This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Petraitis, V. Articles by Walsh, T. J. Search for Related Content PubMed PubMed Citation Articles by Petraitis, V. Articles by Walsh, T. J.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, October 2004, p. 3959-3967, Vol. 48, No. 10
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.10.3959-3967.2004

Efficacy of PLD-118, a Novel Inhibitor of Candida Isoleucyl-tRNA Synthetase, against Experimental Oropharyngeal and Esophageal Candidiasis Caused by Fluconazole-Resistant C. albicans

Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda,¹ SAIC-Frederick, Inc., Frederick,² Surgery Service, Veterinary Resources Program, Office of Research Services, National Institutes of Health, Bethesda, Maryland,³ Department of Pediatric Hematology/Oncology, University Children's Hospital, Muenster, Germany⁴

Received 31 December 2003/ Returned for modification 10 February 2004/ Accepted 17 June 2004

PLD-118, formerly BAY 10-8888, is a synthetic antifungal derivative of the naturally occurring ß-amino acid cispentacin. We studied the activity of PLD-118 in escalating dosages against experimental oropharyngeal and esophageal candidiasis (OPEC) caused by fluconazole (FLC)-resistant Candida albicans in immunocompromised rabbits. Infection was established by fluconazole-resistant (MIC > 64 µg/ml) clinical isolates from patients with refractory esophageal candidiasis. Antifungal therapy was administered for 7 days. Study groups consisted of untreated controls; animals receiving PLD-118 at 4, 10, 25, or 50 mg/kg of body weight/day via intravenous (i.v.) twice daily (BID) injections; animals receiving FLC at 2 mg/kg/day via i.v. BID injections; and animals receiving desoxycholate amphotericin B (DAMB) i.v. at 0.5 mg/kg/day. PLD-118- and DAMB-treated animals showed a significant dosage-dependent clearance of C. albicans from the tongue, oropharynx, and esophagus in comparison to untreated controls (P 0.05, P 0.01, P 0.001, respectively), while FLC had no significant activity. PLD-118 demonstrated nonlinear plasma pharmacokinetics across the investigated dosage range, as was evident from a dose-dependent increase in plasma clearance and a dose-dependent decrease in the area under the plasma concentration-time curve. The biochemical safety profile was similar to that of FLC. In summary, PLD-118 demonstrated dosage-dependent antifungal activity and nonlinear plasma pharmacokinetics in treatment of experimental FLC-resistant oropharyngeal and esophageal candidiasis.

This article has been cited by other articles:

• Hasenoehrl, A., Galic, T., Ergovic, G., Marsic, N., Skerlev, M., Mittendorf, J., Geschke, U., Schmidt, A., Schoenfeld, W. (2006). In Vitro Activity and In Vivo Efficacy of Icofungipen (PLD-118), a Novel Oral Antifungal Agent, against the Pathogenic Yeast Candida albicans.. Antimicrob. Agents Chemother. 50: 3011-3018 [Abstract] [Full Text]  
• Hurdle, J. G., O'Neill, A. J., Chopra, I. (2005). Prospects for Aminoacyl-tRNA Synthetase Inhibitors as New Antimicrobial Agents. Antimicrob. Agents Chemother. 49: 4821-4833 [Full Text]