Skip to main content
Top
Published in: Infection 1/2018

01-02-2018 | Original Paper

Clinical evaluation of the antifungal effect of sertraline in the treatment of cryptococcal meningitis in HIV patients: a single Mexican center experience

Authors: Hiram Villanueva-Lozano, Rogelio de J. Treviño-Rangel, Gloria M. González, Pedro A. Hernández-Rodríguez, Adrián Camacho-Ortiz, Luis Castillo-Reyna, Sandra G. Galindo-Alvarado, Michel F. Martínez-Reséndez

Published in: Infection | Issue 1/2018

Login to get access

Abstract

Purpose

Cryptococcal meningitis is a potentially fatal fungal infection associated with a significant attributable morbidity and mortality, especially among HIV/AIDS patients. The first-line therapy for the treatment of this clinical entity is the combinatory therapy of amphotericin B plus flucytosine. However, the high cost, toxic effects, and limited repertoire of effective antifungal drugs have led to the investigation of novel molecules. This is a prospective, double-blinded, and randomized study performed in a Mexican tertiary care center to evaluate the antifungal activity of sertraline in the treatment of cryptococcal meningitis in HIV patients.

Methods

During June 2015–December 2016, patients were recruited and included in one of two study groups: group A was given standard antifungal treatment plus sertraline 200 mg/day, while group B was given standard antifungal plus placebo. Lumbar punctures were performed on days 0, 7, and 14 of the study, and cryptococcal antigenemia and quantitative fungal culture in cerebrospinal fluid at each time point were evaluated to measure the rate of fungal clearance.

Results

The fungal loads and cryptococcal antigenemia titers showed a marked tendency to decrease by day 14 in both groups. Otherwise, group B exhibited a slightly higher nonstatistical rate of fungal clearance (−0.2868 ± 0.08275 log CFU/ml/day) than group A (−0.2496 ± 0.08340 log CFU/ml/day).

