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Aim: Pharmacokinetic studies in children are limited, in part due to challenges in blood sampling. We compare the use of capillary microsampling and conventional sampling techniques in pediatric patients to show results that can be used in the pharmacokinetic analysis of Cefazolin. Patients & Methods: Paired blood samples (n = 48) were collected from 12 patients (median age/weight 49 months/18 kg). Results: The United States Federal Drug Administration incurred sample reanalysis acceptance criteria was used and identified 79% of paired samples achieved a difference of less than 20% in magnitude with a capillary microsampling bias of -10% (SD 20%). With exclusion of PK outliers, this rose to 88%. Conclusion: Capillary microsampling is reliable, meets acceptance criteria and can be used in pharmacokinetic studies.ACTRN: 12618001469202.
What is this article about? This study assesses a novel method of blood sample collection (capillary microsampling) for the analysis of a common antibiotic, cefazolin. In this study, we compare the results from samples collected using this method to blood tests taken in the traditional way.Capillary microsampling collects a very small volume of blood (about a drop of blood or 0.05 ml) taken from a skin prick and collected in a capillary tube. Traditional blood sampling collects a larger volume of blood (typically from 1 to 3 ml) taken from an artery or a vein. In this study, the patients (10 male and 2 female) had a mean age of 49 months and a mean weight of 18 kg. The amount of cefazolin in the blood samples were analyzed using the same methodology and results compared with assess the variability and reliability of the capillary microsampling method.What were the results? The results showed that difference of the two sample types is within the accepted criteria of the United States Federal Drug Administration and the European Medicines Agency, meaning the results are reliable.What do the results of the study mean? Blood samples for cefazolin can be small and easily obtained from a skin prick as a capillary microsample and can give reliable results. This greatly aids the ability to study the metabolism of cefazolin in children, particularly those that are not able to give a large amount of blood.
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BACKGROUND: This study describes the population pharmacokinetics of cefoxitin in obese patients undergoing elective bariatric surgery and evaluates different dosing regimens for achievement of pre-defined target exposures. METHODS: Serial blood samples were collected during surgery with relevant clinical data. Total serum cefoxitin concentrations were measured by chromatographic assay and analysed using a population PK approach with Pmetrics®. The cefoxitin unbound fraction (fu) was estimated. Dosing simulations were performed to ascertain the probability of target attainment (PTA) to achieve cefoxitin fu above minimum inhibitory concentrations (MIC) from surgical incision to wound closure. Fractional target attainment (FTA) was calculated against MIC distributions of common pathogens. RESULTS: A total of 123 obese patients (median BMI 44.3 kg/m2) were included with 381 cefoxitin concentration values. Cefoxitin was best described by a one-compartment model, with a mean clearance and volume of distribution of 10.9 ± 6.1 L/h and 23.4 ± 10.5 L, respectively. In surgery <2 h, a 2 and a 4 g doses were sufficient for an MIC up to 4 and 8 mg/L (fu 50%), respectively. In prolonged surgery (2-4 h), only continuous infusion enabled optimal PTA for an MIC up to 16 mg/L. Optimal FTAs were obtained against Staphylococcus aureus and Escherichia Coli only when simulating with 50% cefoxitin protein binding (intermittent regimen) and regardless of the protein binding for the continuous infusion. CONCLUSION: Intermittent dosing regimens resulted in optimal FTAs against susceptible MIC distributions of S. aureus and E. coli when simulating with 50% cefoxitin protein binding. Continuous infusion of cefoxitin may improve FTA regardless of protein binding. STUDY REGISTRATION: Registration on ClinicalTrials.gov, NCT03306290.
