RESUMEN
The antimicrobial agent linezolid is approved for the treatment of severe infections caused by, e.g., methicillin-resistant Staphylococcus strains. In order to evaluate the penetration of linezolid into the interstitial space fluid (ISF) of subcutaneous adipose tissue and skeletal muscle of the target population, a microdialysis study was performed with 12 patients with sepsis or septic shock after multiple intravenous infusions. Unbound linezolid concentrations were determined for plasma and microdialysates by use of a validated high-performance liquid chromatography method. Individual compartmental pharmacokinetic (PK) analysis was performed using WinNonlin. In vivo microdialysis was found to be feasible for the determination of unbound linezolid concentrations at steady state in the ISF of critically ill patients. On average, linezolid showed good distribution into ISF but with high interindividual variability. A two-compartment model was fitted to unbound concentrations in plasma with a geometric mean distribution volume of 62.9 liters and a mean clearance of 9.18 liters/h at steady state. However, disposition characteristics changed intraindividually within the time course. In addition, an integrated model for simultaneous prediction of concentrations in all matrices was developed and revealed similar results. Based on the model-predicted unbound concentrations in ISF, a scheme of more-frequent daily dosing of linezolid for some critically ill patients might be taken into consideration to avoid subinhibitory unbound concentrations in the infected tissue. The developed integrated model will be a valuable basis for further PK data analysis to explore refined dosing guidelines that achieve effective antimicrobial therapy in all patients by use of the population PK approach.
Asunto(s)
Acetamidas/farmacocinética , Antibacterianos/farmacocinética , Espacio Extracelular/metabolismo , Microdiálisis/métodos , Músculo Esquelético/metabolismo , Oxazolidinonas/farmacocinética , Grasa Subcutánea/metabolismo , Acetamidas/administración & dosificación , Acetamidas/sangre , Anciano , Antibacterianos/administración & dosificación , Antibacterianos/sangre , Enfermedad Crítica , Humanos , Linezolid , Oxazolidinonas/administración & dosificación , Oxazolidinonas/sangre , Sepsis/tratamiento farmacológico , Choque Séptico/tratamiento farmacológico , Distribución TisularRESUMEN
In the present pilot study we investigated the effect of food ingestion on target site pharmacokinetics of linezolid, the first clinically approved oxazolidinone. For this purpose we determined free concentrations of linezolid at steady state in the interstitial space fluid of skeletal muscle and subcutaneous adipose tissue under fasting and non-fasting conditions in healthy volunteers (n = 9) by means of in vivo microdialysis. Ingestion of food led to a marked delay in the time to reach the peak concentration (T(max)), whereas the area under the concentration-time curve from 0 to 24 h (AUC(0-24 h)) remained unchanged. These data suggest that the rate of linezolid absorption is decreased by food intake. However, the overall extent of linezolid absorption and the distribution of linezolid were not affected. Tissue levels of linezolid appeared sufficiently high to eradicate pathogens with a minimum inhibitory concentration of Asunto(s)
Acetamidas/sangre
, Acetamidas/farmacocinética
, Antibacterianos/sangre
, Antibacterianos/farmacocinética
, Oxazolidinonas/sangre
, Oxazolidinonas/farmacocinética
, Acetamidas/administración & dosificación
, Tejido Adiposo/metabolismo
, Administración Oral
, Anciano
, Antibacterianos/administración & dosificación
, Líquido Extracelular/metabolismo
, Femenino
, Alimentos
, Humanos
, Absorción Intestinal
, Linezolid
, Masculino
, Microdiálisis
, Persona de Mediana Edad
, Músculo Esquelético/metabolismo
, Oxazolidinonas/administración & dosificación
, Proyectos Piloto
, Distribución Tisular
RESUMEN
AIMS: The study was designed to evaluate the relative bioavailability of diclofenac in plasma, subcutaneous adipose and skeletal muscle tissue after repeated topical administration using MIKA Diclofenac Spray Gel (4%), a novel formulation, and after oral dosing using VOLTAREN 50 mg enteric coated tablets. METHODS: Diclofenac (48 mg) was administered topically three times daily for 3 days onto a defined area of the thigh of 12 healthy males. After a 14-day wash out period, subjects were orally treated with 50 mg diclofenac three times daily for 3 days. In vivo microdialysis in subcutaneous and muscle tissues was performed immediately after the final doses from both treatments on day 4, and 48 h later. Plasma samples were taken simultaneously. RESULTS: The relative bioavailability of diclofenac in subcutaneous adipose and skeletal muscle tissue was substantially higher after topical compared with oral dosing (324% and 209%, respectively) whereas relative plasma bioavailability was 50-fold lower. Plasma C(max) values were approximately 250-fold lower after topical compared with oral drug administration (i.e. median values = 4.89 ng mL(-1); 95% CI: 3.37-7.68 and 1240 ng mL(-1); 95% CI: 787-1389 ng mL(-1)). Both treatments were well tolerated. CONCLUSIONS: Owing to its favourable penetration characteristics and low systemic availability, MIKA Diclofenac Spray Gel 4% is a rational alternative to oral diclofenac formulations for the treatment of inflammatory soft tissue conditions.
