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Carbapenems are intravenous lifesaving hospital antibiotics. Once patients leave the hospital, they are sent home with antibiotics other than carbapenems since they cannot be administered orally due to lack of oral absorption prim...
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Carbapenems are intravenous lifesaving hospital antibiotics. Once patients leave the hospital, they are sent home with antibiotics other than carbapenems since they cannot be administered orally due to lack of oral absorption primarily because of very highly polarity. A prodrug approach is a bona fide strategy to improve oral absorption of compounds. Design and synthesis, in vitro and in vivo evaluation of diversified prodrugs of ertapenem, one of the only once daily dosed carbapenems is described. Many of the prodrugs prepared for evaluation are rapidly hydrolyzed in rat plasma. Only bis-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (medoxomil) ester prodrug was rapidly hydrolyzed in most of the plasmas including rat, human, dog, and monkey. Although the rate of conversion of ertapenem diethyl ester prodrug (6) was slow in in vitro plasma hydrolysis, it showed the best in vivo pharmacokinetic profile in dog by an intraduodenal dosing giving >31% total oral absorption.
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A sensitive reversed-phase high-performance liquid chromatographic (RP-HPLC) assay with on-line extraction was developed for quantifying ertapenem in human cerebrospinal fluid (CSF). This assay is at least five times more sensitiv...
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A sensitive reversed-phase high-performance liquid chromatographic (RP-HPLC) assay with on-line extraction was developed for quantifying ertapenem in human cerebrospinal fluid (CSF). This assay is at least five times more sensitive than previously published ertapenem methods with a lower limit of quantitation at 0.025 g/ml. In this assay, a CSF sample is extracted on-line using a RP extraction column and an aqueous acidic mobile phase (0.1% formic acid) to wash away polar endogenous materials, while ertapenem is retained on the column. Ertapenem is then back-flushed off the extraction column and directed to a RP analytical column using an acidic mobile phase with an organic modifier (acetonitrile/0.1% formic acid, 15:85 (v/v)) and detected using UV absorbance. The acidic mobile phase provided a sharper chromatographic peak and on-line extraction allowed large injection volumes (≥150 μl) of buffered CSF to be injected without compromising column integrity. These assay conditions were necessary to quantify ertapenem at levels expected to be found in human CSF (<0.05 μg/ml). The method was successfully validated and implemented for a clinical study: intraday precision and accuracy of the CSF assay for calibration standards (0.025–10 μg/ml) and quality control samples (0.1, 0.5, and 2.5 μg/ml) were <6.2% coefficient of variation and 96.8–104.0% of nominal concentration, respectively.
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A column-switching, reversed-phase high-performance liquid chromatographic (HPLC) assay for a new structurally unique carbapenem antibiotic, ertapenem, in urine has been improved for selectivity and automated using a Packard Multi...
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A column-switching, reversed-phase high-performance liquid chromatographic (HPLC) assay for a new structurally unique carbapenem antibiotic, ertapenem, in urine has been improved for selectivity and automated using a Packard MultiPROBE II EX pipetting station. The method uses column-switching for on-line extraction of the urine sample. The extraction column, analytical column, mobile phase, and timing of the column-switching valve have been changed to enhance selectivity for the analyte over endogenous background material. Sample transfer and dilution prior to direct-injection into the HPLC system have been accomplished using a Packard MultiPROBE II EX robotic liquid handling system.
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Ertapenem is a new once-a-day antibiotic with excellent coverage of common community gram negative and gram positive aerobes and anaerobes. It demonstrates nonlinear protein binding in human plasma (about 94% bound). An assay for ...
