A Prospective Study of Mortality from Cryptococcal Meningitis following Treatment Induction with 1200mg Oral Fluconazole in Blantyre, Malawi

Gaskell, Katherine M; Rothe, Camilla; Gnanadurai, Roshina; Goodson, Patrick; Jassi, Chikondi; Heyderman, Robert S.; Allain, Theresa J.; Harrison, Thomas S.; Lalloo, David G.; Sloan, Derek J.; Feasey, Nicholas A.

doi:10.1371/journal.pone.0110285

Cited by 61 publications

(41 citation statements)

References 16 publications

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“…Based on tissue levels of sertraline and our MIC data, therapeutic levels of sertraline should be obtainable in humans (35). Combined with its current approval for use as an antidepressant in humans, these data make sertraline a promising new antifungal drug, and detailed clinical trials analyzing the efficacy of sertraline for the treatment of cryptococcal meningitis are warranted.…”

Section: Discussionmentioning

confidence: 98%

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Increased Antifungal Drug Resistance in Clinical Isolates of Cryptococcus neoformans in Uganda

Smith

Achan

Hullsiek

et al. 2015

Antimicrob Agents Chemother

166

132

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iCryptococcal antigen screening is recommended among people living with AIDS when entering HIV care with a CD4 count of <100 cells/l, and preemptive fluconazole monotherapy treatment is recommended for those with subclinical cryptococcal antigenemia. Yet, knowledge is limited of current antimicrobial resistance in Africa. We examined antifungal drug susceptibility in 198 clinical isolates collected from Kampala, Uganda, between 2010 and 2014 using the CLSI broth microdilution assay. In comparison with two previous studies from 1998 to 1999 that reported an MIC 50 of 4 g/ml and an MIC 90 of 8 g/ml prior to widespread human fluconazole and agricultural azole fungicide usage, we report an upward shift in the fluconazole MIC 50 to 8 g/ml and an MIC 90 value of 32 g/ml, with 31% of isolates with a fluconazole MIC of >16 g/ml. We observed an amphotericin B MIC 50 of 0.5 g/ml and an MIC 90 of 1 g/ml, of which 99.5% of isolates (197 of 198 isolates) were still susceptible. No correlation between MIC and clinical outcome was observed in the context of amphotericin B and fluconazole combination induction therapy. We also analyzed Cryptococcus susceptibility to sertraline, with an MIC 50 of 4 g/ml, suggesting that sertraline is a promising oral, low-cost, available, novel medication and a possible alternative to fluconazole. Although the CLSI broth microdilution assay is ideal to standardize results, limit human bias, and increase assay capacity, such assays are often inaccessible in low-income countries. Thus, we also developed and validated an assay that could easily be implemented in a resource-limited setting, with similar susceptibility results (P ‫؍‬ 0.52).

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Section: Discussionmentioning

confidence: 98%

“…Fluconazole monotherapy is already a suboptimal option for treatment of cryptococcal meningitis, with 10-week survival of only ϳ40% (13,35). Yet, fluconazole is the most common treatment given in Africa.…”

Section: Discussionmentioning

confidence: 99%

Increased Antifungal Drug Resistance in Clinical Isolates of Cryptococcus neoformans in Uganda

Smith

Achan

Hullsiek

et al. 2015

Antimicrob Agents Chemother

166

132

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“…In 10% (4/41) of included studies, the period of observation began prior to 2000. Seventeen countries were represented, with greatest representation from South Africa (14 studies) [34,[37][38][39][40][41][42][43][44][45][46][47][48][49], Ethiopia (three studies) [50][51][52] and Uganda (three studies) [53][54][55]; other countries had two or fewer studies [11,35,36,[56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74]. Amphotericin B-based induction therapy (with or without fluconazole) was the predominant induction regimen in 16 studies, fluconazole in 13 studies, and a mix of treatments (45% fluconazole and 43% amphotericin B) in one study [44], with antifungal regimens not specified in 11 studies.…”

Section: Overall Search Findingsmentioning

confidence: 99%

Mortality from HIV‐associated meningitis in sub‐Saharan Africa: a systematic review and meta‐analysis

