Killing of Coccidioides by drugs

Coccidioidomycosis has long been regarded as one of the most difficult mycoses to eradicate in patients with progressive infection. There are few published studies of inhibition of Coccidioides in vitro, comparing the results with various drugs as measured by minimal inhibitory concentration (MIC). An ability to kill Coccidioides, at achievable concentrations in the host, may be necessary to produce a cure. Five hundred fifty-seven killing assays of Coccidioides clinical isolates in vitro, with minimum fungicidal concentrations (MFCs), are reported here. Heterogeneity of MFCs for all drugs is shown. Thus, many antifungals can kill Coccidioides, in addition to just inhibiting growth. The drug most commonly requiring the highest concentrations for killing was fluconazole, and posaconazole generally the lowest concentrations tested. For all the major drugs in use, some MFCs could not be exceeded by achievable blood (and presumably tissue) concentrations by usual dosing methods. MFCs were overwhelmingly within one twofold dilution of the MIC, but for ~5% of the major drugs, MFCs were ≥8-fold higher than the MIC. The distribution of the MFCs shown for each drug, and particularly the probability of having one of the minority of isolates with a high MFC value, might be of interest to the clinician in choosing a drug or its dose, particularly if susceptibility results will not be available, or before susceptibility results are available. MIC or MFC results in vitro are but a starting place for correlations with in vivo outcome in therapy. MFCs could be explored for incorporation into pharmacodynamic indices.