotoxicidade. As doses antifúngicas devem ser cuidadosamente monitoradas e as interações medicamentosas com imunossupressores devem ser consideradas.[67]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322.
https://academic.oup.com/cid/article/50/3/291/392360
http://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com
A terapia de indução é seguida por terapia de consolidação com fluconazol por 8 semanas e, em seguida, terapia de manutenção com fluconazol por pelo menos 6 a 12 meses.[67]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322.
https://academic.oup.com/cid/article/50/3/291/392360
http://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com
Pacientes com cultura do LCR inicial positiva devem passar por uma nova punção lombar após 2 semanas, ou antes, caso haja preocupações sobre falha do tratamento ou aumento da pressão intracraniana.[67]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322.
https://academic.oup.com/cid/article/50/3/291/392360
http://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com
A mediana de tempo para cultura negativa do LCR após o início do tratamento é de 10 dias.[69]Singh N, Lortholary O, Alexander BD, et al. Antifungal management practices and evolution of infection in organ transplant recipients with Cryptococcus neoformans infection. Transplantation. 2005 Oct 27;80(8):1033-9.
https://journals.lww.com/transplantjournal/fulltext/2005/10270/antifungal_management_practices_and_evolution_of.6.aspx
http://www.ncbi.nlm.nih.gov/pubmed/16278582?tool=bestpractice.com
Revise os medicamentos imunossupressores do paciente. Os imunossupressores devem ser reduzidos gradualmente ou sequencialmente; considere reduzir a dose de corticosteroide primeiro.[67]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322.
https://academic.oup.com/cid/article/50/3/291/392360
http://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com
A retirada abrupta pode precipitar a síndrome inflamatória da reconstituição imune (SIRI) ou a rejeição de órgãos.[67]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322.
https://academic.oup.com/cid/article/50/3/291/392360
http://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com
Pessoas sem HIV: não receptor de transplante de órgãos com doença do SNC ou doença pulmonar grave ou alto título de CrAg sérico
Título de CrAg ≥1:512 indica alta carga fúngica e requer tratamento intensivo.[67]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322.
https://academic.oup.com/cid/article/50/3/291/392360
http://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com
Pacientes com meningite criptocócica sem HIV ou história de transplante de órgão sólido são uma população heterogênea, incluindo pessoas imunocompetentes saudáveis, bem como pessoas com outros comprometimentos imunológicos (por exemplo, câncer, cirrose, doença do tecido conjuntivo e uso prolongado de corticosteroides).[35]Chang CC, Harrison TS, Bicanic TA, et al. Global guideline for the diagnosis and management of cryptococcosis: an initiative of the ECMM and ISHAM in cooperation with the ASM. Lancet Infect Dis. 2024 Aug;24(8):e495-512. [Erratum in: Lancet Infect Dis. 2024 Aug;24(8):e485.]
https://www.idsociety.org/globalassets/idsa/practice-guidelines/diagnosis-and-management-of-crypto/global-guideline-for-the-diagnosis-and-management-of-cryptococcosis-an-initiative-of-the-ecmm-and-isham-in-cooperation-with-the-asm.pdf
http://www.ncbi.nlm.nih.gov/pubmed/38346436?tool=bestpractice.com
[67]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322.
https://academic.oup.com/cid/article/50/3/291/392360
http://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com
Os esquemas de tratamento e a duração são adaptados às necessidades individuais.[35]Chang CC, Harrison TS, Bicanic TA, et al. Global guideline for the diagnosis and management of cryptococcosis: an initiative of the ECMM and ISHAM in cooperation with the ASM. Lancet Infect Dis. 2024 Aug;24(8):e495-512. [Erratum in: Lancet Infect Dis. 2024 Aug;24(8):e485.]
https://www.idsociety.org/globalassets/idsa/practice-guidelines/diagnosis-and-management-of-crypto/global-guideline-for-the-diagnosis-and-management-of-cryptococcosis-an-initiative-of-the-ecmm-and-isham-in-cooperation-with-the-asm.pdf
http://www.ncbi.nlm.nih.gov/pubmed/38346436?tool=bestpractice.com
[67]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322.
https://academic.oup.com/cid/article/50/3/291/392360
http://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com
Terapia de indução antifúngica
As diretrizes dos EUA recomendam terapia de indução com anfotericina B desoxicolato associada a flucitosina.[67]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322.
https://academic.oup.com/cid/article/50/3/291/392360
http://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com
A terapia de indução geralmente é administrada por pelo menos 4 semanas. O período de indução pode ser reduzido para 2 semanas em pacientes que foram diagnosticados precocemente, tiveram uma excelente resposta à terapia de indução e não apresentaram nenhuma comorbidade não controlada ou comprometimento imunológico.[67]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322.
