Objectives In neutropenic patients long-term antibiotic prophylaxis or treatment creates a selective environment for fungal growth and Candida spp. are the most frequently isolated agents. Fluconazole administration during neutropenic attacks may have the risk of selecting fluconazole-resistant Candida spp. which can further lead to serious infections. In order to overcome this resistance, we investigated the synergistic activity between fluconazole and achievable levels of sertraline, an antidepressant drug, which was previously shown to have antifungal activity in higher concentrations than that of serum levels. Methods: Antifungal susceptibility testing (NCCLS M27-A) of nonalbicans Candida isolates were performed and five fluconazole resistant Candida (three C. krusei, two C. glabrata) strains which have MICs for fluconazole and sertraline in th ranges of 32-128 mcg/ml and 24-48 mcg/ml respectively, were tested for synergy between these two drugs. To do this checkerboard assay and electron microscopy were used. Results: The MIC values of fluconazole dropped to 4-32 mcg/ml at sertraline's plasma achieveable concentrations (0.09-0.18 mcg/ml) and fractional inhibition concentration (FIC) indices were found to be 0.06-0.5 indicating the presence of synergy. We also observed irreversible changes of the cell morphologies including disruption of the cell wall and discharge of the cytoplasmic content, both at MIC levels of drugs and their synergistic concentrations under electron microscope (Fig 1). Conclusion: In the case of candidiasis due to fluconazole resistant strains, routine dosages of sertraline can be added to treatment protocol, provided that these in vitro results are furtherly confirmed with in vivo studies. Our findings also suggest that, as a broad spectrum efflux inhibitor, sertraline may also be tested for synergistic effect against other microorganisms with efflux mediated resistance.
Full conference title:
16th European Congress of Clinical Microbiology and Infectious Diseases
- ECCMID 16th (2006)