The pharmacokinetics of tigecycline, when given as a 100-mg loading dose followed by 50 mg every 12 h, were determined in serum and blister fluid. The peak tigecycline concentration and half-life in serum were greater than those in blister fluid. Tigecycline penetrates into blister fluid well, with a mean penetration rate of 74%.Tigecycline is the first of the glycylcyclines, a novel class of antimicrobials structurally related to the tetracyclines, to undergo clinical development (19). Tigecycline is an expanded broad-spectrum antibiotic with activity against gram-negative, gram-positive, anaerobic, and atypical pathogens. It shows in vitro activity against tetracycline-resistant organisms containing genes responsible for efflux or ribosomal protection resistance mechanisms, as well as other resistant pathogens, such as methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis, penicillin-resistant Streptococcus pneumoniae, and vancomycin-resistant enterococci (1,2,5,6,12).Limited pharmacokinetic data are available for tigecycline, and no studies evaluating tigecycline's ability to penetrate the skin have been published. In phase 2 studies, tigecycline has demonstrated good clinical efficacy in the treatment of skin and skin structure infections (17).In the context of skin and soft tissue infections, the evaluation of drug concentrations by using the cantharidin-induced skin blister model mimics situations within an infected tissue (13). Previous studies using this model have been successfully performed at the Center for Anti-Infective Research and Development, Hartford Hospital (14). The purpose of this study was to determine the steady-state pharmacokinetic profile of tigecycline in serum and blister fluid when tigecycline is administered intravenously over 30 min as a 100-mg loading dose followed by 50 mg every 12 h for a total of seven doses.This study was approved by Hartford Hospital's Institutional Review Board. All subjects were given a detailed description of the study, and all provided written informed consent. Ten healthy subjects were enrolled in this single-center, multipledose, open-label study. The subjects were 20 to 37 years of age (mean age, 26.7 years), 172 to 185 cm in height (mean height, 177.3 cm), and 69.5 to 89.1 kg in weight (mean weight, 80.1 kg). Participation included a screening evaluation within 3 weeks of tigecycline administration on day 1 and a 6-day (5-night) inpatient period. Subjects were enrolled after the screening evaluation, and laboratory evaluations (including hematologies, blood chemistries, and urinalyses) and electrocardiograms revealed no clinically significant abnormalities.Each subject received a loading dose of 100 mg of tigecycline (Wyeth Pharmaceuticals, Collegeville, Pa.) infused over 30 min on study day 1, followed by 50 mg infused over 30 min every 12 h, for a total of seven doses. Subjects were served mediumfat meals approximately 30 min before tigecycline administration. Fluids were allowed ad libitum. Consumption of any caffeine-containin...
Oritavancin is a novel glycopeptide currently being developed for the treatment of complicated skin and skin structure infections (cSSSI), including those caused by multidrug resistant gram-positive pathogens. The disposition of oritavancin in skin structures was investigated using a cantharide-induced blister fluid model. Seventeen healthy male subjects received oritavancin, but only 16 subjects were evaluated after one subject discontinued study drug. Each subject (eight per dose group) received 200 mg of oritavancin once a day for 3 days (group A) or 800 mg as one single dose (group B). Group A plasma samples and exudates from blister fluid were collected on days 3, 4, 7, 9, and 12 and on days 3, 4, 7, and 9, respectively. Group B samples and exudates were collected on days 1, 2, 5, 7, and 10 and on days 1, 2, 5, and 7, respectively. Drug concentrations were determined using a liquid chromatography-tandem mass spectrometry assay and, subsequently, pharmacokinetic analysis was performed. Differences between treatment groups in ratios for area under the concentration-time curve for blister fluid and plasma (AUC blister fluid /AUC plasma ratios) were evaluated using a t test ( The antibacterial spectrum of oritavancin includes Staphylococcus aureus, including methicillin-resistant strains; Staphylococcus epidermidis and other coagulase-negative staphylococci, including methicillin-resistant and some teicoplanin-resistant strains; enterococci, including vancomycin-resistant, teicoplanin-resistant (vanA) isolates of Enterococcus faecium and Enterococcus faecalis and the intrinsically vancomycin-resistant species Enterococcus gallinarum and Enterococcus casseliflavus; and streptococci, including Streptococcus pyogenes and Streptococcus pneumoniae, including penicillin-resistant isolates. Rapid bactericidal in vitro activity against most isolates of E. faecalis and E. faecium is a property of oritavancin that distinguishes it from vancomycin, ampicillin, linezolid, and quinupristin-dalfopristin.A phase 1 study in healthy subjects has demonstrated the elimination of oritavancin to be very slow, with approximately 6% of the dose eliminated from the body within a 1-week period after single-dose intravenous infusion (1). The plasma pharmacokinetics (PK) of oritavancin have been evaluated in several single-and multiple-dose clinical pharmacology studies. Across studies, oritavancin displayed linear pharmacokinetics for weight-based doses ranging from 0.02 to 3 mg/kg of body weight and fixed doses from 100 to 600 mg. Based on population pharmacokinetic analyses, oritavancin plasma concentrations display a multiexponential decline and are well described by a three-compartment model with corresponding apparent tissue distribution (␣ and ) and plasma terminal (␥) half-lives of 2.4, 18, and 360 h, respectively (J. S. Owen, S. M. Bhavnani, J. Fiedler-Kelly, J. S. Loutit, S. B. Porter, and L. Phillips, Abstr. 44th Intersci. Conf. Antimicrob. Agents Chemother., abstr. A-20, 2004).Oritavancin has been shown to be effective in tw...
Cefepime was evaluated in vivo against two inoculum sizes of four strains of Escherichia coli that produced extended-spectrum beta-lactamases (ESBLs) in a murine neutropenic thigh infection model to characterize the pharmacodynamic activity of cefepime in the presence of ESBL-producing bacteria and to evaluate if differences in lengths of cefepime exposure are required with various inocula. Three strains possessed a single enzyme each: TEM-10, TEM-12, and TEM-26. The fourth strain possessed two TEM-derived ESBLs and a third uncharacterized enzyme. Two non-ESBL-producing E. coli strains were included for comparison. Mice received various doses of cefepime to achieve a spectrum of percentages of time the drug was above the MIC (%T>MICs) for each isolate at both inocula. No significant difference in cefepime exposure was required to achieve similar bactericidal effects for ESBL-and non-ESBL-producing isolates when the starting inoculum was 10 5 CFU of E. coli per thigh. The increased MICs observed in vitro for the ESBL-producing strains at 10 7 CFU/ml did not predict the amount of exposure required to achieve a comparable level of bactericidal activity in vivo at the corresponding starting inoculum of 10 7 CFU/thigh. Compared to the cefepime exposure in tests with the lower inoculum (10 5 CFU/thigh), less exposure was required when the starting inoculum was 10 7 CFU/thigh (%T>MIC, 6% versus 26%), such that similar doses (in milligrams per kilogram of body weight) produced similar bactericidal effects with both inocula of ESBL-producing isolates. Equivalent exposures of cefepime produced similar effects against the microorganisms regardless of the presence of ESBL production. Pharmacodynamic profiling undertaken with conventional cefepime MIC determinations predicted in vivo microbial outcomes at both inoculum sizes for the ESBL-producing isolates evaluated in this study. These data support the use of conventional MIC determinations in the pharmacodynamic assessment of cefepime.
Tigecycline rapidly achieved high intracellular concentrations in PMNs and exhibited static activity against S. aureus supporting its potential clinical utilization.
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