https://academic.oup.com/cid/article/50/3/291/392360
http://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com
Um total de 6 semanas de terapia de indução pode ser administrado a pacientes com complicações neurológicas.[67]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322.
https://academic.oup.com/cid/article/50/3/291/392360
http://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com
A punção lombar é realizada após 2 semanas de tratamento; pacientes com LCR persistentemente positivo podem necessitar de um período de indução mais longo.[67]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322.
https://academic.oup.com/cid/article/50/3/291/392360
http://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com
Formulações lipídicas ou lipossomais de anfotericina B são usadas se o paciente não tolerar a anfotericina B desoxicolato.[67]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322.
https://academic.oup.com/cid/article/50/3/291/392360
http://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com
Formulações lipídicas ou lipossomais de anfotericina B podem ser usadas nas 2 semanas seguintes do período de indução se ocorrer toxicidade com anfotericina B desoxicolato.[67]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322.
https://academic.oup.com/cid/article/50/3/291/392360
http://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com
Foi demonstrado que a flucitosina é um forte preditor independente de esterilização do LCR em 2 semanas em pessoas com doença do SNC.[64]Jarvis JN, Dromer F, Harrison TS, et al. Managing cryptococcosis in the immunocompromised host. Curr Opin Infect Dis. 2008 Dec;21(6):596-603.
http://www.ncbi.nlm.nih.gov/pubmed/18978527?tool=bestpractice.com
Entretanto, a redução da contagem plaquetária ou de neutrófilos exclui o uso da flucitosina.[60]Limper AH, Knox KS, Sarosi GA, et al; American Thoracic Society Fungal Working Group. An official American Thoracic Society statement: treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med. 2011 Jan 1;183(1):96-128.
https://www.atsjournals.org/doi/10.1164/rccm.2008-740ST
http://www.ncbi.nlm.nih.gov/pubmed/21193785?tool=bestpractice.com
Se a terapia de indução não incluir flucitosina, considere a monoterapia com anfotericina B lipossomal, complexo lipídico de anfotericina B ou anfotericina B desoxicolato por pelo menos 4 a 6 semanas.[67]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322.
https://academic.oup.com/cid/article/50/3/291/392360
http://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com
Os efeitos adversos associados à anfotericina B incluem elevação da creatinina sérica, hipocalemia, hipomagnesemia, acidose tubular renal, sequelas hematológicas, náuseas, vômitos, febre e calafrios.[1]Chayakulkeeree M, Perfect JR. Cryptococcosis. Infect Dis Clin North Am. 2006 Sep;20(3):507-44.
http://www.ncbi.nlm.nih.gov/pubmed/16984867?tool=bestpractice.com
[67]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322.
https://academic.oup.com/cid/article/50/3/291/392360
http://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com
A função renal deve ser monitorada com frequência nos pacientes que estiverem recebendo ciclos prolongados (>2 semanas) de terapia com anfotericina B e flucitosina, e deve-se fazer o ajuste apropriado da dosagem (preferencialmente por meio do monitoramento dos níveis séricos de flucitosina medidos 2 horas após a dose e após 3 a 5 doses terem sido administradas com níveis ideais de 25-100 mg/L) a fim de se prevenir supressão da medula óssea e toxicidade gastrointestinal. Caso não seja possível determinar os níveis de flucitosina, podem ser feitos hemogramas com frequência (isto é, pelo menos duas vezes por semana) para detectar citopenia.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
terapia de consolidação antifúngica
A terapia de consolidação é feita com fluconazol oral.[35]Chang CC, Harrison TS, Bicanic TA, et al. Global guideline for the diagnosis and management of cryptococcosis: an initiative of the ECMM and ISHAM in cooperation with the ASM. Lancet Infect Dis. 2024 Aug;24(8):e495-512. [Erratum in: Lancet Infect Dis. 2024 Aug;24(8):e485.]
https://www.idsociety.org/globalassets/idsa/practice-guidelines/diagnosis-and-management-of-crypto/global-guideline-for-the-diagnosis-and-management-of-cryptococcosis-an-initiative-of-the-ecmm-and-isham-in-cooperation-with-the-asm.pdf
http://www.ncbi.nlm.nih.gov/pubmed/38346436?tool=bestpractice.com
[67]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322.
https://academic.oup.com/cid/article/50/3/291/392360
http://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com
A lógica para essa abordagem é o controle rápido da infecção com o esquema terapêutico mais fungicida, seguido por terapia oral menos tóxica para tratamento contínuo e prevenção da recidiva, além de minimizar a toxicidade dose-dependente da anfotericina B.[23]World Health Organization. Guidelines for diagnosing, preventing and managing cryptococcal disease among adults, adolescents and children living with HIV. Jun 2022 [internet publication].
