Paradoxical Growth (PG) of Candida Tropicalis (Ct) in Response to Micafungin (MCFG).

T. NAKAI1, T. SUZUKI 2, M. IKEDO 2, K. HATANO 1, S. MATSUMOTO 1, F. IKEDA 1, K. MAKI 1;

Author address: 

1Astellas Pharma Inc., Osaka, Japan, 2Eiken Chemical Co., Ltd., Tochigi, Japan.

Abstract: 

Background: In our recent susceptibility testing for clinical isolates of Candida species, some Ct isolates exhibited PG at high concentrations of MCFG. This study was done to clarify the characteristics of this PG with Ct and its relevance to therapeutic efficacy. Methods: The frequency of PG was examined for 45 clinical isolates of Ct using RPMI/MOPS medium according to the CLSI M27-A2 methodology, and MIC and MFC were determined for 12 selected isolates. The possibility of constitutive resistance was examined by repeat susceptibility testing using the paradoxically grown organism as an inoculum. The influence of growth media on PG was studied by using AM3 medium with added graduated concentrations of supplements. Therapeutic efficacies of 0.3 to 10 mg/kg MCFG were determined by CFU recovery from the kidneys of neutropenic ICR mice, which were systemically infected with 2 PG-positive and 2 PG-negative Ct. Results: At 24 h of incubation, no isolates showed PG. PG became visible with 12 of 45 isolates (27%) at 48 h, and another 11 isolates (24%) if incubation was prolonged up to 72 h. The quantity of PG was so small that the PG could be negligible if using an MIC end point of prominent decrease in turbidity. The MFC assay revealed that visually clear wells between the sub-MIC growth and the PG produced no colonies (>99% killing). The repeated susceptibility testing reproduced PG, suggesting that it was unlikely due to constitutive resistance. The PG-positive Ct exhibited neither PG nor tolerance in response to MCFG in AM3, but PG was reproduced under increased osmotic pressure by addition of 320 mM sorbitol or 165 mM MOPS to AM3. In mouse infection, all isolates tested were similarly sterilized from kidneys by MCFG treatment in a dose-dependent manner, whether with or without PG. Conclusions: These results suggest that PG is produced only under the hyper-osmotic conditions and has no relevance to in vivo efficacy of MCFG.
2006

abstract No: 

M-1761

Full conference title: 

46th Interscience Conference on Antimicrobial Agents and Chemotherapy
    • ICAAC 46th