Relationship between in vitro antifungal resistance and in vivo response in coccidioidomycosis

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Coccidioidomycosis is an invasive fungal infection that is caused by Coccidioides species and is increasing in the US. Fluconazole is the drug most frequently used for mild to moderate infection. Decreased susceptibility of Coccidioides isolates to fluconazole was documented in >37% of isolates in a large in vitro study by our group. This raises the question of whether fluconazole, a drug frequently used against these infections, or other azoles should be utilized in those situations. The objective of Project 2 is to evaluate the in vivo and clinical significance of in vitro resistance to the azole antifungals and evaluate the efficacy of alternative therapeutic strategies to treat CNS and pulmonary coccidioidomycosis. The ultimate goal of these studies is to provide data that may help guide clinical therapy and improve the outcomes of patients with coccidioidomycosis. To achieve this objective, we will determine the in vivo significance of decreased Coccidioides susceptibility to azole antifungals using murine models of CNS and pulmonary coccidioidomycosis (Aim 1). Both Coccidioides immitis and C. posadasii isolates with different in vitro fluconazole susceptibilities will be used in established murine models of CNS and pulmonary infections. Treatment efficacy with azoles will be compared for azole-susceptible and azole-resistant clinical isolates in order to determine the significance of in vitro resistance on in vivo response. We will also determine the in vivo effectiveness of novel compounds against CNS and pulmonary coccidioidomycosis caused by azole-resistant isolates (Aim 2). Azole-resistant C. immitis and C. posadasii isolates will be used to evaluate different therapeutic approaches in the CNS and pulmonary models of coccidioidomycosis. This will include the evaluation of novel compounds identified in Project 1 and the Drug Screening Core with in vitro or in vivo activity against wild-type Coccidioides isolates. Promising candidates will be tested in combination with promising vaccine strategies in Project 3. Finally, we assess the correlation between in vitro susceptibility to fluconazole and other azoles and clinical outcomes over time in patients with coccidioidomycosis (Aim 3). Patients infected with fluconazole susceptible (MIC <8 g/ml) and resistant (MIC >32 g/ml) Coccidioides isolates will be identified from a clinical susceptibility database. Retrospective reviews of medical histories will be conducted to determine responses to fluconazole and other azole therapy and these will be correlated with in vitro susceptibility results. Other variables that will be assessed will include host factors, extent of disease, and other factors that may influence clinical outcomes. Changes in azole MIC patterns over time will also be measured to determine whether reduced susceptibility is a continuing problem. The results of Project 2 will further our understanding of the relationship between in vitro antifungal resistance of Coccidioides isolates to antifungals and in vivo responses and clinical outcomes in coccidioidomycosis.