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In vitro synergistic effects of chlorpromazine and sertraline in combination with amphotericin B against Cryptococcus neoformans var. grubii

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Abstract

Cryptococcus neoformans is encapsulated yeast that causes cryptococcosis. The cryptococcal meningitis may cause neuropsychiatric symptoms. Here, we evaluated the in vitro activity of amphotericin B (AMB), chlorpromazine (CLOR), and sertraline (SERT) alone or in combination against clinical isolates of C. neoformans considering the capsular induction in vitro. Susceptibility tests were carried out using the broth microdilution method in accordance with the CLSI document M27-A3. The combination [CLOR + AMB] exhibited synergism for 50 and 67 % of strains before capsular induction (group I) and after capsular induction (group II), respectively. The combination [SERT + AMB] showed 60 % of synergism against the both groups. Antagonism was not observed. Our results show the therapeutic potential of chlorpromazine and sertraline in combination with amphotericin B against neurocryptococcosis.

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References

  • Abergwistedt A (1989) The antidepressant effects of 5-HT uptake inhibitors. Br J Psychiatry 155:32–40

    Google Scholar 

  • Afeltra J, Verweij PE (2003) Antifungal activity of nonantifungal drugs. Eur J Clin Microbiol Infect Dis 22:397–407. doi:10.1007/s10096-003-0947-x

    Article  CAS  PubMed  Google Scholar 

  • Amaral L, Kristiansen JE (2000) Phenothiazines: an alternative to conventional therapy for the initial management of suspected multidrug resistant tuberculosis. A call for studies. Int J Antimicrob Agents 14:173–176. doi:10.1016/S0924-8579(99)00153-3

    Article  CAS  PubMed  Google Scholar 

  • Asberg M, Martensson B (1993) Serotonin selective antidepressant drugs—past, present, future. Clin Neuropharmacol 16:S32–S44

    PubMed  Google Scholar 

  • Bulatova NR, Darwish RM (2008) Effect of chemosensitizers on minimum inhibitory concentrations of fluconazole in Candida albicans. Med Princ Pract 17:117–121. doi:10.1159/000112964

    Article  PubMed  Google Scholar 

  • Butts A, DiDone L, Koselny K, Baxter BK, Chabrier-Rosello Y, Wellington M, Krysan DJ (2013) A repurposing approach identifies off-patent drugs with fungicidal cryptococcal activity, a common structural chemotype, and pharmacological properties relevant to the treatment of cryptococcosis. Eukaryot Cell 12:278–287. doi:10.1128/EC.00314-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Clinical and Laboratory Standards Institute (2008) Reference method for broth dilution antifungal susceptibility testing of yeasts : approved standard. Clinical and Laboratory Standards Institute, Wayne

    Google Scholar 

  • de Ibanez-Valdes L, Foyaca-Sibat H, Mfenyana K, Chandia J, Gonzalez-Aguilera H (2005) Neuropsychiatry manifestations in patients presenting cryptococcal meningitis. Internet J Neurol 5

  • Eilam Y, Polacheck I, Bengigi G, Chernichovsky D (1987) Activity of phenothiazines against medically important yeasts. Antimicrob Agents Chemother 31:834–836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Galgoczy L, Papp T, Kovacs L, Ordogh L, Vagvolgyi C (2009) In vitro activity of phenothiazines and their combinations with amphotericin B against Zygomycetes causing rhinocerebral zygomycosis. Med Mycol 47:331–335. doi:10.1080/13693780802378853

    Article  CAS  PubMed  Google Scholar 

  • Galgoczy L, Bacsi A, Homa M, Viragh M, Papp T, Vagvolgyi C (2011) In vitro antifungal activity of phenothiazines and their combination with amphotericin B against different Candida species. Mycoses 54:E737–E743. doi:10.1111/j.1439-0507.2010.02010.x

    Article  CAS  PubMed  Google Scholar 

  • Goodman LS, Gilman A, Brunton LL (2008) Goodman & Gilman’s manual of pharmacology and therapeutics. McGraw-Hill Medical, New York

    Google Scholar 

  • Grechi J et al (2011) Glucuronoxylomannan from Cryptococcus neoformans down-regulates the enzyme 6-phosphofructo-1-kinase of macrophages. J Biol Chem 286:14820–14829. doi:10.1074/jbc.M110.177030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jacob R, Zhimin Z, Rayapureddy S, Isaacs RT (2013) Cryptococcal meningitis presenting as acute psychosis in a HIV positive patient. Asian J Psychiatr 6:624–625. doi:10.1016/j.ajp.2013.06.002

