Efficacy of PLD-118, a novel inhibitor of candida isoleucyl-tRNA synthetase, against experimental oropharyngeal and esophageal candidiasis caused by fluconazole-resistant C. albicans.

Abstract

PLD-118, formerly BAY 10-8888, is a synthetic antifungal derivative of the naturally occurring beta-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 microg/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.

• Authors: Vidmantas Petraitis, Ruta Petraitiene, Amy M Kelaher, Alia A Sarafandi, Tin Sein, Diana Mickiene, John Bacher, Andreas H Groll, Thomas J Walsh
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 48 Issue 10 Pg. 3959-67 (Oct 2004) ISSN: 0066-4804 [Print] United States
• PMID: 15388459 (Publication Type: Journal Article)

Chemical References

• Antifungal Agents
• Enzyme Inhibitors
• Cycloleucine
• Fluconazole
• Isoleucine-tRNA Ligase
• 2-amino-4-methylenecyclopentane-1-carboxylic acid

Topics

• Animals
• Antifungal Agents (pharmacology)
• Area Under Curve
• Candida albicans (drug effects, enzymology)
• Candidiasis (microbiology)
• Candidiasis, Oral (microbiology)
• Cycloleucine (adverse effects, analogs & derivatives, pharmacokinetics, therapeutic use)
• Drug Resistance, Fungal
• Enzyme Inhibitors (adverse effects, pharmacokinetics, pharmacology)
• Esophageal Diseases (microbiology)
• Female
• Fluconazole (pharmacology)
• Half-Life
• Immunosuppression Therapy
• Isoleucine-tRNA Ligase (antagonists & inhibitors)
• Rabbits