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1.
J Empir Res Hum Res Ethics ; 17(3): 242-253, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35414297

RESUMEN

Debate is ongoing concerning the activities and functioning of Research Ethics Committees (REC), especially a possible science-or-ethics dichotomy in research ethics review. We retrospectively analyzed 145 letters issued by a French REC over 18 months. All queries were classified in three levels: qualification (definition of the problem), category (aggregation of broader topics) and finally fields (ethical, scientific, or administrative). Overall, 971 queries were identified, of which 407 (42%), 379 (39%), and 135 (14%) were deemed ethical, scientific, and administrative queries, respectively. The most frequent concern was about participants' information. The main influencing factor was the profession of the reporting readers-scientific queries were more frequently raised by a methodologist, whereas ethical queries were more frequently raised by an ethicist. These results indicate that research ethics review is a multidimensional task that should be considered a collaborative effort.


Asunto(s)
Comités de Ética en Investigación , Ética en Investigación , Revisión Ética , Humanos , Estudios Retrospectivos
2.
J Transl Int Med ; 7(4): 155-169, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32010602

RESUMEN

BACKGROUND: Hemofiltration rate, changes in blood and ultrafiltration flow, and discrepancies between the prescribed and administered doses strongly influence pharmacokinetics (PK) and pharmacodynamics (PD) of antimicrobial agents during continuous veno-venous hemofiltration (CVVH) in critically ill patients. METHODS: Ancillary data were from the prospective multicenter IVOIRE (hIgh VOlume in Intensive caRE) study. High volume (HV, 70 mL/kg/h) was at random compared with standard volume (SV, 35 mL/kg/h) CVVH in septic shock patients with acute kidney injury (AKI). PK/PD parameters for all antimicrobial agents used in each patient were studied during five days. RESULTS: Antimicrobial treatment met efficacy targets for both percentage of time above the minimal inhibitory concentration and inhibitory quotient. A significant correlation was observed between the ultrafiltration flow and total systemic clearance (Spearman test: P < 0.005) and between CVVH clearance and drug elimination half-life (Spearman test: P < 0.005). All agents were easily filtered. Mean sieving coefficient ranged from 38.7% to 96.7%. Mean elimination half-life of all agents was significantly shorter during HV-CVVH (from 1.29 to 28.54 h) than during SV-CVVH (from 1.51 to 33.85 h) (P < 0.05). CONCLUSIONS: This study confirms that CVVH influences the PK/PD behavior of most antimicrobial agents. Antimicrobial elimination was directly correlated with convection rate. Current antimicrobial dose recommendations will expose patients to underdosing and increase the risk for treatment failure and development of resistance. Dose recommendations are proposed for some major antibiotic and antifungal treatments in patients receiving at least 25 mL/kg/h CVVH.

3.
Am J Health Syst Pharm ; 70(23): 2137-42, 2013 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-24249764

RESUMEN

PURPOSE: The 72-hour chemical stability of refrigerated syringes of azacitidine suspension prepared via a cold-chain method is investigated. METHODS: Three 25-mg/mL azacitidine suspensions were prepared from different lots of powdered drug. The suspensions were stored in 2-mL polypropylene syringes at 2-8 °C and protected from light. The concentrations of azacitidine and the mean area under the concentration-time curve (AUC) values for its degradation products were determined after 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours using high-performance liquid chromatography with ultraviolet detection. RESULTS: The degradation process was slow during the first 48 hours and then accelerated. During the first 48 hours of storage, 4.23% of the azacitidine was lost relative to the mean concentration measured at time zero, which complied with International Conference on Harmonisation (ICH) guidance specifying a maximum change of 5% from the initial measured value. Two degradation products were present immediately after syringe preparation; N-formylribosylguanylurea formed rapidly (as indicated by a 35.62% increase from the baseline AUC in the first 12 hours), whereas ribosylguanylurea formation occurred more slowly (a 7.69% mean increase from the baseline AUC at 12 hours) but then rapidly accelerated. The study results indicate that properly prepared azacitidine syringes for injection can be administered up to two days later while maintaining conformance with ICH stability standards. CONCLUSION: Azacitidine 25-mg/mL suspensions reconstituted with refrigerated water (2-8 °C) and stored in propylene syringes were chemically stable during the first 48 hours when stored protected from light at 2-8 °C.


