RESUMEN

BACKGROUND: In neonatal and pediatric intensive care units, Gram -positive infections are a significant cause of morbidity and mortality. The increase in infections caused by methicillin-resistant Staphylococcus aureus and methicillin-resistant coagulase-negative Staphylococci have led to the increased use of glycopeptides, which treat invasive infections caused by Gram -positive organisms, particularly those resistant to beta-lactam antibiotics. Teicoplanin has bacteriostatic activity against Gram -positive bacteria, but its pharmacokinetics in children is highly variable, with most children failing to reach target levels at the recommended dose. This study aimed to develop a cost-effective method for determining concentrations using dried blood spot (DBS). METHODS: A method to determine the concentrations of teicoplanin in 20 µL blood or plasma using the Whatman 903 Protein Saver filter was evaluated. High-performance liquid chromatography with ultraviolet detection high-performance liquid chromatography with ultraviolet/vis was used, with internal standard ketoconazole. In addition, a method to quantify teicoplanin using 50 µL of liquid plasma was established to compare the results with the values obtained by DBS and dried plasma methods. RESULTS: The method was successfully developed and validated for 20 µL DBS. Furthermore, 50 µL of plasma was used to quantify teicoplanin with a lower limit of quantification of 10 mg/L. Precision and accuracy ranged from 2.3% to 10.7% and 95%-114.2%, respectively. A consistent factor (1.15) was used to calculate teicoplanin plasma concentrations from whole blood, indicating the reliability of the DBS method for therapeutic drug monitoring of teicoplanin. CONCLUSIONS: A simple, reliable, and cost-effective method using high-performance liquid chromatography with ultraviolet/vis was established to determine pediatric teicoplanin concentrations in both small plasma sample volumes and whole blood using DBS, and an accurate correlation factor for estimating teicoplanin plasma concentrations from DBS was identified. This method is suitable for the use in pediatrics.

Asunto(s)

Antibacterianos , Pruebas con Sangre Seca , Monitoreo de Drogas , Teicoplanina , Teicoplanina/sangre , Humanos , Cromatografía Líquida de Alta Presión/métodos , Monitoreo de Drogas/métodos , Pruebas con Sangre Seca/métodos , Antibacterianos/sangre , Antibacterianos/uso terapéutico , Reproducibilidad de los Resultados , Niño

RESUMEN

The lack of individual pure standard has hampered the application of therapeutic drug monitoring (TDM) for multi-component antibiotics in clinical laboratories. Here, we aimed to develop an integrated identification-quantification (ID-Quant) workflow based on ultra-high-performance liquid chromatography coupled with quadrupole/time-of-flight mass spectrometry (UHPLC-QTOF-MS) to enable the comprehensive determination of all teicoplanin components without needing pure standards. The workflow comprises three steps. First, non-targeted MSE full scanning was used to detect and identify all potential ingredients. Then, characteristic product ions were selected to generate a quantitative time-of-flight multiple reaction monitoring (Tof-MRM) method. Finally, the constituent composition of teicoplanin injection was determined and utilized as an alternative reference standard to monitor the teicoplanin ingredients in human serum samples. As a result, nine teicoplanin analogs were identified from teicoplanin injection (Sanofi-Aventis, France). The overall performance of the Tof-MRM method was satisfactory in terms of linearity, precision, accuracy, and limits of detection. Utilizing the drug as standard, the individual concentrations for each component in patient serum were determined to be 0.120 µg/mL (A3-1), 0.020 µg/mL (N-1), 0.550 µg/mL (N-2), 0.730 µg/mL (A2-1), 4.26 µg/mL (A2-2,3), 4.79 µg/mL (A2-4,5), and 0.290 µg/mL (N-3), respectively. The distribution pattern of teicoplanin components was also discovered to differ from that in the drug injection. Overall, this integrated ID-Quant workflow based on UHPLC-QTOF-MS enables the robust quantitation of all teicoplanin analogs without the need for individual pure standard. This approach could help address the standard unavailability problem in the TDM of multi-component antibiotics.

Asunto(s)

Antibacterianos , Monitoreo de Drogas , Límite de Detección , Espectrometría de Masas , Teicoplanina , Teicoplanina/química , Teicoplanina/sangre , Teicoplanina/análisis , Cromatografía Líquida de Alta Presión/métodos , Antibacterianos/sangre , Antibacterianos/análisis , Antibacterianos/química , Monitoreo de Drogas/métodos , Humanos , Reproducibilidad de los Resultados , Modelos Lineales , Espectrometría de Masas/métodos , Flujo de Trabajo

