Diagnostic and therapeutic strategies in cryptococcosis: impact on outcome.

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Term Occurence Count Dictionary
dexamethasone 6 infectiousdiseasesdrugs
fluconazole 41 infectiousdiseasesdrugs
flucytosine 25 infectiousdiseasesdrugs
fungal meningitis 1 infectiousdiseases
meningitis 7 infectiousdiseases
AIDS 4 infectiousdiseases
cryptococcosis 9 infectiousdiseases

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Select Drug Character Offset Drug Term Instance
dexamethasone 16574 mortality in some sub-groups. In CM IDSA guidelines ([41]), experts recommend to consider the use of dexamethasone at high doses for patients having immune reconstitution inflammatory syndrome with severe central nervous
dexamethasone 16910 trial, conducted in 6 countries over Africa and Asia, aimed to demonstrate the efficacy of adjunctive dexamethasone but was stopped after the enrolment of 451 patients (on an overall of 880 planned) for safety reasons
dexamethasone 17204 combination antifungal therapy with amphotericin B and fluconazole, and were randomised to receive either dexamethasone (intravenous for the first two weeks, and then orally, tapered doses until the 6th week) or placebo
dexamethasone 17456 survival until 10 weeks after randomisation. There was no difference between groups – 47% in the dexamethasone group and 41% in the placebo group died. EFA was measured and during the first two weeks of treatment,
dexamethasone 17573 group and 41% in the placebo group died. EFA was measured and during the first two weeks of treatment, dexamethasone was significantly associated with slower rates of decline in the EFA in CSF than was placebo. Even if
dexamethasone 17689 was significantly associated with slower rates of decline in the EFA in CSF than was placebo. Even if dexamethasone was significantly associated with a better reduction in CSF opening pressure during the first two weeks
fluconazole 2722 of ART ([29], [32]). CrAg screening of patients before initiation of ART associated with preemptive fluconazole treatment once CrAg is positive was associated with low number of cases of CM ([30]). This combined
fluconazole 2961 a significantly reduced mortality ([33]).As such, systematic pre-ART CrAg screening and preemptive fluconazole is recommended for those presenting with < 100 CD4 cell counts ([51]). Though promising as a strategy
fluconazole 4663 (IQR: 5-7) (Temfack et al., unpublished observations). CrAg-positive patients who were not offered fluconazole pre-emptive therapy are at higher risk of CM and death ([15], [22]). More so, about a third of CrAg-positive
fluconazole 4884 asymptomatic patients have evidence of CM ([50]). In CrAg positive patients who received preemptive fluconazole initiated at 800 mg/day, there was a significant decrease in the relative risk of developing CM (from
fluconazole 6116 toxicity. The preferred therapy for pulmonary-limited disease, or non-disseminated disease is based on fluconazole therapy alone.The aim of CM therapy is to improve survival thanks to rapid yeast clearance from the
fluconazole 8252 amphotericin B plus flucytosine than in any of the three other arms (amphotericin B alone, amphotericin B plus fluconazole , or a triple therapy with amphotericin B, fluconazole and flucytosine), in 64 HIV-infected patients
fluconazole 8306 arms (amphotericin B alone, amphotericin B plus fluconazole, or a triple therapy with amphotericin B, fluconazole and flucytosine), in 64 HIV-infected patients with CM ([11]).This strategy was then also shown to be
fluconazole 9394 the combination of amphotericin B and flucytosine was significantly superior to Amphotericin B and fluconazole , leading to a substantial mortality reduction [hazard ratio for death at 10 weeks with flucytosine vs.