https://www.who.int/publications/i/item/9789240052178
A fase de consolidação recomendada do tratamento consiste em um ciclo de 8 semanas com fluconazol.[67]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322.
https://academic.oup.com/cid/article/50/3/291/392360
http://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com
Após 8 semanas, o paciente deve passar a fluconazol em doses baixas como terapia de manutenção de longa duração.[67]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322.
https://academic.oup.com/cid/article/50/3/291/392360
http://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com
Terapia antifúngica de manutenção
Depois da terapia de indução e da terapia de consolidação bem-sucedidas (isto é, melhora clínica e cultura do LCR negativa), a terapia de manutenção antifúngica com fluconazol oral deve ser mantida por, pelo menos, 6 a 12 meses.[67]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322.
https://academic.oup.com/cid/article/50/3/291/392360
http://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com
Os esquemas de indução, consolidação e manutenção para o Cryptococcus variante gattii são os mesmos que para o C neoformans.[67]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322.
https://academic.oup.com/cid/article/50/3/291/392360
http://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com
A cirurgia pode ser considerada para criptococomas pulmonares muito grandes ou múltiplos.[67]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322.
https://academic.oup.com/cid/article/50/3/291/392360
http://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com
Pessoas com HIV: antigenemia assintomática isolada com baixos títulos de CrAg sérico
Os títulos baixos de CrAg sérico são <1:640 por ensaio de fluxo lateral (LFA) e <1:160 por ensaio imunoenzimático (EIE) ou aglutinação em látex.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
Todas as pessoas com HIV, incluindo aquelas assintomáticas, necessitam de terapia antifúngica preventiva devido ao alto risco de infecção disseminada ou do SNC.[67]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322.
https://academic.oup.com/cid/article/50/3/291/392360
http://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com
[70]Thursky KA, Playford EG, Seymour JF, et al. Recommendations for the treatment of established fungal infections. Intern Med J. 2008 Jun;38(6b):496-520.
http://www.ncbi.nlm.nih.gov/pubmed/18588522?tool=bestpractice.com
A coleta de amostra de LCR em pacientes totalmente assintomáticos com antigenemia criptocócica isolada é orientada pelo título de CrAg e pelo risco de doença criptocócica (por exemplo, pacientes com imunossupressão avançada que não estejam tomando terapia antirretroviral [TAR] estariam em maior risco). Pacientes de menor risco com título sérico de CrAg ≤1:80 por LFA (ou <1:20 com EIE ou aglutinação em látex) que são assintomáticos podem ser tratados sem punção lombar. Todos os pacientes sintomáticos devem ser submetidos à coleta de amostra do LCR para descartar doença do SNC.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
Pacientes com LCR normal, sem sintomas e baixos títulos séricos de CrAg são tratados com fluconazol por 6 meses. Doses mais altas são usadas nas primeiras 12 semanas de tratamento.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
Pessoas com HIV: infiltrados pulmonares focais não relacionados ao SNC com sintomas leves e CrAg sérico negativo
Para pacientes com sintomas leves e infiltrados pulmonares focais, o tratamento com um antifúngico associado a TAR é apropriado.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
Todos os pacientes devem ser submetidos a testes no LCR para descartar doença no SNC.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
Terapia antifúngica
Em geral, o fluconazol oral é o tratamento antifúngico de primeira escolha nesses pacientes. As diretrizes dos EUA recomendam tratamento oral com fluconazol na mesma dose por 6 a 12 meses, com duração orientada pela resolução dos sintomas.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
Outras diretrizes podem ser diferentes. Por exemplo, as diretrizes da Organização Mundial da Saúde (OMS) recomendam o tratamento oral com fluconazol por 2 semanas com uma dose mais alta e 8 semanas com uma dose mais baixa, seguido por terapia de manutenção.[23]World Health Organization. Guidelines for diagnosing, preventing and managing cryptococcal disease among adults, adolescents and children living with HIV. Jun 2022 [internet publication].
https://www.who.int/publications/i/item/9789240052178
O fluconazol pode ser descontinuado de acordo com a resposta à TAR (isto é, contagens de CD4 ≥100 células/microlitro, cargas virais indetectáveis na TAR, mínimo de 1 ano de terapia de manutenção crônica com antifúngico azólico após o tratamento bem-sucedido da criptococose).[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
TAR
Pessoas com HIV: doença do SNC e/ou disseminada; doença extrapulmonar não relacionada ao SNC, doença pulmonar difusa ou sintomas não relacionados ao SNC com LCR normal e altos títulos de CrAg sérico
Pacientes assintomáticos com altos títulos séricos de CrAg (isto é, ≥1:160 pelo ensaio de fluxo lateral) devem receber o mesmo tratamento que pacientes com doença do SNC, devido ao aumento do risco de mortalidade e envolvimento do SNC.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
Terapia de indução antifúngica
De acordo com as diretrizes dos EUA, o esquema de indução de primeira escolha é de 2 semanas de anfotericina B lipossomal intravenosa associada a flucitosina oral.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
A anfotericina B desoxicolato pode ser usada como uma formulação alternativa se o risco de disfunção renal for baixo ou se o custo for proibitivo.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
[62]Botero Aguirre JP, Restrepo Hamid AM. Amphotericin B deoxycholate versus liposomal amphotericin B: effects on kidney function. Cochrane Database Syst Rev. 2015 Nov 23;(11):CD010481.