Asunto(s)
Antimetabolitos Antineoplásicos/química , Azacitidina/química , Cromatografía Líquida de Alta Presión/métodos , Polipropilenos/química , Área Bajo la Curva , Estabilidad de Medicamentos , Almacenaje de Medicamentos , Inyecciones , Refrigeración , Suspensiones , Jeringas , Factores de Tiempo
4.
J Chemother ; 25(1): 1-17, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23433439

RESUMEN

OBJECTIVE: To assess the relative strengths and weaknesses of carbapenems by considering their microbiological, clinical, pharmacokinetics and pharmacokinetic/pharmacodynamic (PK/PD) properties and defining optimal conditions of uses of the new generation of carbapenems. METHODS: Literature review. RESULTS: Except for ertapenem, the spectrum of activity is similar for all carbapenems, with little differences in activities of individual agents. The absence or reduced expression of two major porins in combination with various beta-lactamases and alteration of some penicillin binding proteins have been implicated in carbapenem resistance. All carbapenems are not alike, although they have very similar pharmacokinetic properties. The most important PK/PD parameter predicting bacteriological and clinical efficacy is T(>MIC). There is some circumstantial evidence, such as clinical data in severe critically ill septic patients, impaired renal function patients and neutropenic patients that imipenem has to exceed 66% of T(>MIC) to result in good clinical outcome. Continuous or extend infusion of carbapenems should result in at least equal efficacy to that of intermittent infusion in the treatment of infections with susceptible bacteria and appear highly appropriate for use in critically ill patients. CONCLUSIONS: Maximizing clinical outcomes and minimizing antibiotic resistance using individualized doses may be best achieved with therapeutic drug monitoring of carbapenems.


Asunto(s)
Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Carbapenémicos/farmacología , Carbapenémicos/uso terapéutico , Antibacterianos/farmacocinética , Bacterias/efectos de los fármacos , Carbapenémicos/farmacocinética , Farmacorresistencia Microbiana , Humanos
5.
J Antimicrob Chemother ; 67(5): 1207-10, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22351682

RESUMEN

OBJECTIVES: This study aimed to determine the steady-state serum and alveolar concentrations of linezolid administered by continuous infusion to critically ill patients with ventilator-associated pneumonia (VAP). PATIENTS AND METHODS: This was a prospective, open-label study performed in an intensive care unit and research ward in a university hospital. Twelve critically ill adult patients with VAP received 600 mg of linezolid as a loading dose followed by 1200 mg/day by continuous infusion. After 2 days of therapy, the steady-state serum and alveolar (collected by a mini-bronchoalveolar procedure) concentrations of linezolid were determined by HPLC. RESULTS: The median (IQR) serum and epithelial lining fluid (ELF) linezolid concentrations at steady state (C(ss)) were 7.1 (6.1-9.8) and 6.9 (5.8-8.6) mg/L, respectively, and the median (IQR) AUC (AUC(0-24)) values were 169 (146-235) and 164 (139-202) mg · h/L, respectively, corresponding to a median (IQR) linezolid alveolar diffusion of 97% (80%-108%). CONCLUSIONS: Our study shows that the continuous infusion of 1200 mg of linezolid daily in critically ill patients with VAP provides satisfactory pharmacokinetic results, with a linezolid alveolar diffusion of 100% and concentrations exceeding almost twice the susceptibility breakpoint for Staphylococcus aureus (4 mg/L) in both serum and ELF for 100% of the time. However, the clinical benefit of continuous infusion in comparison with standard intermittent infusion is still to be determined.


Asunto(s)
Acetamidas/farmacocinética , Antibacterianos/farmacocinética , Oxazolidinonas/farmacocinética , Neumonía Asociada al Ventilador/tratamiento farmacológico , Alveolos Pulmonares/química , Acetamidas/administración & dosificación , Adulto , Antibacterianos/administración & dosificación , Enfermedad Crítica , Femenino , Humanos , Infusiones Intravenosas , Linezolid , Masculino , Persona de Mediana Edad , Oxazolidinonas/administración & dosificación , Neumonía Estafilocócica/tratamiento farmacológico , Estudios Prospectivos , Suero/química , Staphylococcus aureus/efectos de los fármacos
6.
J Pharm Pharmacol ; 63(12): 1559-65, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22060286

RESUMEN

INTRODUCTION: Liquid chromatography coupled with mass spectrometry for the quantification of raltegravir in human plasma and peripheral blood mononuclear cells has been developed. METHODS: Sample preparations were based on a fully automated solid-phase extraction process. Mass spectrometric data were acquired in a single-ion monitoring method. Raltegravir and quinoxaline, the internal standard, were well separated in a gradient mode over 15 min. KEY FINDINGS: Validation study exhibited excellent linearity, with good intra- and inter-day precision and accuracy. CONCLUSIONS: The assay was successfully applied to the raltegravir quantification in HIV-infected patients.