Conclusions

A statistical difference between study groups was not found. This is the first study in Latin America that reports the experience of using sertraline as an adjuvant in the antifungal management of cryptococcal meningitis in HIV patients.
Literature
1.
go back to reference Maziarz EK, Perfect JR. Cryptococcosis. Infect Dis Clin N Am. 2016;30:179–206.CrossRef Maziarz EK, Perfect JR. Cryptococcosis. Infect Dis Clin N Am. 2016;30:179–206.CrossRef
2.
go back to reference Park BJ, Wannemuehler KA, Marston BJ, Govender N, Pappas PG, Chiller TM. Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS. AIDS. 2009;23:525–30.CrossRefPubMed Park BJ, Wannemuehler KA, Marston BJ, Govender N, Pappas PG, Chiller TM. Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS. AIDS. 2009;23:525–30.CrossRefPubMed
3.
go back to reference Marr KA, Datta K, Pirofski LA, Barnes R. Cryptococcus gattii infection in healthy hosts: a sentinel for subclinical immunodeficiency? Clin Infect Dis. 2012;54:153–4.CrossRefPubMed Marr KA, Datta K, Pirofski LA, Barnes R. Cryptococcus gattii infection in healthy hosts: a sentinel for subclinical immunodeficiency? Clin Infect Dis. 2012;54:153–4.CrossRefPubMed
4.
go back to reference Jarvis JN, Bicanic T, Loyse A, Namarika D, Jackson A, Nussbaum JC, et al. Determinants of mortality in a combined cohort of 501 patients with HIV-associated Cryptococcal meningitis: implications for improving outcomes. Clin Infect Dis. 2014;58:736–45.CrossRefPubMed Jarvis JN, Bicanic T, Loyse A, Namarika D, Jackson A, Nussbaum JC, et al. Determinants of mortality in a combined cohort of 501 patients with HIV-associated Cryptococcal meningitis: implications for improving outcomes. Clin Infect Dis. 2014;58:736–45.CrossRefPubMed
5.
go back to reference Rajasingham R, Smith RM, Park BJ, Jarvis JN, Govender NP, Chiller TM et al. Global burden of disease of HIV-associated cryptococcal meningitis: an updated analysis. Lancet Infect Dis. 2017;17:873–81. doi:10.1016/S1473-3099(17)30243-8. Rajasingham R, Smith RM, Park BJ, Jarvis JN, Govender NP, Chiller TM et al. Global burden of disease of HIV-associated cryptococcal meningitis: an updated analysis. Lancet Infect Dis. 2017;17:873–81. doi:10.​1016/​S1473-3099(17)30243-8.
7.
go back to reference Perfect JR, Dismukes WE, Dromer F, Goldman DL, Graybill JR, Hamill RJ, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of America. Clin Infect Dis. 2010;50:291–322.CrossRefPubMed Perfect JR, Dismukes WE, Dromer F, Goldman DL, Graybill JR, Hamill RJ, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of America. Clin Infect Dis. 2010;50:291–322.CrossRefPubMed
8.
go back to reference van der Horst CM, Saag MS, Cloud GA, Hamill RJ, Graybill JR, Sobel JD, et al. Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. National Institute of Allergy and Infectious Diseases Mycoses Study Group and AIDS Clinical Trials Group. N Engl J Med. 1997;337:15–21.CrossRefPubMed van der Horst CM, Saag MS, Cloud GA, Hamill RJ, Graybill JR, Sobel JD, et al. Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. National Institute of Allergy and Infectious Diseases Mycoses Study Group and AIDS Clinical Trials Group. N Engl J Med. 1997;337:15–21.CrossRefPubMed
9.
go back to reference Dismukes WE, Cloud G, Gallis HA, Kerkering TM, Medoff G, Craven PC, et al. Treatment of cryptococcal meningitis with combination amphotericin B and flucytosine for four as compared with six weeks. N Engl J Med. 1987;317:334–41.CrossRefPubMed Dismukes WE, Cloud G, Gallis HA, Kerkering TM, Medoff G, Craven PC, et al. Treatment of cryptococcal meningitis with combination amphotericin B and flucytosine for four as compared with six weeks. N Engl J Med. 1987;317:334–41.CrossRefPubMed
11.
go back to reference Harrison TS, Griffin GE, Levitz SM. Conditional lethality of the diprotic weak bases chloroquine and quinacrine against Cryptococcus neoformans. J Infect Dis. 2000;182:283–9.CrossRefPubMed Harrison TS, Griffin GE, Levitz SM. Conditional lethality of the diprotic weak bases chloroquine and quinacrine against Cryptococcus neoformans. J Infect Dis. 2000;182:283–9.CrossRefPubMed
