RESUMEN

BACKGROUND AND OBJECTIVE: Renal replacement therapy (RRT) plays a critical role in antimicrobial removal, particularly for low-molecular-weight drugs with low plasma protein binding, low distribution volume and hydrophilicity. Medium cut-off (MCO) membranes represent a new generation in dialysis technology, enhancing diffusive modality efficacy and increasing the cut-off from 30 to 45 kDa, crucial for middle molecule removal. This monocentric randomized crossover pilot study aimed to evaluate the impact of continuous haemodialysis with MCO membrane (MCO-CVVHD) on the removal of piperacillin, tazobactam and meropenem compared with continuous veno-venous hemodiafiltration with standard high-flux membrane (HFM-CVVHDF). METHODS: Twenty patients were randomized to undergo MCO-CVVHD followed by HFM-CVVHDF or vice versa. Extraction ratio (ER), effluent clearance (Cleff) and treatment efficiency were assessed at various intervals. Antibiotic nadir plasma levels were measured for both treatment days. RESULTS: HFM-CVVHDF showed greater ER compared with MCO-CVVHD for meropenem (ß = - 8.90 (95% CI - 12.9 to - 4.87), p < 0.001) and tazobactam (ß = - 8.29 (95% CI - 13.5 to - 3.08), p = 0.002) and Cleff for each antibiotic (meropenem ß = - 10,206 (95% CI - 14,787 to - 5787), p = 0.001); tazobactam (ß = - 4551 (95% CI - 7781 to - 1322), p = 0.012); piperacillin (ß = - 3913 (95% CI - 6388 to - 1437), p = 0.002), even if the carryover effect influenced the Cleff for meropenem and tazobactam. No difference was observed in nadir plasma concentrations or efficiency for any antibiotic. Piperacillin (ß = - 38.1 (95% CI - 47.9 to - 28.3), p < 0.001) and tazobactam (ß = - 4.45 (95% CI - 6.17 to - 2.72), p < 0.001) showed lower nadir plasma concentrations the second day compared with the first day, regardless the filter type. CONCLUSION: MCO demonstrated comparable in vivo removal of piperacillin, tazobactam and meropenem to HFM.

Asunto(s)

Antibacterianos , Terapia de Reemplazo Renal Continuo , Estudios Cruzados , Meropenem , Diálisis Renal , Choque Séptico , Humanos , Antibacterianos/farmacocinética , Antibacterianos/uso terapéutico , Antibacterianos/sangre , Masculino , Femenino , Persona de Mediana Edad , Anciano , Choque Séptico/terapia , Choque Séptico/tratamiento farmacológico , Choque Séptico/sangre , Proyectos Piloto , Terapia de Reemplazo Renal Continuo/métodos , Diálisis Renal/métodos , Meropenem/uso terapéutico , Meropenem/administración & dosificación , Meropenem/farmacocinética , Tazobactam/uso terapéutico , Tazobactam/farmacocinética , Piperacilina/farmacocinética , Piperacilina/uso terapéutico , Piperacilina/administración & dosificación , Hemodiafiltración/métodos

RESUMEN

This study aimed to develop a physiologically based pharmacokinetic/pharmacodynamic model (PBPK/PD) of meropenem for critically ill patients. A PBPK model of meropenem in healthy adults was established using PK-Sim software and subsequently extrapolated to critically ill patients based on anatomic and physiological parameters. The mean fold error (MFE) and geometric mean fold error (GMFE) methods were used to compare the differences between predicted and observed values of pharmacokinetic parameters Cmax, AUC0-∞, and CL to evaluate the accuracy of the PBPK model. The model was verified using meropenem plasma samples obtained from Intensive Care Unit (ICU) patients, which were determined by HPLC-MS/MS. After that, the PBPK model was combined with a PKPD model, which was developed based on f%T > MIC. Monte Carlo simulation was utilized to calculate the probability of target attainment (PTA) in patients. The developed PBPK model successfully predicted the meropenem disposition in critically ill patients, wherein the MFE average and GMFE of all predicted PK parameters were within the 1.25-fold error range. The therapeutic drug monitoring (TDM) of meropenem was conducted with 92 blood samples from 31 ICU patients, of which 71 (77.17%) blood samples were consistent with the simulated value. The TDM results showed that meropenem PBPK modeling is well simulated in critically ill patients. Monte Carlo simulations showed that extended infusion and frequent administration were necessary to achieve curative effect for critically ill patients, whereas excessive infusion time (> 4 h) was unnecessary. The PBPK/PD modeling incorporating literature and prospective study data can predict meropenem pharmacokinetics in critically ill patients correctly. Our study provides a reference for dose adjustment in critically ill patients.

