A research report submitted to the University of the Witwatersrand, Johannesburg in partial fulfillment for the requirements of the degree of Master of Medicine 2017. / Background Cryptococcal meningitis (CM) remains an ongoing and devastating disease with detrimental outcomes accounting for up to 44% of acquired immune deficiency syndrome (AIDS) related mortality. A significant portion of the cases have been attributed to recurrences, thought to be largely preventable. In the first world the recurrence rate is estimated at <5% but it is more than double that rate in developing countries. In the era of freely available antiretroviral therapy (ART) and secondary prophylaxis with fluconazole, we endeavoured to study the prevalence along with the clinical and laboratory features of patients with recurrence of CM in our setting. Objectives 1. Determine the prevalence of recurrent CM at Chris Hani Baragwanath Academic Hospital (CHBAH) for patients with the incident presentation between the years 2012-2013. 2. Determine the use of ART and fluconazole in patients with recurrent CM. The patients were divided into 4 groups reliant on whether they were on ART and fluconazole at the time of diagnosis of recurrent CM. a. Patients on ART and fluconazole. b. Patients on ART alone. c. Patients on fluconazole alone. d. Patients on no therapy. 3. Describe the clinical and laboratory features of patients with recurrent CM, as a cohort and by group. The groups were comparatively analysed. The variables studied included clinical presentation, mortality and cerebrospinal fluid (CSF) findings. Methods This was a retrospective review of adult patients presenting to Chris Hani Baragwanath Academic Hospital (CHBAH) with recurrent CM. The patients were identified using the Group for Enteric, Respiratory, and Meningeal disease Surveillance for South Africa (GERMS-SA) database. This is a nationwide network of clinical microbiology laboratories (both in the public and private sector) participating in an active laboratory-based surveillance programme for bacterial and fungal pathogens of public health importance. Specimen of patients identified to have CM are submitted to the National Institute of Communicable Diseases for confirmation and further characterisation. CHBAH is one of 25 enhanced surveillance sites where additional data including demographics, clinical findings and laboratory results were recorded. Hospital records and laboratory results were used to supplement the data. Patients with recurrent CM were identified between February 2012 and April 2014. The incident episode of CM had to have been from January 2012 to December 2013. The number of incident cases in that period was the denominator for the rate of recurrence. Results A total of 51 patients were identified from the database from an incident cohort of 658 patients with CM giving a prevalence rate for recurrent CM of 7.8%. These 51 patients had a total of 62 recurrent episodes of CM. Eight (15.7%) patients had multiple recurrences. There were 30 (58.8%) males and the median CD4 count was 85/mm3 (IQR: 3-393/mm3). The median time to recurrence was 143 days (IQR: 32-633 days). Data on the use of ART and fluconazole was available for 56 (90.3%) of recurrent episodes in 45 patients. A total of 37 (66.1%) recurrent episodes were in patients on ART and 26 (46.4%) were on fluconazole. The 56 episodes of recurrent CM were grouped as follows: 1. A total of 20 (35.7%) recurrent episodes were in patients on both ART and fluconazole. Immune reconstitution syndrome (IRIS) contributed 14 cases. 2. A total of 17 (30.4%) of recurrent episodes were in patients only on ART. 3. A total of 6 (10.7%) of the recurrent episodes were in patients on fluconazole prophylaxis only. 4. A total of 13 (23.2%) of the recurrent episodes were in patients on no therapy. The patients presented clinically with headaches (76.8%), meningism (57.1%), a Glasgow Coma Scale (GCS) <15 (30.4%) and seizures (14.3%). Twenty-seven (48.2%) cases died in hospital. Mortality was significantly higher in those with a GCS of less than 15 (82% vs. 33%, P=0.0008) and those with seizures (86% vs. 42%, P=0.0197). No statistically significant differences were noted amongst the 4 groups with respect to the clinical presentation, cerebrospinal fluid profile, the time to recurrence and mortality. Conclusion The prevalence of recurrent CM was midway between that of the developed world and a pre-ART study in Gauteng. Recurrent CM had a high mortality. The finding that one-third of patients were not on ART and that more than half were not on fluconazole at the time of diagnosis of recurrent CM, together with the high rate of multiple recurrence requires further investigation. Explicit steps need to be taken to link patients with health care facilities to ensure reliable provision of fluconazole and the initiation of ART. / MT2017

Stellenbosch University. Faculty of Medicine and Health Sciences. Interdisciplinary Health Sciences. Family Medicine and Primary Care. / Thesis (MFamMed) -- Stellenbosch University, 2010. / Bibliography / ENGLISH ABSTRACT: Introduction: This thesis summarises the findings of a medical audit on the management of Cryptococcal Meningitis (CM). The study population of HIV positive adults (N = twenty five) were admitted during November 2009 – June 2010 to five hospitals of the Cape Winelands (East) District, Western Cape, South Africa. In the context of the HIV pandemic, CM has become the most common cause of community-acquired meningitis, and has poor outcomes if left untreated. The South African HIV Clinician Society has published treatment guidelines in 2007. These guidelines have been used by the audit team to compile a list of measurable criteria (with set targets) to evaluate the structure, process and outcome of CM management. A pilot