Antimicrobial agents and chemotherapy
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Antimicrob. Agents Chemother. · Jul 2011
Multicenter Study Clinical TrialPopulation pharmacokinetics of colistin methanesulfonate and formed colistin in critically ill patients from a multicenter study provide dosing suggestions for various categories of patients.
With increasing clinical emergence of multidrug-resistant Gram-negative pathogens and the paucity of new agents to combat these infections, colistin (administered as its inactive prodrug colistin methanesulfonate [CMS]) has reemerged as a treatment option, especially for critically ill patients. There has been a dearth of pharmacokinetic (PK) data available to guide dosing in critically ill patients, including those on renal replacement therapy. In an ongoing study to develop a population PK model for CMS and colistin, 105 patients have been studied to date; these included 12 patients on hemodialysis and 4 on continuous renal replacement therapy. ⋯ Covariates included creatinine clearance on the total clearance of CMS and colistin, as well as body weight on the central volume of CMS. Model-fitted parameter estimates were used to derive suggested loading and maintenance dosing regimens for various categories of patients, including those on hemodialysis and continuous renal replacement. Based on our current understanding of colistin PK and pharmacodynamic relationships, colistin may best be used as part of a highly active combination, especially for patients with moderate to good renal function and/or for organisms with MICs of ≥ 1.0 mg/liter.
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Antimicrob. Agents Chemother. · Jul 2011
Randomized Controlled TrialComparison of the efficacy and safety of oritavancin front-loaded dosing regimens to daily dosing: an analysis of the SIMPLIFI trial.
Oritavancin is a novel lipoglycopeptide with demonstrated effectiveness against complicated skin and skin structure infections (cSSSI) caused by Gram-positive pathogens, including those caused by methicillin-resistant Staphylococcus aureus (MRSA). The pharmacokinetic and pharmacodynamic profile of oritavancin is favorable for single or infrequent dosing. A phase 2, multicenter, randomized, double-blind, parallel, active-comparator study (ClinicalTrials.gov identifier, NCT00514527) of single and infrequent dosing of intravenous (i.v.) oritavancin for the treatment of cSSSI caused by Gram-positive pathogens (wound infections, major abscess, and cellulitis) was undertaken to evaluate the noninferiority of front-loaded dosing regimens compared to a daily-dosing regimen. ⋯ In patients with MRSA at baseline, the cure rates were 78.3% (18/23), 73.0% (27/37), and 87.0% (20/23) in the daily-, 1,200-mg-single-, and infrequent-dose groups, respectively; however, the study was not powered to assess outcomes in the MRSA subpopulation, and given the heterogeneity of the types of infection and the small sample size, these do not suggest any true differences in efficacy rates for these pathogens. The frequencies of adverse events were similar among treatment groups. The results of this study show that single- and infrequent-dosing schedules of oritavancin were as efficacious as daily administration and had a similar safety profile in treating cSSSI caused by Gram-positive pathogens, including MRSA.
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Antimicrob. Agents Chemother. · Jul 2011
Clinical TrialPenetration of ertapenem into muscle measured by in vivo microdialysis in mechanically ventilated patients.
Ertapenem at 1 g once daily has been suggested to be underdosed in intensive care unit (ICU) patients to attain optimal concentrations in target tissues. Therefore, our study aimed to assess the kinetics of ertapenem in plasma and skeletal muscle in ICU patients using microdialysis. ⋯ In a few patients, the concentrations were below the MIC values. The clinical efficiency of ertapenem at 1 g once daily should be evaluated in a large population of ICU patients.
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Antimicrob. Agents Chemother. · Jul 2011
Applying new diagnostic criteria for acute kidney injury to facilitate early identification of nephrotoxicity in vancomycin-treated patients.
Acute kidney injury (AKI) associated with high-dose vancomycin (VAN) therapy is a clinical concern, but no uniform diagnostic criteria exist. The AKI Network (AKIN) proposed new criteria to diagnose AKI based on abrupt changes in serum creatinine or urine output. We conducted a prospective observational study to determine the incidence and severity of AKI and associated outcomes using the AKIN criteria versus traditional definitions. ⋯ Compared to non-AKI patients, more AKI patients resided in the intensive care unit (ICU) (47% [20/43] versus 27% [50/184]; P = 0.017), had a prior AKI episode (19% [8/43] versus 7% [5/184]; P = 0.001), and received vasopressor (28% [12/43] versus 14% [25/184]; P = 0.04) and/or nephrotoxins (84% [36/43] versus 67% [123/184]; P = 0.04). Seventeen of the AKI patients met traditional criteria, of whom more patients had stage 2 and 3 AKI (76% versus 8%; P = 0.0001), dosage adjustment (41% versus 15%) and renal consultation (35% versus 12%), prolonged length of stay after AKI (11 versus 7.5 days) and died (29% versus 12%) than those diagnosed by AKIN criteria (P value not significant). Use of AKIN criteria for AKI has the potential to improve care of VAN-treated patients by facilitating early detection of AKI and warrants confirmation in large prospective trials.
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Antimicrob. Agents Chemother. · Jul 2011
Effect of moxifloxacin combined with cefotaxime compared to cefotaxime-gentamicin combination on prevention of white matter damage associated with Escherichia coli sepsis in neonatal rats.
Relative to the cefotaxime-gentamicin combination, the moxifloxacin-cefotaxime combination significantly reduced microglial activation and immature oligodendrocyte cell death and delayed myelination in the developing white matter of neonatal rats with experimental Escherichia coli sepsis. These neuroprotective effects were not due to differences in in vivo bactericidal activities or in the systemic inflammatory responses and could be related to the intrinsic immunomodulatory properties of moxifloxacin. Molecular mechanisms underlying the neuroprotective effect of moxifloxacin remain to be elucidated.