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1.
Sensors (Basel) ; 18(5)2018 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-29734646

RESUMO

INTRODUCTION: The use of antibiotics is mandatory in patients during extracorporeal membrane oxygenation (ECMO) support. Clinical studies have shown high variability in the antibiotic concentrations, as well as sequestration of them by the ECMO circuit, suggesting that the doses and/or interval administration used during ECMO may not be adequate. Thus, a fast response sensor to estimate antibiotic concentrations in this setting would contribute to improve dose adjustments. The biosensor PenP has been shown to have a dynamic range, sensitivity and specificity useful for pharmacokinetic (PK) tests in healthy subjects. However, the use of this biosensor in the context of a complex critical condition, such as ECMO during acute respiratory distress syndrome (ARDS), has not been tested. OBJECTIVES: To describe, by using PenP Biosensor, the pharmacokinetic of meropenem in a 24-h animal ARDS/ECMO model. METHODS: The PK of meropenem was evaluated in a swine model before and during ECMO. RESULTS: The PK parameters such as maximum concentration (Cmax), elimination rate constant (Ke), and cleareance (Cl), were not significantly altered during ECMO support. CONCLUSIONS: (a) ECMO does not affect the PK of meropenem, at least during the first 24 h; and (b) PenP has the potential to become an effective tool for making medical decisions associated with the dose model of antibiotics in a critical patient context.


Assuntos
Antibacterianos/farmacocinética , Técnicas Biossensoriais , Tienamicinas/análise , beta-Lactamases/metabolismo , Animais , Antibacterianos/análise , Antibacterianos/uso terapêutico , Área Sob a Curva , Modelos Animais de Doenças , Oxigenação por Membrana Extracorpórea , Meia-Vida , Meropeném , Curva ROC , Síndrome do Desconforto Respiratório/tratamento farmacológico , Suínos , Tienamicinas/farmacocinética , Tienamicinas/uso terapêutico
2.
J Pharm Biomed Anal ; 151: 170-177, 2018 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-29331796

RESUMO

Meropenem is a widely used antimicrobial for the treatment of infections associated with the use of invasive medical devices in intensive care unit patients. These treatments are not always effective, in fact, in-vitro studies have demonstrated the difficulty of antimicrobials to penetrate into the biofilm, however in-vivo studies of the effect of these compounds is a trend, mostly because of the complexity of pulmonary samples extracted from ETTs. Therefore, the objective of this study was to evaluate in-tube solid phase microextraction (in-tube SPME) coupled to capillary liquid chromatography (CapLC) with DAD to determine meropenem in ETTs in order to estimate the penetration capability into the biofilm. Firstly, different parameter affecting in-tube SPME, such as processed sample volume, capillary length, flow and capillary coating were studied. The best analytical response was achieved by processing 500 µL of standards/samples at 9 µL/seg with a 60-cm capillary column coated with 35%-diphenyl 65%-polydimethylsiloxane. Under these conditions, the analytical performance of in-tube SPME-CapLC-DAD, using acetonitrile-water in gradient mode as mobile phase, showed satisfactory results for estimation of meropenem in terms of sensitivity (LOD = 3 µg/L) and precision (RSD < 10%). Once the experimental conditions were stablished for in-tube SPME, the extraction of meropenem from the ETTs was studied. Liquid extraction, vortex-assisted liquid extraction (VALE) and ultrasound-extraction (UAE) extraction were tested. The results indicated that meropenem could be quantitatively extracted (91 ±â€¯6%) from ETTs, for its subsequent determination by in-tube SPME-CapLC-DAD using water as extraction solvent and 1 min as extraction time. Finally, samples from ETTs used for critically ill patients with different antimicrobial treatments were analysed with successful results.


Assuntos
Antibacterianos/análise , Eletrocromatografia Capilar/métodos , Intubação Intratraqueal/instrumentação , Microextração em Fase Sólida/métodos , Tienamicinas/análise , Cromatografia Líquida/métodos , Humanos , Limite de Detecção , Meropeném
3.
Water Res ; 128: 61-70, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29091805

RESUMO

This paper deals with the photochemical fate of two representative carbapenem antibiotics, namely imipenem and meropenem, in aqueous solutions under solar radiation. The analytical method employed for the determination of the target compounds in various aqueous matrices, such as ultrapure water, municipal wastewater treatment plant effluents, and river water, at environmentally relevant concentrations, was liquid chromatography coupled with hybrid triple quadrupole-linear ion trap-mass spectrometry. The absorption spectra of both compounds were measured in aqueous solutions at pH values from 6 to 8, and both compounds showed a rather strong absorption band centered at about 300 nm, while their molar absorption coefficient was in the order from 9 × 103-104 L mol-1 cm-1. The kinetics of the photochemical degradation of the target compounds was studied in aqueous solutions under natural solar radiation in a solar reactor with compound parabolic collectors. It was found that the photochemical degradation of both compounds at environmentally relevant concentrations follows first order kinetics and the quantum yield was in the order of 10-3 mol einsten-1. Several parameters were studied, such as solution pH, the presence of nitrate ions and humic acids, and the effect of water matrix. In all cases, it was found that the presence of various organic and inorganic constituents in the aqueous matrices do not contribute significantly, either positively or negatively, to the photochemical degradation of both compounds under natural solar radiation. In a final set of photolysis experiments, the effect of the level of irradiance was studied under simulated solar radiation and it was found that the quantum yield for the direct photodegradation of both compounds remained practically constant by changing the incident solar irradiance from 28 to 50 W m-2.


