Antimicrobial agents and chemotherapy
-
Antimicrob. Agents Chemother. · Sep 2010
Impact of multidrug-resistant Pseudomonas aeruginosa bacteremia on patient outcomes.
Trends of rising rates of resistance in Pseudomonas aeruginosa make selection of appropriate empirical therapy increasingly difficult, but whether multidrug-resistant (MDR) P. aeruginosa is associated with worse clinical outcomes is not well established. The objective of this study was to determine the impact of MDR (resistance to three or more classes of antipseudomonal agents) P. aeruginosa bacteremia on patient outcomes. We performed a retrospective cohort study of adult patients with P. aeruginosa bacteremia from 2005 to 2008. ⋯ Multivariate regression revealed that 30-day mortality was associated with multidrug resistance (odds ratio [OR], 6.8; 95% confidence interval [CI], 1.9 to 24.0), immunosuppression (OR, 5.0; 95% CI, 1.4 to 17.5), and an APACHE II score of > or = 22 (OR, 29.0; 95% CI, 5.0 to 168.2). Time to mortality was also shorter in the MDR cohort (P = 0.011). Multidrug resistance is a significant risk factor for 30-day mortality in patients with P. aeruginosa bacteremia; efforts to curb the spread of MDR P. aeruginosa could be beneficial.
-
Antimicrob. Agents Chemother. · Aug 2010
Multicenter Study Comparative Study Clinical TrialVoriconazole pharmacokinetics and safety in immunocompromised children compared to adult patients.
The aim of this study was to investigate the pharmacokinetics and safety of voriconazole after intravenous (i.v.) administration in immunocompromised children (2 to 11 years old) and adults (20 to 60 years old) who required treatment for the prevention or therapy of systemic fungal infections. Nine pediatric patients were treated with a dose of 7 mg/kg i.v. every 12 h for a period of 10 days. Three children and 12 adults received two loading doses of 6 mg/kg i.v. every 12 h, followed by a maintenance dose of 5 mg/kg (children) or 4 mg/kg (adults) twice a day during the entire study period. ⋯ Voriconazole exhibits nonlinear pharmacokinetics in the majority of children. Voriconazole therapy was safe and well tolerated in pediatric and adult patients. The European Medicines Agency-approved i.v. dose of 7 mg/kg can be recommended for children aged 2 to <12 years.
-
Antimicrob. Agents Chemother. · Aug 2010
Generic vancomycin products fail in vivo despite being pharmaceutical equivalents of the innovator.
Generic versions of intravenous antibiotics are not required to demonstrate therapeutic equivalence with the innovator because therapeutic equivalence is assumed from pharmaceutical equivalence. To test such assumptions, we studied three generic versions of vancomycin in simultaneous experiments with the innovator and determined the concentration and potency of the active pharmaceutical ingredient by microbiological assay, single-dose pharmacokinetics in infected mice, antibacterial effect by broth microdilution and time-kill curves (TKC), and pharmacodynamics against two wild-type strains of Staphylococcus aureus by using the neutropenic mouse thigh infection model. The main outcome measure was the comparison of magnitudes and patterns of in vivo efficacy between generic products and the innovator. ⋯ Despite such similarities, all generic products failed in vivo to kill S. aureus, while the innovator displayed the expected bactericidal efficacy: maximum antibacterial effect (Emax) (95% confidence interval [CI]) was 2.04 (1.89 to 2.19), 2.59 (2.21 to 2.98), and 3.48 (2.92 to 4.04) versus 5.65 (5.52 to 5.78) log10 CFU/g for three generics and the innovator product, respectively (P<0.0001, any comparison). Nonlinear regression analysis suggests that generic versions of vancomycin contain inhibitory and stimulatory principles within their formulations that cause agonistic-antagonistic actions responsible for in vivo failure. In conclusion, pharmaceutical equivalence does not imply therapeutic equivalence for vancomycin.
-
Antimicrob. Agents Chemother. · Aug 2010
Randomized Controlled TrialEarly bactericidal activity and pharmacokinetics of PA-824 in smear-positive tuberculosis patients.
PA-824 is a novel nitroimidazo-oxazine being evaluated for its potential to improve tuberculosis (TB) therapy. This randomized study evaluated safety, tolerability, pharmacokinetics, and extended early bactericidal activity of PA-824 in drug-sensitive, sputum smear-positive, adult pulmonary tuberculosis patients. Fifteen patients per cohort received 1 of 4 doses of oral PA-824: 200, 600, 1,000, or 1,200 mg per day for 14 days. ⋯ PA-824 appeared safe and well tolerated; the incidence of adverse events potentially related to PA-824 appeared dose related. We conclude that PA-824 demonstrated bactericidal activity over the dose range of 200 to 1,200 mg daily over 14 days. Because maximum efficacy was unexpectedly achieved at the lowest dosage tested, the activity of lower dosages should now be explored.