12.
go back to reference Steinbach WJ, Reedy JL, Cramer RA Jr, Perfect JR, Heitman J. Harnessing calcineurin as a novel anti-infective agent against invasive fungal infections. Nat Rev Microbiol. 2007;5:418–30.CrossRefPubMed Steinbach WJ, Reedy JL, Cramer RA Jr, Perfect JR, Heitman J. Harnessing calcineurin as a novel anti-infective agent against invasive fungal infections. Nat Rev Microbiol. 2007;5:418–30.CrossRefPubMed
13.
go back to reference Zhai B, Wu C, Wang L, Sachs MS, Lin X. The antidepressant sertraline provides a promising therapeutic option for neurotropic cryptococcal infections. Antimicrob Agents Chemother. 2012;56:3758–66.CrossRefPubMedPubMedCentral Zhai B, Wu C, Wang L, Sachs MS, Lin X. The antidepressant sertraline provides a promising therapeutic option for neurotropic cryptococcal infections. Antimicrob Agents Chemother. 2012;56:3758–66.CrossRefPubMedPubMedCentral
14.
go back to reference Smith KD, Achan B, Hullsiek KH, McDonald TR, Okagaki LH, Alhadab AA, et al. Increased antifungal drug resistance in clinical isolates of Cryptococcus neoformans in Uganda. Antimicrob Agents Chemother. 2015;59:7197–204.CrossRefPubMedPubMedCentral Smith KD, Achan B, Hullsiek KH, McDonald TR, Okagaki LH, Alhadab AA, et al. Increased antifungal drug resistance in clinical isolates of Cryptococcus neoformans in Uganda. Antimicrob Agents Chemother. 2015;59:7197–204.CrossRefPubMedPubMedCentral
15.
go back to reference Treviño-Rangel Rde J, Villanueva-Lozano H, Hernández-Rodríguez P, Martínez-Reséndez MF, García-Juárez J, Rodríguez-Rocha H, et al. Activity of sertraline against Cryptococcus neoformans: in vitro and in vivo assays. Med Mycol. 2016;54:280–6.CrossRefPubMed Treviño-Rangel Rde J, Villanueva-Lozano H, Hernández-Rodríguez P, Martínez-Reséndez MF, García-Juárez J, Rodríguez-Rocha H, et al. Activity of sertraline against Cryptococcus neoformans: in vitro and in vivo assays. Med Mycol. 2016;54:280–6.CrossRefPubMed
16.
go back to reference Bicanic T, Meintjes G, Wood R, Hayes M, Rebe K, Bekker LG, et al. Fungal burden, early fungicidal activity, and outcome in cryptococcal meningitis in antiretroviral-naive or antiretroviral-experienced patients treated with amphotericin B or fluconazole. Clin Infect Dis. 2007;45:76–80.CrossRefPubMed Bicanic T, Meintjes G, Wood R, Hayes M, Rebe K, Bekker LG, et al. Fungal burden, early fungicidal activity, and outcome in cryptococcal meningitis in antiretroviral-naive or antiretroviral-experienced patients treated with amphotericin B or fluconazole. Clin Infect Dis. 2007;45:76–80.CrossRefPubMed
17.
go back to reference Clinical and Laboratory Standards Institute. Reference method for broth dilution antifungal susceptibility testing of yeasts. 3rd ed. Wayne: CLSI; 2008 (Approved standard M27-A3). Clinical and Laboratory Standards Institute. Reference method for broth dilution antifungal susceptibility testing of yeasts. 3rd ed. Wayne: CLSI; 2008 (Approved standard M27-A3).
18.
go back to reference Graybill JR, Sobel J, Saag M, van Der Horst C, Powderly W, Cloud G, et al. Diagnosis and management of increased intracranial pressure in patients with AIDS and cryptococcal meningitis. The NIAID Mycoses Study Group and AIDS Cooperative Treatment Groups. Clin Infect Dis. 2000;30:47–54.CrossRefPubMed Graybill JR, Sobel J, Saag M, van Der Horst C, Powderly W, Cloud G, et al. Diagnosis and management of increased intracranial pressure in patients with AIDS and cryptococcal meningitis. The NIAID Mycoses Study Group and AIDS Cooperative Treatment Groups. Clin Infect Dis. 2000;30:47–54.CrossRefPubMed
19.