et al. 2020

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Introduction HIV‐associated cryptococcal, TB and pneumococcal meningitis are the leading causes of adult meningitis in sub‐Saharan Africa (SSA). We performed a systematic review and meta‐analysis with the primary aim of estimating mortality from major causes of adult meningitis in routine care settings, and to contrast this with outcomes from clinical trial settings. Methods We searched PubMed, EMBASE and the Cochrane Library for published clinical trials (defined as randomized‐controlled trials (RCTs) or investigator‐managed prospective cohorts) and observational studies that evaluated outcomes of adult meningitis in SSA from 1 January 1990 through 15 September 2019. We performed random effects modelling to estimate pooled mortality, both in clinical trial and routine care settings. Outcomes were stratified as short‐term (in‐hospital or two weeks), medium‐term (up to 10 weeks) and long‐term (up to six months). Results and discussion Seventy‐nine studies met inclusion criteria. In routine care settings, pooled short‐term mortality from cryptococcal meningitis was 44% (95% confidence interval (95% CI):39% to 49%, 40 studies), which did not differ between amphotericin (either alone or with fluconazole) and fluconazole‐based induction regimens, and was twofold higher than pooled mortality in clinical trials using amphotericin based treatment (21% (95% CI:17% to 25%), 17 studies). Pooled short‐term mortality of TB meningitis was 46% (95% CI: 33% to 59%, 11 studies, all routine care). For pneumococcal meningitis, pooled short‐term mortality was 54% in routine care settings (95% CI:44% to 64%, nine studies), with similar mortality reported in two included randomized‐controlled trials. Few studies evaluated long‐term outcomes. Conclusions Mortality rates from HIV‐associated meningitis in SSA are very high under routine care conditions. Better strategies are needed to reduce mortality from HIV‐associated meningitis in the region.

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“…7 Most countries therefore rely on generic or donated fluconazole induction monotherapy; however, the rate of fungal clearance with fluconazole is slower than that with amphotericin B, even at an elevated dosage, and mortality associated with this treatment is 50 to 60% at 10 weeks and is higher than 70% at 1 year even in study cohorts. 8,9 Phase 2 studies have defined several promising treatment strategies that are associated with fungal clearance similar to that with 2-week amphotericin B regimens and that have more favorable safety profiles. An oral combination of fluconazole and flucytosine was found to be associated with a rate of clearance of infection similar to that with amphotericin B alone and to be associated with higher survival rates than those with fluconazole alone.…”

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confidence: 99%

Antifungal Combinations for Treatment of Cryptococcal Meningitis in Africa

et al. 2018

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BACKGROUNDCryptococcal meningitis accounts for more than 100,000 human immunodeficiency virus (HIV)-related deaths per year. We tested two treatment strategies that could be more sustainable in Africa than the standard of 2 weeks of amphotericin B plus flucytosine and more effective than the widely used fluconazole monotherapy. METHODSWe randomly assigned HIV-infected adults with cryptococcal meningitis to receive an oral regimen (fluconazole [1200 mg per day] plus flucytosine [100 mg per kilogram of body weight per day] for 2 weeks), 1 week of amphotericin B (1 mg per kilogram per day), or 2 weeks of amphotericin B (1 mg per kilogram per day). Each patient assigned to receive amphotericin B was also randomly assigned to receive fluconazole or flucytosine as a partner drug. After induction treatment, all the patients received fluconazole consolidation therapy and were followed to 10 weeks. RESULTSA total of 721 patients underwent randomization. Mortality in the oral-regimen, 1-week amphotericin B, and 2-week amphotericin B groups was 18.2% (41 of 225), 21.9% (49 of 224), and 21.4% (49 of 229), respectively, at 2 weeks and was 35.1% (79 of 225), 36.2% (81 of 224), and 39.7% (91 of 229), respectively, at 10 weeks. The upper limit of the one-sided 97.5% confidence interval for the difference in 2-week mortality was 4.2 percentage points for the oral-regimen group versus the 2-week amphotericin B groups and 8.1 percentage points for the 1-week amphotericin B groups versus the 2-week amphotericin B groups, both of which were below the predefined 10-percentage-point noninferiority margin. As a partner drug with amphotericin B, flucytosine was superior to fluconazole (71 deaths [31.1%] vs. 101 deaths [45.0%]; hazard ratio for death at 10 weeks, 0.62; 95% confidence interval [CI], 0.45 to 0.84; P = 0.002). One week of amphotericin B plus flucytosine was associated with the lowest 10-week mortality (24.2%; 95% CI, 16.2 to 32.1). Side effects, such as severe anemia, were more frequent with 2 weeks than with 1 week of amphotericin B or with the oral regimen.

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A Prospective Study of Mortality from Cryptococcal Meningitis following Treatment Induction with 1200mg Oral Fluconazole in Blantyre, Malawi

Cited by 61 publications

References 16 publications

Increased Antifungal Drug Resistance in Clinical Isolates of Cryptococcus neoformans in Uganda

Increased Antifungal Drug Resistance in Clinical Isolates of Cryptococcus neoformans in Uganda

Mortality from HIV‐associated meningitis in sub‐Saharan Africa: a systematic review and meta‐analysis

Antifungal Combinations for Treatment of Cryptococcal Meningitis in Africa

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