fluconazole 9509 leading to a substantial mortality reduction [hazard ratio for death at 10 weeks with flucytosine vs. fluconazole , 0.62; 95% confidence interval (CI), 0.45 to 0.84; p = 0.002] ([35]).Amphotericin B with fluconazole
fluconazole 9610 fluconazole, 0.62; 95% confidence interval (CI), 0.45 to 0.84; p = 0.002] ([35]).Amphotericin B with fluconazole - When flucytosine is unavailable, the combination of amphotericin B with fluconazole is still recommended
fluconazole 9696 ([35]).Amphotericin B with fluconazole - When flucytosine is unavailable, the combination of amphotericin B with fluconazole is still recommended ([41]). In an open-label, three-arm, phase II trial including 143 HIV-infected
fluconazole 9853 open-label, three-arm, phase II trial including 143 HIV-infected patients, combination of amphotericin B with fluconazole 800 mg/day was found to have significantly better long-term outcomes than amphotericin B and fluconazole
fluconazole 9958 fluconazole 800 mg/day was found to have significantly better long-term outcomes than amphotericin B and fluconazole 400 mg/day or amphotericin alone ([40]). However, this have not been observed in the study conducted
fluconazole 10166 conducted by [14], with no statistically survival benefit found for patients receiving amphotericin with fluconazole 800 mg/day compared to those with amphotericin B alone. More so, in the ACTA trial, the treatment arm
fluconazole 10309 with amphotericin B alone. More so, in the ACTA trial, the treatment arm combining Amphotericin B and fluconazole had the worse outcome, clearly demonstrating that the combination of Amphotericin B and fluconazole
fluconazole 10409 fluconazole had the worse outcome, clearly demonstrating that the combination of Amphotericin B and fluconazole is a not recommended for induction treatment ([35]).Amphotericin B with voriconazole - The use of voriconazole
fluconazole 10589 with voriconazole - The use of voriconazole at the dosage of 300 mg twice daily, instead of highdose fluconazole (800 mg or 1200 mg/day) in induction therapy associated with amphotericin B was tested in a randomised
fluconazole 11884 study in Uganda, based on 30 HIV-infected patients, a short 5-day course of amphotericin with highdose fluconazole 1200 mg/day was found to have a better EFA than findings with fluconazole alone in previous studies,
fluconazole 11958 amphotericin with highdose fluconazole 1200 mg/day was found to have a better EFA than findings with fluconazole alone in previous studies, suggesting that shorter courses of amphotericin may be used ([37]).The multi-centre
fluconazole 12186 trial, testing short courses amphotericin B deoxycholate based therapies with either flucytosine or fluconazole , also showed a better survival with a 7-day course of amphotericin B and flucytosine compared with 14-day
fluconazole 12505 B IV therapy with flucytosine as first line induction therapy (followed by seven days of high-dose fluconazole ) in low and middle-income countries ([52]).Fluconazole and flucytosine - Before the highly active antiretroviral
fluconazole 12700 highly active antiretroviral therapy era, an open-label, single-arm, prospective trial studied the fluconazole (400 mg daily) and flucytosine (150 mg/kg daily) combination therapy for a 10-week antifungal therapy
fluconazole 12964 survival at 10 weeks which appeared to be better than previously reported with amphotericin B alone or fluconazole alone ([27]).More recently, a randomised clinical trial compared combination therapy with high dose
fluconazole 13076 alone ([27]).More recently, a randomised clinical trial compared combination therapy with high dose fluconazole (1200 mg daily) and flucytosine (100 mg/kg daily) to high dose fluconazole alone for the 2-week induction
fluconazole 13151 combination therapy with high dose fluconazole (1200 mg daily) and flucytosine (100 mg/kg daily) to high dose fluconazole alone for the 2-week induction therapy, in 41 HIV-infected patients with CM in Malawi, and found better
fluconazole 13453 including 721 randomised HIV-infected patients also showed that a combination oral therapy with high dose fluconazole (1200 mg/day) and flucytosine (100 mg/kg/day) for the 2-week induction therapy was non-inferior to the
fluconazole 13644 was non-inferior to the standard 2-week courses of amphotericin B based therapy with flucytosine or fluconazole ([35]). That made authors conclude that this regimen is an acceptable and effective option for CM therapy
fluconazole 13908 or not recommended.FLUCONAZOLE MONOTHERAPYBoth 2010 IDSA and 2011 WHO guidelines recommend high-dose fluconazole monotherapy (1200 mg/ day) for 10-12 weeks if amphotericin and flucytosine are not available ([41],