Asunto(s)
Fármacos Anti-VIH/análisis , Pirrolidinonas/análisis , Adulto , Fármacos Anti-VIH/sangre , Calibración , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Indicadores y Reactivos , Límite de Detección , Masculino , Persona de Mediana Edad , Monocitos/química , Pirrolidinonas/sangre , Control de Calidad , Quinoxalinas/análisis , Raltegravir Potásico , Estándares de Referencia , Reproducibilidad de los Resultados , Extracción en Fase Sólida , Espectrometría de Masas en Tándem
7.
Br J Clin Pharmacol ; 72(5): 823-31, 2011 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-21518387

RESUMEN

AIM: To give a panorama of the selectivity and agreement of French university hospitals' drug formularies (HDF) for nine competitive classes. METHODS: All university hospitals were asked to send their HDF and selection criteria as of January 2009 for nine competitive pharmacological classes (proton pump inhibitors, serotonin antagonists, low molecular weight heparins, erythropoietins, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, statins, α-adrenoreceptor antagonists and selective serotonin re-uptake inhibitors). Selectivity of HDF was estimated by the percentage of drug entities selected by the hospital within the pharmacological class. Agreement between hospitals was assessed with modified kappa coefficients for multi-raters. RESULTS: Twenty-one out of the 29 hospitals agreed to participate. These hospitals selected between 34% and 63% of the drug entities available for the nine classes, which represented 18 to 35 agents. Regarding the nature of chosen drug entities, the overall level of agreement was 'fair' and varied with pharmacological classes. Selection criteria were sent by only 12 hospitals. The technical component was the most important element in all hospitals. The weight of the economic component varied between 20% and 40% in the tender's grade. DISCUSSION: Large variations were seen in the number and nature of drugs selected by university hospitals which can be attributable to two successive decision-making processes (evaluation by the Drug and Therapeutics Committee followed by the purchasing process).


Asunto(s)
Prescripciones de Medicamentos/estadística & datos numéricos , Utilización de Medicamentos/tendencias , Formularios de Hospitales como Asunto , Servicio de Farmacia en Hospital/tendencias , Estudios Transversales , Prescripciones de Medicamentos/economía , Utilización de Medicamentos/economía , Francia , Hospitales Universitarios , Humanos , Servicio de Farmacia en Hospital/economía , Encuestas y Cuestionarios
8.
Anal Bioanal Chem ; 400(7): 2073-84, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21445661

RESUMEN

The extended use of protein drugs in therapeutics has created the need for their quantification in human plasma. A methodology using the therapeutic protein itself as internal standard for quantitative analysis by multiple reaction monitoring (MRM) has been designed and applied to epoetin beta, a recombinant human erythropoietin (rhEPO). After depletion of major proteins, plasma samples were desalted and enriched in rhEPO by reversed phase liquid chromatography prior to tryptic cleavage. Differential isotopic labeling of peptides was performed by derivatization with 2-methoxy-4,5-dehydro-imidazole. A light version (four hydrogen atoms) of this reagent was used for plasma peptides. Tryptic peptides obtained from pure rhEPO were derivatized with a heavy version (four deuterium atoms) of the same reagent and used as internal standards. Two rhEPO tryptic peptides with three MRM transitions per peptide were selected for quantification. This strategy provided a quantification limit close to 50 amol of epoetin beta per microliter of plasma (equivalent to 1.7 ng/mL), i.e., well below the expected therapeutic concentrations in plasma (around 100-500 amol/µL).


Asunto(s)
Eritropoyetina/sangre , Espectrometría de Masas en Tándem/métodos , Cromatografía Liquida , Eritropoyetina/química , Humanos , Mapeo Peptídico , Proteínas Recombinantes , Estándares de Referencia , Tripsina/química
9.
Arthritis Res Ther ; 12(6): R217, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-21176194

RESUMEN

INTRODUCTION: The aim of this study was to determine whether mycophenolate mofetil (MMF) pharmacokinetics (PK) under combined MMF and prednisone remission-maintenance therapy can predict systemic lupus erythematosus (SLE) clinical flares. METHODS: At inclusion, steady-state PK parameters of the MMF active form, mycophenolic acid (MPA), and its glucuronide metabolite (MPAG) were determined for 25 stable SLE patients without renal manifestations. Disease activity was assessed during 6 months of follow-up. Potential relationships between those entry MMF-PK variables and clinical outcome were analyzed. RESULTS: MMF controlled disease activity in 17 patients (successes) and failed to do so for 8 others (failures). For failures and successes, respectively, entry MPA areas under the time-concentration curve between 0 and 12 hours (AUC(0-12 h)) (medians: 37.7 vs 73.1 mg/h/L, P = 0.003) and MPA 12-hour trough concentrations (C(12 h)) (medians: 1.5 vs 3.7 mg/L, P = 0.008) were significantly lower, and inclusion MPAG/MPA C(12 h) ratios (medians: 18.7 vs 10.2, P = 0.02) were significantly higher. According to our receiver operating characteristics curve analysis, MPA C(12 h) was best able to discriminate a flare during follow-up (93% sensitivity, 85% specificity). A 3-mg/L cut-off had 92% negative-predictive value for developing a flare during follow-up. CONCLUSIONS: For our SLE patients without renal manifestations, clinical flares developing under maintenance therapy were associated with steady-state inclusion MPA C(12 h) < 3 mg/L.