RESUMEN

A reverse micelle mediated dispersive liquid-liquid microextraction (RM-DLLME) combined with high performance liquid chromatography-ultraviolet detector (HPLC-UV) was developed for extraction and determination of 5 A2 components of teicoplanin (TA2-1, TA2-2, TA2-3, TA2-4, TA2-5) in human plasma, and the mechanism of RM-DLLME was analysed and explored. In this method, 80 µL of the reverse micelle solution of cetylpyridinium chloride/n-hexanol (15 mmol/L) was used as the extraction solvent for the separation, extraction and enrichment of the teicoplanin in plasma sample. All factors affecting the extraction efficiencies of the target analytes, such as the amounts of acetonitrile and chloroform, the type and volume of reverse micelle solution, pH and volume of sample phase, dispersant, salt addition, extraction mode and time, centrifugation rate and time, were investigated and optimized. Under the optimum conditions, the 5 A2 components of teicoplanin achieved effective enrichment with the enrichment factors of 228-347 and obtained good linearity in the range of 0.8375-100.5 µg/mL with correlation coefficients higher than 0.9960. The limits of detection were ranged between 0.5025-3.015 µg/mL. Relative standard deviation values of the method precisions were lower than 10.6% and the average recoveries were in the range of 82.7-111.3%. The determination results of the method were demonstrated with favorable characteristics, such as high enrichment, good selectivity and sensitivity, satisfactory precision and accuracy, and this method could be employed to analysis of the teicoplanin in human plasma samples.

Asunto(s)

Cromatografía Líquida de Alta Presión/métodos , Microextracción en Fase Líquida/métodos , Micelas , Teicoplanina/sangre , Humanos , Concentración de Iones de Hidrógeno , Límite de Detección , Reproducibilidad de los Resultados , Espectrofotometría Ultravioleta , Teicoplanina/química , Teicoplanina/aislamiento & purificación

RESUMEN

BACKGROUND: Teicoplanin is used to treat serious gram-positive infections. Optimal teicoplanin trough levels are considered to be ≥ 10 µg/mL. Despite its wide use in various clinical settings, data on teicoplanin trough level in pediatric patients are limited. Therefore, the aim of this study was to investigate the therapeutic drug level monitoring of teicoplanin in Korean pediatric patients, including those with impaired renal function. METHODS: A retrospective study was performed in pediatric patients (age ≤ 18 years old) who received teicoplanin from September 2014 to April 2018. The regimen included a loading dose of 10 mg/kg/dose at 12 hours' interval three times in a row, and a maintenance dose of 10 mg/kg/dose commenced at 24 hours of interval after the loading dose, with a maximum of 400 mg/dose, respectively. The first therapeutic drug levels were measured. Distribution and characteristics of trough levels in patients with decreased renal function and those with bacteremia were also assessed. RESULTS: A total of 187 trough levels were collected from 143 patients. Hematologic and oncologic diseases were the most common underlying diseases (83.2%, n = 119). One hundred eighty trough levels were first measured, and their median value was 16.2 µg/mL (range, 2.3-100 µg/mL) and the median interval between initial teicoplanin injection and 1st trough level was 96.5 hours (range 47.6-179.3 hours). Lower steady-state levels were observed in younger age group (median, 13.5 vs. 18.0 µg/mL, P = 0.038). Median trough levels were higher in patients with decreased renal functions (P < 0.001). In addition, among eight with gram-positive bacteremia, seven of them had a favorable outcome. CONCLUSION: This study provides additive information on trough level monitoring of teicoplanin in children with impaired renal function and treatment effect in patients with gram-positive bacteremia. Careful monitoring for steady state trough levels of teicoplanin is warranted.

Asunto(s)

Antibacterianos/sangre , Riñón/fisiología , Teicoplanina/sangre , Administración Intravenosa , Adolescente , Antibacterianos/administración & dosificación , Niño , Preescolar , Cromatografía Líquida de Alta Presión , Esquema de Medicación , Femenino , Tasa de Filtración Glomerular , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Enfermedades Hematológicas/tratamiento farmacológico , Humanos , Lactante , Recién Nacido , Masculino , República de Corea , Estudios Retrospectivos , Espectrometría de Masas en Tándem , Teicoplanina/administración & dosificación

RESUMEN

Sepsis and septic shock are characterized by a release of cytokines into the circulation. These mediators contribute to the detrimental hemodynamic and metabolic effects in the early phase of septic shock. Recently, a new polystyrene-based hemoadsorption device was introduced into clinical practice (CytoSorb®). The adsorber binds a variety of molecules including cytokines and removes them from the circulation. Studies in septic patients have shown an improved clinical course following hemoadsorption but no increased survival. We hypothesize that not only cytokines but also antibiotics may be removed which potentially may negate any beneficial effect of the adsorber. To test this hypothesis, we performed polystyrene-based hemoadsorption in three patients in septic shock and analysed glycopeptide elimination by measuring serum levels pre- and post-adsorber. We administered both teicoplanin and vancomycin via a 60-min infusion and vancomycin via continuous infusion, additionally. When applied as 60 min infusion, vancomycin and teicoplanin were removed immediately by the adsorber. However, the adsorptive capacity of the device was saturable. Serum levels of vancomycin, but not teicoplanin, decreased to subtherapeutic levels. With continuous infusion of vancomycin, removal was less and serum levels remained in the therapeutic range. In conclusion, we show effective glycopeptide adsorption using a polystyrene-based hemoadsorber in septic patients. The dose of these antibiotics should be adjusted appropriately and early therapeutic drug monitoring is highly recommended.