Assuntos
Carbapenêmicos/efeitos da radiação , Imipenem/efeitos da radiação , Tienamicinas/efeitos da radiação , Poluentes Químicos da Água/efeitos da radiação , Carbapenêmicos/análise , Carbapenêmicos/química , Cromatografia Líquida , Substâncias Húmicas/análise , Imipenem/análise , Imipenem/química , Cinética , Meropeném , Fotólise , Rios/química , Luz Solar , Tienamicinas/análise , Tienamicinas/química , Águas Residuárias/química , Água/química , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/química
4.
J Antimicrob Chemother ; 73(1): 95-101, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29029070

RESUMO

OBJECTIVES: Antibiotic therapy is of vital importance for the control of infectious exacerbations in cystic fibrosis (CF) patients. However, very little is known regarding the fraction of systemically administered antibiotics reaching the lower respiratory tract secretions. We developed and validated a method to measure the concentrations of piperacillin, ceftazidime, meropenem and aztreonam in CF sputum, and present the validation data. METHODS: Ultra-performance LC coupled to tandem MS was used. A single sample can be measured in 2.5 min with multiple reaction monitoring in positive electrospray ionization mode. Deuterated internal standards were used and a concentration range of 0.7-160 mg/L was covered. The method was validated according to the EMA guideline on analytical method validation. RESULTS: The boundaries within which a reliable measurement in CF sputum can be performed were determined. A few constraints are linked to the instability of the antibiotics in sputum. Piperacillin showed limited stability at room temperature and during freeze-thaw cycles. Autosampler instability was observed after 15 h for aztreonam at low concentrations. CONCLUSIONS: The method allows a reliable measurement of the selected antibiotics, if precautions are taken regarding the limited stability of piperacillin at room temperature. Due to freeze-thaw instability, piperacillin should always be analysed on the day of sampling. Quick review of the analytical data and reanalysis are needed as low concentrations of aztreonam are not stable in the autosampler.


Assuntos
Antibacterianos/análise , Aztreonam/análise , Ceftazidima/análise , Cromatografia Líquida de Alta Pressão/métodos , Piperacilina/análise , Escarro/química , Espectrometria de Massas em Tandem/métodos , Tienamicinas/análise , Fibrose Cística , Humanos , Meropeném
5.
Infect Dis (Lond) ; 49(11-12): 831-839, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28758820

RESUMO

BACKGROUND: Acinetobacter baumannii(ACBN) is a MDR organism causing pneumonia in ventilated patients. High MICs often result in insufficient lung exposures, thus poor outcomes have been observed with parenteral antimicrobials. Amikacin Inhale(AMK-I), is a drug-device combination of amikacin and a Pulmonary Drug Delivery System device. We aimed to describe the pharmacodynamic profile of human simulated epithelial lining fluid(ELF) exposures of AMK-I and intravenous meropenem alone and in combination against ACBN with variable susceptibility profiles. METHODS: AMK-I ELF exposures and the ELF profile of meropenem achieved after intravenous administration were evaluated in an in vitro pharmacodynamic model. Nine ACBN with amikacin/meropenem MICs of 2-512/2 to >64 mg/L were utilized. MICs were repeated post exposure to assess the development of resistance. RESULTS: AMK-I monotherapy rapidly achieved and sustained bactericidal activity for isolates with amikacin MIC ≤128 mg/L. For isolates with MICs of 256 and 512 mg/L initial reductions in bacterial density were observed followed by regrowth. The combination produced similar bactericidal activity against ACBN with amikacin MICs of ≤128. While the combination regimen produced initial reductions and prolonged the duration of activity against organisms with MICs of 256 and 512 mg/L, regrowth and MIC elevations were noted during the 72-h exposure period. CONCLUSION: The combination achieved rapid and sustained efficacy when amikacin MICs were ≤128 mg/L and prolonged the duration of activity compared to monotherapy for organisms with MICs 256 mg/L and 512 mg/L. These data support the utility of AMK-I as an adjunct for the treatment of pneumonia caused by A. baumannii with MICs above current susceptibility break-points.