Asunto(s)

Antibacterianos , Enfermedad Crítica , Meropenem , Meropenem/farmacocinética , Meropenem/administración & dosificación , Humanos , Masculino , Femenino , Persona de Mediana Edad , Antibacterianos/farmacocinética , Antibacterianos/administración & dosificación , Adulto , Anciano , Modelos Biológicos , Método de Montecarlo , Monitoreo de Drogas , Unidades de Cuidados Intensivos , Pruebas de Sensibilidad Microbiana

RESUMEN

BACKGROUND: Novel beta-lactams show activity against many multidrug-resistant Gram-negative bacteria that cause severe lung infections. Understanding pharmacokinetic/pharmacodynamic characteristics of these agents may help optimise outcomes in the treatment of pneumonia. OBJECTIVES: To describe and appraise studies that report pulmonary pharmacokinetic and pharmacodynamic data of cefiderocol, ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/cilastatin/relebactam and meropenem/vaborbactam. METHODS: MEDLINE (PubMed), Embase, Web of Science and Scopus libraries were used for the literature search. Pulmonary population pharmacokinetic and pharmacokinetic/pharmacodynamic studies on adult patients receiving cefiderocol, ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/cilastatin/relebactam, and meropenem/vaborbactam published in peer-reviewed journals were included. Two independent authors screened, reviewed and extracted data from included articles. A reporting guideline for clinical pharmacokinetic studies (ClinPK statement) was used for bias assessment. Relevant outcomes were included, such as population pharmacokinetic parameters and probability of target attainment of dosing regimens. RESULTS: Twenty-four articles were included. There was heterogeneity in study methods and reporting of results, with diversity across studies in adhering to the ClinPK statement checklist. Ceftolozane/tazobactam was the most studied agent. Only two studies collected epithelial lining fluid samples from patients with pneumonia. All the other phase I studies enrolled healthy subjects. Significant population heterogeneity was evident among available population pharmacokinetic models. Probabilities of target attainment rates above 90% using current licensed dosing regiments were reported in most studies. CONCLUSIONS: Although lung pharmacokinetics was rarely described, this review observed high target attainment using plasma pharmacokinetic data for all novel beta-lactams. Future studies should describe lung pharmacokinetics in patient populations at risk of carbapenem-resistant pathogen infections.

Asunto(s)

Antibacterianos , Cefalosporinas , Combinación de Medicamentos , Bacterias Gramnegativas , Inhibidores de beta-Lactamasas , beta-Lactamas , Humanos , Inhibidores de beta-Lactamasas/farmacocinética , Inhibidores de beta-Lactamasas/uso terapéutico , Inhibidores de beta-Lactamasas/farmacología , Antibacterianos/farmacocinética , Antibacterianos/uso terapéutico , Antibacterianos/farmacología , beta-Lactamas/farmacocinética , beta-Lactamas/uso terapéutico , beta-Lactamas/farmacología , Cefalosporinas/farmacocinética , Cefalosporinas/uso terapéutico , Cefalosporinas/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Tazobactam/farmacocinética , Tazobactam/uso terapéutico , Tazobactam/farmacología , Neumonía Bacteriana/tratamiento farmacológico , Compuestos de Azabiciclo/farmacocinética , Compuestos de Azabiciclo/uso terapéutico , Compuestos de Azabiciclo/farmacología , Carbapenémicos/farmacocinética , Carbapenémicos/uso terapéutico , Carbapenémicos/farmacología , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Ceftazidima/farmacocinética , Ceftazidima/uso terapéutico , Cefiderocol , Meropenem/farmacocinética , Meropenem/uso terapéutico , Meropenem/farmacología , Imipenem/farmacocinética , Imipenem/uso terapéutico , Farmacorresistencia Bacteriana Múltiple , Pruebas de Sensibilidad Microbiana , Combinación Cilastatina e Imipenem/farmacocinética , Combinación Cilastatina e Imipenem/uso terapéutico , Ácidos Borónicos , Compuestos Heterocíclicos con 1 Anillo

RESUMEN

The optimal method for administering meropenem remains controversial. This study was conducted to explore the optimal two-step infusion strategy (TIT), and to investigate whether TIT is superior to intermittent infusion therapy (IIT) and prolonged infusion therapy (PIT). A physiologically based pharmacokinetics model for critically ill patients was established and evaluated. The validated model was utilized to evaluate the pharmacokinetics/pharmacodynamics (PK/PD) target attainment of meropenem. The PK/PD target attainment of different TITs varied greatly, and the total infusion duration and the first-step dose greatly affected these values. The optimal TIT was 0.25 g (30 min) + 0.75 g (150 min) at MICs of ≤2 mg/L, and 0.25 g (45 min) + 0.75 g (255 min) at MICs of 4-8 mg/L. The PK/PD target attainment of optimal TIT, PIT, and IIT were 100 % at MICs of ≤1 mg/L. When MIC increased to 2-8 mg/L, the PK/PD target attainment of optimal TIT was similar to that of PIT and higher than IIT. In conclusion, TIT did not significantly improve the PK/PD target attainment of meropenem compared with PIT. IIT is adequate at MICs of ≤1 mg/L, and PIT may be the optimal meropenem infusion method in critically ill patients with MICs of 2-8 mg/L.