Asunto(s)
Inmunosupresores/farmacocinética , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/tratamiento farmacológico , Ácido Micofenólico/análogos & derivados , Adulto , Área Bajo la Curva , Estudios de Cohortes , Femenino , Humanos , Inmunosupresores/uso terapéutico , Masculino , Espectrometría de Masas , Persona de Mediana Edad , Ácido Micofenólico/farmacocinética , Ácido Micofenólico/uso terapéutico
10.
Int J Pharm ; 396(1-2): 140-2, 2010 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-20542102

RESUMEN

The aim of this study (SITEPO) is to evaluate the influence of the intravenous injection site (drip chamber injection site, venous injection site or venous fistula needle) on plasma concentration of epoetin beta (Neorecormon, Roche), a recombinant Human Erythropoietin (rHuEPO), at the end of in vitro hemodialysis sessions. No practical administration guidelines are available. Twenty 1-h dialysis sessions are performed. Before each dialysis, the circuit is filled with 270ml, of heparinized total human blood whose hematocrit is adjusted to 35%. A common dosage of epoetin beta in clinical practice (3000IU) is studied for the three injection sites and for reference experiments in which rHuEPO is not injected into the dialysis circuit. Plasma concentrations of erythropoietin are measured by ELISA. The physiologically endogenous erythropoietin concentration is systematically determined and removed from the total epoetin beta concentration. Average epoetin beta plasma levels returned are not significantly different between the three injection sites and no significant rHuEPO loss is observed after injection into the drip chamber, the venous injection site and the venous fistula needle compared with reference experiments. The three intravenous injection sites of rHuEPO can be used at the end of dialysis without significant epoetin beta loss.


Asunto(s)
Eritropoyetina/administración & dosificación , Hematínicos/administración & dosificación , Diálisis Renal , Derivación Arteriovenosa Quirúrgica , Cateterismo Venoso Central/instrumentación , Catéteres de Permanencia , Ensayo de Inmunoadsorción Enzimática , Diseño de Equipo , Eritropoyetina/sangre , Hematínicos/sangre , Hematócrito , Humanos , Inyecciones Intravenosas , Cinética , Punciones , Proteínas Recombinantes
11.
Expert Opin Pharmacother ; 11(5): 689-99, 2010 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-20210680

RESUMEN

OBJECTIVE: Mycophenolic acid (MPA), the active form of mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS), is used to treat systemic lupus erythematosus (SLE). MMF and EC-MPS pharmacokinetics were examined to devise guidance for therapeutic drug monitoring (TDM) for SLE patients with normal renal function. RESEARCH DESIGN AND METHODS: This observational study included 21 patients receiving MMF (1000 mg twice daily) and 14 taking EC-MPS (720 mg twice daily). MPA AUC between 0 and 12 h (AUC(0-12h)), C(max), T(max), and 12-h trough concentrations (C(12h)) were determined. RESULTS: Means of dose-normalized MMF- or EC-MPS-MPA C(max) were 64.6 +/- 25 and 61.4 +/- 27.1 h mg/l, respectively. MPA T(max) for EC-MPS was longer and more variable than for MMF. MMF-MPA AUC(0-12h) and C(12h) were correlated (r = 0.78, p = 0.0001), but EC-MPS-MPA C(max) and single concentrations were weakly correlated. A limited-sampling strategy (LSS) combining C(max) and C(12h) gave satisfactory predictive performance to estimate MPA AUC(0-12h) after EC-MPS administration. CONCLUSIONS: For TDM in SLE patients with GFR > 60 ml/min/1.73 m(2), C(12h) after MMF ingestion could predict MPA AUC(0-12h), while an LSS around T(max) should be used for patients on EC-MPS.