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Ertapenem is a new once-a-day antibiotic with excellent coverage of common community gram negative and gram positive aerobes and anaerobes. It demonstrates nonlinear protein binding in human plasma (about 94% bound). An assay for unbound drug was developed to study the pharmacokinetics of unbound ertapenem in plasma. Unbound drug is separated from plasma samples (1.0 ml) by ultrafiltration using a Centrifree centrifugal filter device. Ertapenem (vulnerable to hydrolysis of the beta-lactam moiety) is stabilized in the filtrate by adding an equal volume of 0.1 M MES buffer, pH 6.5 and then is analyzed by reversed-phase high-performance liquid chromatography (HPLC) with ultraviolet (UV) absorbance detection (300 nm). Non-specific binding to the Centrifree device is <3%. A suitable internal standard is not available. The assay is specific and linear over the concentration range of 0.25 to 100 μg/ml in plasma filtrate. The lower limit of quantitation (LLOQ) is 0.25 μg/ml. Intra-day precision is C.V.<10% and accuracy ranges from 97 to 101% of nominal concentration. Inter-day precision and accuracy were determined using quality control samples (QCs) prepared in plasma ultrafiltrate at 0.5, 12 and 80 μg/ml and stored at -70 ℃ with stabilizer. Inter-day assay accuracy and precision ranged from 100 to 111% of nominal concentration and 1.8 to 5.3% C.V. (n = 40), respectively. The assay has been used to analyze plasma samples from subjects receiving 500 and 2000 mg i.v. doses of ertapenem (30 min infusion).
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Ertapenem,a carbapenem-type beta-lactam antibiotic,demonstrates broad-spectrum efficacy against a wide range of Gram-positive and Gram-negative bacteria,including aerobes and anaerobes. Importantly,it demonstrates resistance to vi...
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Ertapenem,a carbapenem-type beta-lactam antibiotic,demonstrates broad-spectrum efficacy against a wide range of Gram-positive and Gram-negative bacteria,including aerobes and anaerobes. Importantly,it demonstrates resistance to virtually all beta-lactamases,including the extended spectrum beta-lactamases (ESBLs). Haematologic complications such as thrombocytosis,haemolysis,anaemia,and neutropenia are infrequent side effects associated with this drug. In this report,we present a rare case of ertapenem-induced thrombocytosis in a 62-year-old female patient who was admitted for a complicated urinary tract infection caused by?Escherichia coli.
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There are no comparative data evaluating outcomes of ertapenem treatment for infections with AmpC-producing Enterobacteriaceae. This retrospective matched case-control study was conducted between 2009 and 2012. Sixteen cases treat...
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There are no comparative data evaluating outcomes of ertapenem treatment for infections with AmpC-producing Enterobacteriaceae. This retrospective matched case-control study was conducted between 2009 and 2012. Sixteen cases treated with ertapenem were matched 1:2 with 32 control cases treated with cefepime based on age, culture source, and hospital service. There were more cefepime-resistant organisms in the ertapenem group (cefepime resistance present in 44% of patients treated with ertapenem compared with 0% of control patients, p< 0.001). Ertapenem was used empirically in 25% of patients compared with 88% who received cefepime empirically (p< 0.001). Consequently, 56% of patients on ertapenem received inappropriate initial therapy compared with 9% of patients on cefepime (p< 0.001). No differences in clinical success were identified (69% for ertapenem vs 88% for cefepime, p = 0.138). Although a trend favoring cefepime could be suspected, it should be noted that no statistically significant difference in clinical success was detected despite the presence of more resistant organisms and delays in initiation of appropriate therapy among patients receiving ertapenem.
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The aims of this study were to evaluate pharmacokinetic (PK) parameters of total and unbound ertapenem (ERT) in burns patients and to identify which covariates influence these PK parameters. ERT plasma concentrations were measured...
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The aims of this study were to evaluate pharmacokinetic (PK) parameters of total and unbound ertapenem (ERT) in burns patients and to identify which covariates influence these PK parameters. ERT plasma concentrations were measured in burns patients (n = 8) who received a 0.5-h infusion of ERT (1000 mg) every 24 h. PK parameters were estimated by a non-compartmental approach and the influence of covariates was estimated by multivariate analysis using a population approach. Clearance (CL) and the volume of distribution (V) of total ERT were lower than the results for unbound ERT [CL, 22.2 ± 5.6 mL/min vs. 279.4 ± 208.2 mL/min; V, 9.7 ± 1.4 L vs. 120.6 ± 130.6 L (mean ± standard deviation)]. Creatinine clearance (CL_(Cr)) and the burned surface area (BSA) were the covariates identified that significantly (P < 0.01) affected the pharmacokinetics of total ERT [CL (L/h) = 0.373 + {0.00666 x CL_(Cr) (mL/min)}] and unbound ERT [peripheral volume of distribution (L) = 3.05 + {0.959 x BSA (% of the total body surface)}], respectively. The influences of albuminaemia, glomerular filtration and burn wound on ERT pharmacokinetics are proposed to explain these results. These first results support that the ERT plasma concentration should be closely monitored particularly for patients with high values of BSA and/or CL _(Cr) to avoid suboptimal exposure.
