In vitro synergistic effect of minocycline combined with antifungals against Cryptococcus neoformans |
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| Authors: | Lihua Tan Haiyan Shi Mei Chen Zikuo Wang Zhaoqian Yao Yi Sun |
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| Institution: | 1. Yangtze University, Jingzhou, Hubei, China;2. Department of Dermatology, Jingzhou Hospital, Yangtze University, Candidate Branch of National Clinical Research Center for Skin and Immune Diseases, Jingzhou, Hubei, China;1. Pathological Anatomy Sector (SAP), Department of Epidemiology and Public Health, Federal Rural University of Rio de Janeiro (UFRuralRJ), BR-465 Km 7, Seropédica, RJ 23.890-001, Brazil;2. Centro Universitario de Tacuarembó, Universidad de la República, Ruta 5 Km 386, Tacuarembó, TA 45000, Uruguay;5. Post-Graduate Program in Animal Science in the Tropics, Federal University of Bahia, Salvador, BA, Brazil;1. Jilin Provincial Key Laboratory on Molecular and Chemical Genetics, The Second Hospital of Jilin University, Changchun 130041, China;2. School of Medicine and Holistic Integrative Medicine, Nanjing University of Traditional Chinese Medicine, Nanjing 210023, China;3. Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun 130041, China;4. Eye Center, The Second Hospital of Jilin University, Changchun 130024, China;1. Sección de Micología, Hospital General \"Dr. Manuel Gea González\", Tlalpan 14080, Ciudad de México, México;2. Laboratorio de Micología, Centro Dermatológico \"Dr. Fernando Latapi”, Yucatán 97000, México;3. Departamento de Ecología de Agentes Patógenos. Hospital General “Dr. Manuel Gea González”, Tlalpan 14080. Ciudad de México, México;4. Departamento de Patología, Facultad de Medicina Veterinaria y Zootecnia. Universidad Nacional Autónoma de México, 04510 Coyoacán, Ciudad de México, México;5. Laboratorio de Bacteriología Intestinal, Hospital Infantil de México “Dr. Federico Gómez”, Cuauhtémoc 06720, Ciudad de México, México;1. Instituto de Medicina Tropical “Alexander von Humboldt”, Universidad Peruana Cayetano Heredia, Lima, Perú;2. School of Medicine, Universidad Peruana Cayetano Heredia, Lima, Perú;3. Hospital Cayetano Heredia, Lima, Perú;4. Genomic Research Unit, Universidad Peruana Cayetano Heredia, Lima, Perú;5. Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/Consejo Superior de Investigaciones Científicas/Universidad de Sevilla, and Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública, Hospital Universitario Virgen del Rocío, Seville, Spain;6. Groupe d''Étude des Interactions Hôte-Pathogène (GEIHP)-Université d''Angers, Université de Brest, Brest, France;7. Laboratoire de Mycologie et Parasitologie, CHRU de Brest, Brest, France;8. Centre for Clinical Research in Infection and Sexual Health, Institute for Global Health, University College London, London, United Kingdom;9. Clinical Research Department, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom;10. Programa de Microbiología y Micología, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina Universidad de Chile, Santiago, Chile;1. Clinic of Infectious Diseases, University of Bari, University Hospital Policlinico, Piazza Giulio Cesare n. 11, 70124 Bari Italy;2. Microbiology and Virology Unit, University of Bari, University Hospital Policlinico, Piazza Giulio Cesare n. 11, 70124 Bari Italy |
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| Abstract: | BackgroundCryptococcus neoformans infections occur in immunocompromised patients, especially those with HIV infection, chemoradiotherapy after cancer, and organ transplantation. Infection can cause pneumonia and meningoencephalitis in severe cases with a high mortality rate if not treated. Although fluconazole and amphotericin B are the first-line treatments for cryptococcosis, the rate of fluconazole resistance has increased significantly due to long-term use. Minocycline is a derivative of tetracycline that exerts its antibacterial effect through inhibition of bacterial protein synthesis. It is also able to pass the blood-brain barrier to act on the central nervous system. The present study investigates the effects of minocycline in combination with antifungals in treating C. neoformans.ObjectiveTo determine in vitro interactions of minocycline combined with itraconazole, voriconazole, posaconazole, fluconazole and amphotericin B against C. neoformans.MethodsThe minimum inhibitory concentrations (MIC) of the antifungals were determined by the CLSI Clinical and Laboratory Standards Institute M27-A3 microdilution method. The in vitro synergistic effects of minocycline combined with itraconazole, voriconazole, posaconazole, fluconazole, and amphotericin B on C. neoformans were detected by the broth microdilution checkerboard technique and disk diffusion testing.Results and ConclusionThe working concentration ranges were 0.125–4 µg/mL for itraconazole, 0.03–0.125 µg/ml for voriconazole, 0.03–1 µg/ml for posaconazole, 0.25–16 µg/ml for fluconazole, and 0.125–2 µg/ml for amphotericin B. The synergistic rates of minocycline combinations against C. neoformans were 55% with itraconazole, 10% with voriconazole, 85% with posaconazole, 20% with fluconazole, and 70% with amphotericin B. The effective MIC value of minocycline in the synergistic combination decreased to 2–32 µg/ml, while the MIC of itraconazole decreased to 0.03–0.125 µg/ml, voriconazole 0.03–0.125 µg/ml, posaconazole 0.03–0.125 µg/ml, 0.125–4 µg/ml fluconazole, and 0.06–0.50 µg/ml amphotericin B. The disk diffusion assay showed that the plates containing minocycline and antifungal drugs produced inhibition zones with diameters larger than the single drug plates. Minocycline showed no antagonistic effect in the combinations. In conclusion, the combination of minocycline and azoles or amphotericin B has synergistic effects against C. neoformans in vitro. |
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| Keywords: | Cryptococcal meningitis Minocycline Antifungals Corresponding author |
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