Asunto(s)

Adsorción , Monitoreo de Drogas/métodos , Plasmaféresis , Choque Séptico , Teicoplanina , Vancomicina , Adulto , Anciano , Antibacterianos/administración & dosificación , Antibacterianos/sangre , Antibacterianos/farmacocinética , Vías de Eliminación de Fármacos , Femenino , Glicopéptidos/farmacocinética , Humanos , Masculino , Plasmaféresis/efectos adversos , Plasmaféresis/instrumentación , Plasmaféresis/métodos , Poliestirenos/química , Choque Séptico/sangre , Choque Séptico/fisiopatología , Choque Séptico/terapia , Teicoplanina/administración & dosificación , Teicoplanina/sangre , Teicoplanina/farmacocinética , Vancomicina/administración & dosificación , Vancomicina/sangre , Vancomicina/farmacocinética

RESUMEN

Our objective was to develop a population pharmacokinetic (PK) model in order to evaluate the currently recommended dosing regimen in term and preterm neonates. By using an optimal design approach, a prospective PK study was designed and implemented in 60 neonates with postmenstrual ages (PMA) of 26 to 43 weeks. A loading dose of 16 mg/kg was administered at day 1, followed by a maintenance dose of 8 mg/kg daily. Plasma concentrations were quantified by high-pressure liquid chromatography-mass spectrometry. Population PK (popPK) analysis was performed using NONMEM software. Monte-Carlo (MC) simulations were performed to evaluate currently recommended dosing based on a pharmacodynamic index of area under the concentration-time curve (AUC)/MIC ratio of ≥400. A two-compartment model with linear elimination best described the data by the following equations: clearance (CL) = 0.0227 × (weight [wt]/1,765)0.75 × (estimated creatinine clearance [eCRCL]/22)0.672, central compartment volume of distribution (V1) = 0.283 (wt/1,765), intercompartmental clearance (Q) = 0.151 (wt/1,765)0.75, and peripheral compartment volume (V2) = 0.541 (wt/1,765). The interindividual variability estimates for CL, V1, and V2 were 36.5%, 45.7%, and 51.4%, respectively. Current weight (wt) and estimated creatinine clearance (eCRCL) significantly explained the observed variability. MC simulation demonstrated that, with the current dosing regimen, an AUC/MIC ratio of ≥400 was reached by only 68.5% of neonates with wt of <1 kg when the MIC was equal to 1 mg/kg, versus 82.2%, 89.7%, and 92.7% of neonates with wt of 1 to <2, 2 to <3, or ≥3 kg, respectively. Augmentation of a maintenance dose up to 10 or 11 mg/kg for preterm neonates with wt of 1 to <2 or <1 kg, respectively, increases the probability of reaching the therapeutic target; the recommended doses seem to be adequate for neonates with wt of ≥2 kg. Teicoplanin PK are variable in neonates, with wt and eCRCL having the most significant impact. Neonates with wt of <2 kg need higher doses, especially for Staphylococcus spp. with an MIC value of ≥1 mg/liter.

Asunto(s)

Antibacterianos/farmacocinética , Sepsis/tratamiento farmacológico , Infecciones Estafilocócicas/tratamiento farmacológico , Teicoplanina/farmacocinética , Antibacterianos/sangre , Femenino , Edad Gestacional , Humanos , Recién Nacido , Masculino , Pruebas de Sensibilidad Microbiana , Método de Montecarlo , Nacimiento Prematuro , Sepsis/microbiología , Staphylococcus/efectos de los fármacos , Teicoplanina/sangre

RESUMEN

WHAT IS KNOWN AND OBJECTIVE: Teicoplanin is widely used for the treatment of infections caused by drug-resistant Gram-positive bacteria. Since there is a good correlation between trough levels and clinical outcome, therapeutic drug monitoring (TDM) is recommended to achieve better clinical curative effects. However, TDM of teicoplanin is not routine in China. So, a programme was initiated in 2017, including both HPLC method establishment and interlaboratory quality assessment, for the measurement of teicoplanin. METHODS: A main centre and a quality control centre were set up in the study. An HPLC-based method of teicoplanin determination in plasma was developed by the main centre. Analysis was performed using a Waters Symmetry C18 column (250 mm × 4.6 mm, 5 µm). The mobile phase was NaH2 PO4 (0.01 mol/L) and acetonitrile (75:25 v/v; pH 3.3), with a flow rate of 1.0 mL/min and a detection wavelength of 215 nm. Piperacillin sodium was selected as an internal standard (IS). Twenty-six additional TDM centres were then recruited to adopt this method. Then, all the centres were asked to take part in a quality control assessment evaluated by the quality control centre. RESULTS: For all TDM centres, linearity of teicoplanin concentration ranges was between 3.125 and 100 µg/mL. Intraday and interday accuracies ranged from 87.1% to 118.4%. Intraday and interday precision ranged from 0.3% to 13.8%. Therapeutic drug monitoring centres all passed inter-room quality assessment. All samples tested met the acceptance criteria. Then, 542 samples were collected. Patients with sub-optimal (≤10 mg/L) plasma teicoplanin concentrations constituted 42% of the total study population. WHAT IS NEW AND CONCLUSIONS: For the first time, a simple, rapid and accurate HPLC method for determining teicoplanin levels was successfully applied to therapeutic drug monitoring in clinical practice for twenty-seven TDM centres in China. The results demonstrated excellent interlaboratory agreement for teicoplanin testing and provide support for clinical laboratory quality management and results inter-accreditation.

