Antimicrobial agents and chemotherapy
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Antimicrob. Agents Chemother. · Aug 2010
Targeted surveillance of methicillin-resistant Staphylococcus aureus and its potential use to guide empiric antibiotic therapy.
The present study aimed to determine the frequency of methicillin-resistant Staphylococcus aureus (MRSA)-positive clinical culture among hospitalized adults in different risk categories of a targeted MRSA active surveillance screening program and to assess the utility of screening in guiding empiric antibiotic therapy. We completed a prospective cohort study in which all adults admitted to non-intensive-care-unit locations who had no history of MRSA colonization or infection received targeted screening for MRSA colonization upon hospital admission. Anterior nares swab specimens were obtained from all high-risk patients, defined as those who self-reported admission to a health care facility within the previous 12 months or who had an active skin infection on admission. ⋯ Only 2.4% of patients deemed to be at high risk but found to be screening negative had a sample positive for MRSA by clinical culture, and 1.6% of patients deemed to be at low risk had a sample positive for MRSA by clinical culture. The risk of MRSA infection was far higher in those who were deemed to be at high risk and who were surveillance culture positive. Targeted MRSA active surveillance may be beneficial in guiding empiric anti-MRSA therapy.
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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.
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Antimicrob. Agents Chemother. · Jun 2010
Population pharmacokinetics of doripenem based on data from phase 1 studies with healthy volunteers and phase 2 and 3 studies with critically ill patients.
A population pharmacokinetic model of doripenem was constructed using data pooled from phase 1, 2, and 3 studies utilizing nonlinear mixed effects modeling. A 2-compartment model with zero-order input and first-order elimination best described the log-transformed concentration-versus-time profile of doripenem. The model was parameterized in terms of total clearance (CL), central volume of distribution (V(c)), peripheral volume of distribution (V(p)), and distribution clearance between the central and peripheral compartments (Q). ⋯ Creatinine clearance was the most significant predictor of doripenem clearance. Mean Bayesian clearance was approximately 33%, 55%, and 76% lower for individuals with mild, moderate, or severe renal impairment, respectively, than for those with normal renal function. The population pharmacokinetic model based on healthy volunteer data and patient data informs us of doripenem disposition in a more general population as well as of the important measurable intrinsic and extrinsic factors that significantly influence interindividual pharmacokinetic differences.
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Antimicrob. Agents Chemother. · Jun 2010
Randomized Controlled Trial Multicenter Study Comparative StudyLong-acting neuraminidase inhibitor laninamivir octanoate (CS-8958) versus oseltamivir as treatment for children with influenza virus infection.
We conducted a double-blind, randomized controlled trial to compare a long-acting neuraminidase inhibitor, laninamivir octanoate, with oseltamivir. Eligible patients were children 9 years of age and under who had febrile influenza symptoms of no more than 36-h duration. Patients were randomized to 1 of 3 treatment groups: a group given 40 mg laninamivir (40-mg group), a group given 20 mg laninamivir (20-mg group), and an oseltamivir group. ⋯ Laninamivir octanoate was an effective and well-tolerated treatment for children with oseltamivir-resistant influenza A (H1N1) virus infection. Further study will be needed to confirm clinical efficacy against influenza A (H3N2) or B virus infection. Its ease of administration is noteworthy, because a single inhalation is required during the course of illness.
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Antimicrob. Agents Chemother. · Jun 2010
Randomized Controlled TrialPharmacokinetics of sulfobutylether-beta-cyclodextrin and voriconazole in patients with end-stage renal failure during treatment with two hemodialysis systems and hemodiafiltration.
Sulfobutylether-beta-cyclodextrin (SBECD), a large cyclic oligosaccharide that is used to solubilize voriconazole (VRC) for intravenous administration, is eliminated mainly by renal excretion. The pharmacokinetics of SBECD and voriconazole in patients undergoing extracorporeal renal replacement therapies are not well defined. We performed a three-period randomized crossover study of 15 patients with end-stage renal failure during 6-hour treatment with Genius dialysis, standard hemodialysis, or hemodiafiltration using a high-flux polysulfone membrane. ⋯ Prediction of steady-state conditions indicated that even with daily hemodialysis, SBECD will still exceed SBECD exposure of patients with normal renal function by a factor of 6.2. SBECD was effectively eliminated during 6 h of renal replacement therapy by all methods, using high-flux polysulfone membranes, whereas elimination of voriconazole was quantitatively insignificant. The SBECD half-life during renal replacement therapy was nearly normalized, but the average SBECD exposure during repeated administration is expected to be still increased.