title: Comparative pharmacodynamics of posaconazole in neutropenic murine models of invasive pulmonary aspergillosis and mucormycosis.
abstract: We used two established neutropenic murine models of pulmonary aspergillosis and mucormycosis to explore the association between the posaconazole area under the concentration-time curve (AUC)-to-MIC ratio (AUC/MIC) and treatment outcome. Posaconazole serum pharmacokinetics were verified in infected mice to ensure that the studied doses reflected human exposures with the oral suspension, delayed-release tablet, and intravenous formulations of posaconazole. Sinopulmonary infections were then induced in groups of neutropenic mice with Aspergillus fumigatus strain 293 (posaconazole MIC, 0.5 mg/liter) or Rhizopus oryzae strain 969 (posaconazole MIC, 2 mg/liter) and treated with escalating daily dosages of oral posaconazole, which was designed to achieve AUCs ranging from 1.10 to 392 mg · h/liter. After 5 days of treatment, lung fungal burden was analyzed by quantitative real-time PCR. The relationships of the total drug AUC/MIC and the treatment response were similar in both models, with 90% effective concentrations (EC90s) corresponding to an AUC/MIC threshold of 76 (95% confidence interval [CI], 46 to 102) for strain 293 versus 87 (95% CI, 66 to 101) for strain 969. Using a provisional AUC/MIC target of >100, these exposures correlated with minimum serum posaconazole concentrations (Cmins) of 1.25 mg/liter for strain 293 and 4.0 mg/liter for strain 969. The addition of deferasirox, but not liposomal amphotericin or caspofungin, improved the activity of a suboptimal posaconazole regimen (AUC/MIC, 33) in animals with pulmonary mucormycosis. However, no combination was as effective as the high-dose posaconazole monotherapy regimen (AUC/MIC, 184). Our analysis suggests that posaconazole pharmacodynamics are similar for A. fumigatus and R. oryzae when indexed to pathogen MICs.
authors.affiliation: Department of Medical Sciences and Surgery, University of Bologna, Bologna, Italy russeledward.lewis@unibo.it dkontoyi@mdanderson.org.
authors.forename: Russell E
authors.initials: RE
authors.lastname: Lewis
authors.affiliation: Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Nathaniel D
authors.initials: ND
authors.lastname: Albert
authors.affiliation: Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA russeledward.lewis@unibo.it dkontoyi@mdanderson.org.
authors.forename: Dimitrios P
authors.initials: DP
authors.lastname: Kontoyiannis
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology; D000818:Animals; D000935:Antifungal Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D001228:Aspergillosis / Q000188:drug therapy / Q000382:microbiology; D001232:Aspergillus fumigatus / Q000187:drug effects; D001565:Benzoates / Q000494:pharmacology; D000077336:Caspofungin; D000077588:Deferasirox; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D054714:Echinocandins / Q000494:pharmacology; D005260:Female; D055744:Invasive Pulmonary Aspergillosis / Q000188:drug therapy* / Q000382:microbiology; D055666:Lipopeptides; D008168:Lung / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D009091:Mucormycosis / Q000188:drug therapy*; D009503:Neutropenia; D012233:Rhizopus / Q000187:drug effects; D016896:Treatment Outcome; D014230:Triazoles / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000935:Antifungal Agents; D001565:Benzoates; D054714:Echinocandins; D055666:Lipopeptides; D014230:Triazoles; C101425:posaconazole; D000666:Amphotericin B; D000077336:Caspofungin; D000077588:Deferasirox