Asunto(s)

Antibacterianos , Enfermedad Crítica , Meropenem , Pruebas de Sensibilidad Microbiana , Meropenem/farmacocinética , Meropenem/administración & dosificación , Meropenem/farmacología , Humanos , Antibacterianos/farmacocinética , Antibacterianos/administración & dosificación , Antibacterianos/farmacología , Infusiones Intravenosas , Masculino , Modelos Biológicos , Persona de Mediana Edad , Femenino , Anciano

Asunto(s)

Antibacterianos , Enfermedad Crítica , Meropenem , Humanos , Enfermedad Crítica/terapia , Meropenem/administración & dosificación , Meropenem/uso terapéutico , Meropenem/farmacocinética , Antibacterianos/administración & dosificación , Antibacterianos/farmacocinética , Antibacterianos/uso terapéutico , Esquema de Medicación

RESUMEN

Meropenem penetration into the cerebrospinal fluid (CSF) is subject to high interindividual variability resulting in uncertain target attainment in CSF. Recently, several authors recommended administering meropenem as a continuous infusion (CI) to optimize CSF exposure. This study aimed to compare the concentrations and pharmacokinetics of meropenem in CSF after intermittent infusion (II) and CI. This prospective, observational study (NCT04426383) included critically ill patients with external ventricular drains who received either II or CI of meropenem. Meropenem pharmacokinetics in plasma and CSF were characterized using population pharmacokinetic modeling (NONMEM 7.5). The developed model was used to compare the concentration-time profile and probability of target attainment (PTA) between II and CI. A total of 16 patients (8 CI, 8 II; samples: nplasma = 243, nCSF = 263) were recruited, with nine patients (5 CI, 4 II) suffering from cerebral and seven patients from extracerebral infections. A one-compartment model described the plasma concentrations adequately. Meropenem penetration into the CSF (partition coefficient (KP), cCSF/cplasma) was generally low (6.0%), exhibiting substantial between-subject variability (coefficient of variation: 84.0%). There was no correlation between the infusion mode and KP, but interleukin (IL)-6 measured in CSF showed a strong positive correlation with KP (P < 0.001). Dosing simulations revealed no relevant differences in CSF concentrations and PTA in CSF between CI and II. Our study did not demonstrate increased penetration rates or higher concentrations of meropenem in the CSF with CI compared with II. CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT04426383.

Asunto(s)

Antibacterianos , Enfermedad Crítica , Meropenem , Humanos , Meropenem/farmacocinética , Meropenem/administración & dosificación , Meropenem/líquido cefalorraquídeo , Meropenem/sangre , Estudios Prospectivos , Masculino , Femenino , Persona de Mediana Edad , Antibacterianos/farmacocinética , Antibacterianos/líquido cefalorraquídeo , Antibacterianos/administración & dosificación , Antibacterianos/sangre , Anciano , Adulto , Infusiones Intravenosas

RESUMEN

The AIDA randomized clinical trial found no significant difference in clinical failure or survival between colistin monotherapy and colistin-meropenem combination therapy in carbapenem-resistant Gram-negative infections. The aim of this reverse translational study was to integrate all individual preclinical and clinical pharmacokinetic-pharmacodynamic (PKPD) data from the AIDA trial in a pharmacometric framework to explore whether individualized predictions of bacterial burden were associated with the trial outcomes. The compiled dataset included for each of the 207 patients was (i) information on the infecting Acinetobacter baumannii isolate (minimum inhibitory concentration, checkerboard assay data, and fitness in a murine model), (ii) colistin plasma concentrations and colistin and meropenem dosing history, and (iii) disease scores and demographics. The individual information was integrated into PKPD models, and the predicted change in bacterial count at 24 h for each patient, as well as patient characteristics, was correlated with clinical outcomes using logistic regression. The in vivo fitness was the most important factor for change in bacterial count. A model-predicted growth at 24 h of ≥2-log10 (164/207) correlated positively with clinical failure (adjusted odds ratio, aOR = 2.01). The aOR for one unit increase of other significant predictors were 1.24 for SOFA score, 1.19 for Charlson comorbidity index, and 1.01 for age. This study exemplifies how preclinical and clinical anti-infective PKPD data can be integrated through pharmacodynamic modeling and identify patient- and pathogen-specific factors related to clinical outcomes - an approach that may improve understanding of study outcomes.

Asunto(s)

Acinetobacter baumannii , Antibacterianos , Meropenem , Pruebas de Sensibilidad Microbiana , Humanos , Acinetobacter baumannii/efectos de los fármacos , Acinetobacter baumannii/aislamiento & purificación , Meropenem/farmacocinética , Meropenem/administración & dosificación , Meropenem/farmacología , Persona de Mediana Edad , Femenino , Masculino , Antibacterianos/farmacocinética , Antibacterianos/administración & dosificación , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Colistina/farmacocinética , Colistina/administración & dosificación , Adulto , Anciano , Animales , Resultado del Tratamiento , Ratones , Infecciones por Acinetobacter/tratamiento farmacológico , Infecciones por Acinetobacter/microbiología , Investigación Biomédica Traslacional , Quimioterapia Combinada/métodos , Modelos Biológicos