Assuntos
Infecções por Acinetobacter/microbiologia , Acinetobacter baumannii/efeitos dos fármacos , Amicacina/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Tienamicinas/farmacologia , Amicacina/administração & dosagem , Amicacina/análise , Amicacina/farmacocinética , Antibacterianos/análise , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Líquidos Corporais/química , Líquidos Corporais/microbiologia , Quimioterapia Combinada , Humanos , Técnicas In Vitro , Meropeném , Testes de Sensibilidade Microbiana , Tienamicinas/análise , Tienamicinas/farmacocinética
6.
J Pharm Biomed Anal ; 145: 307-314, 2017 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-28709127

RESUMO

A sensitive Liquid Chromatography tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantitative analysis of three potential genotoxic impurities (318BP, M9, S5) in meropenem Active Pharmaceutical Ingredient (API). Due to the requirement for LOD values in ppb range, a high concentration of meropenem API (30mg/mL) had to be injected. Therefore, efficient determination of meropenem from its impurities became a critical aim of this study, in order to divert meropenem to waste, via a switching valve. After the selection of the important factors affecting analytes' elution, a Box-Behnken design was utilized to set the plan of experiments conducted with UV detector. As responses, the separation factor s between the last eluting impurity and meropenem, as well as meropenem retention factor k were used. Grid point search methodology was implemented aiming to obtain the optimal conditions that simultaneously comply to the conflicted criteria. Optimal mobile phase consisted of ACN, methanol and 0.09% HCOOH at a ratio 71/3.5/15.5v/v. All impurities and internal standard omeprazole were eluted before 7.5min and at 8.0min the eluents were directed to waste. The protocol was transferred to LC-MS/MS and validated according to ICH guidelines.


Assuntos
Tienamicinas/análise , Cromatografia Líquida de Alta Pressão , Meropeném , Espectrometria de Massas em Tandem
7.
Photochem Photobiol Sci ; 16(2): 170-177, 2017 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-27966712

RESUMO

A sensitive and simple flow injection chemiluminescence (CL) system was constructed for the determination of meropenem, in which the CL intensity of the KMnO4-rhodamine B (Rh B) reaction was enhanced in the presence of CdS quantum dots (QDs). A CL resonance energy transfer (CRET) occurs between CdS QDs as a donor and Rh B as an energy acceptor. Based on the strong specific quenching effect of meropenem on the CL intensity, a novel chemosensor for meropenem sensing was developed. Under the optimized conditions, the quenched CL emission intensity was proportional to the concentration of meropenem in the range of 0.002-10.0 mg L-1 with a detection limit (3σ) of 0.8 µg L-1 Moreover, the feasibility of the induced CL system was studied via the meropenem determination in environmental water samples.


Assuntos
Medições Luminescentes/métodos , Peróxidos/química , Pontos Quânticos/química , Rodaminas/química , Tienamicinas/análise , Compostos de Cádmio/química , Limite de Detecção , Meropeném , Tamanho da Partícula , Espectrofotometria Ultravioleta , Sulfetos/química , Poluentes Químicos da Água/análise
8.
ASAIO J ; 63(3): 293-298, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27922880

RESUMO

We quantified the influence of the elements of the extracorporeal oxygenation (ECMO) circuit on drug sequestration by focusing on the interactions between materials and drugs. Tubing of three different brands (Tygon/Maquet/Terumo) and oxygenators of two different brands (Maquet/Terumo) were used. Drugs included dexmedetomidine, meropenem, and heparin, which were dissolved in deionized water. Tubing was cut into approximately 7 cm sections and allowed drug solutions enclosed inside by clamping both ends. The oxygenator housing, gas membrane, and heat exchanger were dissected into approximately 1 g pieces and submerged into drug solutions. The experimental samples were then immersed in a water bath at 37°C for 1, 6, 12, and 24 h. After 24 h, the dexmedetomidine concentration was significantly reduced in all three types of tubing (<30.1%), the oxygenator heat exchanger from Maquet Inc. (41.8%), and the gas exchanger from Terumo Inc. (8.6%), while no significant losses were found for meropenem and heparin compared with the control group. The heparin concentration within the Maquet gas exchanger, on the contrary, increased significantly compared with the control group at 1 and 12 h (p < 0.05). Our in vitro study reveals that material selection is a vital part of ECMO development.


Assuntos
Dexmedetomidina/análise , Oxigenação por Membrana Extracorpórea , Heparina/análise , Tienamicinas/análise , Humanos , Meropeném
9.
J Microbiol Methods ; 131: 68-72, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27737785