Asunto(s)
Antiinflamatorios no Esteroideos/administración & dosificación , Diclofenaco/administración & dosificación , Tejido Adiposo/metabolismo , Administración Cutánea , Administración Oral , Adulto , Aerosoles , Antiinflamatorios no Esteroideos/análisis , Antiinflamatorios no Esteroideos/farmacocinética , Área Bajo la Curva , Disponibilidad Biológica , Diclofenaco/análisis , Diclofenaco/farmacocinética , Geles , Humanos , Masculino , Músculo Esquelético/metabolismo , Estudios Prospectivos , Absorción Cutánea , ComprimidosRESUMEN
The present study addressed the effect of microcirculatory blood flow on the ability of ciprofloxacin to penetrate soft tissues. Twelve healthy male volunteers were enrolled in an analyst-blinded, clinical pharmacokinetic study. A single intravenous dose of 200 mg of ciprofloxacin was administered over a period of approximately 20 min. The concentrations of ciprofloxacin were measured in plasma and in the warmed and contralateral nonwarmed lower extremities. The microdialysis technique was used for the assessment of unbound ciprofloxacin concentrations in subcutaneous adipose tissue. Microcirculatory blood flow was measured by use of laser Doppler flowmetry. Warming of the extremity resulted in an increase of microcirculatory blood flow by approximately three- to fourfold compared to that at the baseline (P < 0.05) in subcutaneous adipose tissue. The ratio of the maximum concentration (C(max)) of ciprofloxacin for the warmed thigh to the C(max) for the nonwarmed thigh was 2.10 +/- 0.90 (mean +/- standard deviation; P < 0.05). A combined in vivo pharmacokinetic (PK)-in vitro pharmacodynamic (PD) simulation based on tissue concentration data indicated that killing of Pseudomonas aeruginosa (ATCC 27853 and two clinical isolates) was more effective by about 2 log(10) CFU/ml under the warmed conditions than under the nonwarmed conditions (P < 0.05). The improvement of microcirculatory blood flow due to the warming of the extremity was paralleled by an increased ability of ciprofloxacin to penetrate soft tissue. Subsequent PK-PD simulations based on tissue PK data indicated that this increase in tissue penetration was linked to an improved antimicrobial effect at the target site.
Asunto(s)
Antiinfecciosos/farmacocinética , Ciprofloxacina/farmacocinética , Microdiálisis , Grasa Subcutánea/irrigación sanguínea , Grasa Subcutánea/efectos de los fármacos , Adulto , Antiinfecciosos/administración & dosificación , Antiinfecciosos/sangre , Ciprofloxacina/administración & dosificación , Ciprofloxacina/sangre , Simulación por Computador , Humanos , Infusiones Intravenosas , Flujometría por Láser-Doppler , Extremidad Inferior/irrigación sanguínea , Masculino , Microcirculación , Pseudomonas aeruginosa/efectos de los fármacos , Flujo Sanguíneo Regional/efectos de los fármacos , Temperatura Cutánea , TemperaturaRESUMEN
The present study tested the ability of linezolid to penetrate soft tissues in healthy volunteers. Ten healthy volunteers were subjected to linezolid drug intake at a dose of 600 mg twice a day for 3 to 5 days. The first dose was administered intravenously. All following doses were self-administered orally. The tissue penetration of linezolid was assessed by use of in vivo microdialysis. In the single-dose experiments the ratios of the area under the concentration-time curve from 0 to 8 h (AUC0-8) for tissue to the AUC0-8 for free plasma were 1.4+/-0.3 (mean+/-standard deviation) and 1.3+/-0.4 for subcutaneous adipose and muscle tissue, respectively. After multiple doses, the corresponding mean ratios were 0.9+/-0.2 and 1.0+/-0.5, respectively. The ratios of the AUC from 0 to 24 h (AUC0-24) for free linezolid in tissues to the MIC were between 50 and 100 for target pathogens with MICs between 2 and 4 mg/liter. In conclusion, the present study showed that linezolid penetrates rapidly into the interstitial space fluid of subcutaneous adipose and skeletal muscle tissues in healthy volunteers. On the basis of pharmacokinetic-pharmacodynamic calculations, we suggest that linezolid concentrations in soft tissues can be considered sufficient to inhibit the growth of many clinically relevant bacteria.