RESUMEN

BACKGROUND: Continuous infusion of meropenem has been proposed to increase target attainment in critically ill patients, although stability might limit its practical use. This study investigated the impact of meropenem degradation and infusion bag changes on the concentration-time profiles and bacterial growth and killing of P. aeruginosa given different continuous-infusion solutions. METHODS: A semi-mechanistic pharmacokinetic-pharmacodynamic (PK-PD) model quantifying meropenem concentrations (CMEM) and bacterial counts of a resistant P. aeruginosa strain (ARU552, MIC = 16 mg/L) over 24 h was used to translate in vitro antibiotic effects to patients with severe infections. Concentration-dependent drug degradation of saline infusion solutions was considered using an additional compartment in the population PK model. CMEM, fT>MIC (time that concentrations exceed the MIC) and total bacterial load (BTOT) after 24 h were simulated for different scenarios (n = 144), considering low- and high-dose regimens (3000/6000 mg/day±loading dose), clinically relevant infusion solutions (20/40/50 mg/mL), different intervals of infusion bag changes (every 8/24 h, q8/24 h), and varied renal function (creatinine clearance 40/80/120 mL/min) and MIC values (8/16 mg/L). RESULTS: Highest deviations between changing infusion bags q8h and q24h were observed for 50 mg/mL solutions and scenarios with CMEM_24h close to the MIC, with differences (Δ) in CMEM_24h up to 4.9 mg/L, ΔfT>MIC≤65.7%, and ΔBTOT_24h≤1.1 log10 CFU/mL, thus affecting conclusions on whether bacteriostasis was reached. CONCLUSIONS: In summary, this study indicated that for continuous infusion of meropenem, eight-hourly infusion bag changes improved PK/PD target attainment and might be beneficial particularly for high meropenem concentrations of saline infusion solutions and for plasma concentrations in close proximity to the MIC.

Asunto(s)

Antibacterianos , Meropenem , Pruebas de Sensibilidad Microbiana , Pseudomonas aeruginosa , Meropenem/farmacocinética , Meropenem/farmacología , Meropenem/administración & dosificación , Pseudomonas aeruginosa/efectos de los fármacos , Antibacterianos/farmacocinética , Antibacterianos/farmacología , Antibacterianos/administración & dosificación , Humanos , Infusiones Intravenosas , Infecciones por Pseudomonas/tratamiento farmacológico , Infecciones por Pseudomonas/microbiología , Carga Bacteriana/efectos de los fármacos , Viabilidad Microbiana/efectos de los fármacos , Estabilidad de Medicamentos

RESUMEN

BACKGROUND: The most effective dosing strategy of meropenem for patients undergoing continuous renal replacement therapy (CRRT) remains uncertain. This study aimed to analyze the population pharmacokinetics (popPKs) of unbound meropenem and establish an appropriate dosing approach. METHODS: This prospective study involved 19 patients for the development of a popPK model and an additional 10 for its validation. Ethical approval was obtained. RESULTS: The clearance of unbound meropenem was influenced by the sequential organ failure assessment (SOFA) score [=2.22 × (SOFA score/12)^1.88] and the effluent flow rate from the CRRT device, with an interindividual variability of 44.5%. The volume of distribution was affected by the simplified acute physiology score II [=23.1 × (simplified acute physiology score II/52)^1.54]. Monte Carlo simulations suggested meropenem doses ranging from 1.0 to 3.0 g/d using continuous infusion to achieve a target time above the 4 times of minimum inhibitory concentration of the unbound form (% f T >4×MIC ) of 100% for definitive therapy. For empirical therapy, a dose of 1.0 g/d using continuous infusion was recommended to target % f T >MIC of 100%. CONCLUSIONS: This study developed a popPK model for unbound meropenem in patients undergoing CRRT and formulated dosing guidelines. CLINICAL TRIAL REGISTRATION: UMIN000024321.

Asunto(s)

Antibacterianos , Terapia de Reemplazo Renal Continuo , Meropenem , Modelos Biológicos , Humanos , Meropenem/farmacocinética , Terapia de Reemplazo Renal Continuo/métodos , Masculino , Femenino , Anciano , Persona de Mediana Edad , Estudios Prospectivos , Antibacterianos/farmacocinética , Método de Montecarlo , Estudios de Cohortes , Anciano de 80 o más Años , Pruebas de Sensibilidad Microbiana , Adulto

RESUMEN

This study aimed to explore the changes of pharmacokinetic parameters after meropenem in patients with abdominal septic shock after gastrointestinal perforation, and to simulate the probability of different dosing regimens achieving different pharmacodynamic goals. The study included 12 patients, and utilized high performance liquid chromatography-tandem mass spectrometry to monitor the plasma concentration of meropenem. The probability of target attainment (PTA) for different minimum inhibitory concentration (MIC) values and %fT > 4MIC was compared among simulated dosing regimens. The results showed that in 96 blood samples from 12 patients, the clearance (CL) of meropenem in the normal and abnormal creatinine clearance subgroups were 7.7 ± 1.8 and 4.4 ± 1.1 L/h, respectively, and the apparent volume of distribution (Vd) was 22.6 ± 5.1 and 17.2 ± 5.8 L, respectively. 2. Regardless of the subgroup, 0.5 g/q6h infusion over 6 h regimen achieved a PTA > 90% when MIC ≤ 0.5 mg/L. 1.0 g/q6h infusion regimen compared with other regimen, in most cases, the probability of making PTA > 90% is higher. For patients at low MIC, 0.5 g/q6h infusion over 6 h may be preferable. For patients at high MIC, a dose regimen of 1.0 g/q6 h infusion over 6 h may be preferable. Further research is needed to confirm this exploratory result.