fluconazole 14082 flucytosine are not available ([41], [53]).In a cohort study carried out in Malawi using high dose fluconazole (1200 mg) as induction therapy ([19]), mortality was unacceptably high, as it was in a study using 800
fluconazole 14221 therapy ([19]), mortality was unacceptably high, as it was in a study using 800 mg ([45]), showing that fluconazole monotherapy is not suitable as induction therapy.A recently published CrAg screening study in Ethiopia
fluconazole 14400 published CrAg screening study in Ethiopia in HIV-infected patients, highlighted that the use of high dose fluconazole monotherapy for induction phase is inadequate, leading to a 68% mortality rate at three months, in patients
fluconazole 15588 in the AMBITION preliminary phase II trial comparing different short courses of L-AmB with high dose fluconazole . The single dose arm was non-inferior to the standard 14-days arm in term of early fungicidal activity,
fluconazole 15937 currently taking place to evaluate whether a single high dose (10 mg/kg) of LAmB given with high dose fluconazole and flucytosine is as effective as the newly recommended (based on ACTA trial) one-week daily-dosed
fluconazole 17153 received the locally-available and standard-of-care combination antifungal therapy with amphotericin B and fluconazole , and were randomised to receive either dexamethasone (intravenous for the first two weeks, and then
fluconazole 18621 vivo fungicidal activity against Cryptococcus neoformans, as its action has a synergistic effect with fluconazole in reducing the fungal burden in brain, kidney, and spleen ([54]). The first clinical open-label and
fluconazole 18918 HIV-associated CM, to assess the efficacy of adjunctive sertraline, with standard amphotericin B and high-dose fluconazole antifungal therapies ([43]). Authors concluded that patients had faster cryptococcal CSF clearance and
fluconazole 19621 with placebo when receiving standard available induction therapy of amphotericin B deoxycholate and fluconazole 800 mg/day. The trial was stopped after enrolling 460 of the 550 patients planned for futility, showing
fluconazole 19974 antagonist drug usually used for breast cancer, has been shown to be fungicidal and synergistic with fluconazole and amphotericin B in vitro and in vivo in a mouse model of disseminated cryptococcosis ([13]). At acceptably
fluconazole 20147 disseminated cryptococcosis ([13]). At acceptably concentrations for humans, tamoxifen combined with fluconazole decreased brain fungal burden, and has demonstrated to inhibit the growth of C. neoformans within macrophages,
fluconazole 20508 open-label, phase II, randomised trial (“A randomised trial of tamoxifen combined with amphotericin B and fluconazole for cryptococcal meningitis”, NCT03112031) will enrol 50 patients in Vietnam, comparing EFA according
fluconazole 20669 enrol 50 patients in Vietnam, comparing EFA according to the strategy between (amphotericin B plus fluconazole ± tamoxifen during the first two weeks).ELEVATED OPENING CEREBROSPINAL FLUID PRESSUREElevated intracranial
flucytosine 5594 ([49]). The 2010 IDSA guidelines ([41]) for management of disseminated disease placed amphotericin B and flucytosine as first choices for induction phase, with amphotericin B deoxycholate (0.7-1.0 mg/kg/day) given intravenously
flucytosine 5742 phase, with amphotericin B deoxycholate (0.7-1.0 mg/kg/day) given intravenously in combination with oral flucytosine 100 mg/ kg/day (at least two weeks for HIV-infected patients and organ transplant recipients, and four
flucytosine 7074 cryptococcosis outcome and survival in the last decades.COMBINATION ANTIFUNGAL THERAPYAmphotericin B with flucytosine - The use of flucytosine combined with amphotericin B for CM therapy was already observed in a study
flucytosine 7099 survival in the last decades.COMBINATION ANTIFUNGAL THERAPYAmphotericin B with flucytosine - The use of flucytosine combined with amphotericin B for CM therapy was already observed in a study in 1979, before the HIV
flucytosine 7697 408 HIV-infected patients evidenced that the use of a combination therapy with amphotericin B plus flucytosine for induction therapy was associated with an increased rate of CSF sterilisation and a better outcome
flucytosine 8161 significantly faster in the arm in which patients were treated with the combination of amphotericin B plus flucytosine than in any of the three other arms (amphotericin B alone, amphotericin B plus fluconazole, or a triple
flucytosine 8322 B alone, amphotericin B plus fluconazole, or a triple therapy with amphotericin B, fluconazole and flucytosine ), in 64 HIV-infected patients with CM ([11]).This strategy was then also shown to be superior in the
