Although
amphotericin B-
azole combination
therapy has traditionally been questioned due to potential antagonistic interactions, it is often used successfully to treat refractory invasive
aspergillosis. So far, pharmacodynamic (PD) interactions have been assessed with conventional in vitro tests, which do not mimic human serum concentrations and animal models using limited doses. We therefore simulated the human serum concentration profiles of
amphotericin B and
voriconazole in an in vitro dialysis/diffusion closed pharmacokinetic-pharmacodynamic (PK-PD) model and studied the pharmacodynamic interactions against an
azole-resistant and an
azole-susceptible Aspergillus fumigatus isolate, using Bliss independence and canonical mixture response surface analyses.
Amphotericin B dosing regimens with the
drug administered every 24 h (q24h) were combined with
voriconazole q12h dosing regimens. In vitro PK-PD combination data were then combined with human PK data by using Monte Carlo analysis. The target attainment rate and the serum concentration/MIC ratio were calculated for isolates with different MICs. Synergy (20 to 31%) was observed at low
amphotericin B-high
voriconazole exposures, whereas antagonism (-6 to -16%) was found at high
amphotericin B-low
voriconazole exposures for both isolates. Combination
therapy resulted in 17 to 48% higher target attainment rates than those of monotherapy regimens for isolates with
voriconazole/
amphotericin B MICs of 1 to 4 mg/liter. Optimal activity was found for combination regimens with a 1.1 total minimum concentration of
drug in serum (tCmin)/MIC ratio for
voriconazole and a 0.5 total maximum concentration of
drug in serum (tCmax)/MIC ratio for
amphotericin B, whereas the equally effective monotherapy regimens required a
voriconazole tCmin/MIC ratio of 1.8 and an
amphotericin B tCmax/MIC ratio of 2.8.
Amphotericin B-
voriconazole combination regimens were more effective than monotherapy regimens. Therapeutic
drug monitoring can be employed to optimize antifungal combination
therapy with low-dose (≤0.6 mg/kg)
amphotericin B-based combination regimens against resistant isolates for minimal toxicity.