Asunto(s)

Antibacterianos/sangre , Monitoreo de Drogas/métodos , Laboratorios/normas , Teicoplanina/sangre , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antibacterianos/administración & dosificación , China , Cromatografía Líquida de Alta Presión , Humanos , Persona de Mediana Edad , Control de Calidad , Reproducibilidad de los Resultados , Teicoplanina/administración & dosificación , Adulto Joven

RESUMEN

Teicoplanin is an antibiotic agent used for the treatment of Gram-positive infections. The clinical benefit of teicoplanin is associated with its blood concentrations, but the optimal dosing regimen is not yet known. To explore the optimal individual dosing regimen, we performed a population pharmacokinetic (PK) and pharmacodynamic (PD) analysis targeting a large-scale population, including patients with a wide range of ages, body weights, and renal functions. The PK of teicoplanin was described with a 2-compartment model, and the PD of C-reactive protein (CRP) concentrations was described with a turnover maximum inhibition model. The elimination half-life of teicoplanin calculated from the final estimated parameters was 169 hours, and renal function was a significant covariate of teicoplanin clearance. The teicoplanin concentration producing 50% of the maximum inhibition of CRP production was estimated to be 2.66 mg/L. The minimum concentration of teicoplanin in patients with higher loading doses (15 mg/kg) reached the target range (15-30 mg/L) with a probability of >50% in the dosing simulation. We described the influence of body size, body composition, and renal function on the PK of teicoplanin. The population PKPD model of teicoplanin and CRP in this study should provide useful information for development of a dosing strategy including the sequential clinical benefit of teicoplanin.

Asunto(s)

Antibacterianos/farmacocinética , Infecciones Bacterianas/tratamiento farmacológico , Proteína C-Reactiva/efectos de los fármacos , Teicoplanina/farmacocinética , Adulto , Anciano , Anciano de 80 o más Años , Antibacterianos/administración & dosificación , Antibacterianos/sangre , Antibacterianos/farmacología , Infecciones Bacterianas/metabolismo , Infecciones Bacterianas/microbiología , Composición Corporal/fisiología , Peso Corporal/fisiología , Proteína C-Reactiva/análisis , Simulación por Computador , Monitoreo de Drogas/métodos , Femenino , Bacterias Grampositivas/efectos de los fármacos , Bacterias Grampositivas/aislamiento & purificación , Semivida , Humanos , Pruebas de Función Renal/métodos , Masculino , Persona de Mediana Edad , Albúmina Sérica/metabolismo , Teicoplanina/administración & dosificación , Teicoplanina/sangre , Teicoplanina/farmacología

RESUMEN

Dalbavancin is a lipoglycopeptide antibiotic with a prolonged half-life. A phase 1 study assessed dalbavancin levels in epithelial lining fluid (ELF) in 35 healthy adults using ELF bronchial microsampling up to 168 h after administration of 1,500 mg dalbavancin. The penetration of dalbavancin into ELF was 36%. ELF levels of dalbavancin exceeded the MIC90s of Streptococcus pneumoniae and Staphylococcus aureus for ≥7 days.

Asunto(s)

Antibacterianos/farmacocinética , Mucosa Respiratoria/química , Teicoplanina/análogos & derivados , Adulto , Antibacterianos/administración & dosificación , Antibacterianos/análisis , Antibacterianos/sangre , Humanos , Infusiones Intravenosas , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Neumonía Bacteriana/tratamiento farmacológico , Neumonía Neumocócica/tratamiento farmacológico , Neumonía Estafilocócica/tratamiento farmacológico , Staphylococcus aureus/efectos de los fármacos , Streptococcus pneumoniae/efectos de los fármacos , Teicoplanina/administración & dosificación , Teicoplanina/análisis , Teicoplanina/sangre , Teicoplanina/farmacocinética , Adulto Joven

