Drug Interactions for Inhibition or Killing of Coccidioides Species

Coccidioidomycosis is of concern because of its rising incidence, the spread of its endemicity, the virulence of its progressive infections, and the difficulty of achieving successful therapy, particularly durable responses. As a result, clinicians will often attempt combination therapy with amphotericin B and an azole. However, the effects of such combinations on the inhibition or killing of the fungus are largely unknown. The present report details studies of these drug interactions against Coccidioides in vitro with checkerboard arrangements, with 239 interactions for inhibition and 76 for killing detailed. The frequency of synergy in inhibition was similar for the five most common azoles, accounting for about one third of outcomes. Synergistic and/or additive effects were noted about half of the time. Of concern, antagonism in inhibition was noted in 14-23% of cases (slightly less in the interactions for killing). These data inform clinicians of the probability of the type of interaction that may be seen with a particular azole, but of more interest in therapy selection are the interactions with the patient's individual isolate. It is emphasized that the interactions detailed are described for in vitro studies, and must be substantiated by studies in vivo; however, the data highlights the framework needed for validation studies, and highlights the importance of an awareness of the potential downsides of such combinations in individual patients.