RESUMO

It has been described that the sensitivity of the Carba NP test may be low in the case of OXA-48-like carbapenamases and mass spectrometry based methods as well as a colorimetry based method have been described as alternatives. We evaluated 84 Enterobacteriaceae isolates including 31 OXA-48-like producing isolates and 13 isolates that produced either an imipenemase (IMP; n=8), New Delhi metallo-ß-lactamase (NDM; n=3), or Klebsiella pneumoniae carbapenemase (KPC; n=2), as well as 40 carbapenemase negative Enterobacteriaceae isolates. We used the Neo-Rapid CARB kit, assessing the results with the unaided eye and compared it with a colorimetric approach. Furthermore, we incubated the isolates in growth media with meropenem and measured the remaining meropenem after one and 2h of incubation, respectively, using liquid chromatography tandem mass spectrometry (LC-MS/MS). Whilst all carbapenemase producing isolates with the exception of the OXA-244 producer tested positive for both the Neo-rapid CARB test using the unaided eye or colorimetry, and the 13 isolates producing either IMP, NDM or KPC hydrolysed the meropenem in the media almost completely after 2h of incubation, the 31 OXA-48-like producing isolates exhibited very variable hydrolytic activity when incubated in growth media with meropenem. In our study, the Neo-Rapid CARB test yielded a sensitivity of 98% for both the traditional and the colorimetric approach with a specificity of 95% and 100% respectively. Our results indicate that the Neo-Rapid CARB test may have use for the detection of OXA-48 type carbapenemases and that it may be particularly important to ensure bacterial lysis for the detection of these weaker hydrolysers.


Assuntos
Proteínas de Bactérias/análise , Proteínas de Bactérias/isolamento & purificação , Técnicas Bacteriológicas/métodos , Colorimetria/métodos , Enterobacteriaceae/enzimologia , Ensaios Enzimáticos/métodos , Espectrometria de Massas em Tandem/métodos , beta-Lactamases/análise , beta-Lactamases/isolamento & purificação , Antibacterianos/farmacologia , Bactérias/enzimologia , Bactérias/genética , Proteínas de Bactérias/genética , Técnicas Bacteriológicas/instrumentação , Sequência de Bases , Colorimetria/instrumentação , Meios de Cultura/química , DNA Bacteriano , Enterobacteriaceae/efeitos dos fármacos , Enterobacteriaceae/isolamento & purificação , Genes Bacterianos/genética , Klebsiella pneumoniae/enzimologia , Meropeném , Testes de Sensibilidade Microbiana , Sensibilidade e Especificidade , Espectrometria de Massas em Tandem/instrumentação , Tienamicinas/análise , Tienamicinas/farmacologia
10.
Artigo em Inglês | MEDLINE | ID: mdl-27414982

RESUMO

For pharmacokinetic/pharmacodynamic (PK/PD) assessment of antibiotics combinations in in vitro infection models, accurate and precise quantification of drug concentrations in bacterial growth medium is crucial for derivation of valid PK/PD relationships. We aimed to (i) develop a high-performance liquid chromatography (HPLC) assay to simultaneously quantify linezolid (LZD), vancomycin (VAN) and meropenem (MER), as typical components of broad-spectrum antibiotic combination therapy, in bacterial growth medium cation-adjusted Mueller-Hinton broth (CaMHB) and (ii) determine the stability profiles of LZD, VAN and MER under conditions in in vitro infection models. To separate sample matrix components, the final method comprised the pretreatment of 100µL sample with 400µL methanol, the evaporation of supernatant and its reconstitution in water. A low sample volume of 2µL processed sample was injected onto an Accucore C-18 column (2.6µm, 100×2.1mm) coupled to a Dionex Ultimate 3000 HPLC+ system. UV detection at 251, 240 and 302nm allowed quantification limits of 0.5, 2 and 0.5µg/mL for LZD, VAN and MER, respectively. The assay was successfully validated according to the relevant EMA guideline. The rapid method (14min) was successfully applied to quantify significant degradation of LZD, VAN and MER in in vitro infection models: LZD was stable, VAN degraded to 90.6% and MER to 62.9% within 24h compared to t=0 in CaMHB at 37°C, which should be considered when deriving PK/PD relationships in in vitro infection models. Inclusion of further antibiotics into the flexible gradient-based HPLC assay seems promising.


Assuntos
Antibacterianos/análise , Cromatografia Líquida de Alta Pressão/métodos , Meios de Cultura/química , Linezolida/análise , Tienamicinas/análise , Vancomicina/análise , Estabilidade de Medicamentos , Limite de Detecção , Meropeném
11.
Int J Antimicrob Agents ; 48(2): 151-7, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27345269