Asunto(s)
Monitoreo de Drogas/métodos , Inmunosupresores/farmacocinética , Lupus Eritematoso Sistémico/tratamiento farmacológico , Ácido Micofenólico/análogos & derivados , Administración Oral , Adulto , Área Bajo la Curva , Femenino , Tasa de Filtración Glomerular , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Ácido Micofenólico/administración & dosificación , Ácido Micofenólico/farmacocinética , Ácido Micofenólico/uso terapéutico , Comprimidos Recubiertos , Factores de Tiempo
12.
Antimicrob Agents Chemother ; 54(4): 1443-52, 2010 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-20100878

RESUMEN

The influence of antibiotic dosages and bacterial mutator phenotypes on the emergence of linezolid-resistant mutants was evaluated in an in vitro pharmacokinetic-pharmacodynamic model. A twice-daily 0.5-h infusion of a 200-, 600-, or 800-mg dose for 48 h was simulated against four strains (MIC, 2 microg/ml): Staphylococcus aureus RN4220 and its mutator derivative MutS2, Enterococcus faecalis ATCC 29212, and a mutator clinical strain of E. faecalis, Ef1497. The peak concentrations (4.38 to 4.79, 13.4 to 14.6, and 19.2 to 19.5 microg/ml) and half-lives at beta-phase (5.01 to 6.72 h) fit human plasma linezolid pharmacokinetics. Due to its bacteriostatic property, the cumulative percentages of the dosing interval during which the drug concentration exceeded the MIC (T > MIC), 66.6 and 69.1% of the dosing interval, were not significant, except for Ef1497, with an 800-mg dose and a T > MIC of 80.9%. At the standard 600-mg dosage, resistant mutants (2- to 8-fold MIC increases) were selected only with Ef1497. A lower, 200-mg dosage did not select resistant mutants of E. faecalis ATCC 29212, but a higher, 800-mg dosage against Ef1497 did not prevent their emergence. For the most resistant mutant (MIC, 16 microg/ml), characterization of 23S rRNA genes revealed the substitution A2453G in two of the four operons, which was previously described only in in vitro mutants of archaebacteria. Nevertheless, this mutant did not yield further mutants under 600- or 200-mg treatment. In conclusion, linezolid was consistently efficient against S. aureus strains. The emergence of resistant E. faecalis mutants was probably favored by the rapid decline of linezolid concentrations against a strong mutator, a phenotype less exceptional in E. faecalis than in S. aureus.


Asunto(s)
Acetamidas/farmacología , Acetamidas/farmacocinética , Antibacterianos/farmacología , Antibacterianos/farmacocinética , Enterococcus faecalis/efectos de los fármacos , Enterococcus faecalis/genética , Oxazolidinonas/farmacología , Oxazolidinonas/farmacocinética , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/genética , Acetamidas/administración & dosificación , Antibacterianos/administración & dosificación , Secuencia de Bases , Cartilla de ADN/genética , Relación Dosis-Respuesta a Droga , Farmacorresistencia Bacteriana/genética , Humanos , Técnicas In Vitro , Linezolid , Pruebas de Sensibilidad Microbiana , Modelos Biológicos , Oxazolidinonas/administración & dosificación , Fenotipo , Mutación Puntual , ARN Bacteriano/genética , ARN Ribosómico 23S/genética , Especificidad de la Especie
14.
J Pharm Biomed Anal ; 50(5): 932-8, 2009 Dec 05.
Artículo en Inglés | MEDLINE | ID: mdl-19608374

RESUMEN

A simple, specific and automatable HPLC assay was developed for a simultaneous determination of systemic azoles (fluconazole, posaconazole, voriconazole, itraconazole and its metabolite hydroxyl-itraconazole, and ketoconazole) in plasma. The major advantage of this assay was sample preparation by a fully automatable solid phase extraction with Varian Plexa cartridges. C6-phenyl column was used for chromatographic separation, and UV detection was set at a wavelength of 260 nm. Linezolid was used as an internal standard. The assay was specific and linear over the concentration range of 0.05 to 40 microg/ml excepted for fluconazole which was between 0.05 and 100 microg/ml, and itraconazole between 0.1 and 40 microg/ml. Validation data for accuracy and precision for intra- and inter-day were good and satisfied FDA's guidance: CV between 0.24% and 11.66% and accuracy between 93.8% and 108.7% for all molecules. This assay was applied to therapeutic drug monitoring on patients hospitalized in intensive care and onco-hematologic units.