RESUMEN

Therapeutic drug monitoring (TDM) of teicoplanin is aimed at minimizing the clinical impact of pharmacokinetic variability; however, its benefits are still being defined. We performed a retrospective study of teicoplanin TDM focusing on the dose-serum concentration relationship and clinical outcomes in a clinical setting. From January 2017 to December 2018, patients receiving teicoplanin ≥ 72 h with TDM were enrolled. Patients were divided into three groups: non-loading (NL) group, low-dose loading (LD) group (loading dose < 9 mg/kg), and high-dose loading (HD) group (≥ 9 mg/kg). Serum teicoplanin trough concentration (Cmin) and adverse events (AEs) were evaluated in each regimen. A subgroup of patients with bacteremia was analyzed to evaluate clinical efficacy. Among 65 patients, 12, 18, and 35 were grouped in NL, LD, and HD, respectively. Achievement rates of Cmin > 20 mg/L within 10 days were significantly different among the groups (25.0%, 38.9%, and 68.6% in the NL, LD, and HD groups, respectively; P = 0.014). Fourteen patients (21.5%) had AEs, and higher Cmin over 10 days (adjusted odds ratio 2.08 per every 20 mg/L increases, 95% CI 1.13-3.84, P = 0.019) and age ≥ 65 years (P = 0.009) were identified as independent risk factors. In the subgroup analysis, HD regimen (P = 0.050) and high mean Cmin over 10 days (P = 0.025) were significantly associated with treatment success. Although HL regimen could achieve Cmin targets and improve clinical outcome during teicoplanin treatment, high Cmin was associated with AEs during treatment. Routine TDM can be helpful to optimize teicoplanin administration.

Asunto(s)

Antibacterianos/administración & dosificación , Esquema de Medicación , Monitoreo de Drogas , Teicoplanina/administración & dosificación , Adulto , Anciano , Antibacterianos/efectos adversos , Antibacterianos/sangre , Bacteriemia/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Teicoplanina/efectos adversos , Teicoplanina/sangre , Resultado del Tratamiento

RESUMEN

Antibiotic therapy is a crucial aspect of the management of hospitalized patients, however, current standard dosing protocols have been shown to often attain inadequate plasmatic concentrations which may impair the clinical outcome and promote the selection of multidrug-resistant bacteria. The aim of this study is to establish and validate a robust and fast liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous analysis of four commonly used antibiotics (Meropenem, Piperacillin, Linezolid and Teicoplanin) in human plasma according to the European Medicines Agency (EMA) guidelines. Samples preparation was performed using a commercially available extraction kit which needs a very small amount of sample (50 µl). Antibiotics were detected, following a 7 min gradient separation, in multiple reactions monitoring (MRM) mode using a Qtrap 5500 triple quadrupole instrument equipped with an electrospray source operating in positive ion mode. The method, covering the antibiotics' clinically relevant concentration ranges, is also able to quantify, individually, the major teicoplanin components. The high reproducibility and the need of a small amount of sample, associated with the use of a commercial kit, together with a short chromatographic time, makes the method particularly suited for high-throughput routine analysis. Monitoring of plasma antibiotic levels, as part of the clinical routine, would result in a quick therapy adjustment leading to a higher probability of eradicating the infection as well as a potential reduction of multidrug-resistance prevalence. The method was successfully applied to monitor the antibiotic concentration of 49 patients under therapy.

Asunto(s)

Linezolid/sangre , Meropenem/sangre , Piperacilina/sangre , Teicoplanina/sangre , Antibacterianos/sangre , Cromatografía Liquida , Monitoreo de Drogas/métodos , Humanos , Límite de Detección , Reproducibilidad de los Resultados , Espectrometría de Masas en Tándem/métodos

RESUMEN

Teicoplanin is a glycopeptide antibiotic used for treatment of severe Gram-positive bacterial infection. The aim of this study was to develop and validate a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for therapeutic drug monitoring (TDM) of teicoplanin and to review our clinical experience. We established an LC-MS/MS method to analyze serum concentration of teicoplanin using simple protein precipitation with a 5 min run time for each sample. The linearity, lower limit of quantitation, detection accuracy, precision, carryover, matrix effect, and extraction recovery were evaluated. From September 2014 to June 2017, a total of 421 serum teicoplanin concentrations was measured in 223 patients. We collected demographic and clinical data, medication history, and laboratory findings through retrospective review of medical records. The LC-MS/MS method was linear for serum teicoplanin concentrations in the range of 12.0-89.0 µg/mL. The intra- and inter-assay precisions were below CV 7.5%. The accuracy was less than ±10% bias. The lower limit of quantification was 0.2 µg/mL. The extraction recovery ranged from 88.8% to 96.6%. Of 421 measurements, 87 (20.7%) were subtherapeutic (< 10 µg/mL), and four (0.9%) were above the toxic threshold (≥ 60 µg/mL). Serum teicoplanin concentration was measured once in 140 patients (63%), and multiple measurements were completed for the others (83 patients, 37%). Intra-patient variability in teicoplanin concentration was found (CV 33%, range 2-94%). Our simple and rapid LC-MS/MS method was successfully applied in TDM of teicoplanin in clinical practice. Such TDM of teicoplanin may be useful for individualized dose adjustment.