RESUMO

This study aimed to describe the pharmacokinetic (PK) characteristics of meropenem in children with severe infections and to assess the pharmacokinetic/pharmacodynamic (PK/PD) profiles of various meropenem dosage regimens in these patients. Fourteen children with severe infections received intravenous (i.v.) bolus doses of meropenem (20 mg/kg/dose) every 8 h (q8h). Serum samples were obtained before and serially after the second dose of meropenem, and a population PK analysis was performed. The final model was used to simulate serum concentration-time profiles with various dosage regimens. The PK/PD target was to achieve a serum meropenem concentration higher than the minimum inhibitory concentration (MIC) of the causative organism (i.e. Pseudomonas aeruginosa and Enterobacteriaceae) for ≥40% of the dosing interval (40%T>MIC). The median age and weight of the children were 6.0 years and 20.0 kg, respectively. Meropenem serum concentration-time profiles were best described by a two-compartmental model with first-order elimination. The simulations showed that the probabilities of target attainment (PTAs) for organisms with an MIC of 1 mg/L were 0.678 and 1.000 following i.v. bolus and 3-h infusion of meropenem (20 mg/kg/dose), respectively. Using a 3-h infusion of a 20 mg/kg/dose, the PTA was 0.999 and 0.765 for organisms with MICs of 4 mg/L and 8 mg/L, respectively. Meropenem given as i.v. bolus doses of 20 mg/kg/dose q8h appeared to be inadequate for PK/PD target attainment for organisms with an MIC of 1 mg/L. The simulations showed that meropenem administration via a 3-h infusion using the same dose improved the PTA.


Assuntos
Antibacterianos/farmacologia , Antibacterianos/farmacocinética , Infecções por Enterobacteriaceae/tratamento farmacológico , Infecções por Pseudomonas/tratamento farmacológico , Tienamicinas/farmacologia , Tienamicinas/farmacocinética , Administração Intravenosa , Antibacterianos/administração & dosagem , Antibacterianos/análise , Criança , Pré-Escolar , Simulação por Computador , Estado Terminal , Enterobacteriaceae/efeitos dos fármacos , Feminino , Humanos , Masculino , Meropeném , Testes de Sensibilidade Microbiana , Pseudomonas aeruginosa/efeitos dos fármacos , Soro/química , Tienamicinas/administração & dosagem , Tienamicinas/análise , Fatores de Tempo
12.
Minerva Anestesiol ; 81(3): 283-7, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25220554

RESUMO

BACKGROUND: Meropenem is a relatively unstable compound when dissolved. Currently, all available data have been derived from tests on the original product from Astrazeneca, and it is unsure if these data can be extrapolated to the stability of other commercially available vials. The aim of this study was therefore to assess the stability of four different brands of meropenem to be used as a prolonged or continuous infusion. METHODS: Commercially available meropenem vials were reconstituted and mixed with 0.9% sodium chloride to produce solutions with concentrations of 10.20 and 40 mg/mL in polypropylene syringes, which were kept at 25 °C. Samples were taken immediately after preparation and up to 12 hours. Solutions retaining >90% of the initial concentration were considered stable. RESULTS: The stability was concentration-dependent. At 25 °C, all 10 and 20 mg/mL solutions were stable for 12 hours in 0.9% sodium chloride, while the 40 mg/mL solutions were stable for a maximum of 8 hours. Stability of the different vials of meropenem was comparable for the time period tested (related samples Friedman's two way of analysis of variance by ranks, P=0.282). CONCLUSION: All tested commercially available vials of meropenem in a concentration of 10 and 20 mg/mL were stable for 12 hours at 25 °C when diluted in 0.9% sodium chloride. The 40 mg/mL solutions were stable for a maximum of 8 hours. This report is the first to show equivalent stability between different commercially available vials of meropenem.


Assuntos
Antibacterianos/análise , Tienamicinas/análise , Cromatografia Líquida de Alta Pressão , Composição de Medicamentos , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Soluções Isotônicas , Meropeném , Cloreto de Sódio , Seringas
13.
Acta Pol Pharm ; 71(2): 255-60, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25272645

RESUMO

A stability-indicating LC assay method was developed and validated for a simultaneous determination of meropenem and potassium clavulanate in the presence of degradation products formed during acid-base hydrolysis, oxidation and thermolysis. The isocratic RP-HPLC method was developed with a LiChrospher RP-18 (250 mm x 4.6 mm, 5 microm) column and gradient elution of 12 mmol/L ammonium acetate and acetonitrile. The flow rate of the mobile phase was 1.0 mL/min, the detection wavelength 220 nm and the temperature 303 K. The method was validated with regard to linearity, accuracy, precision, selectivity and robustness, and was applied successfully for the determination of meropenem and potassium clavulanate separately as well as jointly in pharmaceutical formulations.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Ácido Clavulânico/análise , Tienamicinas/análise , Antibacterianos/administração & dosagem , Antibacterianos/análise , Antibacterianos/química , Cromatografia de Fase Reversa/métodos , Ácido Clavulânico/administração & dosagem , Ácido Clavulânico/química , Estabilidade de Medicamentos , Quimioterapia Combinada , Meropeném , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Tienamicinas/administração & dosagem , Tienamicinas/química
14.
Anal Bioanal Chem ; 406(20): 4997-5007, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24879538

