Efficacy of posaconazole against three clinical Aspergillus fumigatus isolates with mutations in the cyp51A gene.
The in vivo efficacy of posaconazole against 4 clinical Aspergillus fumigatus isolates with posaconazole MICs ranging from 0.03 to 16 mg/liter, as determined by CLSI method M38A, was assessed in a nonneutropenic murine model of disseminated aspergillosis. The underlying resistance mechanisms of the isolates included substitutions in the cyp51A gene at codon 220 (M220I), codon 54 (G54W), and codon 98 (L98H). The latter was combined with a 34-bp tandem repeat in the gene promoter region (TR L98H). The control isolate exhibited a wild-type phenotype without any known resistance mechanism. Oral posaconazole therapy was started 24 h after infection and was given once daily for 14 consecutive days. Mice were treated with four different doses (1 to 64 mg/kg of body weight), and survival was used as the end point. Survival was dependent both on the dose and on the MIC. The Hill equation with a variable slope fitted the relationship between the dose/MIC ratio and 14-day survival well (R2, 0.92), with a 50% effective dose (ED50) of 29.0 mg/kg (95% confidence interval [CI], 15.6 to 53.6 mg/kg). This also applied to the relationship between the area under the plasma concentration-time curve (AUC)/MIC ratio and 14-day survival (50% effective pharmacodynamic index [EI50], 321.3 [95% CI, 222.7 to 463.4]). Near-maximum survival was reached at an AUC/MIC ratio of nearly 1,000. These results indicate that treatment of infections with A. fumigatus strains for which MICs are 0.5 mg/liter requires doses exceeding the present licensed doses. Increasing the standard dosing regimen may have some effect and may be clinically useful if no alternatives are available.
Mavridou
Eleftheria
E
Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, and Department of Medical Microbiology and Infectious Diseases, Canisius Wilhelmina Hospital, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
Brüggemann
Roger J M
RJ
Melchers
Willem J G
WJ
Mouton
Johan W
JW
Verweij
Paul E
PE
D000284:Administration, Oral; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D019540:Area Under Curve; D001228:Aspergillosis / Q000188:drug therapy / Q000382:microbiology*; D001232:Aspergillus fumigatus / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005260:Female; D005656:Fungal Proteins / Q000235:genetics*; D051379:Mice; D008826:Microbial Sensitivity Tests; D009154:Mutation; D014230:Triazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use
D000935:Antifungal Agents; D005656:Fungal Proteins; D014230:Triazoles; C101425:posaconazole; D003577:Cytochrome P-450 Enzyme System; C465526:cytochrome P-450 CYP51A, Aspergillus