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The efficacy of dual carbapenem therapy under various conditions, including increased MIC, different immune status and treatment duration and use of a higher ertapenem dose, was evaluated in a murine thigh model. Three KPC-produci...
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The efficacy of dual carbapenem therapy under various conditions, including increased MIC, different immune status and treatment duration and use of a higher ertapenem dose, was evaluated in a murine thigh model. Three KPC-producing Klebsiella pneumoniae isolates with different phenotypic profiles were used. Human-simulated doripenem and ertapenem doses were given alone or in combination. Three isolates were tested over 24 h in immunocompetent and immunocompromised ICR mice. Two of the isolates were also evaluated over 72 h in neutropenic mice. High-dose ertapenem regimens were also evaluated. The efficacy of combination therapy was enhanced in the immunocompetent model over the neutropenic model (P < 0.05 for all three isolates). In the immunocompetent model, bacterial density was further reduced with use of combination therapy over doripenem monotherapy for two isolates with doripenem MICs ≤ 16 mg/L (statistically greater for one isolate; P < 0.05). Whilst not statistically different at 24 h in neutropenic mice, combination therapy demonstrated significantly greater efficacy over doripenem alone for one of two isolates at 72 h (P < 0.05). Use of ertapenem 2 g did not enhance efficacy over ertapenem 1 g (P > 0.05). The beneficial effects of dual carbapenem therapy and potential difference in efficacy based on doripenem MICs are evident at 24 h in an immunocompetent setting. Within a neutropenic setting, enhanced efficacy with combination therapy may only be evident with continued therapy. Dual carbapenem regimens may represent a promising option for infections caused by KPC-producing isolates, particularly when the MIC is low.
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Sir,We read with interest the article on the faecal carriage of NDM-1 Enterobacteriaceae from patients in a military hospital in Pakistan,1 implying the potential for spread in the community. At a tertiary care centre in Mumbai, w...
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Sir,We read with interest the article on the faecal carriage of NDM-1 Enterobacteriaceae from patients in a military hospital in Pakistan,1 implying the potential for spread in the community. At a tertiary care centre in Mumbai, we screened for the presence of carbapenem resistance over a 6 month period (January to June 2011) by examining 1000 consecutive faecal samples from healthy individuals (not patients) reporting for routine health screening. This study was ethically approved by the National Health and Education Society, P. D. Hinduja National Hospital and Medical Research Centre.
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Previously, ertapenem 50 mg/kg every 6 h given subcutaneously to mice achieved a similar 24-h cumulative free time above the minimum inhibitory concentration (fT > MIC) to 1g every 24h in humans. However, this simplified regimen (...
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Previously, ertapenem 50 mg/kg every 6 h given subcutaneously to mice achieved a similar 24-h cumulative free time above the minimum inhibitory concentration (fT > MIC) to 1g every 24h in humans. However, this simplified regimen (SR) does not provide a superimposable concentration-time profile to that observed in humans, thus allowing concentrations to fluctuate above and below the minimum inhibitory concentration (MIC) throughout the 24-h period. Herein, we compared a complex regimen (CR; 9 various mglkg doses over 24 h) providing a near superimposable concentration-time profile with the SR to determine implications on bacterial kill against eight extended-spectrum beta-lactamase (ESBL)-producing isolates over a wide MIC range. The CR resulted in a similar ( +/- 5%) 24-h cumulative fT > MIC to ertapenem 1 g every 24 h in humans over an MIC range of 0.032 mg/L to 16 mg/L. Similar bacterial kill was observed with both regimens against all eight ESBL-producing isolates examined. In mouse models, it appears that the 24-h cumulativefr > MIC and not the distribution of theft > MIC over 24 h drives efficacy. (c) 2006 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
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