Asunto(s)

Antibacterianos , Meropenem , Pruebas de Sensibilidad Microbiana , Choque Séptico , Humanos , Meropenem/farmacocinética , Meropenem/administración & dosificación , Meropenem/uso terapéutico , Choque Séptico/tratamiento farmacológico , Masculino , Femenino , Persona de Mediana Edad , Anciano , Estudios Prospectivos , Antibacterianos/farmacocinética , Antibacterianos/administración & dosificación , Antibacterianos/uso terapéutico , Adulto , Perforación Intestinal , Anciano de 80 o más Años

RESUMEN

Numerous studies have suggested that intra-articular administration of antibiotics following primary revision surgery may be one of the methods for treating prosthetic joint infection (PJI). Vancomycin and meropenem are the two most commonly used antibiotics for local application. Determining the concentrations of vancomycin and meropenem in the serum and synovial fluid of patients with PJI plays a significant role in further optimizing local medication schemes and effectively eradicating biofilm infections. This study aimed to establish a rapid, sensitive, and accurate ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for determining the concentrations of vancomycin and meropenem in human serum and synovial fluid. Serum samples were processed using acetonitrile precipitation of proteins and dichloromethane extraction, while synovial fluid samples were diluted before analysis. Chromatographic separation was achieved in 6 min on a Waters Acquity UPLC BEH C18 column, with the mobile phase consisting of 0.1% formic acid in water (solvent A) and acetonitrile (solvent B). Quantification was carried out using a Waters XEVO TQD triple quadrupole mass spectrometer with an electrospray ionization (ESI) source in positive ion mode. The multiple reaction monitoring (MRM) mode was employed to detect the following quantifier ion transitions: 717.95-99.97 (norvancomycin), 725.90-100.04 (vancomycin), 384.16-67.99 (meropenem). The method validation conformed to the guidelines of the FDA and the Chinese Pharmacopoeia. The method demonstrated good linearity within the range of 0.5-50 µg/ml for serum and 0.5-100 µg/ml for synovial fluid. Selectivity, intra-day and inter-day precision and accuracy, extraction recovery, matrix effect, and stability validation results all met the required standards. This method has been successfully applied in the pharmacokinetic/pharmacodynamic (PK/PD) studies of patients with PJI.

Asunto(s)

Antibacterianos , Meropenem , Infecciones Relacionadas con Prótesis , Líquido Sinovial , Espectrometría de Masas en Tándem , Vancomicina , Humanos , Espectrometría de Masas en Tándem/métodos , Vancomicina/sangre , Vancomicina/análisis , Vancomicina/farmacocinética , Líquido Sinovial/química , Meropenem/análisis , Meropenem/sangre , Meropenem/farmacocinética , Cromatografía Líquida de Alta Presión/métodos , Infecciones Relacionadas con Prótesis/tratamiento farmacológico , Infecciones Relacionadas con Prótesis/sangre , Antibacterianos/sangre , Antibacterianos/análisis , Antibacterianos/farmacocinética , Antibacterianos/uso terapéutico , Reproducibilidad de los Resultados , Masculino , Límite de Detección , Persona de Mediana Edad , Cromatografía Líquida con Espectrometría de Masas

RESUMEN

OBJECTIVE: The timing and dosing of antimicrobial therapy are key in the treatment of pneumonia in critically ill patients. It is uncertain whether the presence of lung inflammation and injury affects tissue penetration of intravenously administered antimicrobial drugs. The effects of lung inflammation and injury on tissue penetration of two antimicrobial drugs commonly used for pneumonia were determined in an established model of unilateral lung injury. METHODS: Unilateral lung injury was induced in the left lung of 13 healthy pigs through cyclic rinsing; the right healthy lung served as control. Infusions of meropenem and vancomycin were administered and concentrations of these drugs in lung tissue, blood, and epithelial lining fluid (ELF) were compared over a period of 6 h. RESULTS: Median vancomycin lung tissue concentrations and penetration ratio were higher in inflamed and injured lungs compared with uninflamed and uninjured lungs (AUC0-6h: P = 0.003 and AUCdialysate/AUCplasma ratio: P = 0.003), resulting in higher AUC0-24/MIC. Median meropenem lung tissue concentrations and penetration ratio in inflamed and injured lungs did not differ from that in uninflamed and uninjured lungs (AUC0-6: P = 0.094 and AUCdialysate/AUCplasma ratio: P = 0.173). The penetration ratio for both vancomycin and meropenem into ELF was similar in injured and uninjured lungs. CONCLUSION: Vancomycin penetration into lung tissue is enhanced by acute inflammation and injury, a phenomenon barely evident with meropenem. Therefore, inflammation in lung tissue influences the penetration into interstitial lung tissue, depending on the chosen antimicrobial drug. Measurement of ELF levels alone might not identify the impact of inflammation and injury.

