Antifungal activity and potential mechanism of action of caspofungin in combination with ribavirin against Candida albicans |
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| Institution: | 1. Department of Clinical Pharmacy, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Engineering and Technology Research Center for Pediatric Drug Development, Shandong Medicine and Health Key Laboratory of Clinical Pharmacy, Jinan, Shandong Province, People''s Republic of China;2. Department of Pharmacy, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, Weihai, Shandong Province, People''s Republic of China;3. Department of Pharmacy, Shandong Second Provincial General Hospital, Jinan, Shandong Province, People''s Republic of China;1. UMR 1173, Versailles Saint-Quentin University, Versailles, France;2. Raymond Poincaré Paris Saclay University Hospital, Garches, France;3. FHU PROTHEE, St Louis Hospital, Paris-Cité University, Paris, France;4. CIC, Raymond Poincaré Paris Saclay University Hospital, Garches, France;5. Microbiology Unit, Raymond Poincaré Paris Saclay University Hospital, Garches, France;6. Toxicology Unit, Bichat Paris Nord University Hospital, Paris, France;7. Institut for Infectious Agents, Department of Bacteriology - CNR des staphylocoques, Croix-Rousse Hospital, North Biology Centre, Hospices Civils de Lyon, Lyon, France;8. Team “Staphylococcal pathogenesis”, International Centre for Infectiology Research, INSERM U1111 - CNRS UMR5308 - ENS Lyon - Lyon 1 University, Lyon, France;1. Department of Infectious Diseases, The Alfred and Central Clinical School, Monash University, Melbourne, VIC, Australia;2. Pharmacy Department, Alfred Health, Melbourne, VIC, Australia;3. Microbiology Unit, Alfred Health, Melbourne, VIC, Australia;4. Centre for Medicines Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia;5. Infection and Immunity Program, Monash Biomedicine Discovery Institute, Department of Microbiology, Monash University, Clayton, VIC, Australia;6. Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia;7. Department of Intensive Care and Hyperbaric Medicine, The Alfred, Melbourne, VIC, Australia;1. Division of Infectious Diseases, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan;2. Department of Microbiology and Immunology, School of Medicine, China Medical University, Taichung, Taiwan;3. Department of Internal Medicine, China Medical University Hospital, School of Medicine, China Medical University, Taichung, Taiwan;4. Department of Laboratory Medicine, China Medical University Hospital, School of Medicine, China Medical University, Taichung, Taiwan;5. PhD Program for Aging, School of Medicine, China Medical University, Taichung, Taiwan;6. Departments of Laboratory Medicine and Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan;1. CHU de Bordeaux, Service des Maladies Infectieuses et Tropicales, Hôpital Pellegrin, Bordeaux, France;2. CHU de Bordeaux, Virology Laboratory, Bordeaux, France;3. Bordeaux Population Health Research Center, INSERM U1219, CIC-EC 1401, Univ. Bordeaux - ISPED, 33076, Bordeaux, France;4. CHU de Bordeaux, Service d''information médicale, Bordeaux, France;5. CHU de Bordeaux, COREVIH Nouvelle Aquitaine, Bordeaux, France;6. CHU de Bordeaux, Service de Médecine Interne, Hôpital Saint-André, Bordeaux, France;7. CHU de Bordeaux, Service de Médecine Interne et Maladies Infectieuses, Hôpital Haut-Lévêque, Pessac, France;8. CH Bayonne Service des Maladies Infectieuses, Bayonne, France;9. Université de Bordeaux, Fundamental Microbiology and Pathogenicity Laboratory, Bordeaux, France;10. CHU de Bordeaux, Service de Médecine Interne et Maladies Infectieuses, Hôpital Saint-André, Bordeaux, France;1. North-Western Tuscany Blood Bank, Pisa University Hospital, Pisa, Italy;2. Department of Medicine, Johns Hopkins School of Public Health and School of Medicine, Baltimore, MD, USA;3. Laboratory of Virology, National Institute for Infectious Diseases “Spallanzani”, Rome, Italy;4. Department of Molecular Medicine, Sapienza University of Rome, and Sapienza University Hospital “Policlinico Umberto I”, Rome, Italy |
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| Abstract: | The number of invasive fungal infections has increased dramatically, resulting in high morbidity and mortality among immunocompromised patients. With increasing use of caspofungin (CAS), resistant strains have emerged frequently and led to limitations in the treatment of patients with severe invasive Candida albicans infections. Combination therapy is an important method to deal with this issue. As such, this study investigated the activity of CAS in combination with ribavirin (RBV) against C. albicans. The results of this in-vitro study showed that the minimum inhibitory concentrations (MICs) of CAS and RBV when they were used as monotherapy were 0.5–1 μg/mL and 2–8 μg/mL, respectively, while the MIC of CAS decreased from 0.5–1 μg/mL to 0.0625–0.25 μg/mL when used in combination with RBV, with a fractional inhibitory concentration index (FICI) ≤0.5. In addition, the RBV + CAS combination group displayed synergistic effects against C. albicans biofilm over 4 h; the sessile MIC (sMIC) of CAS decreased from 0.5–1 µg/mL to 0.0625–0.25µg/mL and the sMIC of RBV decreased from 4–16 µg/mL to 1–2 µg/mL, with FICI <0.5. The survival of C. albicans-infected Galleria mellonella was prolonged, the fungal burden was decreased, and the area of tissue damage was reduced after combination therapy. Further study showed that the mechanisms of action of the synergistic effect were related to the inhibition of biofilm formation, the inhibition of hyphal growth, and the activation of metacaspases, but were not related to the accumulation of reactive oxygen species. It is hoped that these findings will contribute to the understanding of drug resistance in C. albicans, and provide new insights for the application of RBV. |
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