129,130 However, investigators demonstrated the complex interaction may be mitigated by increasing the voriconazole dose and reducing the efavirenz dose.130 These investigators showed that increasing the voriconazole dose to 50% (600 mg daily in divided doses) and lowering efavirenz dose to 25% from the prior study (300 mg selleck chemicals llc daily) produced slightly lower reductions in voriconazole exposure (55%) and maximum serum concentrations (36%).130 These reductions
were ultimately minimised when the dose of voriconazole was doubled (800 mg daily in divided doses) and the efavirenz was lowered to 25% (300 mg daily) from the original study and the regimens produced pharmacokinetic parameters similar to those achieved by monotherapy with the individual agents.130 Efavirenz induces CYP3A4, but whether it produces similar effects on CYP2C19 or CYP2C9 remains unknown. Nonetheless, investigators speculate that the interaction is due to induction of these ITF2357 concentration three enzymes by efavirenz.129,130 Changes in antifungal disposition produced by enzyme induction can be striking.157,158 In addition, the onset of induction varies with each antifungal and inducing agent. Preclinical toxicology studies animal data suggest that voriconazole may auto-induce its own CYP3A4 metabolism, but the same study clearly demonstrated no evidence of such a phenomenon in humans.34 Antifungal agents are
often prescribed in critically ill patients who are receiving many other
medications. The amphotericin B formulations interact with other medicines by reducing their renal elimination or producing additive toxicities. The azoles interact with other medicines primarily by inhibiting their CYP-mediated biotransformation. Select azoles can also affect drug distribution Cyclic nucleotide phosphodiesterase and elimination, often with significant consequences, via inhibition of important drug transport proteins. The echinocandins have the lowest propensity to interact with other medicines. The clinical relevance of antifungal–drug interactions varies substantially. Some interactions are benign and result in little or no untoward clinical outcomes. Other interactions, if they manifest, can produce significant toxicity or compromise efficacy if not properly managed through monitoring and dosage adjustment. However, certain interactions produce significant toxicity or compromise efficacy to such an extent that they cannot be managed. In this latter case, the particular combination of antifungal and interacting medicine should be avoided. To use antifungal agents safely and effectively, clinicians must consider their potential interaction with other medicines and adjust their regimens accordingly. “
“Long-term continuous flow culture allows the investigation of dynamic biofilms under microaerophilic or aerobic conditions.
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