AbstractBackground: Voriconazole is a first line agent for the treatment for invasive pulmonary aspergillosis. There are increasing reports of Aspergillus fumigatus isolates with reduced susceptibility to voriconazole. I investigated the pharmacodynamics of voriconazole against drug susceptible and drug resistant strains of Aspergillus fumigatus through the development of a novel dynamic in vitro model of the human alveolus. I then investigated whether combination therapy with voriconazole and anidulafungin would be beneficial in the treatment of infection with these isolates.Methods: An in vitro dynamic model of IPA was developed that enabled simulation of human-like voriconazole pharmacokinetics. Galactomannan was used as a biomarker. The pharmacodynamics of voriconazole against wild-type and three resistant strains of A. fumigatus were defined. The results were bridged to humans to provide decision support for setting breakpoints for voriconazole using Clinical Laboratory Standards Institute (CLSI) and European Committee of Antimicrobial Susceptibility Testing (EUCAST) methodology. The interaction of voriconazole and anidulafungin in an in vitro static model was described using the Greco model.Results: Isolates with higher MICs required higher area under the concentration time curve (AUCs) to achieve suppression of galactomannan. An AUC:MIC using CLSI and EUCAST methodology that achieved suppression of galactomannan was 55 and 32.1, respectively. A trough concentration:MIC using CLSI and EUCAST methodology that achieved suppression of galactomannan was 1.68 and 1, respectively. Potential CLSI breakpoints for voriconazole are: susceptible smaller or equal to 0.5 mg/L; resistant > 1 mg/L. Potential EUCAST breakpoints for voriconazole are: susceptible smaller or equal to 1 mg/L; resistant > 2 mg/L. Galactomannan concentrations were only marginally reduced by anidulafungin monotherapy in the static model. An additive effect between voriconazole and anidulafungin was apparent.Conclusions: Voriconazole resistance mechanisms can be overcome with higher drug exposures, but this may require concentrations likely to cause toxicity in humans. The addition of anidulafungin does not markedly alter the exposure-response relationship of voriconazole. A rise in serum galactomannan during combination therapy with voriconazole and anidulafungin should be interpreted as treatment failure and not attributed to a paradoxical reaction related to echinocandin treatment. The dynamic in vitro model is a useful tool to address many remaining questions related to treatment of invasive fungal infection.
|Date of Award
|31 Dec 2013
|Malcolm Richardson (Supervisor) & William Hope (Supervisor)