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD010481.pub2/full
http://www.ncbi.nlm.nih.gov/pubmed/26595825?tool=bestpractice.com
Para pacientes em ambientes com recursos limitados, a OMS recomenda um esquema de indução que consiste em uma única dose alta de anfotericina B lipossomal com 14 dias de flucitosina e fluconazol.[23]World Health Organization. Guidelines for diagnosing, preventing and managing cryptococcal disease among adults, adolescents and children living with HIV. Jun 2022 [internet publication].
https://www.who.int/publications/i/item/9789240052178
Um esquema alternativo recomendado pela OMS (quando a anfotericina B lipossomal não estiver disponível) é 1 semana de anfotericina B desoxicolato e flucitosina seguida por 1 semana de fluconazol.[23]World Health Organization. Guidelines for diagnosing, preventing and managing cryptococcal disease among adults, adolescents and children living with HIV. Jun 2022 [internet publication].
https://www.who.int/publications/i/item/9789240052178
[71]Tenforde MW, Shapiro AE, Rouse B, et al. Treatment for HIV-associated cryptococcal meningitis. Cochrane Database Syst Rev. 2018 Jul 25;(7):CD005647.
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD005647.pub3/full
http://www.ncbi.nlm.nih.gov/pubmed/30045416?tool=bestpractice.com
[
]
For people with HIV‐associated cryptococcal meningitis, how do one‐ and two‐week induction therapies compare?/cca.html?targetUrl=https://www.cochranelibrary.com/cca/doi/10.1002/cca.2681/fullMostre-me a resposta
[
]
For people with HIV‐associated cryptococcal meningitis, how do different two‐week induction therapies compare?/cca.html?targetUrl=https://www.cochranelibrary.com/cca/doi/10.1002/cca.2683/fullMostre-me a resposta
Os esquemas de indução alternativos recomendados pelas diretrizes dos EUA são 2 semanas de complexo lipídico de anfotericina B intravenoso associado a flucitosina oral, ou 1 semana de anfotericina B desoxicolato associada a flucitosina oral, seguida de 1 semana de fluconazol oral.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
A monoterapia com fluconazol é acentuadamente inferior à anfotericina B na meningite criptocócica relacionada ao HIV e está associada a uma mortalidade 30% maior a 10 semanas.[72]Rajasingham R, Rolfes MA, Birkenkamp KE, et al. Cryptococcal meningitis treatment strategies in resource-limited settings: a cost-effectiveness analysis. PLoS Med. 2012 Sep 25;9(9):e1001316.
https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1001316
http://www.ncbi.nlm.nih.gov/pubmed/23055838?tool=bestpractice.com
As diretrizes da OMS observam que os esquemas contendo flucitosina são superiores e devem ser usados sempre que possível.[23]World Health Organization. Guidelines for diagnosing, preventing and managing cryptococcal disease among adults, adolescents and children living with HIV. Jun 2022 [internet publication].
https://www.who.int/publications/i/item/9789240052178
A flucitosina mostrou ser um forte preditor independente da esterilização do LCR com 2 semanas, tanto em pessoas com HIV quanto na população total de pacientes.[12]Dromer F, Mathoulin-Pelissier S, Launay O, et al; French Cryptococcosis Study Group. Determinants of disease presentation and outcome during cryptococcosis: the CryptoA/D study. PLoS Med. 2007 Feb;4(2):e21.
https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.0040021
http://www.ncbi.nlm.nih.gov/pubmed/17284154?tool=bestpractice.com
[64]Jarvis JN, Dromer F, Harrison TS, et al. Managing cryptococcosis in the immunocompromised host. Curr Opin Infect Dis. 2008 Dec;21(6):596-603.
http://www.ncbi.nlm.nih.gov/pubmed/18978527?tool=bestpractice.com
Entretanto, a redução da contagem plaquetária ou de neutrófilos impossibilita o uso da flucitosina.[60]Limper AH, Knox KS, Sarosi GA, et al; American Thoracic Society Fungal Working Group. An official American Thoracic Society statement: treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med. 2011 Jan 1;183(1):96-128.