audit (2008) at the regional hospital has demonstrated that certain target standards were not met. Aims and Objectives: The aim was to improve the quality of the clinical care of HIV-patients diagnosed with CM in the Cape Winelands (East) district. The objectives included the review of the audit criteria and target standards, demonstrating improvement in quality of CM care at the Level 1 and 2 hospitals, identifying new interventions based on the findings and providing recommendations to the health facilities. Methods In 2009, the researcher formed a new audit team, reviewed the audit criteria and held teaching interventions based on the national treatment guidelines. An intervention, based on the findings of the pilot audit, aimed at improving the clinical team’s adherence to the treatment guidelines. Results The audit identified the following areas that did not meet the target standards: the availability of Amphotericin B (Ampho B) and spinal manometers; the use of manometry in all initial lumbar punctures (LPs); completing fourteen days of the required Ampho B treatment; renal monitoring in patients on Ampho B; commencement of antiretroviral treatment (ART) by week four; and, the two-month survival figures post-diagnosis. The re-audit at the Level 2 hospital highlighted the need for improved medical record keeping to aid the audit process. Arrangement of inpatient ART counselling happened more consistently at the Level 1 hospitals. Adherence to the ART target and measures to prevent Ampho B related morbidity is comparable to that of the Level 2 hospital. The audit has also provided insight to the researcher and audit team on the practical challenges of conducting a prospective data collection technique across different care settings. Recommendations Level 1 hospitals should continue to manage CM patients. The availability of spinal manometers and closer adherence to renal monitoring require attention. Formal feedback to the audit team and clinical teams is planned. A multimodal interdisciplinary Quality Improvement approach (such as an integrated care pathway) is recommended and a future re-audit is encouraged to assess improved adherence to the CM management guidelines. The buy-in of stakeholders (management, health care workers and patients), the ongoing support of an audit team and a committed Quality Improvement environment will allow the medical audit process to become ingrained in the South African public healthcare setting. / AFRIKAANSE OPSOMMING: Inleiding Hierdie tesis bied ‘n opsomming van die sleutelbevindinge van ‘n mediese oudit van Cryptokokkale Menigitis (CM) sorg. Die studie groep van MIV-positiewe volwassenes (N = vyf-en-twintig) het binne-pasiënt behandeling ontvang gedurende November 2009 tot Junie 2010 in vyf hospitale van die Kaapse Wynland (Oos) distrik. In die konteks van die MIV pandemie het CM die mees algemene oorsaak van gemeenskapsverworwe meningitis geword, en het swak uitkomste indien onbehandeld. Die Suid-Afrikaanse HIV Clinici Vereniging het in 2007 behandelingsriglyne gepubliseer. Hierdie riglyne het die oudit span gebruik om ‘n lys van meetbare kriteria (met teiken standaarde) saam te stel om die struktuur, proses en uitkoms fasette van CM sorg te evalueer. ‘n Proef oudit (2008) by die streekshospitaal het getoon dat sekere teiken standaarde nie behaal was nie. Doelstelling Die doelstelling was om die kwaliteit van kliniese sorg van MIV-pasiënte met CM (in die Kaapse Wynland (Oos) distrik) te verbeter. Die doelstelling sluit in die hersiening van die oudit kriteria, die bevesting van verbetering in kwaliteit CM sorg by vlak 1 en 2 hospitale, identifisering van nuwe ingreep-moontlikhede gebaseer op die bevindinge en die verskaffing van toepaslike aanbevelings aan die gesondheidsorg fasiliteite. Metodes Die navorser het in 2009 ‘n nuwe oudit span gevorm, die oudit kriteria hersien en opleidingsingrepe geskoei op die nasionale riglyne gefasiliteer. Opleidingsingrepe, gebaseer op bevindinge van die proef oudit, het ten doel gehad dat die kliniese span die nasionale riglyne nakom. Resultate Die oudit het die volgende areas uitgelig waar daar nie aan die teikenstandaarde voldoen was nie: the beskikbaarheid van Amphotericin B (Ampho B) en spinale manometers; die gebruik van manometrie in alle aanvanklike lumbaal punksies (LPs); voltooi van die veertien dae Ampho B behandelingsteiken; nierfunksie monitoring van pasiënte op Ampho B; aanvang van anti-retovirale behandeling teen week vier; en, die twee maande oorlewing post-diagnose syfers. Die opvolg oudit by die vlak 2 hospitaal bevestig die belang van verbeterde kliniese notas om die oudit proses te vergemaklik. Die reël van binne-pasiënt ART berading gebeur meer bestendig in Vlak 1 hospitale. Bereiking van die ART teiken en maatreëls om Ampho B verwante morbiditeit te voorkom, is vergelykbaar met die bevindinge by die vlak 2 hospitaal. Die oudit het die navorser en die oudit span ingelig rakende die praktiese uitdagings om ‘n prospektiewe data insamelingsmetode te poog in verskillende kliniese kontekste. Aanbevelings Vlak 1 hospitale kan steeds CM pasiënte versorg. Die beskikbaarheid van spinale manometers en deeglike nierfunksie monitering sal die behaling van teiken standaarde vergemaklik. Formele terugvoer aan die oudit span en kliniese span word beoog. ‘n Multimodale interdissiplinêre Kwaliteitsverbeterings benadering (soos ‘n geïntegreerde sorgplan) word aanbeveel en ‘n toekomstige oudit word aangemoedig om verbetering in toepassing van die CM riglyne te evalueer. Dit is belangrik om die sleutelspelers (bestuur, gesondheidswerkers en pasiënte) te betrek. Verder word voortgesette ondersteuning van die oudit span en ‘n toegewyde omgewing van kwaliteitsverbetering aanbeveel. Sodoende sal die oudit proses in Suid-Afrikaanse publieke sorg geintegreer word.

