Ketorolac-fluconazole: A New Combination Reverting Resistance in Candida albicans from Acute Myeloid Leukemia Patients on Induction Chemotherapy: In vitro Study

Shereen A Sayed,1 Ehsan AB Hassan,2 Muhamad R Abdel Hameed,3 Michael N Agban,2 Mostafa F Mohammed Saleh,3 Hayam H Mohammed,4 Abu-Baker M Abdel-Aal,5 Sherein G Elgendy2 1Department of Microbiology and Immunology, Faculty of Veterinary Medicine, Assiut University, Assiut, Egypt; 2Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt; 3Department of Internal Medicine & Hematology Unit, Assiut University Hospitals and Bone Marrow Transplantation Unit, South Egypt Cancer Institute, Assiut University, Assiut, Egypt; 4Department of Clinical Pathology, South Egypt Cancer Institute, Assiut University, Assiut, Egypt; 5Department of Organic Chemistry, Faculty of Pharmacy, Assiut University, Assiut, EgyptCorrespondence: Muhamad R Abdel HameedDepartment of Internal Medicine & Hematology Unit, Assiut University Hospitals and Bone Marrow Transplantation Unit, South Egypt Cancer Institute, Assiut University, Assiut, 71515, EgyptTel +20 1097510010Fax +20 88-2080278Email [email protected] G ElgendyDepartment of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, 71515, EgyptTel +20 1021887728Fax +20 88-2080278Email [email protected] and Objectives: Candida albicans is a significant source of morbidity and mortality for patients with acute myeloid leukemia (AML). Prolonged use of fluconazole as empirical antifungal prophylaxis in AML patients leads to overexpression of efflux pump genes that resulted in the emergence of azole-resistant species. Consequently, the introduction of a new strategy to improve the management of C. albicans infections is an urgent need. Nonsteroidal anti-inflammatory drug (NSAID) ketorolac is associated with a reduction in cancer relapses. The present study was performed to investigate the use of ketorolac-fluconazole combination to reverse fluconazole resistance in C. albicans isolated from AML patients on induction chemotherapy.Patients and Methods: One hundred and seventy AML patients were evaluated. Fifty C. albicans were isolated and subjected to disc diffusion assay and broth microdilution for fluconazole alone and combined with different concentrations of ketorolac. Efflux pump gene (CDR1, CDR2, and MDR1) expressions were quantified by real-time PCR.Results: The tested ketorolac acted synergistically with fluconazole against resistant C. albicans with the minimum inhibitory concentration (MIC) of fluconazole decreased from > 160 μg/mL to 0.3– 1.25 μg/mL in (93.8%) of resistant isolates with fractional inhibitory concentration index (FICI) value of 0.25. The majority of the resistant isolates overexpressed CDR1 (71.1%) and MDR1 (60%).Conclusion: Ketorolac-fluconazole in vitro combination would be a promising strategy for further clinical in vivo trials to overcome fluconazole resistance in AML patients on induction chemotherapy.Keywords: ketorolac, fluconazole resistance, acute myeloid leukemia, CDR1, MDR