Asunto(s)
Acetamidas/farmacocinética , Tejido Adiposo/metabolismo , Antiinfecciosos/farmacocinética , Líquido Extracelular/metabolismo , Músculo Esquelético/metabolismo , Oxazolidinonas/farmacocinética , Acetamidas/administración & dosificación , Antiinfecciosos/administración & dosificación , Área Bajo la Curva , Humanos , Linezolid , Microdiálisis/métodos , Oxazolidinonas/administración & dosificaciónRESUMEN
By use of microdialysis we assessed the concentrations of telithromycin in muscle and adipose tissue to test its ability to penetrate soft tissues. The ratios of the area under the concentration-versus-time curve from 0 to 24 h to the MIC indicated that free concentrations of telithromycin in tissue and plasma might be effective against Streptococcus pyogenes but not against staphylococci and human and animal bite pathogens.
Asunto(s)
Antibacterianos/farmacocinética , Cetólidos/farmacocinética , Adolescente , Adulto , Antibacterianos/sangre , Área Bajo la Curva , Proteínas Sanguíneas/metabolismo , Cromatografía Líquida de Alta Presión , Semivida , Humanos , Indicadores y Reactivos , Cetólidos/sangre , Masculino , Microdiálisis , Músculo Esquelético/metabolismo , Unión Proteica , Estándares de Referencia , Piel/metabolismoRESUMEN
AIMS: The present study addressed the ability of levofloxacin to penetrate into subcutaneous adipose tissues in patients with soft tissue infection. METHODS: Tissue concentrations of levofloxacin in inflamed and healthy subcutaneous adipose tissue were measured in six patients by microdialysis after administration of a single intravenous dose of 500 mg. Levofloxacin was assayed by high-performance liquid chromatography. RESULTS: The mean concentration vs time profile of free levofloxacin in plasma was identical to that in inflamed and healthy tissues. The ratios of the mean area under the free levofloxacin concentration vs time curve from 0 to 10 h (AUC(0,10 h)) in tissue to that in plasma were 1.2 +/- 1.0 for inflamed and 1.1 +/- 0.6 for healthy subcutaneous adipose tissue (mean +/- SD). The mean difference in the ratio of the AUC(tissue) : AUC(plasma) for inflamed and healthy tissue was 0.09 (95% confidence interval -0.58, 0.759, P > 0.05). Interindividual variability in tissue penetration was high, as indicated by a coefficient of variation of approximately 82% for AUC(tissue) : AUC(plasma) ratios. CONCLUSIONS: The penetration of levofloxacin into tissue appears to be unaffected by local inflammation. Our plasma and tissue data suggest that an intravenous dose of 500 mg levofloxacin provides effective antibacterial concentrations at the target site. However, in treatment resistant patients, tissue concentrations may be sub-therapeutic.
Asunto(s)
Tejido Adiposo/metabolismo , Antiinfecciosos/farmacocinética , Levofloxacino , Ofloxacino/farmacocinética , Infecciones de los Tejidos Blandos/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antiinfecciosos/administración & dosificación , Cromatografía Líquida de Alta Presión/métodos , Femenino , Humanos , Infusiones Intravenosas , Masculino , Microdiálisis/métodos , Persona de Mediana Edad , Ofloxacino/administración & dosificación , Infecciones de los Tejidos Blandos/metabolismo , Distribución TisularRESUMEN
High-performance liquid chromatography (HPLC) was used to analyze microdialysis samples obtained in vivo from human subcutaneous adipose tissue after topical application of the nonsteroidal anti-inflammatory drug diclofenac. For the reliable determination of diclofenac two different detection principles were applied in two different laboratories. One HPLC method utilized UV-detection at 280 nm, the other one used selected reaction monitoring mass spectrometry (MS). The HPLC-UV and -MS methods offered low limits of quantification of 10 and 1 ng/ml and an accuracy between 94.0-126.7 and 89.3-110.9%, respectively. However, a comparison showed that the HPLC-UV method failed to determine diclofenac in biological matrices, as both false negative and positive values were found. HPLC-MS is clearly superior to HPLC-UV due to a much more selective detection, increased sensitivity and shorter run times.