Master of Public Health - MPH / Meningitis is a common opportunistic infection and an important cause of mortality among people living with HIV and AIDS globally. This study investigated meningitis in adults living with HIV and AIDS admitted to the medical wards of Livingstone tertiary hospital in Port Elizabeth in 2018 and determined the prevalence of its aetiological types, clinical presentations, diagnostic challenges, treatment outcomes and predictors of prognosis.

What is known and objective: Liposomal amphotericin B (L-AmB) is the cornerstone of many serious invasive fungal infections. Despite lower frequencies of commonly reported adverse events in clinical trials compared to conventional formulations, post-marketing complications continue to mount. Case description: We present a case of chest pain following the initial dose of L-AmB for cryptococcal meningitis. Electrocardiogram demonstrated no acute electrocardiogram findings. Upon rechallenge, the chest pain worsened was subsequently accompanied by ST-segment elevation. Emergent coronary angiography found no acute findings. What is new and conclusion: Providers should be aware of cardiac complications with L-AmB, including non-occlusive ST-segment elevation.

Introdução: A meningite criptocócica causa elevada mortalidade, sobretudo em pacientes acometidos de alguma condição imunossupressora. O objetivo deste estudo foi identificar fenômenos de baixa suscetibilidade a antifúngicos e outros preditores clínicos que possam explicar falha terapêutica e recidiva da neurocriptococose Metodologia: Foram avaliados 96 casos com coleta de dados clínicos epidemiológicos e laboratoriais. Os isolados foram identificados quanto a genótipo molecular, suscetibilidade de anfotericina B (AMB) e fluconazol (FCZ) pela determinação da concentração inibitória mínima (Minimal Inhibitory Concentration, MIC), nível de heteroresistência ao FCZ (NHF) e determinação do tempo de morte frente AMB (Time-Kill, TK). Foram selecionados isolados heterorresistentes para análise quantitativa de DNA por PCR em tempo Real, expressão de bombas de efluxo por citometria de fluxo e isolados tolerantes a AMB para estudo de resistência ao estresse oxidativo. Foi realizada análise univariável e múltipla usando regressão logística para identificar preditores de óbito hospitalar e de um desfecho composto definido pelo óbito, encaminhamento para unidade de terapia intensiva ou recidiva 6 meses após alta hospitalar. Resultados: A maioria dos pacientes eram imunodeprimidos, com CD4 de 2 a 722 cel./mm3 e 96,7% eram portadores do HIV. Foram identificados 93 isolados de C. neoformans, sendo 76 do genótipo VNI e 17 VNII e 3 C. gattii, todos VGII. MIC de AMB variou de 0,012 a 0,94 mg/L e MIC de FCZ estiverem entre 0,12 e 64 mg/L. Resistência a FCZ (MIC>16mg/L) foi maior em VNI do que em VNII (p=0,03). Dentre os isolados VNI, 64,5% sofreu atividade fungicida até as 24h (TK24) de exposição à AMB e 6 cepas VNI não sofreram ação fungicida (TK>72). A maioria dos isolados VNII (64,7%) apresentou TK24. Os 3 isolados VGII sofreram atividade fungicida a partir de TK24. A maioria dos isolados VNI, VNII e todos os isolados VGII apresentaram alto NHF (>32mg/L). Diferença no NHF de acordo com os genótipos foi observada (p=0,005). No modelo múltiplo, as variáveis associadas significativamente ao óbito foram: idade em anos (OR=1,08;IC95%=1,02-1,15), contagem de leveduras no líquido cefalorraquidiano em logaritmo (LCR) (OR=1,66;IC95%=1,21-2,28) e uma variável composta por hipertensão arterial sistêmica ou diagnóstico de edema cerebral ou dilatação ventricular por tomografia (OR=35,68;IC95%=4,97-256,31). Para o desfecho composto, as variáveis associadas foram: contagem de leveduras do 1D em logaritmo (OR=1,50; IC95%=;1,20-1,86; p=<0,001), cultura de sangue positiva para Cryptococcus spp. (OR=3,30; IC95%=0,86-12,59; p=0,08) e descrição de neurotoxoplasmose (OR=18,62; IC95%=1,85-187,5; p=0,01). As associações foram consistentes em modelos de sobrevida. Conclusão: Foi possível descrever genótipos mais frequentes e identificar fatores genéticos, como aumento da expressão de genes e bombas de efluxo, relacionados à resistência aos fármacos. Nenhum dos testes de suscetibilidade esteve associado com os desfechos. Variáveis obtidas nos primeiros dias de internação mostraram utilidade para predizer o prognóstico em pacientes com meningite criptocóccica. Estes preditores podem ajudar a identificar os casos com maior potencial de óbito e que necessitam da otimização dos recursos terapêuticos. / Background: Cryptococcal meningitis causes high mortality in immunocompromised patients. The objective of this study was to identify the phenomena of low susceptibility to antifungal and other clinical predictors that may explain therapeutic failure and relapse of neurocryptococcosis Methodology: It was analyzed 96 cases with clinical and epidemiological data. The respective isolates were identified for genotype, susceptibility profile by Minimal Inhibitory Concentration (MIC), FCZ heteroresistance level (NHF), and time to death determination against 1 mg / L BMA (Time-Kill, TK). We isolated heteroresistant DNA expression analysis by real-time