Asunto(s)

Antibacterianos/sangre , Monitoreo de Drogas/métodos , Teicoplanina/sangre , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Calibración , Niño , Cromatografía Liquida , Monitoreo de Drogas/instrumentación , Femenino , Humanos , Límite de Detección , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Espectrometría de Masas en Tándem , Adulto Joven

RESUMEN

Aim of the study: Here, we investigated the risk factors for decreased teicoplanin plasma trough concentrations relative to the initial dosing in critically ill patients. Patients and methods: Data obtained from 80 eligible critically ill patients who received intravenous teicoplanin were retrospectively analyzed. Risk factors for decreases in teicoplanin trough concentrations 72 h after administration of teicoplanin of more than 30% relative to predicted concentrations based on initial dosing setting were identified by logistic regression analysis. Results: Although prediction trough concentration and total dose of two days no significant differences were seen between the variation group and the non-variation group, actual trough concentration was significantly different between two groups (19.9±5.6 µg/ml vs 10.3±2.2 µg/ml, p < 0.001). In multivariate analysis, serum albumin ≤ 2.2 mg/dl (odds ratio [OR] = 3.003, 95% CI 1.072-8.408; p = 0.036) and SOFA score ≥ 9 (OR = 3.498, 95% CI 1.171-10.450; p = 0.025) were significant risk factors for decreased teicoplanin plasma trough concentrations. Conclusion: In critically ill patients, high SOFA score and low serum albumin were risk factors for decreased teicoplanin plasma trough concentration during initial dosing.

Asunto(s)

Antibacterianos/sangre , Infecciones/sangre , Infecciones/tratamiento farmacológico , Teicoplanina/sangre , Administración Intravenosa , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antibacterianos/administración & dosificación , Enfermedad Crítica , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Teicoplanina/administración & dosificación , Adulto Joven

RESUMEN

OBJECTIVES: The antibiotic teicoplanin, used for the treatment of infections caused by Gram-positive bacteria, is highly bound to plasma proteins (percentage protein binding, %PB, around 90%) and therapeutic plasma levels of total teicoplanin are 10-100 mg/L. Because of the low free concentrations (i.e. <1-10 mg/L), current immunoassays are not able to quantify free teicoplanin concentrations, although they might be more relevant in therapeutic drug monitoring than total concentrations. DESIGN AND METHODS: In this study, an ultra-high performance liquid chromatography - high resolution mass spectrometry (UHPLC-HRMS) method for the quantification of total and free teicoplanin in K2EDTA plasma samples was developed and validated. Furthermore, %PB obtained by ultrafiltration was compared with that obtained by equilibrium dialysis using spiked samples from healthy subjects. Analytes were separated using a phenylhexyl column, gradient mobile phase analysis was used, total run time was 4.5 min and teicoplanin was detected by orbitrap MS. RESULTS: The precision and accuracy were below 15% and within ±15%, respectively and teicoplanin was found to be stable for at least 14 days in plasma at 4 °C. The %PB of teicoplanin in spiked plasma from healthy subjects as obtained by ultrafiltration (94.1 ±â€¯1.3%) was in good agreement with that obtained by equilibrium dialysis (93.6 ±â€¯0.4%), whereas mean %PB of teicoplanin in samples from infected patients who received the antibiotic was 87.7 ±â€¯4.2% (range: 79.6-95.4%). CONCLUSION: A novel highly sensitive UHPLC-HRMS method was developed and validated for the quantification of total and free teicoplanin in human K2EDTA plasma samples. Amongst others, this method is suitable for therapeutic drug monitoring.

Asunto(s)

Cromatografía Líquida de Alta Presión/métodos , Teicoplanina/sangre , Cromatografía Liquida , Voluntarios Sanos , Humanos , Control de Calidad

RESUMEN

AIM: An ultra pressure liquid chromatography (UPLC)/MS/MS method for vancomycin and teicoplanin determination in human plasma was developed in accordance with analytical quality by design (AQbD) concept and fully validated. MATERIALS & METHODS: Chromatographic separation was performed on ACQUITY UPLC C18 charge surface hybrid (CSH) column (2.1 mm × 50 mm, 1.7 µm particle size) in gradient mode and the mobile phase consisted of 0.1% formic acid in water and pure acetonitrile. The experimental design methodology was used for the definition of optimal chromatographic and protein precipitation conditions. RESULTS: The linearity ranges were 0.05-10 µg ml-1 for vancomycin and 0.5-200 µg ml-1 for total teicoplanin. The relative standard deviations for precision estimation were below 15% and the accuracy was within 85-115% for all quality control levels. CONCLUSION: The method was utilized for glycopeptide antibiotics bioanalysis.