flucytosine 8611 with cryptococcal infection with a mycological failure at week two of 26% in the amphotericin B and flucytosine group compared to a treatment failure of 56% with any other treatments (p < 0.001) ([17], [16]).Moreover,
flucytosine 8998 amphotericin alone, with a reduction of about 40% in the relative risk of death at 10 weeks with addition of flucytosine ([14]).Finally, the recently completed “Advancing Cryptococcal Meningitis Treatment for Africa”
flucytosine 9333 countries in Sub-Saharan Africa, definitively evidenced that the combination of amphotericin B and flucytosine was significantly superior to Amphotericin B and fluconazole, leading to a substantial mortality reduction
flucytosine 9493 fluconazole, leading to a substantial mortality reduction [hazard ratio for death at 10 weeks with flucytosine vs. fluconazole, 0.62; 95% confidence interval (CI), 0.45 to 0.84; p = 0.002] ([35]).Amphotericin B
flucytosine 9629 95% confidence interval (CI), 0.45 to 0.84; p = 0.002] ([35]).Amphotericin B with fluconazole - When flucytosine is unavailable, the combination of amphotericin B with fluconazole is still recommended ([41]). In an
flucytosine 11077 cryptococcosis, this combination would be marginally used.Short courses therapy - The amphotericin B and flucytosine combination regimen remains unavailable in most parts of the world harbouring the highest burden of
flucytosine 12171 multi-centre ACTA trial, testing short courses amphotericin B deoxycholate based therapies with either flucytosine or fluconazole, also showed a better survival with a 7-day course of amphotericin B and flucytosine
flucytosine 12271 flucytosine or fluconazole, also showed a better survival with a 7-day course of amphotericin B and flucytosine compared with 14-day course (HR 0.56 (0.35-0.91)) ([35]). This prompted WHO experts to now recommend
flucytosine 12424 (0.35-0.91)) ([35]). This prompted WHO experts to now recommend a 7-days amphotericin B IV therapy with flucytosine as first line induction therapy (followed by seven days of high-dose fluconazole) in low and middle-income
flucytosine 12576 (followed by seven days of high-dose fluconazole) in low and middle-income countries ([52]).Fluconazole and flucytosine - Before the highly active antiretroviral therapy era, an open-label, single-arm, prospective trial
flucytosine 12731 therapy era, an open-label, single-arm, prospective trial studied the fluconazole (400 mg daily) and flucytosine (150 mg/kg daily) combination therapy for a 10-week antifungal therapy in 32 patients with AIDS, and
flucytosine 13108 randomised clinical trial compared combination therapy with high dose fluconazole (1200 mg daily) and flucytosine (100 mg/kg daily) to high dose fluconazole alone for the 2-week induction therapy, in 41 HIV-infected
flucytosine 13483 HIV-infected patients also showed that a combination oral therapy with high dose fluconazole (1200 mg/day) and flucytosine (100 mg/kg/day) for the 2-week induction therapy was non-inferior to the standard 2-week courses of
flucytosine 13629 induction therapy was non-inferior to the standard 2-week courses of amphotericin B based therapy with flucytosine or fluconazole ([35]). That made authors conclude that this regimen is an acceptable and effective option
flucytosine 13983 guidelines recommend high-dose fluconazole monotherapy (1200 mg/ day) for 10-12 weeks if amphotericin and flucytosine are not available ([41], [53]).In a cohort study carried out in Malawi using high dose fluconazole (1200
flucytosine 15953 place to evaluate whether a single high dose (10 mg/kg) of LAmB given with high dose fluconazole and flucytosine is as effective as the newly recommended (based on ACTA trial) one-week daily-dosed amphotericin B deoxycholate
flucytosine 16106 (based on ACTA trial) one-week daily-dosed amphotericin B deoxycholate based induction therapy with flucytosine as an induction therapy ([34]). This trial will be the largest therapeutic trial on CM with 850 patients
flucytosine 18039 HIV-infected patients randomised in three different arms [standard therapy with amphotericin B plus flucytosine , standard therapy with two doses of interferon-gamma (INF-γ), and standard therapy with six doses of
Select Disease Character Offset Disease Term Instance
AIDS 4477 with caution.Pre-ART CrAg screening and pre-emptive therapy - In HIV-infected patients with advanced AIDS disease, the prevalence of CrAg positivity ranged from 2-21%, with a median of 6% (IQR: 5-7) (Temfack
