Antimicrobial agents and chemotherapy
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Antimicrob. Agents Chemother. · Apr 2009
Randomized Controlled TrialPopulation pharmacokinetics of high-dose, prolonged-infusion cefepime in adult critically ill patients with ventilator-associated pneumonia.
A population pharmacokinetic model of cefepime was constructed from data from adult critical care patients with ventilator-associated pneumonia (VAP). A total of 32 patients treated with high-dose cefepime, 2 g every 8 h (3-h infusion) or a renal function-adjusted equivalent dose, were randomized into two groups--26 for the initial model and 6 for model validation. Serum samples of cefepime were collected at steady state. ⋯ Time-concentration profiles were assessed for various dosing regimens, using 5,000-patient Monte Carlo simulations. Among the regimens, the likelihoods of 2 g every 8 h (3-h infusion) achieving free drug concentrations above the MIC for 50% of the dosing interval were 91.8%, 78.1%, and 50.3% for MICs of 8, 16, and 32 microg/ml, respectively. This study provides a pharmacokinetic model capable of predicting cefepime concentrations in critically ill patients with VAP.
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Antimicrob. Agents Chemother. · Apr 2009
A novel gene, erm(41), confers inducible macrolide resistance to clinical isolates of Mycobacterium abscessus but is absent from Mycobacterium chelonae.
Mycobacterium abscessus infections tend to respond poorly to macrolide-based chemotherapy, even though the organisms appear to be susceptible to clarithromycin. Circumstantial evidence suggested that at least some M. abscessus isolates might be inducibly resistant to macrolides. Thus, the purpose of this study was to investigate the macrolide phenotype of M. abscessus clinical isolates. ⋯ The ability to confer resistance to clindamycin and telithromycin, but not quinupristin, was demonstrated by expressing erm(41) in Maycobacterium smegmatis. Exposure of M. abscessus to the macrolide-lincosamide-streptogramin B-ketolide agents increased the levels of erm(41) mRNA 23- to 250-fold within 24 h. The inducible macrolide resistance phenotype of some M. abscessus isolates may explain the lack of efficacy of macrolide-based chemotherapy against this organism.
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Antimicrob. Agents Chemother. · Apr 2009
Azithromycin in Pseudomonas aeruginosa biofilms: bactericidal activity and selection of nfxB mutants.
Azithromycin (AZM) has shown promising results in the treatment of Pseudomonas aeruginosa chronic lung infections such as those occurring in cystic fibrosis (CF) patients. We evaluated the effect of hypermutation and alginate hyperproduction on the bactericidal activity and resistance development to AZM in P. aeruginosa biofilms. Strains PAO1, its microcA mutant (PAOMA), and their respective mutS-deficient hypermutable derivatives (PAOMS and PAOMSA) were used. ⋯ The role of nfxB mutation in AZM resistance was further confirmed through the characterization of nfxB and mexD knockout mutants. Results from this work show that, although AZM exhibits bactericidal activity against P. aeruginosa biofilms, resistant mutants are readily selected and that, furthermore, they frequently show cross-resistance to other unrelated antipseudomonal agents such as ciprofloxacin or cefepime but hypersusceptibility to others such as imipenem or tobramycin. Therefore, these results should help guide the selection of appropriate antipseudomonal therapies in CF patients under AZM maintenance treatment.
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Antimicrob. Agents Chemother. · Feb 2009
Randomized Controlled TrialDrug-drug interaction study of ketoconazole and ritonavir-boosted saquinavir.
Saquinavir, a potent human immunodeficiency virus protease inhibitor, is extensively metabolized by CYP3A4. Saquinavir is coadministered with ritonavir, a strong CYP3A4 inhibitor, to boost its exposure. Ketoconazole is a potent CYP3A inhibitor. ⋯ The C(max) and AUC(0-12) of ketoconazole, dosed at 200 mg once daily, were increased by 45% (90% confidence interval = 32 to 59%) and 168% (90% confidence interval = 146 to 193%), respectively, after 2 weeks of concomitant dosing with ritonavir-boosted saquinavir (1,000 mg of saquinavir/100 mg of ritonavir given twice daily). The greater exposure to ketoconazole when given in combination with saquinavir/ritonavir was not associated with unacceptable safety or tolerability. No dose adjustment for saquinavir/ritonavir (1,000/100 mg twice daily) is required when coadministered with 200 mg of ketoconazole once daily, and high doses of ketoconazole (>200 mg/day) are not recommended.