RESUMO

Meropenem is a broad-spectrum antibiotic, often used for the empirical treatment of infections in critically ill patients with acute kidney injury. Meropenem has clinically insignificant protein binding and, as a carbapenem antibiotic, shows time-dependent bacterial killing, meaning that the unbound or free antibiotic concentration in blood should be maintained above the minimal inhibitory concentration of the pathogen for at least 40 % of the dosing interval. We developed and validated simple chromatographic methods by ultra-performance liquid chromatography-tandem mass spectrometry to measure plasma, filtrate-dialysate, and urine concentrations of meropenem. Chromatographic separation was achieved using an Acquity(®) UPLC(®) BEH(TM) (2.1 × 100 mm id, 1.7 µm) reverse-phase C(18) column, with a water/acetonitrile linear gradient containing 0.1 % formic acid at a 0.4-mL/min flow rate. Meropenem and its internal standard (ertapenem) were detected by electrospray ionization mass spectrometry in positive ion multiple reaction monitoring mode. The limits of quantification were 0.27, 0.24, and 1.22 mg/L, and linearity was observed between 0.27-150, 0.24-150, and 1.22-2,000 mg/L for plasma, filtrate-dialysate, and urine samples, respectively. Coefficients of variation and relative biases were less than 13.5 and 8.0 % for all biological fluids. Recovery values were greater than 68.3 %. Evaluation of the matrix effect showed ion suppression for meropenem and ertapenem. No carry-over was observed. The validated methods are useful for both therapeutic drug monitoring and pharmacokinetic studies. It could be applied to daily clinical laboratory practice to measure the concentration of meropenem in plasma, filtrate-dialysate, and urine.


Assuntos
Antibacterianos/análise , Líquidos Corporais/química , Cromatografia Líquida/métodos , Monitoramento de Medicamentos , Espectrometria de Massas por Ionização por Electrospray/métodos , Tienamicinas/análise , Injúria Renal Aguda/sangue , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/urina , Antibacterianos/farmacologia , Estado Terminal/terapia , Humanos , Meropeném , Terapia de Substituição Renal , Sepse/sangue , Sepse/tratamento farmacológico , Sepse/urina , Tienamicinas/farmacologia
15.
Artigo em Inglês | MEDLINE | ID: mdl-24861874

RESUMO

To support the development of a dynamic in vitro human pharmacokinetic/pharmacodynamic simulation model for biofilm-mediated infections and study stability of meropenem, an LC-MS/MS method for the determination of meropenem in Luria Bertani (LB) media was developed and validated in an API2000 LC-MS/MS system. A partial validation was also performed in M9 media. Sample aliquots of 100µL (or 25µL for M9 media) were mixed with the internal standard (IS) ceftazidime and filtered. The filtrate was directly injected onto a C8 column eluted with ammonium formate (10mM, pH 4) and acetonitrile (0.1% formic acid) in a gradient mode. ESI(+) and MRM with ion pair m/z 384→68 for meropenem and m/z 547→468 for the IS were used for quantification. The calibration curve concentration range was 50 to 25,000ng/mL. The recovery was over 98%. In LB media, significant signal suppression was observed throughout the time period of detection when compared with mobile phase solvents, but the matrix effect was compensated well with the IS. In M9 media, much less signal suppression was observed. The method is simple, fast, and reliable. Using the method, stability of meropenem in LB and M9 media were tested. No significant degradation was observed for at least 8h in both LB media (37°C) and M9 media (30°C), but more than 15% degradation was observed overnight (∼20h). The method was transferred to an API5000 LC-MS/MS system using meropenem-d6 as the IS.


Assuntos
Meios de Cultura/química , Tienamicinas/análise , Calibragem , Cromatografia Líquida/métodos , Estabilidade de Medicamentos , Meropeném , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/métodos
16.
J Asian Nat Prod Res ; 16(6): 648-57, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24827508

RESUMO

Meropenem is a carbapenem antibiotic with a wide spectrum of activity against both Gram-positive and Gram-negative bacteria. Because of its clinical efficacy, meropenem is an excellent choice for the treatment of serious infections in both adults and children. The knowledge of tissue concentrations of antibiotic in an infection site is valuable for the prediction of treatment outcome. The aim of the present study is to investigate the effect of borneol on the concentration of meropenem in rat brain and blood and to find the potential relationships of the combined use of medicine and traditional Chinese medicine. Analysis of meropenem in the dialysates was achieved using the microdialysis technique and HPLC. At 40 min after the administration of an intraperitoneal injection of meropenem, the concentration of meropenem in brain in borneol+meropenem group was 2.25 (0.35) µg ml(-1), which was significantly higher than that in meropenem group [1.20 (0.12) µg ml(-1); P < 0.01]. Within 80 min of drug administration, the AUCbrain/AUCblood (area under the curve, AUC) in the borneol+meropenem group was 1.2 times that of the meropenem group. Borneol can increase the concentration of meropenem in the cerebrospinal fluid, but has no influence on its blood concentration. This study represents a successful application of the microdialysis technique, which is an effective method for the study of pharmacokinetics of meropenem.