Asunto(s)
Química Farmacéutica/métodos , Cromatografía Líquida de Alta Presión/métodos , Fluconazol/sangre , Itraconazol/sangre , Cetoconazol/sangre , Pirimidinas/sangre , Espectrofotometría Ultravioleta/métodos , Triazoles/sangre , Calibración , Monitoreo de Drogas/métodos , Estabilidad de Medicamentos , Humanos , Control de Calidad , Reproducibilidad de los Resultados , Factores de Tiempo , Rayos Ultravioleta , Voriconazol
15.
J Antimicrob Chemother ; 63(6): 1251-5, 2009 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19336453

RESUMEN

BACKGROUND: The efficacy of raltegravir plus optimized background therapy (OBT) has been demonstrated for antiretroviral (ARV)-experienced HIV-1-infected patients in randomized clinical trials. We studied viro-immunological response, pharmacokinetic parameters and genotypic test results in an observational cohort of multiple ARV class-experienced patients starting a raltegravir-based regimen. METHODS: Already enrolled ANRS CO3 Aquitaine Cohort patients with virological failure were included in this study after starting a raltegravir-based regimen (400 mg twice a day, week 0). Virological success was defined by the plasma HIV-1 RNA level [viral load (VL)] <2.7 log(10) copies/mL at week 12 and <1.7 log(10) copies/mL at week 24. One patient was excluded from further analysis (no follow-up after week 4). RESULTS: Fifty-one patients [male/female = 43/8, median age = 48 (interquartile range = 43, 55) years] were included. At week 0, median CD4 count was 244 (110; 310)/mm(3) and median VL was 4.2 (3.6, 4.7) log(10) copies/mL. At week 24, 39 (78%) patients experienced virological success: 4 (44%), 14 (82%) and 21 (87%) patients with a genotypic sensitivity score <1, > or =1 and <2 and > or =2 (P = 0.02), respectively. Raltegravir-related mutations emerged in 9 of 11 failing patients (82%): Q148H/R (n = 5), N155S/H (n = 3) and S230N (n = 1). Median CD4 increases from week 0 to week 4 and week 24 were 28 (-4, 85) and 57 (0, 156) cells/mm(3), respectively. A poor immune response was independently associated with a lower VL decline (week 0 to week 12) [odds ratio (OR): 3.5, 95% confidence interval (CI): 1.4, 8.4, for 1 log(10) less] and CD4+% at baseline (OR: 2.6, 95% CI: 0.97, 8.3, for 10% lower). CONCLUSIONS: Raltegravir plus OBT provided a good virological success rate in highly pre-treated patients under clinical routine conditions.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa , Infecciones por VIH/tratamiento farmacológico , VIH-1/aislamiento & purificación , Pirrolidinonas/uso terapéutico , Adulto , Fármacos Anti-VIH/farmacocinética , Recuento de Linfocito CD4 , Estudios de Cohortes , Farmacorresistencia Viral , Femenino , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/clasificación , VIH-1/genética , Humanos , Masculino , Persona de Mediana Edad , Pirrolidinonas/farmacocinética , Raltegravir Potásico , Resultado del Tratamiento , Carga Viral
16.
J Antimicrob Chemother ; 62(3): 518-21, 2008 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-18544595

RESUMEN

BACKGROUND AND AIMS: Listeria monocytogenes and Staphylococcus aureus invade and multiply in THP-1 monocytes. Fluoroquinolones accumulate in these cells, but are less active against intracellular than extracellular forms of L. monocytogenes and S. aureus. We examined whether differentiation of THP-1 monocytes into adherent, macrophage-like cells increases fluoroquinolone uptake and activity. METHODS: THP-1 monocytes were differentiated with phorbol myristate acetate (PMA) and compared with unstimulated cells for: (i) moxifloxacin and levofloxacin accumulation; and (ii) activity against phagocytosed L. monocytogenes and S. aureus (5 h contact). RESULTS: The differentiation of THP-1 monocytes caused: (i) a 3- to 4-fold increase in moxifloxacin uptake and a significant increase in its activity against intracellular L. monocytogenes (from 1.3 log(10) to 2.1 log(10) cfu decrease compared with the post-phagocytosis inoculum), but not against S. aureus (1.0-1.2 log(10) cfu decrease throughout); and (ii) no change in levofloxacin accumulation and intracellular activity against either L. monocytogenes or S. aureus. CONCLUSIONS: Although differentiation of monocytes enhances the uptake and activity of moxifloxacin against L. monocytogenes, this cannot be extended to other intracellular bacteria and to levofloxacin. These results further demonstrate that antibiotic intracellular accumulation and activity are not necessarily linked and suggest that intracellular drug and pathogen combinations must be studied individually.


