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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. Vidmantas Petraitis, 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 .
Adherence of Candida albicans to Silicone Induces Immediate Enhanced Tolerance to Fluconazole. Carolina Mateus, 2004.Wild-type and efflux pump-deficient cells of Candida albicans adhering to silicone were compared with planktonic cells by flow cytometry for their relative resistance to fluconazole (FCZ) . Flow cytometry data on cells carrying a fusion of green fluorescent protein to efflux pump promoters confirmed that enhanced tolerance of attached cells to FCZ was due in part to increased expression of CaMDR1 and CDR1 promoters . Within 2 h of their attachment to silicone, the adherent cells demonstrated levels of FCZ tolerance shown by cells from 24-h biofilms . Following their mechanical detachment, this subset of cells retained a four- to eightfold increase in tolerance compared with the tolerance of planktonic cells for at least two generations . Enhanced efflux pump tolerance to FCZ appeared to be induced within the initial 15 min of attachment in a subset of cells that were firmly attached to the substrata . Presence of Acylated Homoserine Lactones (AHLs) and AHL-Producing Bacteria in Meat and Potential Role of AHL in Spoilage of Meat. Jesper Bartholin Bruhn, 2004.Quorum-sensing (QS) signals (N-acyl homoserine lactones [AHLs]) were extracted and detected from five commercially produced vacuum-packed meat samples . Ninety-six AHL-producing bacteria were isolated, and 92 were identified as Enterobacteriaceae . Hafnia alvei was the most commonly identified AHL-producing bacterium . Thin-layer chromatographic profiles of supernatants from six H . alvei isolates and of extracts from spoiling meat revealed that the major AHL species had an Rf value and shape similar to N-3-oxo-hexanoyl homoserine lactone (OHHL) . Liquid chromatography-mass spectrometry (MS) (high-resolution MS) analysis confirmed the presence of OHHL in pure cultures of H . alvei . Vacuum-packed meat spoiled at the same rate when inoculated with the H . alvei wild type compared to a corresponding AHL-lacking mutant . Addition of specific QS inhibitors to the AHL-producing H . alvei inoculated in meat or to naturally contaminated meat did not influence the spoilage of vacuum-packed meat . An extracellular protein of approximately 20 kDa produced by the H . alvei wild-type was not produced by the AHL-negative mutant but was restored in the mutant when complemented by OHHL, thus indicating that AHLs do have a regulatory role in H . alvei . Coinoculation of H . alvei wild-type with an AHL-deficient Serratia proteamaculans B5a, in which protease secretion is QS regulated, caused spoilage of liquid milk . By contrast, coinoculation of AHL-negative strains of H . alvei and S . proteamaculans B5a did not cause spoilage . In conclusion, AHL and AHL-producing bacteria are present in vacuum-packed meat during storage and spoilage, but AHL does not appear to influence the spoilage of this particular type of conserved meat . Our data indicate that AHL-producing H . alvei may induce food quality-relevant phenotypes in other bacterial species in the same environment . H . alvei may thus influence spoilage of food products in which Enterobacteriaceae participate in the spoilage process .
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