Assuntos
Antibacterianos/farmacocinética , Canfanos/farmacocinética , Tienamicinas/análise , Tienamicinas/farmacocinética , Adulto , Animais , Antibacterianos/análise , Antibacterianos/sangue , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Canfanos/análise , Canfanos/sangue , Canfanos/química , Criança , Cromatografia , Cromatografia Líquida de Alta Pressão , Feminino , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Masculino , Medicina Tradicional Chinesa , Meropeném , Microdiálise , Estrutura Molecular , Ratos , Ratos Wistar , Tienamicinas/administração & dosagem , Tienamicinas/sangue , Tienamicinas/química
17.
Artigo em Inglês | MEDLINE | ID: mdl-24495837

RESUMO

UV spectrophotometric and high performance liquid chromatography (HPLC) methods were developed for simultaneous determination of meropenem (MERM) and sulbactam sodium (SB) in injection. UV spectrophotometric methods were developed using 0.1N sodium hydroxide as solvent. The Beer's plot for dual wavelength method was linear in the range of 4-24 µg mL(-1) and 2-12 µg mL(-1) for MERM and SB, respectively. The percent recoveries were found to be 98.52±1.23% for MERM and 101.45±1.1% for SB. Chemometrics assisted UV spectrophotometry was performed using Partial Least Square (PLS) analysis model and Principal Component Regression (PCR) analysis model. The % recoveries of the MERM were found to be 100.61±0.06% and 101.31±0.12% using PLS and PCR, respectively. The % recoveries of the SB were found to be 98.29±0.09% and 97.61±0.13% using PLS and PCR, respectively. Chromatography was performed on Hypersil BDS C18 column using methanol:acetonitrile:water (10:20:70 v/v/v) as mobile phase. The retention times of MERM and SB were found to be 2.9 min and 2.25 min, respectively. Developed HPLC method was found to be linear in the range of 50-250 µg mL(-1) and 25-125 µg mL(-1) for MERM and SB, respectively. The % recoveries were found to be 98.85±0.25% and 98.63±0.34% for MERM and SB, respectively. The developed analytical methods did not show any interference of the excipients when applied to pharmaceutical dosage form.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Formas de Dosagem , Luz , Sulbactam/análise , Tienamicinas/análise , Análise de Variância , Calibragem , Cromatografia de Fase Reversa , Concentração de Íons de Hidrogênio , Análise dos Mínimos Quadrados , Meropeném , Análise de Componente Principal , Padrões de Referência , Análise de Regressão , Reprodutibilidade dos Testes , Soluções , Espectrofotometria Ultravioleta , Sulbactam/química , Tienamicinas/química
18.
Zhonghua Wai Ke Za Zhi ; 52(10): 775-80, 2014 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-25573219

RESUMO

OBJECTIVE: To study the concentrations and pharmacokinetics of 6 different kinds of antibiotics in rabbit bile, and evaluate their microbicidal potential. METHODS: Thirty-six health rabbits were randomly divided into 6 groups, and each group was 6 rabbits. After anaesthesia, the common bile duct of rabbit was isolated and cumulated with a silicone tube. The rabbits were administered intravenously with the equal-effect dose of antibiotics. Bile (1.5 ml) was collected at different time points after administration, and the concentration of antibiotics of bile was assayed by high performance liquid chromatography. The bile drug concentration-time data were processed by software to figure out the pharmacokinetic parameters such as maximum concentration (C(max)), peak time (T(max)), half-life time (T(1/2)), clearance (CL) and apparent volume of distribution (VD). The bile antibiotics concentration contrasted to the minimum inhibitory concentration (MIC), and attained the bactericidal index (C(max)/MIC) and the time when the drug concentration exceeded the MIC (T(>MIC)). RESULTS: The C(max) and T1/2 of each antibiotic were as the followings: piperacillin (7 950 ± 3 023) mg/L and (1.97 ± 1.23) h, ceftriaxone (1 104 ± 248) mg/L and (3.14 ± 0.57) h, cefoperazone (5 215 ± 2 225) mg/L and (0.89 ± 0.13) h, meropenem (31.97 ± 12.44) mg/L and (0.36 ± 0.11) h, levofloxacin (66.3 ± 36.9) mg/L and (3.32 ± 2.57) h, metronidazole (28.2 ± 10.2) mg/L and (0.81 ± 0.33) h, respectively. Piperacillin/tazobactam and cefoperazone/sulbactam had the largest bactericidal index and the longest T(>MIC), and their bactericidal indexes were (62.1 ± 23.6) - (993.8 ± 377.9) and (164.8 ± 69.0) - (659.3 ± 275.9), their T(>MIC) were (6.00 ± 2.53) - (8.00 ± 0.00) h and (6.33 ± 1.97) - (8.00 ± 0.00) h. The bactericidal index and T(>MIC) of levofloxacin were the smallest, which were (2.1 ± 1.2) - (8.3 ± 4.6) and (0.54 ± 0.25) - (2.67 ± 1.03) h . Ceftriaxone and meropenem were as the medium, and their bactericidal indexes and T(>MIC) were (4.3 ± 1.0) - (69.2 ± 15.5) , (1.42 ± 0.65) - (8.00 ± 0.00) h and (2.0 ± 0.8) - (1 031.3 ± 401.4) , (0.29 ± 0.10) - (1.83 ± 0.26) h. The bactericidal index of metronidazole to anaerobic ranged from 7.4 to 294.9, and the T(>MIC) ranged from 1.88 to 5.00 h. CONCLUSIONS: The bile concentrations of six antibiotics all exceed their effective bactericidal concentrations. The concentration-time curves of piperacillin, cefoperazone, meropenem and metronidazole conformed to one-compartment model, and ceftriaxone and levofloxacin are conformed to two-compartment model. Piperacillin/tazobactam and cefoperazone/sulbactam have the largest bactericidal index and the longest T(>MIC), so they can be chosen as the first choice for the therapy of hepatobiliary infection.For the anaerobic, the microbicidal potential of metronidazole is high.


