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

  1. Author:
    Petraitis, V.
    Petraitiene, R.
    Kelaher, A. M.
    Sarafandi, A. A.
    Sein, T.
    Mickiene, D.
    Bacher, J.
    Groll, A. H.
    Walsh, T. J.

  2. Author Address

    NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. SAIC Frederick Inc, Frederick, MD USA. NIH, Surg Serv, Vet Resources Program, Off Res Serv, Bethesda, MD 20892 USA. Univ Munster, Childrens Hosp, Dept Pediat Hematol Oncol, D-4400 Munster, Germany Walsh, TJ, NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bldg 10,Rm 13N240,Ctr Dr, Bethesda, MD 20892 USA
    1. Year: 2004
    2. Date: OCT
  2. Journal: Antimicrobial Agents and Chemotherapy
    1. 48
    2. 10
    3. Pages: 3959-3967
  4. Type of Article: Article
  1. 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 mug/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 less than or equal to 0.05, P less than or equal to 0.01, P less than or equal to 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

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External Sources

  1. View record in Web of Science®
  2. WOS: 000224217000045

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