Asunto(s)

Antibacterianos , Modelos Animales de Enfermedad , Lesión Pulmonar , Pulmón , Meropenem , Vancomicina , Animales , Meropenem/farmacocinética , Meropenem/administración & dosificación , Vancomicina/farmacocinética , Vancomicina/administración & dosificación , Porcinos , Antibacterianos/farmacocinética , Antibacterianos/administración & dosificación , Pulmón/metabolismo , Lesión Pulmonar/tratamiento farmacológico , Neumonía/tratamiento farmacológico , Femenino , Pruebas de Sensibilidad Microbiana

RESUMEN

INTRODUCTION: Antibiotic concentration target attainment is known to be poor in critically ill patients. Dose adjustment is recommended in patients with altered clearance, obesity and those with bacterial species with intermediate susceptibility. The aim of this study was to investigate the variation of antibiotic concentration in critically ill patients with standard or adjusted dosing regimens. METHODS: The concentration of three beta-lactam antibiotics used in the intensive care unit (ICU) setting, cefotaxime, piperacillin/tazobactam, and meropenem, was measured in patients with confirmed or suspected infection. Mid-dose and trough values were collected during a single dosing interval. The pharmacokinetic endpoints were a free antibiotic concentration that, during the whole dosing interval, was above MIC (100% ƒT > MIC, primary endpoint) or above four times MIC (100% ƒT > 4MIC, secondary endpoint). Non-species related MIC breakpoints were used (1 mg/L for cefotaxime, 8 mg/L for piperacillin/tazobactam, and 2 mg/L for meropenem). RESULTS: We included 102 patients (38 cefotaxime, 30 piperacillin/tazobactam, and 34 meropenem) at a single ICU, with a median age of 66 years. In total, 73% were males, 40% were obese (BMI ≥30) and the median SAPS 3 score was 63 points. Of all patients, 78 patients (76%) reached the primary endpoint (100%ƒT > MIC), with 74% for cefotaxime, 67% for piperacillin/tazobactam and 88% for meropenem. Target attainment for 100% ƒT > 4MIC was achieved in 40 (39%) patients, overall, with 34% for cefotaxime, 30% for piperacillin/tazobactam and 53% for meropenem. In patients with standard dose 71% attained 100%ƒT > MIC and 37% for 100%ƒT > 4MIC. All patients with reduced dose attained 100%ƒT > MIC and 27% attained 100% ƒT > 4MIC. In patients with increased dose 79% attained 100%ƒT > MIC and 48% 100%ƒT > 4MIC respectively. CONCLUSIONS: Beta-lactam antibiotics concentration vary widely in critically ill patients. The current standard dosing regimens employed during the study were not sufficient to reach 100% ƒT > MIC in approximately a quarter of the patients. In patients where dose adjustment was performed, the group with increased dose also had low target attainment, as opposed to patients with dose reduction, who all reached target. This suggests the need for further individualization of dosing where therapeutic drug monitoring can be an alternative to further increase target attainment.

Asunto(s)

Enfermedad Crítica , Piperacilina , Masculino , Humanos , Anciano , Femenino , Meropenem/farmacocinética , Piperacilina/farmacocinética , Enfermedad Crítica/terapia , Antibacterianos/uso terapéutico , Combinación Piperacilina y Tazobactam , Monobactamas , Cefotaxima , Antibióticos Betalactámicos

RESUMEN

BACKGROUND: Ex situ normothermic liver perfusion (NMP) in a blood-based perfusate is associated with a risk of microbe growth, resulting in life-threatening posttransplant sepsis. Antibiotics are widely used, but the pharmacokinetics of these agents are unknown as is their efficacy. We wished to assess the perfusate concentrations of the meropenem and fluconazole that we use and to audit the incidence of infection with this antimicrobial therapy. METHODS: Fluconazole and meropenem (100 mg each) were added to the perfusate before NMP began, and serial samples were taken and assayed for drug concentrations. Perfusate cultures were available from 210 of the 242 perfusions performed between February 1, 2018, and April 6, 2023; these were reviewed. RESULTS: Following administration of 100 mg fluconazole, levels fell slightly from a median of 24.9 mg/L at 1 h to 22.6 mg/L at 10 h. In contrast, meropenem concentrations fell over time, from a median of 21.8 mg/L at 1 h to 9.4 mg/L at 10 h. There were 4 significant microorganisms grown in the perfusions, including 3 Candida species and an Enterococcus faecium . All the Candida -infected livers were transplanted with no adverse consequences, the recipients being treated with anidulafungin upon identification of the infecting organism; the Enterococcus -infected liver was not transplanted. CONCLUSIONS: Serious infection is a risk with NMP but appears to be mitigated with a protocol combining fluconazole and meropenem. This combination may not be appropriate in areas where resistance is prevalent. Routine culture of NMP perfusate is essential to identify breakthrough organisms early and enable recipient treatment.

Asunto(s)

Fluconazol , Trasplante de Hígado , Meropenem , Perfusión , Humanos , Meropenem/farmacocinética , Meropenem/administración & dosificación , Trasplante de Hígado/efectos adversos , Fluconazol/farmacocinética , Fluconazol/administración & dosificación , Incidencia , Masculino , Femenino , Persona de Mediana Edad , Antibacterianos/farmacocinética , Antibacterianos/administración & dosificación , Antifúngicos/farmacocinética , Antifúngicos/administración & dosificación , Antifúngicos/uso terapéutico , Preservación de Órganos/métodos , Profilaxis Antibiótica/métodos , Estudios Retrospectivos , Hígado/metabolismo , Hígado/microbiología , Hígado/efectos de los fármacos , Candidiasis/epidemiología , Candidiasis/prevención & control , Candidiasis/tratamiento farmacológico , Candidiasis/diagnóstico