Assuntos
Antibacterianos/análise , Antibacterianos/farmacocinética , Bile/química , Bile/efeitos dos fármacos , Animais , Cefoperazona/análise , Cefoperazona/farmacocinética , Combinação de Medicamentos , Meropeném , Metronidazol/análise , Metronidazol/farmacocinética , Testes de Sensibilidade Microbiana , Ácido Penicilânico/análogos & derivados , Ácido Penicilânico/análise , Ácido Penicilânico/farmacocinética , Piperacilina/análise , Piperacilina/farmacocinética , Combinação Piperacilina e Tazobactam , Coelhos , Distribuição Aleatória , Sulbactam/análise , Sulbactam/farmacocinética , Tienamicinas/análise , Tienamicinas/farmacocinética
19.
Diagn Microbiol Infect Dis ; 76(1): 110-2, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23490010

RESUMO

An ongoing program of international generic antimicrobial potency assays for piperacillin/tazobactam has been summarized here through December 2010, and the initial results for meropenem generic lots from the United States are also presented. Fifteen additional piperacillin/tazobactam generic lots revealed an average of -10% activity (range, +3 to -23%) compared to the branded product (Zosyn®; Wyeth-Pfizer), a finding consistent with prior reports (46 lots) of -16%. In contrast, meropenem branded and generic products had equivalent assay results (5 generic lots from 2 manufacturers [Hospira and Sandoz]). In conclusion, potencies for generic lots of parenteral broad-spectrum ß-lactams can vary widely when directly compared to branded products, requiring documentation by chemical, in vitro activity (potency assays as measured here), and purity testing before considering their addition to a hospital formulary.


Assuntos
Antibacterianos/farmacologia , Medicamentos Genéricos/farmacologia , Ácido Penicilânico/análogos & derivados , Tienamicinas/farmacologia , Antibacterianos/análise , Medicamentos Genéricos/análise , Enterobacter cloacae/efeitos dos fármacos , Meropeném , Testes de Sensibilidade Microbiana , Ácido Penicilânico/análise , Ácido Penicilânico/farmacologia , Piperacilina/análise , Piperacilina/farmacologia , Combinação Piperacilina e Tazobactam , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Tienamicinas/análise , Estados Unidos
20.
J Chromatogr A ; 1282: 153-60, 2013 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-23419350

RESUMO

The elaborated method of micellar electrokinetic chromatography (MEKC) used to separate biapenem from its related substances was successfully implemented using sweeping under an enhanced electric field, followed by UV absorption detection at 200nm. The best results were obtained with formic buffer (22.5mM) pH 4.3 and sodium dodecyl sulfate (150mM) added to the electrolyte as the sweeping agent. Neutral capillary (60/50cm; 50µm ID) with reverse polarity and voltage values of 22kV, were used throughout the investigation. The optimized method of biapenem determination, validated in terms of linearity, accuracy and precision, provides a detection limit of 0.5µg/mL at S/N=3 for biapenem. The repeatability of the CE system, expressed by relative standard deviations (RSD) in the migration times, for biapenem and its degradation products varied from 0.14 to 1.48%, whereas for the corrected peak areas RSD were about 0.68-8.43%. Satisfactory separation was achieved within 20min of electrophoresis; moreover all carbapenems (imipenem, meropenem, ertapenem, doripenem and biapenem) were separated from each other during analysis. The evaluated MEKC method was applied to the analysis of a medicinal product containing biapenem - Omegacin(®) 0.3g for intravenous drip infusion.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Capilar Eletrocinética Micelar/métodos , Tienamicinas/análise , Anti-Infecciosos/análise , Anti-Infecciosos/química , Anti-Infecciosos/isolamento & purificação , Carbapenêmicos/isolamento & purificação , Contaminação de Medicamentos , Limite de Detecção , Modelos Lineares , Soluções Farmacêuticas/química , Reprodutibilidade dos Testes , Tienamicinas/química , Tienamicinas/isolamento & purificação
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