Acute and chronic effects of flucytosine on amphotericin B nephrotoxicity in rats

Abstract

The combination of intravenous flucytosine (FC) in 0.9%o saline (NaCI) and amphotericin B (AmB) provides synergistic antifungal activity and is associated with a lower incidence of nephrotoxicity than with AmB treatment alone. This study was conducted to examine whether flucytosine can influence renal function and whether it can modify the acute and chronic renal responses to AmB in the rat. In the in situ perfused rat kidney, FC at a concentration of 10 mg/kg/min for 15 min had a vasodilator effect, increasing renal blood flow by 2.5 0.7 ml/min, an effect not observed with vehicle. After the infusion of FC was stopped for 15 min, AmB induced a decrease in renal blood flow similar to that with both FC and vehicle. In a second series of studies, AmB (5 mg/kg/day intraperitoneally) was administered to four groups of rats for 7 days. In addition, the following groups received the intravenous daily interventions indicated: group 1, 5% dextrose in water (15 ml/kg/12 h); group 2, FC (150 mgkg/12 h) in 0.9%o saline (15 mlk12 h); group 3, 0.9%o saline (15 mllkg/12 h); and group 4, FC (150 mglkg/12 h) in 5% dextrose in water. Group 1 sustained a 77% decrease in creatinine clearance over the 7 days and a threefold increase in senrm creatinine concentration (P of <0.05). Groups 2, 3, and 4 sustained signiflicantiy less nephrotoxcity, with no change in serum creatinine concentration and only 38, 41, and 53% decreases in creatinine clearance, respectively (P of <0.05), compared with that for group 1. AmB levels in renal tissue varied inversely to creatinine clearance (r of 0.57, P of s0.005). However, no significant differences were found in levels in tissue between groups (P of 0.06). The results ofthis study suggest that FC has a small but sgnificant effect in reducing chronic AmB-induced nephrotoxicity. This amelioration of renal injury is independent of saline administration. There was evidence that the extent of renal uptake of AmB related to the efficiency of renal function at the end of the experiment.Amphotericin B, a polyene antibiotic, still remains the treatment of choice in the management of systemic fungal infections. The major limitation in its use, however, is its potential to induce adverse effects. Of these, the most dose limiting is the development of nephrotoxicity.In recent years, the frequency of opportunistic mycotic infections occurring in immunocompromised patients, such as AIDS patients, transplant patients, or patients receiving chemotherapy, has resulted in increasing use of amphotericin B. This has prompted attempts to learn how to minimize the nephrotoxic potential of this drug. Empiric observations suggest that sodium depletion enhances nephrotoxicity (11). The mechanisms involved in modifying the renal response are still not clearly understood.The combination of flucytosine (4-amino-5-fluro-2-pyrimadone) and amphotericin B has been advocated for inducing synergistic antifungal activity (1). This combination may also offer the advantage of inducing a lower incidence of amphotericin B-induced ne...

Potential Strategies to Control the Risk of Antifungal Resistance in Humans: A Comprehensive Review

“…Flucytosine effectively treats fungal infections caused by Cryptococcus neoformans , Candida spp., and Cryptococcal meningitis [ 48 , 49 , 50 ]. It is also used with amphotericin B to treat systemic mycoses, and this association also reduces the rate of nephrotoxicity in patients compared to treatment of amphotericin B alone [ 51 , 52 ]. Additionally, the combination of these drugs has a higher efficacy rate [ 53 ].…”