    Article  PubMed  Google Scholar 

  • Jia CX, Mehlum L, Qin P (2012) AIDS/HIV infection, comorbid psychiatric illness, and risk for subsequent suicide: a nationwide register linkage study. J Clin Psychiatry 73:1315–1321. doi:10.4088/Jcp.12m07814

    Article  PubMed  Google Scholar 

  • Johannessen DJ, Wilson LG (1988) Mania with cryptococcal meningitis in two AIDS patients. J Clin Psychiatry 49:200–201

    CAS  PubMed  Google Scholar 

  • Johnson FYA, Naraqi S (1993) Manic episode secondary to cryptococcal meningitis in a previously healthy adult. P N G Med J 36:59–62

    CAS  PubMed  Google Scholar 

  • Johnson MD, MacDougall C, Ostrosky-Zeichner L, Perfect JR, Rex JH (2004) Combination antifungal therapy. Antimicrob Agents Chemother 48:693–715. doi:10.1128/Aac.48.3.693-715.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kumar A, Gopinath S, Dinesh KR, Karim S (2011) Infectious psychosis: cryptococcal meningitis presenting as a neuropsychiatry disorder. Neurol India 59:909. doi:10.4103/0028-3886.91379

    Article  PubMed  Google Scholar 

  • Lass-Florl C, Dierich MP, Fuchs D, Semenitz E, Jenewein I, Ledochowski M (2001a) Antifungal properties of selective serotonin reuptake inhibitors against Aspergillus species in vitro. J Antimicrob Chemother 48:775–779. doi:10.1093/Jac/48.6.775

    Article  CAS  PubMed  Google Scholar 

  • Lass-Florl C, Dierich MP, Fuchs D, Semenitz E, Ledochowski M (2001b) Antifungal activity against Candida species of the selective serotonin-reuptake inhibitor, sertraline. Clin Infect Dis 33:135–136. doi:10.1086/324589

    Article  Google Scholar 

  • Levitz SM, Specht CA (2006) The molecular basis for the immunogenicity of Cryptococcus neoformans mannoproteins. FEMS Yeast Res 6:513–524. doi:10.1111/j.1567-1364.2006.00071.x

    Article  CAS  PubMed  Google Scholar 

  • Moody J (2007) Synergism testing: broth microdilution checkerboard and broth macrodilution methods. In: Garcia LS, Isenberg HD (eds) Clinical microbiology procedures handbook, 2nd edn. ASM Press, Washington, DC, pp 1–23

    Google Scholar 

  • O’Donnell K et al (2007) Phylogenetic diversity and microsphere array-based genotyping of human pathogenic Fusaria, including isolates from the multistate contact lens-associated U.S. keratitis outbreaks of 2005 and 2006. J Clin Microbiol 45:2235–2248. doi:10.1128/JCM.00533-07

    Article  PubMed  PubMed Central  Google Scholar 

  • Owe-Larsson B, Sall L, Salamon E, Allgulander C (2009) HIV infection and psychiatric illness. Afr J Psychiatry 12:115–128

    Article  CAS  Google Scholar 

  • Park BJ, Wannemuehler KA, Marston BJ, Govender N, Pappas PG, Chiller TA (2009) Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS. AIDS 23:525–530. doi:10.1097/Qad.0b013e328322ffac

    Article  PubMed  Google Scholar 

  • Perfect JR et al (2010) Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 50:291–322. doi:10.1086/649858

    Article  PubMed  Google Scholar 

  • Pluta K, Morak-Mlodawska B, Jelen M (2011) Recent progress in biological activities of synthesized phenothiazines. Eur J Med Chem 46:3179–3189. doi:10.1016/j.ejmech.2011.05.013

    Article  CAS  PubMed  Google Scholar 

  • Rainey MM, Korostyshevsky D, Lee S, Perlstein EO (2010) The antidepressant sertraline targets intracellular vesiculogenic membranes in yeast. Genetics 185:1221–1233. doi:10.1534/genetics.110.117846

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Siavoshi F, Tavakolian A, Foroumadi A, Hosseini NM, Massarrat S, Pedramnia S, Saniee P (2012) Comparison of the effect of non-antifungal and antifungal agents on Candida isolates from the gastrointestinal tract. Arch Iran Med 15:27–31, 012151/AIM.009

    PubMed  Google Scholar 

  • Sloan DJ, Parris V (2014) Cryptococcal meningitis: epidemiology and therapeutic options. Clin Epidemiol 6:169–182. doi:10.2147/CLEP.S38850