RESUMEN

BACKGROUND: Meropenem is a widely used carbapenem for treating severe pediatric infections. However, few studies have assessed its pharmacokinetics/pharmacodynamics (PK/PD) in pediatric patients. This study aimed to evaluate the proportion of Saudi pediatric patients achieving the PK/PD target of meropenem. METHODS: A prospective observational study was conducted at King Saud University Medical City from July to September 2022. Pediatric patients receiving meropenem for suspected or proven infections were included in the study. The primary outcome was the percentage of patients achieving the recommended PK/PD target for critically ill or non-critically ill pediatric patients. RESULTS: The study included 30 patients (nine neonates and 21 older pediatric patients). All neonates were critically ill. Among them, 55 % achieved the PK/PD target of 100 % free time above the MIC. In older ICU pediatric patients, only 11 % attained this target, whereas 58 % of older pediatrics in the general wards achieved the PK/PD target of 50 % free time above the MIC. Augmented renal clearance (ARC) was identified in 57 % of our pediatric patient population, none of whom achieved the recommended PK/PD targets. The median trough concentrations in patients with and without ARC were 0.75 and 1.3 µg/mL, respectively (P < 0.05). CONCLUSIONS: The majority of patients in our cohort did not achieve the PK/PD target for meropenem. ARC emerged as a major risk factor for target attainment failure in both critically ill and non-critically ill pediatric patients.

Asunto(s)

Antibacterianos , Meropenem , Humanos , Meropenem/farmacocinética , Meropenem/administración & dosificación , Lactante , Antibacterianos/farmacocinética , Antibacterianos/administración & dosificación , Masculino , Preescolar , Estudios Prospectivos , Femenino , Niño , Recién Nacido , Pruebas de Sensibilidad Microbiana , Enfermedad Crítica , Adolescente , Arabia Saudita

RESUMEN

BACKGROUND: Several studies report lack of meropenem pharmacokinetic/pharmacodynamic (PK/PD) target attainment (TA) and risk of therapeutic failure with intermittent bolus infusions in intensive care unit (ICU) patients. The aim of this study was to describe meropenem TA in an ICU population and the clinical response in the first 72 h after therapy initiation. METHODS: A prospective observational study of ICU patients ≥18 years was conducted from 2014 to 2017. Patients with normal renal clearance (NRC) and augmented renal clearance (ARC) and patients on continuous renal replacement therapy (CRRT) were included. Meropenem was administered as intermittent bolus infusions, mainly at a dose of 1 g q6h. Peak, mid, and trough levels were sampled at 24, 48, and 72 h after therapy initiation. TA was defined as 100% T > 4× MIC or trough concentration above 4× MIC. Meropenem PK was estimated using traditional calculation methods and population pharmacokinetic modeling (P-metrics®). Clinical response was evaluated by change in C-reactive protein (CRP), Sequential Organ Failure Assessment (SOFA) score, leukocyte count, and defervescence. RESULTS: Eighty-seven patients were included, with a median Simplified Acute Physiology (SAPS) II score 37 and 90 days mortality rate of 32%. Median TA was 100% for all groups except for the ARC group with 45.5%. Median CRP fell from 175 (interquartile range [IQR], 88-257) to 70 (IQR, 30-114) (p < .001) in the total population. A reduction in SOFA score was observed only in the non-CRRT groups (p < .001). CONCLUSION: Intermittent meropenem bolus infusion q6h gives satisfactory TA in an ICU population with variable renal function and CRRT modality, except for ARC patients. No consistent relationship between TA and clinical endpoints were observed.

Asunto(s)

Antibacterianos , Enfermedad Crítica , Humanos , Meropenem/farmacocinética , Antibacterianos/uso terapéutico , Enfermedad Crítica/terapia , Cuidados Críticos , Unidades de Cuidados Intensivos

RESUMEN

BACKGROUND: Meropenem is frequently used to treat severe infections in critically ill children. However, pharmacokinetic data on meropenem in children with end-stage renal disease (ESRD) undergoing prolonged intermittent renal replacement therapy (PIRRT) is limited. Our objectives were to evaluate meropenem clearance in a child with ESRD with and without PIRRT, compare the results to previous continuous renal replacement therapy studies in children, toddlers and neonates, and assess whether the currently used dose of meropenem is sufficient. CASE DESCRIPTION: A 5-year-old girl with an estimated glomerular filtration rate of 12.8 mL/min/1.73 m 2 was diagnosed with pulmonary infection and treated with 300 mg meropenem once a day. PIRRT was performed for 8 hours every 2 days. We used WinNonlin to evaluate meropenem clearance with and without PIRRT. RESULTS: Our case showed that PIRRT increased the clearance of meropenem from 1.39 (1.3) to 2.42 L/h (2.3 mL/kg/min) and caught up 42.6% of the total clearance. This result is in accordance with previous studies in children but slightly less than seen in toddlers and neonates under continuous renal replacement therapy. The current dose of 300 mg once a day is not sufficient to reach the therapeutic target. CONCLUSIONS: Predicting meropenem clearance in children with ESRD undergoing PIRRT is difficult as clearance will be affected by renal function, PIRRT settings and other factors. Further studies are needed to explore the individual variability of meropenem clearance and optimize the dosing regimen.