go back to reference Bicanic T, Brouwer AE, Meintjes G, Rebe K, Limmathurotsakul D, Chierakul W, et al. Relationship of cerebrospinal fluid pressure, fungal burden and outcome in patients with cryptococcal meningitis undergoing serial lumbar punctures. AIDS. 2009;23:701–6.PubMed Bicanic T, Brouwer AE, Meintjes G, Rebe K, Limmathurotsakul D, Chierakul W, et al. Relationship of cerebrospinal fluid pressure, fungal burden and outcome in patients with cryptococcal meningitis undergoing serial lumbar punctures. AIDS. 2009;23:701–6.PubMed
20.
go back to reference Kabanda T, Siedner MJ, Klausner JD, Muzoora C, Boulware DR. Point-of-care diagnosis and prognostication of cryptococcal meningitis with the cryptococcal antigen lateral flow assay on cerebrospinal fluid. Clin Infect Dis. 2014;58:113–6.CrossRefPubMed Kabanda T, Siedner MJ, Klausner JD, Muzoora C, Boulware DR. Point-of-care diagnosis and prognostication of cryptococcal meningitis with the cryptococcal antigen lateral flow assay on cerebrospinal fluid. Clin Infect Dis. 2014;58:113–6.CrossRefPubMed
21.
go back to reference Boulware DR, Meya DB, Bergemann TL, Wiesner DL, Rhein J, Musubire A, et al. Clinical features and serum biomarkers in HIV immune reconstitution inflammatory syndrome after cryptococcal meningitis: a prospective cohort study. PLoS Med. 2010;7:e1000384.CrossRefPubMedPubMedCentral Boulware DR, Meya DB, Bergemann TL, Wiesner DL, Rhein J, Musubire A, et al. Clinical features and serum biomarkers in HIV immune reconstitution inflammatory syndrome after cryptococcal meningitis: a prospective cohort study. PLoS Med. 2010;7:e1000384.CrossRefPubMedPubMedCentral
22.
go back to reference Brouwer AE, Teparrukkul P, Pinpraphaporn S, Larsen RA, Chierakul W, Peacock S, et al. Baseline correlation and comparative kinetics of cerebrospinal fluid colony-forming unit counts and antigen titers in cryptococcal meningitis. J Infect Dis. 2005;192:681–4.CrossRefPubMed Brouwer AE, Teparrukkul P, Pinpraphaporn S, Larsen RA, Chierakul W, Peacock S, et al. Baseline correlation and comparative kinetics of cerebrospinal fluid colony-forming unit counts and antigen titers in cryptococcal meningitis. J Infect Dis. 2005;192:681–4.CrossRefPubMed
23.
go back to reference Perfect JR, Bicanic T. Cryptococcosis diagnosis and treatment: what do we know now. Fungal Genet Biol. 2015;78:49–54.CrossRefPubMed Perfect JR, Bicanic T. Cryptococcosis diagnosis and treatment: what do we know now. Fungal Genet Biol. 2015;78:49–54.CrossRefPubMed
24.
go back to reference Chen YC, Chang TY, Liu JW, Chen FJ, Chien CC, Lee CH, et al. Increasing trend of fluconazole-non-susceptible Cryptococcus neoformans in patients with invasive cryptococcosis: a 12-year longitudinal study. BMC Infect Dis. 2015;15:277.CrossRefPubMedPubMedCentral Chen YC, Chang TY, Liu JW, Chen FJ, Chien CC, Lee CH, et al. Increasing trend of fluconazole-non-susceptible Cryptococcus neoformans in patients with invasive cryptococcosis: a 12-year longitudinal study. BMC Infect Dis. 2015;15:277.CrossRefPubMedPubMedCentral
26.
go back to reference Rhein J, Morawski BM, Hullsiek KH, Nabeta HW, Kiggundu R, Tugume L, et al. Efficacy of adjunctive sertraline for the treatment of HIV-associated cryptococcal meningitis: an open-label dose-ranging study. Lancet Infect Dis. 2016;16:809–18.CrossRefPubMedPubMedCentral Rhein J, Morawski BM, Hullsiek KH, Nabeta HW, Kiggundu R, Tugume L, et al. Efficacy of adjunctive sertraline for the treatment of HIV-associated cryptococcal meningitis: an open-label dose-ranging study. Lancet Infect Dis. 2016;16:809–18.CrossRefPubMedPubMedCentral
Metadata
Title
Clinical evaluation of the antifungal effect of sertraline in the treatment of cryptococcal meningitis in HIV patients: a single Mexican center experience
Authors
Hiram Villanueva-Lozano
Rogelio de J. Treviño-Rangel
Gloria M. González
Pedro A. Hernández-Rodríguez
Adrián Camacho-Ortiz
Luis Castillo-Reyna
Sandra G. Galindo-Alvarado
Michel F. Martínez-Reséndez
Publication date
01-02-2018
Publisher
Springer Berlin Heidelberg
Published in
Infection / Issue 1/2018
Print ISSN: 0300-8126
Electronic ISSN: 1439-0973
DOI
https://doi.org/10.1007/s15010-017-1059-3

Other articles of this Issue 1/2018

Infection 1/2018 Go to the issue