Asunto(s)
Antibacterianos/metabolismo , Antibacterianos/farmacología , Compuestos Aza/metabolismo , Compuestos Aza/farmacología , Levofloxacino , Listeria monocytogenes/efectos de los fármacos , Monocitos/metabolismo , Monocitos/microbiología , Ofloxacino/metabolismo , Ofloxacino/farmacología , Quinolinas/metabolismo , Quinolinas/farmacología , Staphylococcus aureus/efectos de los fármacos , Línea Celular Tumoral , Recuento de Colonia Microbiana , Citoplasma/química , Citoplasma/microbiología , Fluoroquinolonas , Humanos , Viabilidad Microbiana , Moxifloxacino
17.
Antivir Ther ; 13(2): 271-9, 2008.
Artículo en Inglés | MEDLINE | ID: mdl-18505178

RESUMEN

BACKGROUND: We assessed the association of baseline HIV-1 mutations, phenotypic sensitivity and pharmacokinetics with virological failure (VF) at week 12 (W12) after onset of a darunavir/ritonavir (DRV/r)-based regimen in a cohort of 67 antiretroviral-experienced HIV-patients failing on highly active antiretroviral therapy (HAART). METHODS: VF was defined as HIV RNA >2.3 log10copies/ml at W12. HIV reverse transcriptase and protease sequencing was performed at WO; mutations with a P-value <0.25 in univariable analyses were used for a backward selection to find the best mutation set for VF prediction. Genotypic and phenotypic sensitivity scores were calculated and virtual phenotype predicted fold change (FC) assessed. DRV Cmin, Cmax, AUC(0-->12 h) and genotypic inhibitory quotient (GIQ) were determined. RESULTS: Patients had a median of 15 previous treatments for 10 years. Median W0 values included a T-cell count of 129 cells/microl, 4.7 log10 HIV RNA copies/ml, four major protease and six nucleoside reverse transcriptase inhibitor resistance mutations. At W12, median HIV RNA decrease was -2.1 log10 copies/ml with a gain of +67 CD4+ T-cells/microl; 40% of patients failed. We determined the genotypic score I13V+V32I+L33F/I/V+E35D+ M361/L/V+I47V+F53L+I62V. According to <4, 4-5 and >5 mutations, failure occurred in 11%, 48% and 100% of patients. Failure was associated with CDC stage, baseline CD4+ T-cell count, number of major protease inhibitor resistance mutations, FC and DRV/r score. Pharmacokinetics were not associated with failure, but GIQ was. CONCLUSION: At W12, 60% of heavily pretreated patients responded on DRV/r-based HAART. Genotypic and phenotypic information constituted the main virological response determinant in patients with optimal drug concentrations.


Asunto(s)
Infecciones por VIH , Inhibidores de la Proteasa del VIH/farmacología , VIH-1/efectos de los fármacos , Mutación , Ritonavir/farmacología , Sulfonamidas/farmacología , Adulto , Terapia Antirretroviral Altamente Activa , Estudios de Cohortes , Darunavir , Farmacorresistencia Viral , Quimioterapia Combinada , Femenino , Genotipo , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Proteasa del VIH/genética , Inhibidores de la Proteasa del VIH/farmacocinética , Inhibidores de la Proteasa del VIH/uso terapéutico , Transcriptasa Inversa del VIH/genética , VIH-1/enzimología , VIH-1/genética , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Fenotipo , Ritonavir/farmacocinética , Ritonavir/uso terapéutico , Análisis de Secuencia de ADN , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapéutico , Resultado del Tratamiento
18.
Crit Care Med ; 36(5): 1500-6, 2008 May.
Artículo en Inglés | MEDLINE | ID: mdl-18434883

RESUMEN

OBJECTIVES: To determine the steady-state serum and alveolar concentrations of piperacillin/tazobactam administered in continuous infusion to critically ill patients with ventilator-associated pneumonia and various degrees of renal failure. DESIGN: Prospective comparative study. SETTING: An intensive care unit and research ward in a university hospital. PATIENTS: Forty patients with microbiologically documented ventilator-associated pneumonia. INTERVENTIONS: Patients were randomized to receive piperacillin/tazobactam daily continuous infusions of 12/1.5 g or 16/2 g after a loading dose of 4/0.5 g. The serum and alveolar piperacillin/tazobactam concentrations were determined at steady-state with high performance liquid chromatography. MEASUREMENTS AND MAIN RESULTS: The median (interquartile) serum and alveolar piperacillin concentrations were respectively 25.3 mg/L (23.1-32.6) and 12.7 mg/L (6.7-18.0) for 12/1.5 g/day, and 38.9 mg/L (32.9-59.6) and 19.1 mg/L (14.0-21.5), respectively, for 16/2 g/day in patients with no/mild renal failure. In patients with moderate/advance renal failure, the median (interquartile) serum and alveolar piperacillin concentrations were 102.4 mg/L (97.4-112.6) and 44.1 mg/L (33.4-48.3), respectively, for 12/1.5 g/day, and 135.3 mg/L (119.5-146.2) and 54.9 mg/L (45.2-110.3), respectively, for 16/2 g/day. Our results show great variability in piperacillin/tazobactam concentrations, with an alveolar percentage penetration of 40-50% for piperacillin and 65-85% for tazobactam and a negative association between serum or alveolar concentrations and creatinine clearance. CONCLUSIONS: A target piperacillin serum concentration of at least 35-40 mg/L is probably required to provide alveolar concentrations exceeding the susceptibility breakpoint for gram-negative bacteria (16 mg/L) during ventilator-associated pneumonia. In patients with no/mild renal failure, a continuous daily dose of piperacillin/tazobactam 16/2 g allows reaching this target concentration, which might be not observed with 12/1.5 g/day. In patients with moderate/advanced renal failure, both dosages achieve serum concentrations far above the 35-40 mg/L threshold, suggesting that in that case, therapeutic drug monitoring should be performed in order to adjust the daily dose.