https://www.atsjournals.org/doi/10.1164/rccm.2008-740ST
http://www.ncbi.nlm.nih.gov/pubmed/21193785?tool=bestpractice.com
Os efeitos adversos associados à anfotericina B incluem elevação da creatinina sérica, hipocalemia, hipomagnesemia, acidose tubular renal, sequelas hematológicas, náuseas, vômitos, febre e calafrios.[1]Chayakulkeeree M, Perfect JR. Cryptococcosis. Infect Dis Clin North Am. 2006 Sep;20(3):507-44.
http://www.ncbi.nlm.nih.gov/pubmed/16984867?tool=bestpractice.com
[67]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322.
https://academic.oup.com/cid/article/50/3/291/392360
http://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com
A função renal deve ser monitorada com frequência nos pacientes que estiverem recebendo ciclos prolongados (>2 semanas) de terapia com anfotericina B e flucitosina, e deve-se fazer o ajuste apropriado da dosagem (preferencialmente por meio do monitoramento dos níveis séricos de flucitosina medidos 2 horas após a dose e após 3 a 5 doses terem sido administradas com níveis ideais de 25-100 mg/L) a fim de se prevenir supressão da medula óssea e toxicidade gastrointestinal.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
[67]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322.
https://academic.oup.com/cid/article/50/3/291/392360
http://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com
Caso não seja possível determinar os níveis de flucitosina, podem ser feitos hemogramas com frequência (isto é, pelo menos duas vezes por semana) para detectar citopenia.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
A punção lombar é normalmente realizada nos dias 0, 3, 7 e 14, dependendo da pressão de abertura. Os pacientes com culturas de LCR positivas após 2 semanas de terapia e sem melhora clínica devem manter a anfotericina B até que as culturas de LCR estejam negativas.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
[67]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322.
https://academic.oup.com/cid/article/50/3/291/392360
http://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com
Os pacientes com culturas positivas, mas com sinais de melhora clínica, devem continuar recebendo terapia de consolidação.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
terapia de consolidação antifúngica
A terapia de consolidação é feita com fluconazol oral.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
[23]World Health Organization. Guidelines for diagnosing, preventing and managing cryptococcal disease among adults, adolescents and children living with HIV. Jun 2022 [internet publication].
https://www.who.int/publications/i/item/9789240052178
A lógica para essa abordagem é o controle rápido da infecção com o esquema terapêutico mais fungicida, seguido por terapia oral menos tóxica para tratamento contínuo e prevenção da recidiva, além de minimizar a toxicidade dose-dependente da anfotericina B.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
[23]World Health Organization. Guidelines for diagnosing, preventing and managing cryptococcal disease among adults, adolescents and children living with HIV. Jun 2022 [internet publication].
https://www.who.int/publications/i/item/9789240052178
O itraconazol é uma opção alternativa para pacientes que não toleram o fluconazol ou se o fluconazol não estiver disponível.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
A fase de consolidação recomendada do tratamento é de pelo menos um ciclo de 8 semanas com fluconazol.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
[23]World Health Organization. Guidelines for diagnosing, preventing and managing cryptococcal disease among adults, adolescents and children living with HIV. Jun 2022 [internet publication].
https://www.who.int/publications/i/item/9789240052178
Após, pelo menos, 8 semanas, o paciente deve fazer a troca para fluconazol em doses baixas como terapia de manutenção de longa duração.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
[23]World Health Organization. Guidelines for diagnosing, preventing and managing cryptococcal disease among adults, adolescents and children living with HIV. Jun 2022 [internet publication].
https://www.who.int/publications/i/item/9789240052178
Os pacientes com culturas de LCR positivas, mas que melhoraram clinicamente após 2 semanas de terapia de indução, devem receber uma dose mais alta (1200 mg/dia) de fluconazol para terapia de consolidação, e repetir a punção lombar em 2 semanas.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
De forma alternativa, os pacientes não hospitalizados podem receber flucitosina associada a fluconazol por mais 2 semanas antes de iniciar a terapia de consolidação com um único medicamento.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
A duração da terapia de consolidação deve ser de, pelo menos, 8 semanas a partir do ponto em que as culturas do LCR estiverem negativas.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
[23]World Health Organization. Guidelines for diagnosing, preventing and managing cryptococcal disease among adults, adolescents and children living with HIV. Jun 2022 [internet publication].
https://www.who.int/publications/i/item/9789240052178
TAR
Para pacientes com meningite criptocócica, o início imediato da TAR não é recomendado, pois há um aumento do risco de mortalidade, que se acredita ser causado por SIRI.[73]Boulware DR, Meya DB, Muzoora C, et al. Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis. N Engl J Med. 2014 Jun 26;370(26):2487-98.
https://www.nejm.org/doi/full/10.1056/NEJMoa1312884
http://www.ncbi.nlm.nih.gov/pubmed/24963568?tool=bestpractice.com
[74]Eshun-Wilson I, Okwen MP, Richardson M, et al. Early versus delayed antiretroviral treatment in HIV-positive people with cryptococcal meningitis. Cochrane Database Syst Rev. 2018 Jul 24;(7):CD009012.