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Antibacterianos , Profilaxis Antibiótica , Cirugía Bariátrica , Cefoxitina , Procedimientos Quirúrgicos Electivos , Pruebas de Sensibilidad Microbiana , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Antibacterianos/farmacocinética , Antibacterianos/administración & dosificación , Profilaxis Antibiótica/métodos , Cefoxitina/farmacocinética , Cefoxitina/administración & dosificación , Obesidad/cirugía , Estudios Prospectivos , Infección de la Herida Quirúrgica/prevención & controlRESUMEN
BACKGROUND: Cerebral ventriculitis might be caused by Gram-negative bacteria, including ESBL producers. Temocillin may be a useful treatment option in this scenario; however, no consistent data are available regarding its penetration into the CSF. OBJECTIVES: To describe the population pharmacokinetics of temocillin in plasma and CSF and to determine the probability for different simulated dosing regimens to achieve pharmacokinetic/pharmacodynamic (PK/PD) targets in the CSF. METHODS: Ten post-neurosurgical critically ill adult patients requiring continuous drainage of CSF were included in this monocentric, prospective, open-label, non-randomized study. They received 2 g loading dose temocillin over 30 min IV infusion, followed by a 6 g continuous infusion over 24 h. Total and unbound concentrations were measured in plasma (n = 88 and 86) and CSF (n = 88 and 88) samples and used to build a population PK model. Monte Carlo simulations were performed to estimate the PTA at 100% Css>MIC (steady state concentration above the MIC) in CSF. RESULTS: All patients were infected with Enterobacterales with temocillin MICs ≤8 mg/L. The median (min-max) temocillin penetration in CSF was 12.1% (4.3-25.5) at steady state. Temocillin unbound plasma pharmacokinetics were best described by a one-compartment model. PTA for the applied dosing regimen was >90% for bacteria with MIC ≤ 4 mg/L. CONCLUSIONS: The currently approved dose of 6 g by continuous infusion may be adequate for the treatment of ventriculitis by Enterobacterales with MIC ≤ 4 mg/L if considering 100% Css>MIC as the PK/PD target to reach. Higher maintenance doses could help covering higher MICs, but their safety would need to be assessed.
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Antibacterianos , Ventriculitis Cerebral , Penicilinas , Adulto , Humanos , Ventriculitis Cerebral/tratamiento farmacológico , Estudios Prospectivos , Drenaje , Pruebas de Sensibilidad Microbiana , Enfermedad Crítica , Método de MontecarloRESUMEN
OBJECTIVES: To describe the total and unbound population pharmacokinetics of a 2 g three-times-weekly post-dialysis ceftriaxone regimen in Indigenous Australian patients requiring hemodialysis. METHODS: A pharmacokinetic study was carried out in the dialysis unit of a remote Australian hospital. Adult Indigenous patients on intermittent hemodialysis (using a high-flux dialyzer) and treated with a 2 g three-times-weekly ceftriaxone regimen were recruited. Plasma samples were serially collected over two dosing intervals and assayed using validated methodology. Population pharmacokinetic analysis and Monte Carlo simulations were performed using Pmetrics in R. The probability of pharmacokinetic/pharmacodynamic target attainment (unbound trough concentrations ≥1 mg/L) and toxicity [trough concentrations (total) â≥100 mg/L] were simulated for various dosing strategies. RESULTS: Total and unbound concentrations were measured in 122 plasma samples collected from 16 patients (13 female) with median age 57 years. A two-compartment model including protein-binding adequately described the data, with serum bilirubin concentrations associated (inversely) with ceftriaxone clearance. The 2 g three-times-weekly regimen achieved 98% probability to maintain unbound ceftriaxone concentrations ≥1 mg/L for a serum bilirubin of 5 µmol/L. Incremental accumulation of ceftriaxone was observed in those with bilirubin concentrations >5 µmol/L. Three-times-weekly regimens were less probable to achieve toxic exposures compared with once-daily regimens. Ceftriaxone clearance was increased by >10-fold during dialysis. CONCLUSIONS: A novel 2 g three-times-weekly post-dialysis ceftriaxone regimen can be recommended for a bacterial infection with an MIC ≤1 mg/L. A 1 g three-times-weekly post-dialysis regimen is recommended for those with serum bilirubin ≥10 µmol/L. Administration of ceftriaxone during dialysis is not recommended.