PCR, expression of efflux pumps by flow cytometry and, some isolates tolerant to AMB were selected to study resistance to oxidative stress. Univariable and multiple analyses using logistic regression were performed to identify predictors of in-hospital mortality and a composed outcome defined by death, referral to the intensive care unit and relapse 6 months after hospital discharge. Results: Most of the patients were immunocompromised, with CD4 range from 2 to 722 cells/mm3 and 96.7% patients HIV-positive. It was analyzed 93 strains of Cryptococcus neoformans of which 76 were genotype VNI and 17 were VNII and 3 were C. gattii, all were VGII. AMB MIC ranged from 0.012 to 0.94 mg/L and FCZ MIC were between 0.12 and 64 mg/L. Resistance to FCZ (MIC>16mg/L) was higher to VNI than VNII (p=0.03). Among the VNI strains, 64.5% had fungicidal activity up to 24h (TK24) of exposure to AMB and 6 VNI did not present this activity until 72h (TK> 72). Most VNII strains (64.7%) had TK24. The 3 VGII strains presented fungicidal activity from TK24. According to the MIC, all strains were susceptible to AMB. The majority of VNI strains (93.4%) and VNII (76.5%) and 3 VGII strains showed high NHF (>32mg/L) and it was observed statistical difference according to the genotypes VNI and VNII (p=0.005). At the multiple analysis, the variables significantly associated with the death were the age in years (OR=1.08,95%CI=1.02-1.15), the cerebrospinal fluid (CSF) yeasts count-log (OR=1.66,95%CI=1.21-2.28), and a variable composed of systemic arterial hypertension or diagnosis of cerebral edema or ventricular dilatation by tomography (OR=35.68,95%CI=4.97-256.31). At the composed outcome, the variables associated were: CSF yeasts count-log (OR=1,50; IC95%=;1,20-1,86; p=<0,001), positive blood culture for Cryptococcus spp. (OR=3,30; IC95%=0,86-12,59; p=0,08) and neurotoxoplasmosis (OR=18,62; IC95%=1,85-187,5; p=0,01). The associations were consistent at survival models. Conclusion: It was possible to describe more frequent genotypes and to identify genetic factors, such as increased gene expression and efflux pumps, related to drug resistance. The antifungal susceptibilities were not associated with the outcomes. were not associated with outcomes. Variables available in the first days of hospitalization showed utility to predict the prognosis in patients with cryptococcal meningitis. These predictors can help to identify the cases with higher potential of death and that require the optimization of the therapeutic resources.

Introdução: Dados sobre a relação entre a farmacocinética do fluconazol (FCZ) e anfotericina B (AMB) no líquido cefalorraquidiano (LCR) e a hipertensão intracraniana (HIC) não se encontram disponíveis na literatura. Objetivos: Avaliar a influência da pressão intracraniana na concentração dos antifúngicos AMB e FCZ no LCR de pacientes com meningite criptococócica internados no Hospital de Clínicas de Porto Alegre (HCPA), no período de 1 ano. Métodos: Foram estudados 15 pacientes com meningite criptococócica durante os primeiros 14 dias de tratamento com AmB (1 mg/kg/dia) e FCZ (800 mg/dia). As amostras de LCR foram obtidas por meio de punções lombares de rotina realizadas nos dias 1, 7 e 14 da terapia antifúngica, respectivamente. Os valores das pressões intracranianas de abertura foram obtidos no momento de cada punção lombar. Os níveis de AmB e FCZ no LCR foram medidos pela metodologia de cromatografia líquida de alta performance (HPLC). A concentração inibitória mínima (CIM) para AmB, FCZ, voriconazol (VRZ) e flucitosina (5-FC) de cada isolado de Cryptococcus sp. foi realizada de acordo com o as normas descritas no documento M27-A3, do CLSI, publicado em 2008. Resultados: Entre os 15 pacientes incluídos no estudo, C. gattii foi isolado do LCR de 2 pacientes e C. neoformans foi isolado do LCR de 13 pacientes apresentaram. A condição de imunossupressão encontrada foi a AIDS, seguida de transplante de órgão sólido. Nove pacientes apresentaram cultura negativa de LCR no 14º dia de terapia antifúngica. Os níveis de AmB no LCR foram indetectáveis para a maioria das amostras de LCR durante os 14 dias de terapia antifúngica. Os níveis de FCZ no LCR aumentaram progressivamente do dia 1 ao dia 14 de terapia. Seis pacientes apresentaram HIC no dia 1, com variação da pressão de abertura entre 100 mmH2O e 650 mmH2O no respectivo dia. A pressão intracraniana não interferiu nas concentrações de FCZ no LCR. Não observamos correlação entre a HIC e as concentrações de AMB e FCZ no LCR de acordo com a correlação de Spearman (Spearman p= 0.122). Conclusão: São necessários mais estudos para avaliar o papel da HIC na eficácia terapêutica de diferentes agentes antifúngicos em pacientes com meningite criptococócica. / Introduction: Data considering the relationship between pharmacokinetics of fluconazole (FCZ) and amphotericin B (BPA) in cerebrospinal fluid (CSF) and intracranial hypertension (IH) are not available in the literature. Objectives: To evaluate the influence of intracranial pressure on the concentration of the antifungals AMB and FCZ in the CSF of patients with cryptococcal meningitis admitted at the Hospital de Clínicas de Porto Alegre (HCPA), within a period of one year. Methods: Fifteen patients with cryptococcal meningitis were studied during the first 14 days of treatment with AmB (1 mg / kg / day) and FCZ (800 mg / day). CSF samples were obtained by means of routine lumbar punctures performed on days 1, 7 and 14 of antifungal therapy, respectively. The values of intracranial opening pressures were obtained at the time of each lumbar puncture. The levels of AmB and FCZ in the CSF were measured by high performance liquid chromatography (HPLC) methodology. The minimum inhibitory concentration (MIC) for AmB, FCZ, voriconazole (VRZ) and flucytosine (5-FC) of each isolate of Cryptococcus sp. was performed according to CLSI guideline M27-A3, published in 2008. Results: Among the 15 patients included in the study, C. gattii was isolated from the CSF of 2 patients and C. neoformans was isolated from the CSF of 13 patients presented. The immunosuppressive condition found was AIDS, followed by solid organ transplantation. Nine patients presented negative CSF culture on the 14th day of antifungal therapy. AmB levels in the CSF were undetectable for most of the CSF samples during the 14 days of antifungal therapy. CSF FCZ levels increased progressively from day 1 to day 14 of therapy. Six patients presented IH on day 1, with variation of the opening pressure between 100 mmH2O and 650 mmH2O on the respective day. Intracranial pressure did not interfere with CSF on FCZ concentrations. We did not observe a correlation between IH and the concentrations of AMB and FCZ in the CSF according to the Spearman correlation (Spearman p = 0.122). Conclusion: Further studies are needed to evaluate the role of IH in the therapeutic efficacy of different antifungal agents in patients with cryptococcal meningitis.

Introdução: A meningoencefalite criptocócica é uma doença oportunista causada pelo fungo encapsulado Cryptococcus sp. O quadro clínico é inespecífico e pode compreender cefaléia, febre e alteração do estado mental. A terapia recomendada é a combinação de anfotericina B e flucitosina por 14 dias (fase de indução), seguida de uma fase de consolidação com fluconazol. Os fatores associados a pior prognóstico incluem: alteração do estado mental, idade mais avançada e evidências de alta carga fúngica em líquor inicial. Estudos de coorte de pacientes com criptococose são escassos no Brasil. Objetivos: Identificar o perfil clínico-epidemiológico e fatores prognósticos de uma coorte de indivíduos com meningoencefalite criptocócica no Hospital de Clínicas de Porto Alegre, hospital terciário localizado na região sul do Brasil. Métodos: Estudo de coorte retrospectivo compreendido entre o período de janeiro de 2008 a outubro de 2015. Foram analisados as características clínico-epidemiológicas e os fatores associados à mortalidade dos pacientes internados com meningite criptocócica. Resultados: Foram identificados 79 pacientes com meningite criptocócica. A idade média dos pacientes foi 39,3±12,9 anos, variando de 5 a 67 anos. A maioria dos pacientes foi do sexo masculino (56,96%). A condição mais associada foi a infecção por HIV em 82,3% (n=65), sendo que 52,3% estavam em uso de terapia antirretroviral. A contagem mediana de linfócitos T CD4 foi de 34 céls/mm³. Cryptococcus neoformans correspondeu a 96,2% dos isolados em pacientes com meningite criptocócica. As manifestações clínicas mais comuns foram cefaléia, febre e alteração do estado mental. A pressão de abertura na punção lombar inicial variou de 30 a 130 cmH₂O. Achados em exame de imagem incluíram hidrocefalia e hipodensidades. Dilatação dos espaços de Virchow-Robin foram encontrados em apenas 2 pacientes (2,5%). A maioria dos pacientes dos pacientes (80%) recebeu anfotericina B e flucitosina como terapia de indução. A análise multivariada demonstrou que os fatores de pior prognóstico incluíram idade ≥ 50 anos, antígeno criptocócico no líquor ≥1:1000, proteínas ≥60 mg/dL em líquor de controle e admissão em unidade de terapia intensiva (UTI). Os fatores associados independentemente a mortalidade em 30 e 60 dias incluíram a presença de alteração do estado mental, déficit motor, antígeno criptocócico no líquor ≥1:1000 e admissão em UTI. A mortalidade geral, em 30 e 60 dias foi 41,9% 19,1% e 24,4%, respectivamente. 7 Conclusões: Em um hospital terciário no sul do Brasil, a criptococose meníngea ocorre predominantemente em adultos infectados pelo HIV. Na presença de febre, cefaléia e alteração do estado mental, os clínicos devem considerar um diagnóstico de criptococose meníngea para adultos infectados pelo HIV. Apesar do adequado tratamento antifúngico e do manejo da hipertensão intracraniana, a mortalidade foi alta. Os fatores de risco independentes para a mortalidade incluíram pacientes admitidos em UTI com estado mental alterado, proteína do líquor de controle elevada, títulos de antígeno criptocócico elevados no sangue e no líquor. / Background: Cryptococcal meningoencephalitis is an opportunistic disease caused by the encapsulated fungus Cryptococcus sp. Clinical findings are unspecific and may comprise headache, fever and altered mental status. The current recommended treatment is the combination of amphotericin