Asunto(s)

Antibacterianos/sangre , Cromatografía Líquida de Alta Presión/métodos , Espectrometría de Masas/métodos , Teicoplanina/sangre , Vancomicina/sangre , Humanos

RESUMEN

BACKGROUND: Teicoplanin is a glycopeptide antibiotic that has become increasingly popular with the spread of methicillin-resistant Staphylococcus aureus. The aim of the study was to develop and validate an ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for teicoplanin, and analyze trough teicoplanin concentrations achieved in patients with hematological diseases. METHODS: The UHPLC-MS/MS method for teicoplanin was developed, validated, and applied in a retrospective analysis of trough plasma teicoplanin concentrations from 305 patients receiving standard dose, and 17 patients receiving therapeutic drug monitoring (TDM)-guided individualized dose. RESULTS: The linear range was 3.9-52.9 mg/L. The imprecision was less than 12%, the limits of detection and quantification were less than 0.13 and 0.72 mg/L, respectively. The sample carry-over and ion suppression were insignificant. In the standard dose group, the median teicoplanin concentrations were 7.5 mg/L (days 3-5) and 8.9 mg/L (on days 6-8); and the proportion of trough levels achieving ≥10 mg/L was 20% (days 3-5) and 38% (days 6-8), respectively. In the TDM-guided individualized dose group, median teicoplanin concentration was higher (16.9 mg/L), and the proportion of trough levels ≥10 mg/L was also higher (77%) when compared with the standard dose group. CONCLUSIONS: Based on these results, the present UHPLC-MS/MS method can be considered suitable for routine TDM of teicoplanin. Also, based on the insufficient trough teicoplanin concentrations achieved with standard dose regimen, and the higher trough teicoplanin concentrations achieved with TDM-guided individualized dose regimen, this study highlights the importance of TDM of teicoplanin, especially in high-risk patient groups.

Asunto(s)

Antibacterianos/sangre , Monitoreo de Drogas/métodos , Enfermedades Hematológicas/sangre , Enfermedades Hematológicas/tratamiento farmacológico , Espectrometría de Masas en Tándem/métodos , Teicoplanina/sangre , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antibacterianos/uso terapéutico , Cromatografía Liquida/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Teicoplanina/uso terapéutico , Adulto Joven

RESUMEN

OBJECTIVE: Serum cystatin C (CysC) has recently been proposed as an alternative marker to serum creatinine (SCR) for estimating renal clearance. In the present study, we performed a population pharmacokinetic analysis of teicoplanin (TEIC), which is mainly eliminated through the kidneys, using CysC as a predictor for renal clearance. METHODS: Thirty-six patients with MRSA infections who were administrated to the National Hospital Organization Beppu Medical Center between January 2012 and December 2013 were enrolled and gave 123 sets of blood TEIC concentration data. Renal clearance was estimated by the Hoek equation using CysC, by creatinine clearance predicted by the Cockcroft-Gault equation using SCR, or directly by CysC. One compartment open model with inter-individual variabilities for renal clearance and the volume of distribution as well as an additional residual error model was used to estimate population pharmacokinetic parameters for TEIC. RESULTS: The model with the best predictability was that with CysC as a predictor for renal clearance; it showed better significance than the models using estimated the glomerular filtration rate by the Hoek equation or CLcr. The final model was as follows: CL (L/hr) = 0.510 × (CysC/1.4)-0.68 × Total body weight/600.81, omega (CL) = 19.8% CV, VC (L) = 78.1, omega (V) = 42.7% CV. CONCLUSION: The present results show the usefulness of CysC to more accurately predict the pharmacokinetics of drugs mainly eliminated through the kidneys, such as TEIC. However, since the sample size in this study was relatively small, further investigations on renal clearance predictability using CysC are needed.

Asunto(s)

Antibacterianos/farmacocinética , Cistatina C/sangre , Riñón/fisiología , Eliminación Renal , Teicoplanina/farmacocinética , Anciano , Anciano de 80 o más Años , Antibacterianos/sangre , Antibacterianos/uso terapéutico , Biomarcadores/sangre , Creatinina/sangre , Femenino , Tasa de Filtración Glomerular , Hospitales , Humanos , Masculino , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Infecciones Estafilocócicas/tratamiento farmacológico , Teicoplanina/sangre , Teicoplanina/uso terapéutico

RESUMEN

BACKGROUND: Teicoplanin is a glycopeptide antibiotic currently used for the treatment of methicillin-resistant Staphylococcus aureus. The need for therapeutic drug monitoring of teicoplanin has been increasingly highlighted as important. It is generally accepted that whereas a plasma trough concentration (Cmin) of ≥10 mg/L is appropriate for the majority of infections, it should exceed 20 mg/L for severe infections. The target Cmin of teicoplanin in patients with febrile neutropenia (FN) has not been reported. The aim of this study was to estimate the target Cmin for the treatment of FN in patients with hematological malignancy. METHODS: In this retrospective, single-center, observational cohort study, the records of 52 hospitalized patients with hematological malignancy who were treated with teicoplanin for FN due to bacteriologically documented or presumptive gram-positive infections were analyzed. RESULTS: A significant difference in the first Cmin of teicoplanin was observed between the response and nonresponse groups in patients with bacteremia. The areas under the receiver operating characteristic curves were 0.80 for clinical efficacy. The cut-off value of teicoplanin Cmin on days 4-6 was 15.2 mg/L (sensitivity 80.0%, specificity 75.0%). CONCLUSIONS: The authors propose a target teicoplanin Cmin of ≥15.2 mg/L for FN in patients with hematological malignancy.