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Antibacterianos , Ceftriaxona , Adulto , Humanos , Femenino , Persona de Mediana Edad , Ceftriaxona/farmacocinética , Aborigenas Australianos e Isleños del Estrecho de Torres , Australia , Diálisis Renal , Bilirrubina , Método de Montecarlo , Enfermedad Crítica , Pruebas de Sensibilidad MicrobianaRESUMEN
BACKGROUND: Patients with tuberculosis (TB) may develop multi-organ failure and require admission to intensive care. In these cases, the mortality rates are as high as 78% and may be caused by suboptimal serum concentrations of first-line TB drugs. This study aims to compare the pharmacokinetics of oral rifampin, isoniazid, pyrazinamide and ethambutol patients in intensive care units (ICU) to outpatients and to evaluate drug serum concentrations as a potential cause of mortality. METHODS: A prospective pharmacokinetic (PK) study was performed in Amazonas State, Brazil. The primary PK parameters of outpatients who achieved clinical and microbiological cure were used as a comparative target in a non-compartmental analysis. RESULTS: Thirteen ICU and twenty outpatients were recruited. The clearance and volume of distribution were lower for rifampin, isoniazid, pyrazinamide and ethambutol. ICU thirty-day mortality was 77% versus a cure rate of 89% in outpatients. CONCLUSIONS: ICU patients had a lower clearance and volume of distribution for rifampin, isoniazid, pyrazinamide and ethambutol compared to the outpatient group. These may reflect changes to organ function, impeded absorption and distribution to the site of infection in ICU patients and have the potential to impact clinical outcomes.
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Aim: To describe the stability of nafamostat in infusion solutions, during blood sample collection and in extracted plasma samples in the autosampler. Methods: Nafamostat infusion solutions were stored at room temperature in the light for 24 h. For sample collection stability, fresh blood spiked with nafamostat was subjected to combinations of anticoagulants, added esterase inhibitor and temperature. Nafamostat was monitored in the extracted plasma samples in the autosampler. Results: Nafamostat was stable in infusion solutions. Nafamostat in whole blood was stable for 3 h before centrifugation when collected in sodium fluoride/potassium oxalate tubes (4°C). Nafamostat in extracted plasma samples degraded at 4.7 ± 0.7% per h. Conclusion: Viable samples can be obtained using blood collection tubes with sodium fluoride, chilling and processing promptly.
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Anticoagulantes , Fluoruro de Sodio , Humanos , Infusiones Intravenosas , Anticoagulantes/farmacología , Temperatura , Resultado del TratamientoRESUMEN
Background: Levetiracetam is an antiepileptic drug used to prevent or treat seizure in patients with severe traumatic brain injury. This study aimed to develop and validate methodology suitable for measuring levetiracetam concentrations in human plasma and urine. Methods: Plasma or urine (10 µl) samples were spiked with [2H6]-levetiracetam and processed using an acetonitrile precipitation. ESI-LC-MS/MS was employed for analyte detection. Results: The levetiracetam calibration was linear from 0.1 to 50 mg/l in a combined matrix of plasma and urine. Intra- and inter-assay imprecision and accuracy in plasma were <7.7 and 109%, and in urine were <7.9 and 108%, respectively. Conclusion: The validated method was applied to a pharmacokinetic study of levetiracetam in critically ill patients with severe traumatic brain injury.
Levetiracetam is a drug that is used for the prevention or treatment of seizure. This study aimed to design a method that would be suitable for measuring levetiracetam in human plasma and urine. The method was subsequently applied to a clinical study of patients with severe traumatic brain injury.
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Lesiones Traumáticas del Encéfalo , Espectrometría de Masas en Tándem , Humanos , Levetiracetam , Cromatografía Liquida/métodos , Espectrometría de Masas en Tándem/métodos , Anticonvulsivantes/uso terapéutico , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Reproducibilidad de los Resultados , Cromatografía Líquida de Alta Presión/métodosRESUMEN
Rationale & Objective: Kidney transplant recipients require frequent venipunctures. Microsampling methods that use a finger-prick draw of capillary blood, like volumetric absorptive microsamplers (VAMS), have the potential to reduce the pain, inconvenience, and volume of blood loss associated with venipuncture. This study aimed to provide diagnostic accuracy using VAMS for measurement of tacrolimus and creatinine compared to gold standard venous blood in adult kidney transplant recipients. Study Design: Diagnostic test study. Prospective blood samples for measurement of tacrolimus and creatinine were collected using Mitra VAMS and venipuncture immediately before and 2 hours after tacrolimus dosing. Setting & Participants: A convenience sample of 40 adult kidney transplant participants in the outpatient setting. Tests Compared: Method comparison was assessed by Passing-Bablok regression and Bland-Altman analysis. The predictive performance of VAMS measurement compared to venipuncture was also assessed through estimation of the median prediction error and median absolute percentage prediction error. Results: A total of 74 tacrolimus samples and 70 creatinine samples were analyzed from 40 participants. Passing-Bablok regression showed a systematic difference between VAMS and venipuncture when measuring tacrolimus and creatinine with a slope of 1.08 (95% CI, 1.03-1.13) and a slope of 0.65 (95% CI, 0.6-0.7), respectively. These values were then corrected for the systematic difference. When used for Bland-Altman analysis, corrected values of tacrolimus and creatinine showed a bias of -0.1 µg/L and 0.04 mg/dL, respectively. Tacrolimus (corrected) and creatinine (corrected) microsampling values when compared to corresponding venipuncture values met median prediction error and median absolute percentage prediction error predefined acceptability limits of <15%. Limitations: This study was conducted in a controlled environment using a trained nurse to collect VAMS samples. Conclusions: In this study, VAMS was used to reliably measured tacrolimus and creatinine. This represents a clear opportunity for more frequent and less invasive sampling for patients.