B and flucytosine for 14 days (induction phase), followed by a consolidation period with fluconazole. Risk factors associated with death include: altered mental status, older age and evidence of high fungal burden at initial CSF examination. However, cohort studies are scant in Brazil. Objectives: Identification of clinical and epidemiological characteristics, and risk factors associated with mortality in a cohort of patients with cryptococcal meningoencephalitis admitted at a reference hospital in Brazil. Methods: A retrospective cohort study was conducted from January 2008 to October 2015 in a tertiary care hospital in Southern Brazil. Clinical and epidemiological characteristics, and risk factors associated with mortality were evaluated in patients with cryptococcal meningitis admitted to the hospital. Results: Seventy nine patients were identified. Mean age was 39,3±12,9 years. The age of the patients ranged from 5 to 67 years. Most of the patients were males (56,9%). The most common underlying condition was HIV infection 82,3% (n=65), and 52,3% of them were taking highly active antiretroviral therapy. The median CD4 count was 34 cells/mm³. Cryptococcus neoformans was the most common isolate (96%) identified in patients with cryptococcal meningitis. The most common clinical manifestations included headache, fever, and altered mental status. Initial opening intracranial pressures varied from 30 to 130 cm H20. CNS imaging abnormalities include hydrocephalus, and hypodensities. Widened Virchow- Robin spaces were described in only 2 patients (2.5%). The majority of the patients (80%) received amphotericin B, and flucytosine as induction therapy. Risk factors associated with mortality included age ≥ 50 years, CSF cryptococcal antigen ≥1:1000, CSF proteins ≥60 mg/dL in control lumbar puncture and ICU admission. Risk factors independently associated with death at 30 and 60 days included altered mental status, motor deficit, CSF cryptococcal antigen ≥1:1000 and ICU admission. Overall, 30 and 60-day mortalities were 41,9% 19,1% e 24,4%, respectively. Conclusions: In a terciary care hospital in Southern Brazil, meningeal cryptococcosis occurs predominantly in HIV infected individuals. In the presence of fever, headache and altered mental status, clinicians should consider a diagnosis of meningeal cryptococcosis for HIV 9 infected adults. Despite adequate antifungal treatment and management of intracranial hypertension, mortality was high. Independeted risk factors for mortality included patients admitted to ICU with altered mental status, elevated CSF protein, high blood and CSF cryptococcal antigen titers

Fungal infections are ignored by social and political communities. However, they are estimated to affect more than a billion people, resulting in approximately 11.5 million life-threatening infections in the 'at risk' population and more than 1.5 million deaths annually. Though there have been huge advances in diagnostics and antifungal drug development over the past two decades, however, resource limited settings have not benefited from these advances. The aim of this research was to determine the burden of serious fungal infections in Nigerians with the appropriate underlying diseases. This epidemiological research was conducted across four study populations. Study 1; HIV-infected patients with CD4+ counts < 250 cells/mm³, irrespective of their ART status, a CrAg lateral flow assay was used for detecting cryptococcal antigenaemia (n=214). Study 2; a cross-sectional multicentre survey of TB patients being managed for smear negative or treatment failure TB irrespective of their HIV status (n=208). Study 3; a multicentre histoplasmin skin sensitivity survey amongst healthy HIV-infected and non-HIV infected participants; intradermally; induration ≥ 5 mm was considered to be histoplasmin positive (n=750). Study 4; a prospective cohort study of critically ill patients in a Nigerian ICU (n=71). Two retrospective studies to analyse the clinical picture of serious fungal infections in two at risk populations (HIV/AIDS and neonatal intensive care babies) in Nigerians was also conducted (n=7034; n=2712 respectively). Results revealed an overall seroprevalence of cryptococcal antigenemia of 8.9% with 6 (9.8%) in those with CD4+ cell counts < 100cells/mm³, 4 (5.0%) in the 100-200 group and 9 (12.3%) in 200-250 cells/mm³ group; a CPA prevalence of 8.7% (6.5% had HIV infection and 14.5% were HIV-negative) and a prior subclinical histoplasmosis of 4.4%. The ICU study revealed a 45% healthcare associated infection rate representing an incidence rate of 79/1000 patient-days in the ICU. The retrospective studies revealed a 2.3% rate of neonatal ICI with a case fatality rate of 18.5%. In the 12 years retrospective study 18% had a fungal OI with 88% of patients having initiated ART. In conclusion, serious fungal infections do occur in the at risk population in Nigeria and they constitute a significant public health challenge. Our findings demonstrate that there has been an underestimation of the burden of the problem in Nigerians. There is a dire need to design guidelines for the management of fungal infections in at risk population.