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD009012.pub3/full
http://www.ncbi.nlm.nih.gov/pubmed/30039850?tool=bestpractice.com
As diretrizes da OMS e dos EUA recomendam que a TAR seja iniciada 4-6 semanas após o início do tratamento antifúngico.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
[23]World Health Organization. Guidelines for diagnosing, preventing and managing cryptococcal disease among adults, adolescents and children living with HIV. Jun 2022 [internet publication].
https://www.who.int/publications/i/item/9789240052178
Para a criptococose sem envolvimento do SNC, a TAR pode ser protelada por 2 semanas após o início do tratamento antifúngico.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
Consulte HIV em adultos.
Terapia antifúngica de manutenção
Depois de uma terapia de indução e da terapia de consolidação bem-sucedidas (isto é, melhora clínica e cultura do LCR negativa após se repetir a punção lombar), a terapia de manutenção antifúngica com fluconazol oral pode ser mantida por, pelo menos, 1 ano.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
[23]World Health Organization. Guidelines for diagnosing, preventing and managing cryptococcal disease among adults, adolescents and children living with HIV. Jun 2022 [internet publication].
https://www.who.int/publications/i/item/9789240052178
O itraconazol é uma opção alternativa para pacientes que não toleram o fluconazol ou se o fluconazol não estiver disponível.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
A terapia de manutenção antifúngica pode ser descontinuada se a contagem de CD4 for ≥100 células/microlitro, com cargas virais indetectáveis após TAR, tendo o paciente recebido no mínimo 1 ano de terapia de manutenção crônica com antifúngicos azólicos após o tratamento bem-sucedido da criptococose. A terapia de manutenção deverá ser reiniciada se a contagem de CD4 diminuir para <100 células/microlitro.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
Manejo da hipertensão intracraniana
A hipertensão intracraniana, definida como uma pressão de abertura de >20 cm H₂O, medida com o paciente na posição de decúbito lateral, ocorre em até 80% dos pacientes com meningite criptocócica associada ao HIV, e quando não controlada está associada a uma resposta clínica mais desfavorável.[23]World Health Organization. Guidelines for diagnosing, preventing and managing cryptococcal disease among adults, adolescents and children living with HIV. Jun 2022 [internet publication].
https://www.who.int/publications/i/item/9789240052178
[51]Kambugu A, Meya DB, Rhein J, et al. Outcomes of cryptococcal meningitis in Uganda before and after the availability of highly active antiretroviral therapy. Clin Infect Dis. 2008 Jun 1;46(11):1694-701.
https://pmc.ncbi.nlm.nih.gov/articles/PMC2593910
http://www.ncbi.nlm.nih.gov/pubmed/18433339?tool=bestpractice.com
[52]Bicanic T, Brouwer AE, Meintjes G, et al. Relationship of cerebrospinal fluid pressure, fungal burden and outcome in patients with cryptococcal meningitis undergoing serial lumbar punctures. AIDS. 2009 Mar 27;23(6):701-6.
http://www.ncbi.nlm.nih.gov/pubmed/19279443?tool=bestpractice.com
[53]Meda J, Kalluvya S, Downs JA, et al. Cryptococcal meningitis management in Tanzania with strict schedule of serial lumbar punctures using intravenous tubing sets: an operational research study. J Acquir Immune Defic Syndr. 2014 Jun 1;66(2):e31-6.
http://www.ncbi.nlm.nih.gov/pubmed/24675586?tool=bestpractice.com
O controle da PIC elevada é essencial e envolve punção lombar terapêutica para normalizar a pressão e, quando necessário, intervenções cirúrgicas para elevação persistente.[35]Chang CC, Harrison TS, Bicanic TA, et al. Global guideline for the diagnosis and management of cryptococcosis: an initiative of the ECMM and ISHAM in cooperation with the ASM. Lancet Infect Dis. 2024 Aug;24(8):e495-512. [Erratum in: Lancet Infect Dis. 2024 Aug;24(8):e485.]
https://www.idsociety.org/globalassets/idsa/practice-guidelines/diagnosis-and-management-of-crypto/global-guideline-for-the-diagnosis-and-management-of-cryptococcosis-an-initiative-of-the-ecmm-and-isham-in-cooperation-with-the-asm.pdf
http://www.ncbi.nlm.nih.gov/pubmed/38346436?tool=bestpractice.com
[63]Meya DB, Williamson PR. Cryptococcal disease in diverse hosts. N Engl J Med. 2024 May 2;390(17):1597-610.