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OBJECTIVE: To test the feasibility of conducting a randomised controlled trial to evaluate the impact of a closed-loop blood sampling system and blood conservation bundle. METHODS: Single site, parallel group, pilot randomised control trial comparing open system sampling to closed system sampling and conservation bundle aligned with national guidelines. Randomisation sequence was generated by an independent statistician and allocation concealment maintained via sealed opaque envelopes. The study setting was the general intensive care unit of a major metropolitan public hospital in Queensland, Australia. Participants were ≥ 18 years who had an arterial catheter inserted in intensive care. Main outcome measures included trial feasibility, blood sample loss, haematocrit (HCT) change, and packed red blood cell transfusion use. RESULTS: Eighty patients were randomised (n = 39 open group, n = 41 closed group). Characteristics in each group were equal at baseline with overall median age 60 years (IQR 48.6-70.4), 58 % male, and median APACHE II score 16 (IQR 11-22). The proportion of patients eligible was 29 % and missed eligible was 65 %. Otherwise, feasibility criteria were met with proportion of eligible patients agreeing to enrolment 99 %, 100 % of patients receiving allocated treatment; only 1 % of data missing. Analysis demonstrated a significant reduction in mean daily blood sample losses (open 32.7 (SD 1.58) mL vs closed 15.5 (SD 5.79) mL, t = -8.454, df = 78, p < 0.001). CONCLUSIONS: A large, multi-site trial is feasible with enhanced eligibility criteria, increased recruitment support. The intervention reduced daily blood sample volumes and transfusion use. Further trials are required to provide both effectiveness and implementation outcomes.
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Cuidados Críticos , Unidades de Cuidados Intensivos , Humanos , Masculino , Persona de Mediana Edad , Femenino , Proyectos Piloto , Australia , QueenslandRESUMEN
INTRODUCTION: Neisseria gonorrhoeae infections are common and incidence increasing. Oropharyngeal infections are associated with greater treatment failure compared with other sites and drive transmission to anogenital sites through saliva. Gonococcal resistance is increasing and new treatments are scarce, therefore, clinicians must optimise currently available and emerging treatments in order to have efficacious therapeutic options. This requires pharmacokinetic data from the oral cavity/oropharynx, however, availability of such information is currently limited. METHODS AND ANALYSIS: Healthy male volunteers (participants) recruited into the study will receive single doses of either ceftriaxone 1 g, cefixime 400 mg or ceftriaxone 500 mg plus 2 g azithromycin. Participants will provide samples at 6-8 time points (treatment regimen dependent) from four oral sites, two oral fluids, one anorectal swab and blood. Participants will complete online questionnaires about their medical history, sexual practices and any side effects experienced up to days 5-7. Saliva/oral mucosal pH and oral microbiome analysis will be undertaken. Bioanalysis will be conducted by liquid chromatography-mass spectrometry. Drug concentrations over time will be used to develop mathematical models for optimisation of drug dosing regimens and to estimate pharmacodynamic targets of efficacy. ETHICS AND DISSEMINATION: This study was approved by Royal Melbourne Hospital Human Research Ethics Committee (60370/MH-2021). The study results will be submitted for publication in peer-reviewed journals and reported at conferences. Summary results will be sent to participants requesting them. All data relevant to the study will be included in the article or uploaded as supplementary information. TRIAL REGISTRATION NUMBER: ACTRN12621000339853.