Asunto(s)

Terapia de Reemplazo Renal Intermitente , Fallo Renal Crónico , Meropenem , Preescolar , Femenino , Humanos , Antibacterianos/farmacocinética , Terapia de Reemplazo Renal Continuo , Enfermedad Crítica/terapia , Terapia de Reemplazo Renal Intermitente/métodos , Fallo Renal Crónico/terapia , Fallo Renal Crónico/tratamiento farmacológico , Meropenem/farmacocinética , Vías de Eliminación de Fármacos

RESUMEN

The altered pharmacokinetics of renally cleared drugs such as meropenem in critically ill patients receiving continuous renal replacement therapy (CRRT) might impact target attainment. Model-informed precision dosing (MIPD) is applied to individualize meropenem dosing. However, most population pharmacokinetic (PopPK) models developed to date have not yet been evaluated for MIPD. Eight PopPK models based on adult CRRT patients were identified in a systematic literature research and encoded in NONMEM 7.4. A data set of 73 CRRT patients from two different study centers was used to evaluate the predictive performance of the models using simulation and prediction-based diagnostics for i) a priori dosing based on patient characteristics only and ii) Bayesian dosing by including the first measured trough concentration. Median prediction error (MPE) for accuracy within |20%| (95% confidence intervals including zero) and median absolute prediction error (MAPE) for precision ≤ 30% were considered clinically acceptable. For a priori dosing, most models (n = 5) showed accuracy and precision MPE within |20%| and MAPE <35%. The integration of the first measured meropenem concentration improved the predictive performance of all models (median MAPE decreased from 35.4 to 25.0%; median MPE decreased from 21.8 to 4.6%). The best predictive performance for intermittent infusion was observed for the O'Jeanson model, including residual diuresis as covariate (a priori and Bayesian dosing MPE within |2%|, MAPE <30%). Our study revealed the O'Jeanson model as the best-predicting model for intermittent infusion. However, most of the selected PopPK models are suitable for MIPD in CRRT patients when one therapeutic drug monitoring sample is available.

Asunto(s)

Antibacterianos , Terapia de Reemplazo Renal Continuo , Adulto , Humanos , Meropenem/farmacocinética , Antibacterianos/farmacocinética , Enfermedad Crítica , Teorema de Bayes , Terapia de Reemplazo Renal

RESUMEN

Critically ill patients undergoing continuous renal replacement therapy (CRRT) have medical conditions requiring extensive pharmacotherapy. Continuous renal replacement therapy impacts drug disposition. Few data exist regarding drug dosing requirements with contemporary CRRT modalities and effluent rates. The practical limitations of pharmacokinetic studies requiring numerous plasma and effluent samples, and lack of generalizability of observations from specific CRRT prescriptions, highlight gaps in bedside assessment of CRRT drug elimination and individualized dosing needs. We employed a porcine model using transdermal fluorescence detection of the glomerular filtration rate fluorescent tracer agent MB-102, with the aim to assess the relationship between systemic exposure of MB-102 and meropenem during CRRT. Animals underwent bilateral nephrectomies and received intravenous bolus doses of MB-102 and meropenem. Once MB-102 equilibrated in the animal, CRRT was initiated. Continuous renal replacement therapy prescriptions comprised four combinations of blood pump (low versus high) and effluent (low versus high) flow rates. Changes in transdermal detected MB-102 clearance occurred immediately with a change in CRRT rates. Blood side meropenem clearance mirrored transdermal MB-102 clearance ( r2 : 0.95-0.97, p value all <0.001). We suggest transdermal MB-102 clearance provides real-time personalized assessment of drug elimination and could optimize prescription of drugs for critically ill patients requiring CRRT.

Asunto(s)

Antibacterianos , Terapia de Reemplazo Renal Continuo , Animales , Porcinos , Meropenem/farmacocinética , Antibacterianos/farmacocinética , Enfermedad Crítica , Terapia de Reemplazo Renal/métodos

RESUMEN

In the present study, population pharmacokinetic (PK) analysis was performed based on meropenem data from a prospective study conducted in 114 critically ill patients with a wide range of renal functions and various disease conditions. The final model was a one-compartment model with linear elimination, with creatinine clearance and continuous renal replacement therapy affecting clearance, and total bodyweight impacting the volume of distribution. Our model is a valuable addition to the existing meropenem population PK models, and it could be particularly useful during implementation of a therapeutic drug monitoring program combined with Bayesian forecasting. Based on the final model developed, comprehensive Monte Carlo simulations were performed to evaluate the probability of target attainment (PTA) of 16 different dosing regimens. Simulation results showed that 2 g administered every 8 h with 3-h prolonged infusion (PI) and 4 g/day by continuous infusion (CI) appear to be two empirical dosing regimens that are superior to many other regimens when both target attainment and potential toxicity are considered and renal function information is not available. Following a daily CI dose of 6 g or higher, more than 30% of the population with a creatinine clearance of <60 mL/min is predicted to have neurotoxicity. With the availability of institution- and/or unit-specific meropenem susceptibility patterns, as well as an individual patient's renal function, our PTA results may represent useful references for physicians to make dosing decisions.

Asunto(s)

Antibacterianos , Unidades de Cuidados Intensivos , Humanos , Meropenem/farmacocinética , Antibacterianos/farmacocinética , Estudios Prospectivos , Creatinina , Teorema de Bayes , Enfermedad Crítica/terapia , Método de Montecarlo , Pruebas de Sensibilidad Microbiana