http://www.ncbi.nlm.nih.gov/pubmed/38692293?tool=bestpractice.com
A punção lombar terapêutica pode ser usada para reduzir a PIC elevada e foi associada a uma melhora relativa de 69% na sobrevida, independentemente da PIC inicial.[75]Rolfes MA, Hullsiek KH, Rhein J, et al. The effect of therapeutic lumbar punctures on acute mortality from cryptococcal meningitis. Clin Infect Dis. 2014 Dec 1;59(11):1607-14.
https://academic.oup.com/cid/article/59/11/1607/411943
http://www.ncbi.nlm.nih.gov/pubmed/25057102?tool=bestpractice.com
Faltam dados sobre o manejo da PIC elevada em pessoas sem HIV que têm meningite criptocócica; as recomendações de manejo são extrapoladas do tratamento de pessoas com HIV.[67]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322.
https://academic.oup.com/cid/article/50/3/291/392360
http://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com
Pressão de abertura normal na linha basal (≤20 cm H₂O)
A OMS recomenda que todos os pacientes com meningite criptocócica associada ao HIV realizem uma punção lombar diagnóstica inicial e uma punção lombar repetida precoce com medição da pressão de abertura do LCR para avaliar a PIC elevada, independentemente da presença de sintomas ou sinais de PIC elevada. Mais de uma punção lombar repetida pode ser considerada, como uma terceira punção lombar no dia 3.[23]World Health Organization. Guidelines for diagnosing, preventing and managing cryptococcal disease among adults, adolescents and children living with HIV. Jun 2022 [internet publication].
https://www.who.int/publications/i/item/9789240052178
Não é recomendado monitorar o CrAg sérico e no LCR. Caso ocorram novos sintomas ou achados clínicos, recomenda-se repetir a punção lombar com medida da pressão de abertura na punção lombar e cultura do LCR.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
Pressão de abertura elevada na avaliação inicial (>20 cm H₂O)
A hipertensão intracraniana deve ser reduzida em todos os pacientes que manifestarem confusão, visão turva, papiledema, clônus de membros inferiores ou outros sinais neurológicos de hipertensão intracraniana.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
A principal intervenção para a redução da PIC elevada é a drenagem lombar percutânea.[23]World Health Organization. Guidelines for diagnosing, preventing and managing cryptococcal disease among adults, adolescents and children living with HIV. Jun 2022 [internet publication].
https://www.who.int/publications/i/item/9789240052178
Os deficits neurológicos focais são incomuns na criptococose e devem incitar a realização de imagens radiográficas do cérebro para descartar a presença de uma lesão com efeito de massa. Deve-se realizar uma drenagem lombar suficiente para atingir uma pressão de fechamento de <20 cm H₂O ou 50% da pressão de abertura inicial.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
Inicialmente, os pacientes devem ser submetidos a PLs diárias a fim de estabilizar as pressões de abertura dentro da faixa normal e melhorar os sinais e sintomas.[35]Chang CC, Harrison TS, Bicanic TA, et al. Global guideline for the diagnosis and management of cryptococcosis: an initiative of the ECMM and ISHAM in cooperation with the ASM. Lancet Infect Dis. 2024 Aug;24(8):e495-512. [Erratum in: Lancet Infect Dis. 2024 Aug;24(8):e485.]
https://www.idsociety.org/globalassets/idsa/practice-guidelines/diagnosis-and-management-of-crypto/global-guideline-for-the-diagnosis-and-management-of-cryptococcosis-an-initiative-of-the-ecmm-and-isham-in-cooperation-with-the-asm.pdf
http://www.ncbi.nlm.nih.gov/pubmed/38346436?tool=bestpractice.com
Se a hipertensão intracraniana ou os sinais e sintomas de edema cerebral persistirem após repetição da PL, deve-se considerar uma drenagem lombar ou um shunt ventriculoperitoneal.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
[35]Chang CC, Harrison TS, Bicanic TA, et al. Global guideline for the diagnosis and management of cryptococcosis: an initiative of the ECMM and ISHAM in cooperation with the ASM. Lancet Infect Dis. 2024 Aug;24(8):e495-512. [Erratum in: Lancet Infect Dis. 2024 Aug;24(8):e485.]
https://www.idsociety.org/globalassets/idsa/practice-guidelines/diagnosis-and-management-of-crypto/global-guideline-for-the-diagnosis-and-management-of-cryptococcosis-an-initiative-of-the-ecmm-and-isham-in-cooperation-with-the-asm.pdf
http://www.ncbi.nlm.nih.gov/pubmed/38346436?tool=bestpractice.com
[67]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322.
