Andrew Katende1, Gladys Mbwanji1, Diana Faini1,2, Amina Nyuri1, Aneth Vedastus Kalinjuma1, Dorcas Mnzava1, Katherine H Hullsiek3, Joshua Rhein3,4, Maja Weisser1,5,6, David B Meya3,4,7, David R Boulware3, Emilio Letang1,5,6,8,9. 1. Chronic Diseases Clinic of Ifakara, Ifakara Health Institute, Ifakara, Tanzania. 2. Muhimbili University of Health and Allied sciences, Dar es Salaam, Tanzania. 3. Division of Infectious Diseases & International Medicine, University of Minnesota, Minneapolis, MN, USA. 4. Infectious Diseases Institute, Makerere University, Kampala, Uganda. 5. Swiss Tropical and Public Health Institute, Basel, Switzerland. 6. University of Basel, Basel, Switzerland. 7. School of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda. 8. ISGlobal, Barcelona Centre for International Health Research (CRESIB), Hospital Clínic-Universitat de Barcelona, Barcelona, Spain. 9. Service of Infectious Diseases, Hospital del Mar, Hospital del Mar Research Institute (IMIM), Barcelona, Spain.
Abstract
BACKGROUND: Cryptococcal meningitis accounts for 15% of all AIDS mortality globally. Most cases in low- and middle-income countries are treated with fluconazole monotherapy, which is associated with a high mortality. New available therapies are needed. Short-course amphotericin B has been shown to be a safe and efficient therapeutic option. Sertraline has in vitro fungicidal activity against Cryptococcus and bi-directional synergy with fluconazole. METHODS: We conducted an open-label clinical trial to assess the safety and efficacy of sertraline 400 mg/day and fluconazole 1200 mg/day (n = 28) vs sertraline, fluconazole and additional 5 days of amphotericin B deoxycholate 0.7-1 mg/kg (n = 18) for cryptococcal meningitis. RESULTS: Two-week survival was 64% (18/28) without amphotericin and 89% (16/18) with amphotericin, and 10-week survival was 21% (6/28) vs 61% (11/18), respectively (P = .012). The cerebrospinal fluid (CSF) Cryptococcus clearance rate was 0.264 log10 colony-forming units (CFU)/mL of CSF/day (95% CI: 0.112-0.416) without amphotericin and 0.473 log10 CFU/mL/day (95% CI: 0.344-0.60) with short-course amphotericin (P = .03). Sertraline was discontinued in one participant due to side effects. Four participants receiving amphotericin B experienced hypokalemia <2.4 mEq/L. CONCLUSIONS: Short-course amphotericin substantially increased CSF clearance and 10-week survival. Adjunctive sertraline improved 2-week CSF fungal clearance but did not improve 10-week mortality compared with published data using fluconazole 1200 mg/day monotherapy (early fungicidal activity 0.15 log10 CFU/mL/day).
BACKGROUND:Cryptococcal meningitis accounts for 15% of all AIDSmortality globally. Most cases in low- and middle-income countries are treated with fluconazole monotherapy, which is associated with a high mortality. New available therapies are needed. Short-course amphotericin B has been shown to be a safe and efficient therapeutic option. Sertraline has in vitro fungicidal activity against Cryptococcus and bi-directional synergy with fluconazole. METHODS: We conducted an open-label clinical trial to assess the safety and efficacy of sertraline 400 mg/day and fluconazole 1200 mg/day (n = 28) vs sertraline, fluconazole and additional 5 days of amphotericin B deoxycholate 0.7-1 mg/kg (n = 18) for cryptococcal meningitis. RESULTS: Two-week survival was 64% (18/28) without amphotericin and 89% (16/18) with amphotericin, and 10-week survival was 21% (6/28) vs 61% (11/18), respectively (P = .012). The cerebrospinal fluid (CSF) Cryptococcus clearance rate was 0.264 log10 colony-forming units (CFU)/mL of CSF/day (95% CI: 0.112-0.416) without amphotericin and 0.473 log10 CFU/mL/day (95% CI: 0.344-0.60) with short-course amphotericin (P = .03). Sertraline was discontinued in one participant due to side effects. Four participants receiving amphotericin B experienced hypokalemia <2.4 mEq/L. CONCLUSIONS: Short-course amphotericin substantially increased CSF clearance and 10-week survival. Adjunctive sertraline improved 2-week CSF fungal clearance but did not improve 10-week mortality compared with published data using fluconazole 1200 mg/day monotherapy (early fungicidal activity 0.15 log10 CFU/mL/day).
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