Asunto(s)

Neutropenia Febril/diagnóstico , Neoplasias Hematológicas/complicaciones , Teicoplanina/sangre , Adulto , Anciano , Anciano de 80 o más Años , Antibacterianos/uso terapéutico , Área Bajo la Curva , Bacteriemia/complicaciones , Bacteriemia/tratamiento farmacológico , Estudios de Cohortes , Monitoreo de Drogas , Neutropenia Febril/complicaciones , Neutropenia Febril/tratamiento farmacológico , Femenino , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas , Humanos , Masculino , Persona de Mediana Edad , Curva ROC , Estudios Retrospectivos , Teicoplanina/uso terapéutico , Resultado del Tratamiento

RESUMEN

The aim of this study was to develop a population pharmacokinetic (PK) model for teicoplanin across childhood age ranges to be used as Bayesian prior information in the software constructed for individualized therapy. We developed a nonparametric population model fitted to PK data from neonates, infants, and older children. We then implemented this model in the BestDose multiple-model Bayesian adaptive control algorithm to show its clinical utility. It was used to predict the dosages required to achieve optimal teicoplanin predose targets (15 mg/liter) from day 3 of therapy. We performed individual simulations for an infant and a child from the original population, who provided early first dosing interval concentration-time data. An allometric model that used weight as a measure of size and that also incorporated renal function using the estimated glomerular filtration rate (eGFR), or the ratio of postnatal age (PNA) to serum creatinine concentration (SCr) for infants <3 months old, best described the data. The median population PK parameters were as follows: elimination rate constant (Ke) = 0.03 · (wt/70)-0.25 · Renal (h-1); V = 19.5 · (wt/70) (liters); Renal = eGFR0.07 (ml/min/1.73 m2), or Renal = PNA/SCr (µmol/liter). Increased teicoplanin dosages and alternative administration techniques (extended infusions and fractionated multiple dosing) were required in order to achieve the targets safely by day 3 in simulated cases. The software was able to predict individual measured concentrations and the dosages and administration techniques required to achieve the desired target concentrations early in therapy. Prospective evaluation is now needed in order to ensure that this individualized teicoplanin therapy approach is applicable in the clinical setting. (This study has been registered in the European Union Clinical Trials Register under EudraCT no. 2012-005738-12.).

Asunto(s)

Antibacterianos/farmacocinética , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Infecciones Estafilocócicas/tratamiento farmacológico , Teicoplanina/farmacocinética , Adolescente , Algoritmos , Antibacterianos/sangre , Antibacterianos/uso terapéutico , Teorema de Bayes , Niño , Preescolar , Creatinina/sangre , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Pruebas de Sensibilidad Microbiana , Método de Montecarlo , Programas Informáticos , Teicoplanina/sangre , Teicoplanina/uso terapéutico

RESUMEN

OBJECTIVES: To describe the population pharmacokinetics of teicoplanin in adult patients with haematological malignancies receiving higher than standard doses, and to perform Monte Carlo simulations to determine dosing regimens associated with optimal teicoplanin concentrations. METHODS: This was a hospital-based clinical trial (EudraCT 2013-004535-72). Nine blood samples were collected on Day 3, plus single trough samples on Days 7 and 10, and 24 and 48 hours after the last dose. Teicoplanin minimum inhibitory concentrations were determined for Gram-positive isolates from study patients. Population pharmacokinetic analyses and Monte Carlo dosing simulations were undertaken using Pmetrics. RESULTS: Thirty adult haematological malignancy patients were recruited with a mean (SD) loading dose, age, total body weight, and creatinine clearance of 9.5 (1.9) mg/kg, 63 (12) years, 69.1 (15.8) kg, and 72 (41) mL/min, respectively. A three-compartment linear pharmacokinetic model best described the teicoplanin concentration data. Covariates supported for inclusion in the final model were creatinine clearance for clearance and total body weight for volume of the central compartment. The median (IQR) area under the concentration-time curve from 48 to 72 hours (AUC48-72h) was 679 (319) mg.h/L. There was a strong correlation between the AUC48-72h and trough concentration at 72 hours (Pearson correlation coefficient 0.957, p <0.001). Dosing simulations showed that administration of five loading doses at 12-hourly intervals, stratified by total body weight and creatinine clearance, increased the probability of achieving target concentrations within 72 hours. CONCLUSIONS: To increase the number of patients achieving optimal teicoplanin concentrations an individualized dosing approach, based on body weight and creatinine clearance, is recommended.

Asunto(s)

Antibacterianos/farmacología , Antibacterianos/farmacocinética , Neoplasias Hematológicas/epidemiología , Teicoplanina/farmacología , Teicoplanina/farmacocinética , Anciano , Antibacterianos/sangre , Antibacterianos/uso terapéutico , Monitoreo de Drogas , Femenino , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Infecciones por Bacterias Grampositivas/prevención & control , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Teicoplanina/sangre , Teicoplanina/uso terapéutico