https://academic.oup.com/cid/article/50/3/291/392360
http://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com
Punções lombares repetidas são recomendadas para pacientes com PIC persistentemente elevada (≥25 cm H₂O) ou com sintomas de PIC elevada (por exemplo, cefaleia, estado mental alterado ou alterações na visão). Elas devem ser feitas diariamente ou conforme necessário até que a pressão de abertura se normalize ou os sintomas melhorem.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
Corticosteroides não são recomendados para controlar a PIC elevada em pessoas com HIV.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
Em pacientes sem HIV, como as evidências de benefício ainda não foram estabelecidas, os corticosteroides também não devem ser usados. Não foram demonstrados benefícios da acetazolamida, da terapia diurética e do manitol e essas terapias não são recomendadas.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
[60]Limper AH, Knox KS, Sarosi GA, et al; American Thoracic Society Fungal Working Group. An official American Thoracic Society statement: treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med. 2011 Jan 1;183(1):96-128.
https://www.atsjournals.org/doi/10.1164/rccm.2008-740ST
http://www.ncbi.nlm.nih.gov/pubmed/21193785?tool=bestpractice.com
Fracasso no tratamento e lesões persistentes
O fracasso do tratamento é definido como a ausência de melhora clínica após 2 semanas de terapia (incluindo manejo da pressão intracraniana [PIC] aumentada, com culturas continuadamente positivas) ou recidiva após a resposta clínica inicial (ou seja, recorrência dos sintomas com uma cultura positiva do líquido cefalorraquidiano [LCR] após ≥4 semanas de tratamento).[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
A maioria dos fracassos clínicos é resultado de terapia de indução inadequada, interações medicamentosas ou desenvolvimento de SIRI.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
A resistência ao fluconazol pelo Cryptococcus neoformans é rara; portanto, os testes de suscetibilidade não são rotineiramente recomendados no manejo inicial.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
[68]Brandt ME, Pfaller MA, Hajjeh RA, et al; Cryptococcal Disease Active Surveillance Group. Trends in antifungal drug susceptibility of Cryptococcus neoformans isolates in the United States: 1992 to 1994 and 1996 to 1998. Antimicrob Agents Chemother. 2001 Nov;45(11):3065-9.
https://journals.asm.org/doi/10.1128/aac.45.11.3065-3069.2001
http://www.ncbi.nlm.nih.gov/pubmed/11600357?tool=bestpractice.com
Entretanto, a resistência ao fluconazol é comum entre casos de recidiva.[76]Bicanic T, Harrison T, Niepieklo A, et al. Symptomatic relapse of HIV-associated cryptococcal meningitis after initial fluconazole monotherapy: the role of fluconazole resistance and immune reconstitution. Clin Infect Dis. 2006 Oct 15;43(8):1069-73.
http://www.ncbi.nlm.nih.gov/pubmed/16983622?tool=bestpractice.com
Isolados criptocócicos devem ser avaliados quanto a persistência, recidiva e suscetibilidade. Cepas com concentrações inibitórias mínimas contra fluconazol ≥16 microgramas/mL podem ser consideradas resistentes.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
Pacientes cujo tratamento fracassou após terem sido tratados inicialmente com fluconazol devem submeter-se a terapia modificada com anfotericina B, com ou sem flucitosina, até atingirem resposta clínica.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
Pacientes tratados inicialmente com formulação de anfotericina B devem continuar esse tratamento até que haja resposta clínica.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
Formulações lipídicas de anfotericina B são mais bem toleradas e mais eficazes que formulações com desoxicolato e devem ser consideradas quando o tratamento inicial com outros regimes fracassar.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
Doses mais elevadas de fluconazol com flucitosina também podem ser úteis.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
As equinocandinas não são recomendadas, pois não têm atividade contra o Cryptococcus.[20]Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: cryptococcosis. Oct 2024 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/cryptococcosis
Deve-se considerar cirurgia para pacientes com lesões pulmonares, ósseas ou no SNC que sejam persistentes ou refratárias.[60]Limper AH, Knox KS, Sarosi GA, et al; American Thoracic Society Fungal Working Group. An official American Thoracic Society statement: treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med. 2011 Jan 1;183(1):96-128.
https://www.atsjournals.org/doi/10.1164/rccm.2008-740ST
http://www.ncbi.nlm.nih.gov/pubmed/21193785?tool=bestpractice.com
[67]Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010 Feb 1;50(3):291-322.
https://academic.oup.com/cid/article/50/3/291/392360
http://www.ncbi.nlm.nih.gov/pubmed/20047480?tool=bestpractice.com