title: 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.affiliation: Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Building 10, Rm. 13N240, Center Dr., Bethesda, MD 20892, USA. walsht@mail.nih.gov
authors.forename: Vidmantas
authors.initials: V
authors.lastname: Petraitis
authors.forename: Ruta
authors.initials: R
authors.lastname: Petraitiene
authors.forename: Amy M
authors.initials: AM
authors.lastname: Kelaher
authors.forename: Alia A
authors.initials: AA
authors.lastname: Sarafandi
authors.forename: Tin
authors.initials: T
authors.lastname: Sein
authors.forename: Diana
authors.initials: D
authors.lastname: Mickiene
authors.forename: John
authors.initials: J
authors.lastname: Bacher
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Groll
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Walsh
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D019540:Area Under Curve; D002176:Candida albicans / Q000187:drug effects* / Q000201:enzymology; D002177:Candidiasis / Q000382:microbiology*; D002180:Candidiasis, Oral / Q000382:microbiology; D003515:Cycloleucine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D025141:Drug Resistance, Fungal; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D004935:Esophageal Diseases / Q000382:microbiology; D005260:Female; D015725:Fluconazole / Q000494:pharmacology*; D006207:Half-Life; D007165:Immunosuppression Therapy; D007533:Isoleucine-tRNA Ligase / Q000037:antagonists & inhibitors*; D011817:Rabbits
chemical_list: D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D003515:Cycloleucine; D015725:Fluconazole; D007533:Isoleucine-tRNA Ligase; C114614:2-amino-4-methylenecyclopentane-1-carboxylic acid