AIDS 12834 flucytosine (150 mg/kg daily) combination therapy for a 10-week antifungal therapy in 32 patients with AIDS , and found a clinical survival at 10 weeks which appeared to be better than previously reported with
AIDS 22266 PATIENTSAntiretroviral therapy (ART) is the corner stone of treatment in HIV-infected patients with advanced AIDS disease. In patients with CM, it is now recommended delaying ART for four-six weeks after starting antifungal
AIDS 23450 CONCLUSIONCryptococcal disease is a death-related disease in immunosuppressed patients, especially in advanced AIDS disease patients. Over the past 15 years, many studies and clinical trials have led to improve prevention,
cryptococcosis 83 Title: Memórias do Instituto Oswaldo CruzDiagnostic and therapeutic strategies in cryptococcosis : impact on outcomeTimothée Boyer ChammardElvis TemfackOlivier LortholaryAlexandre AlanioPublication
cryptococcosis 1121 shift.DIAGNOSTIC STRATEGIESThe diagnosis of cryptococcal meningitis (CM) and more broadly, disseminated cryptococcosis , is easily made by direct examination of a pelleted biological fluid using India ink with the typical
cryptococcosis 1780 antifungal therapy or may need longer incubation periods up to three weeks. Another easy way to diagnose cryptococcosis is the detection of cryptococcal antigen (CrAg). CrAg is composed of polysaccharide of the cryptococcal
cryptococcosis 2276 (ELISA) and most recently a lateral flow assay (LFA). CrAg detection in serum is presumptive of active cryptococcosis , especially in HIV patients and detection in cerebrospinal fluid (CSF) is diagnostic of CM ([48]).However,
cryptococcosis 2398 especially in HIV patients and detection in cerebrospinal fluid (CSF) is diagnostic of CM ([48]).However, cryptococcosis is a sub-acute infection. Consequently, CrAg can be detected in blood many weeks before the onset of
cryptococcosis 5121 incident mortality (Temfack et al., unpublished observations).THERAPEUTIC STRATEGIESThe main challenge for cryptococcosis management is for disseminated disease and meningoencephalitis, knowing that the printciple of therapy
cryptococcosis 6968 trials ([36]).Thereafter, we summarise the main studies and clinical trials which have helped to improve cryptococcosis outcome and survival in the last decades.COMBINATION ANTIFUNGAL THERAPYAmphotericin B with flucytosine
cryptococcosis 10972 including rifampicin ([31]). As voriconazole is not available in most of the countries endemic for cryptococcosis , this combination would be marginally used.Short courses therapy - The amphotericin B and flucytosine
cryptococcosis 20059 synergistic with fluconazole and amphotericin B in vitro and in vivo in a mouse model of disseminated cryptococcosis ([13]). At acceptably concentrations for humans, tamoxifen combined with fluconazole decreased brain
fungal meningitis 16398 countries.ADJUVANT THERAPIESSteroids - Adjuvant glucocorticoid therapy is successfully used in patients with non- fungal meningitis such as bacterial or tuberculous meningitis, and reduces mortality in some sub-groups. In CM IDSA guidelines
meningitis 572 strategies for cryptococcal disease with these tests has been showed effective in reducing cryptococcal meningitis (CM) in HIV-infected patients. Recommended induction, consolidation, and maintenance therapeutic strategy
meningitis 1074 resources countries are undergoing a paradigmatic shift.DIAGNOSTIC STRATEGIESThe diagnosis of cryptococcal meningitis (CM) and more broadly, disseminated cryptococcosis, is easily made by direct examination of a pelleted
meningitis 3409 CrAg detection tests are highly sensitive and specific in serum and CSF in predicting the presence of meningitis in HIV positive patients presenting with evocative symptoms. CrAg detection in serum and CSF with symptoms
meningitis 16405 THERAPIESSteroids - Adjuvant glucocorticoid therapy is successfully used in patients with non-fungal meningitis such as bacterial or tuberculous meningitis, and reduces mortality in some sub-groups. In CM IDSA guidelines
meningitis 16449 therapy is successfully used in patients with non-fungal meningitis such as bacterial or tuberculous meningitis , and reduces mortality in some sub-groups. In CM IDSA guidelines ([41]), experts recommend to consider
meningitis 20537 trial (“A randomised trial of tamoxifen combined with amphotericin B and fluconazole for cryptococcal meningitis ”, NCT03112031) will enrol 50 patients in Vietnam, comparing EFA according to the strategy between
meningitis 23623 trials have led to improve prevention, diagnosis, therapy and outcome of patients with cryptococcal meningitis . Efforts are now needed to implement those strategies in middle and low-income settings using affordable

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