Asunto(s)
Antibacterianos/farmacocinética , Ácido Penicilánico/análogos & derivados , Piperacilina/farmacocinética , Neumonía Asociada al Ventilador/metabolismo , Alveolos Pulmonares/metabolismo , Anciano , Antibacterianos/administración & dosificación , Femenino , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Ácido Penicilánico/administración & dosificación , Ácido Penicilánico/farmacocinética , Piperacilina/administración & dosificación , Estudios Prospectivos , Tazobactam
19.
J Chromatogr B Analyt Technol Biomed Life Sci ; 854(1-2): 104-8, 2007 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-17481972

RESUMEN

An isocratic high-performance liquid chromatography (HPLC) method with on-line extraction has been developed to determine linezolid in Mueller-Hinton broth. The loading mobile phase consisting of water-acetonitrile 99:1 (v/v) allowed retention of the analyte on a LiChrocart 4-4 pre-column filled with a LiChrospher 100 RP-8, 5 microm. The transfer of the analyte by a backflush mode to a 150 mm x 4.6 mm I.D. Kromasil C8 5 microm column was performed using a mobile phase of water-acetonitrile 80:20 (v/v). UV detection at 254 nm allowed a quantification limit of 0.39 microg/mL with a 50-microL sample size. The method was successfully applied to in vitro pharmacokinetic-pharmacodynamic studies.


Asunto(s)
Acetamidas/análisis , Antiinfecciosos/análisis , Cromatografía Líquida de Alta Presión/métodos , Medios de Cultivo/química , Oxazolidinonas/análisis , Acetamidas/aislamiento & purificación , Acetamidas/farmacocinética , Antiinfecciosos/aislamiento & purificación , Antiinfecciosos/farmacocinética , Calibración , Linezolid , Oxazolidinonas/aislamiento & purificación , Oxazolidinonas/farmacocinética , Estándares de Referencia , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Espectrofotometría Ultravioleta
20.
Intensive Care Med ; 33(9): 1519-23, 2007 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-17530217

RESUMEN

OBJECTIVE: To evaluate the reliability of mini-bronchoalveolar lavage (mini-BAL) for the measurement of tobramycin concentrations in epithelial lining fluid (ELF) in comparison with conventional bronchoscopic bronchoalveolar lavage (BAL). DESIGN: Prospective, open-label study. SETTING: An intensive care unit and research ward in a university hospital. PATIENTS: Twelve critically ill adult patients with ventilator-associated pneumonia (VAP). INTERVENTIONS: All subjects received intravenous infusions of tobramycin 7-10 mg/kg once daily. After 2 days of therapy, the steady-state serum and ELF concentrations (obtained from BAL and mini-BAL) of tobramycin were determined by means of high-performance liquid chromatography. MEASUREMENTS AND RESULTS: We observed poor penetration of tobramycin in ELF of approximately approximately 12% with ELF peak concentrations of approximately approximately 3 mg/l with both methods. Good agreement in Bland-Altman analysis (mean +/- SD bias = 0.04 +/- 0.38 mg/l) was observed between the two methods of sampling. CONCLUSION: Our results suggest that tobramycin 7-10 mg/kg once daily in critically ill patients with VAP might provide insufficient lung concentrations in the case of difficult-to-treat pathogens. Besides, mini-BAL, which is simple, non-invasive and easily repeatable at the bedside, appears to be a reliable method for the measurement of antibiotic concentrations in ELF in comparison with bronchoscopic BAL in critically ill patients with VAP.


Asunto(s)
Antibacterianos/farmacocinética , Lavado Broncoalveolar , Enfermedad Crítica , Mucosa Respiratoria/metabolismo , Tobramicina/farmacocinética , Adulto , Anciano , Anciano de 80 o más Años , Antibacterianos/administración & dosificación , Antibacterianos/análisis , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Infusiones Intravenosas , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Neumonía Asociada al Ventilador/tratamiento farmacológico , Estudios Prospectivos , Reproducibilidad de los Resultados , Tobramicina/administración & dosificación , Tobramicina/análisis
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