    Article  PubMed  PubMed Central  Google Scholar 

  • Spiegel DR, Bayne CE, Wilcox L, Somova M (2011) A case of mania due to cryptococcal meningitis, successfully treated with adjunctive olanzapine, in a patient with acquired immunodeficiency syndrome. Gen Hosp Psychiatry 33(301):e303–306. doi:10.1016/j.genhosppsych.2010.11.004

    Google Scholar 

  • Spitzer M et al (2011) Cross-species discovery of syncretic drug combinations that potentiate the antifungal fluconazole. Mol Syst Biol 7:499. doi:10.1038/msb.2011.31

    Article  PubMed  PubMed Central  Google Scholar 

  • Srikanta D, Santiago-Tirado FH, Doering TL (2014) Cryptococcus neoformans: historical curiosity to modern pathogen. Yeast 31:47–60. doi:10.1002/yea.2997

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Taylor LE, Schwartzapfel B, Allen S, Jacobs G, Mitty J (2003) Extending treatment for HCV infection to HIV-HCV coinfected individuals with psychiatric illness and drug dependence. Clin Infect Dis 36:1501–1502. doi:10.1086/375065

    Article  PubMed  Google Scholar 

  • Tremaine LM, Welch WM, Ronfeld RA (1989) Metabolism and disposition of the 5-hydroxytryptamine uptake blocker sertraline in the rat and dog. Drug Metab Dispos 17:542–550

    CAS  PubMed  Google Scholar 

  • Vitale RG, Afeltra J, Meis JFGM, Verweij PE (2007) Activity and post antifungal effect of chlorpromazine and trifluoperazine against Aspergillus, Scedosporium and Zygomycetes. Mycoses 50:270–276. doi:10.1111/j.1439-0507.2007.01371.x

    Article  CAS  PubMed  Google Scholar 

  • Vitale RG, Pascuccelli V, Afeltra J (2012) Influence of capsule size on the in vitro activity of antifungal agents against clinical Cryptococcus neoformans var. grubii strains. J Med Microbiol 61:384–388. doi:10.1099/jmm.0.036152-0

    Article  CAS  PubMed  Google Scholar 

  • Wang YL, Casadevall A (1996) Susceptibility of melanized and nonmelanized Cryptococcus neoformans to the melanin-binding compounds trifluoperazine and chloroquine. Antimicrob Agents Chemother 40:541–545

    CAS  PubMed  PubMed Central  Google Scholar 

  • Winek CL, Wahba WW, Winek CL, Balzer TW (2001) Drug and chemical blood-level data 2001. Forensic Sci Int 122:107–123. doi:10.1016/S0379-0738(01)00483-2

    Article  CAS  PubMed  Google Scholar 

  • Wood NC, Nugent KM (1985) Inhibitory effects of chlorpromazine on Candida species. Antimicrob Agents Chemother 27:692–694

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu ES, Rothbard A, Blank MB (2011) Using psychiatric symptomatology to assess risk for HIV infection in individuals with severe mental illness. Community Ment Health J 47:672–678. doi:10.1007/s10597-011-9402-0

    Article  PubMed  Google Scholar 

  • Wurthwein G, Groll AH, Hempel G, Adler-Shohet FC, Lieberman JM, Walsh TJ (2005) Population pharmacokinetics of amphotericin B lipid complex in neonates. Antimicrob Agents Chemother 49:5092–5098. doi:10.1128/Aac.49.12.5092-5098.2005

    Article  PubMed  PubMed Central  Google Scholar 

  • Young TJ, Oliver GP, Pryde D, Perros M, Parkinson T (2003) Antifungal activity of selective serotonin reuptake inhibitors attributed to non-specific cytotoxicity. J Antimicrob Chemother 51:1045–1047. doi:10.1093/Jac/Dkg184

    Article  CAS  PubMed  Google Scholar 

  • Zhai B, Wu C, Wang LQ, Sachs MS, Lin XR (2012) The antidepressant sertraline provides a promising therapeutic option for neurotropic cryptococcal infections. Antimicrob Agents Chemother 56:3758–3766. doi:10.1128/Aac.00212-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

Loreto ES thanks the financial support by PNPD-CAPES from Brazil. Alves SH thanks the financial support provided by the Brazilian Agencies FAPERGS (Grant Proc. 2261-12) and CNPq (Grant Proc. 470229/2012-8).

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Correspondence to Luana Rossato.

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Rossato, L., Loreto, É.S., Zanette, R.A. et al. In vitro synergistic effects of chlorpromazine and sertraline in combination with amphotericin B against Cryptococcus neoformans var. grubii . Folia Microbiol 61, 399–403 (2016). https://doi.org/10.1007/s12223-016-0449-8

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