Introdução: Dados sobre a relação entre a farmacocinética do fluconazol (FCZ) e anfotericina B (AMB) no líquido cefalorraquidiano (LCR) e a hipertensão intracraniana (HIC) não se encontram disponíveis na literatura. Objetivos: Avaliar a influência da pressão intracraniana na concentração dos antifúngicos AMB e FCZ no LCR de pacientes com meningite criptococócica internados no Hospital de Clínicas de Porto Alegre (HCPA), no período de 1 ano. Métodos: Foram estudados 15 pacientes com meningite criptococócica durante os primeiros 14 dias de tratamento com AmB (1 mg/kg/dia) e FCZ (800 mg/dia). As amostras de LCR foram obtidas por meio de punções lombares de rotina realizadas nos dias 1, 7 e 14 da terapia antifúngica, respectivamente. Os valores das pressões intracranianas de abertura foram obtidos no momento de cada punção lombar. Os níveis de AmB e FCZ no LCR foram medidos pela metodologia de cromatografia líquida de alta performance (HPLC). A concentração inibitória mínima (CIM) para AmB, FCZ, voriconazol (VRZ) e flucitosina (5-FC) de cada isolado de Cryptococcus sp. foi realizada de acordo com o as normas descritas no documento M27-A3, do CLSI, publicado em 2008. Resultados: Entre os 15 pacientes incluídos no estudo, C. gattii foi isolado do LCR de 2 pacientes e C. neoformans foi isolado do LCR de 13 pacientes apresentaram. A condição de imunossupressão encontrada foi a AIDS, seguida de transplante de órgão sólido. Nove pacientes apresentaram cultura negativa de LCR no 14º dia de terapia antifúngica. Os níveis de AmB no LCR foram indetectáveis para a maioria das amostras de LCR durante os 14 dias de terapia antifúngica. Os níveis de FCZ no LCR aumentaram progressivamente do dia 1 ao dia 14 de terapia. Seis pacientes apresentaram HIC no dia 1, com variação da pressão de abertura entre 100 mmH2O e 650 mmH2O no respectivo dia. A pressão intracraniana não interferiu nas concentrações de FCZ no LCR. Não observamos correlação entre a HIC e as concentrações de AMB e FCZ no LCR de acordo com a correlação de Spearman (Spearman p= 0.122). Conclusão: São necessários mais estudos para avaliar o papel da HIC na eficácia terapêutica de diferentes agentes antifúngicos em pacientes com meningite criptococócica. / Introduction: Data considering the relationship between pharmacokinetics of fluconazole (FCZ) and amphotericin B (BPA) in cerebrospinal fluid (CSF) and intracranial hypertension (IH) are not available in the literature. Objectives: To evaluate the influence of intracranial pressure on the concentration of the antifungals AMB and FCZ in the CSF of patients with cryptococcal meningitis admitted at the Hospital de Clínicas de Porto Alegre (HCPA), within a period of one year. Methods: Fifteen patients with cryptococcal meningitis were studied during the first 14 days of treatment with AmB (1 mg / kg / day) and FCZ (800 mg / day). CSF samples were obtained by means of routine lumbar punctures performed on days 1, 7 and 14 of antifungal therapy, respectively. The values of intracranial opening pressures were obtained at the time of each lumbar puncture. The levels of AmB and FCZ in the CSF were measured by high performance liquid chromatography (HPLC) methodology. The minimum inhibitory concentration (MIC) for AmB, FCZ, voriconazole (VRZ) and flucytosine (5-FC) of each isolate of Cryptococcus sp. was performed according to CLSI guideline M27-A3, published in 2008. Results: Among the 15 patients included in the study, C. gattii was isolated from the CSF of 2 patients and C. neoformans was isolated from the CSF of 13 patients presented. The immunosuppressive condition found was AIDS, followed by solid organ transplantation. Nine patients presented negative CSF culture on the 14th day of antifungal therapy. AmB levels in the CSF were undetectable for most of the CSF samples during the 14 days of antifungal therapy. CSF FCZ levels increased progressively from day 1 to day 14 of therapy. Six patients presented IH on day 1, with variation of the opening pressure between 100 mmH2O and 650 mmH2O on the respective day. Intracranial pressure did not interfere with CSF on FCZ concentrations. We did not observe a correlation between IH and the concentrations of AMB and FCZ in the CSF according to the Spearman correlation (Spearman p = 0.122). Conclusion: Further studies are needed to evaluate the role of IH in the therapeutic efficacy of different antifungal agents in patients with cryptococcal meningitis.

