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Ketorolac-fluconazole: A New Combination Reverting Resistance in Candida albicans from Acute Myeloid Leukemia
Shereen A Sayed1, Ehsan A B Hassan2, Muhamad R Abdel Hameed3
1Department of Microbiology and Immunology, Faculty of Veterinary Medicine, Assiut University, Assiut, Egypt.
Background 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 microg/mL to 0.3-1.25 microg/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.
Insights
Ketorolac combined with fluconazole effectively reversed fluconazole resistance in Candida albicans, a common infection in acute myeloid leukemia patients. This combination therapy shows promise for managing resistant fungal infections in immunocompromised individuals.
Area of Science:
- Mycology
- Infectious Diseases
- Pharmacology
Background:
- Candida albicans infections pose a significant threat to acute myeloid leukemia (AML) patients.
- Prolonged fluconazole use in AML patients promotes azole resistance through efflux pump gene overexpression.
- Novel strategies are urgently needed to manage fluconazole-resistant C. albicans in AML.
Purpose of the Study:
- To investigate the efficacy of ketorolac-fluconazole combination in reversing fluconazole resistance in C. albicans from AML patients.
- To evaluate the impact of ketorolac on fluconazole susceptibility in resistant isolates.
- To assess the role of efflux pump genes in fluconazole resistance.
Main Methods:
- Disc diffusion and broth microdilution assays were performed on 50 C. albicans isolates from 170 AML patients.
- Fluconazole susceptibility was tested alone and in combination with varying ketorolac concentrations.
- Real-time PCR was used to quantify the expression of efflux pump genes (CDR1, CDR2, MDR1).
Main Results:
- Ketorolac demonstrated synergy with fluconazole, reducing the minimum inhibitory concentration (MIC) of fluconazole from >160 microg/mL to 0.3-1.25 microg/mL in 93.8% of resistant isolates.
- The fractional inhibitory concentration index (FICI) for the combination was 0.25, indicating synergy.
- Overexpression of CDR1 (71.1%) and MDR1 (60%) was prevalent in resistant isolates.
Conclusions:
- The in vitro combination of ketorolac and fluconazole is a promising strategy to overcome fluconazole resistance in C. albicans.
- This combination warrants further investigation in clinical in vivo trials for AML patients undergoing induction chemotherapy.
- Targeting efflux pump mechanisms could be a key to managing azole resistance in opportunistic fungal infections.