Introdução: A meningoencefalite criptocócica é uma doença oportunista causada pelo fungo encapsulado Cryptococcus sp. O quadro clínico é inespecífico e pode compreender cefaléia, febre e alteração do estado mental. A terapia recomendada é a combinação de anfotericina B e flucitosina por 14 dias (fase de indução), seguida de uma fase de consolidação com fluconazol. Os fatores associados a pior prognóstico incluem: alteração do estado mental, idade mais avançada e evidências de alta carga fúngica em líquor inicial. Estudos de coorte de pacientes com criptococose são escassos no Brasil. Objetivos: Identificar o perfil clínico-epidemiológico e fatores prognósticos de uma coorte de indivíduos com meningoencefalite criptocócica no Hospital de Clínicas de Porto Alegre, hospital terciário localizado na região sul do Brasil. Métodos: Estudo de coorte retrospectivo compreendido entre o período de janeiro de 2008 a outubro de 2015. Foram analisados as características clínico-epidemiológicas e os fatores associados à mortalidade dos pacientes internados com meningite criptocócica. Resultados: Foram identificados 79 pacientes com meningite criptocócica. A idade média dos pacientes foi 39,3±12,9 anos, variando de 5 a 67 anos. A maioria dos pacientes foi do sexo masculino (56,96%). A condição mais associada foi a infecção por HIV em 82,3% (n=65), sendo que 52,3% estavam em uso de terapia antirretroviral. A contagem mediana de linfócitos T CD4 foi de 34 céls/mm³. Cryptococcus neoformans correspondeu a 96,2% dos isolados em pacientes com meningite criptocócica. As manifestações clínicas mais comuns foram cefaléia, febre e alteração do estado mental. A pressão de abertura na punção lombar inicial variou de 30 a 130 cmH₂O. Achados em exame de imagem incluíram hidrocefalia e hipodensidades. Dilatação dos espaços de Virchow-Robin foram encontrados em apenas 2 pacientes (2,5%). A maioria dos pacientes dos pacientes (80%) recebeu anfotericina B e flucitosina como terapia de indução. A análise multivariada demonstrou que os fatores de pior prognóstico incluíram idade ≥ 50 anos, antígeno criptocócico no líquor ≥1:1000, proteínas ≥60 mg/dL em líquor de controle e admissão em unidade de terapia intensiva (UTI). Os fatores associados independentemente a mortalidade em 30 e 60 dias incluíram a presença de alteração do estado mental, déficit motor, antígeno criptocócico no líquor ≥1:1000 e admissão em UTI. A mortalidade geral, em 30 e 60 dias foi 41,9% 19,1% e 24,4%, respectivamente. 7 Conclusões: Em um hospital terciário no sul do Brasil, a criptococose meníngea ocorre predominantemente em adultos infectados pelo HIV. Na presença de febre, cefaléia e alteração do estado mental, os clínicos devem considerar um diagnóstico de criptococose meníngea para adultos infectados pelo HIV. Apesar do adequado tratamento antifúngico e do manejo da hipertensão intracraniana, a mortalidade foi alta. Os fatores de risco independentes para a mortalidade incluíram pacientes admitidos em UTI com estado mental alterado, proteína do líquor de controle elevada, títulos de antígeno criptocócico elevados no sangue e no líquor. / Background: Cryptococcal meningoencephalitis is an opportunistic disease caused by the encapsulated fungus Cryptococcus sp. Clinical findings are unspecific and may comprise headache, fever and altered mental status. The current recommended treatment is the combination of amphotericin B and flucytosine for 14 days (induction phase), followed by a consolidation period with fluconazole. Risk factors associated with death include: altered mental status, older age and evidence of high fungal burden at initial CSF examination. However, cohort studies are scant in Brazil. Objectives: Identification of clinical and epidemiological characteristics, and risk factors associated with mortality in a cohort of patients with cryptococcal meningoencephalitis admitted at a reference hospital in Brazil. Methods: A retrospective cohort study was conducted from January 2008 to October 2015 in a tertiary care hospital in Southern Brazil. Clinical and epidemiological characteristics, and risk factors associated with mortality were evaluated in patients with cryptococcal meningitis admitted to the hospital. Results: Seventy nine patients were identified. Mean age was 39,3±12,9 years. The age of the patients ranged from 5 to 67 years. Most of the patients were males (56,9%). The most common underlying condition was HIV infection 82,3% (n=65), and 52,3% of them were taking highly active antiretroviral therapy. The median CD4 count was 34 cells/mm³. Cryptococcus neoformans was the most common isolate (96%) identified in patients with cryptococcal meningitis. The most common clinical manifestations included headache, fever, and altered mental status. Initial opening intracranial pressures varied from 30 to 130 cm H20. CNS imaging abnormalities include hydrocephalus, and hypodensities. Widened Virchow- Robin spaces were described in only 2 patients (2.5%). The majority of the patients (80%) received amphotericin B, and flucytosine as induction therapy. Risk factors associated with mortality included age ≥ 50 years, CSF cryptococcal antigen ≥1:1000, CSF proteins ≥60 mg/dL in control lumbar puncture and ICU admission. Risk factors independently associated with death at 30 and 60 days included altered mental status, motor deficit, CSF cryptococcal antigen ≥1:1000 and ICU admission. Overall, 30 and 60-day mortalities were 41,9% 19,1% e 24,4%, respectively. Conclusions: In a terciary care hospital in Southern Brazil, meningeal cryptococcosis occurs predominantly in HIV infected individuals. In the presence of fever, headache and altered mental status, clinicians should consider a diagnosis of meningeal cryptococcosis for HIV 9 infected adults. Despite adequate antifungal treatment and management of intracranial hypertension, mortality was high. Independeted risk factors for mortality included patients admitted to ICU with altered mental status, elevated CSF protein, high blood and CSF cryptococcal antigen titers