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Gonorrea , Masculino , Humanos , Gonorrea/tratamiento farmacológico , Ceftriaxona/uso terapéutico , Antibacterianos , Cefixima/uso terapéutico , Neisseria gonorrhoeaeRESUMEN
Guidelines for surgical prophylactic dosing of cefazolin in bariatric surgery vary in terms of recommended dose. This study aimed to describe the plasma and interstitial fluid (ISF) cefazolin pharmacokinetics in patients undergoing bariatric surgery and to determine an optimum dosing regimen. Abdominal subcutaneous ISF concentrations (measured using microdialysis) and plasma samples were collected at regular time points after administration of cefazolin 2 g intravenously. Total and unbound cefazolin concentrations were assayed and then modeled using Pmetrics. Monte Carlo dosing simulations (n = 5,000) were used to define cefazolin dosing regimens able to achieve a fractional target attainment (FTA) of >95% in the ISF suitable for the MIC for Staphylococcus aureus in isolates of ≤2 mg · L-1 and for a surgical duration of 4 h. Fourteen patients were included, with a mean (standard deviation [SD]) bodyweight of 148 (35) kg and body mass index (BMI) of 48 kg · m-2. Cefazolin protein binding ranged from 14 to 36% with variable penetration into ISF of 58% ± 56%. Cefazolin was best described as a four-compartment model including nonlinear protein binding. The mean central volume of distribution in the final model was 18.2 (SD 3.31) L, and the mean clearance was 32.4 (SD 20.2) L · h-1. A standard 2-g dose achieved an FTA of >95% for all patients with BMIs ranging from 36 to 69 kg · m-2. A 2-g prophylactic cefazolin dose achieves appropriate unbound plasma and ISF concentrations in obese and morbidly obese bariatric surgery patients.
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Cirugía Bariátrica , Obesidad Mórbida , Antibacterianos , Cefazolina , Líquido Extracelular/metabolismo , Humanos , Obesidad Mórbida/metabolismo , Obesidad Mórbida/cirugíaRESUMEN
OBJECTIVES: To describe the population pharmacokinetics of cefotaxime and desacetylcefotaxime in critically ill paediatric patients and provide dosing recommendations. We also sought to evaluate the use of capillary microsampling to facilitate data-rich blood sampling. METHODS: Patients were recruited into a pharmacokinetic study, with cefotaxime and desacetylcefotaxime concentrations from plasma samples collected at 0, 0.5, 2, 4 and 6â h used to develop a population pharmacokinetic model using Pmetrics. Monte Carlo dosing simulations were tested using a range of estimated glomerular filtration rates (60, 100, 170 and 200â mL/min/1.73â m2) and body weights (4, 10, 15, 20 and 40â kg) to achieve pharmacokinetic/pharmacodynamic (PK/PD) targets, including 100% ƒT>MIC with an MIC breakpoint of 1â mg/L. RESULTS: Thirty-six patients (0.2-12â years) provided 160 conventional samples for inclusion in the model. The pharmacokinetics of cefotaxime and desacetylcefotaxime were best described using one-compartmental model with first-order elimination. The clearance and volume of distribution for cefotaxime were 12.8â L/h and 39.4â L, respectively. The clearance for desacetylcefotaxime was 10.5â L/h. Standard dosing of 50â mg/kg q6h was only able to achieve the PK/PD target of 100% ƒT>MIC in patients >10â kg and with impaired renal function or patients of 40â kg with normal renal function. CONCLUSIONS: Dosing recommendations support the use of extended or continuous infusion to achieve cefotaxime exposure suitable for bacterial killing in critically ill paediatric patients, including those with severe or deep-seated infection. An external validation of capillary microsampling demonstrated skin-prick sampling can facilitate data-rich pharmacokinetic studies.
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Cefotaxima , Enfermedad Crítica , Antibacterianos/farmacología , Bacterias , Cefotaxima/análogos & derivados , Niño , Humanos , Pruebas de Sensibilidad Microbiana , Método de MontecarloRESUMEN
Objectives: This study aimed to develop a piperacillin population PK model for critically ill Brazil-ian patients and describe interethnic variation using an external validation. Methods: Plasma samples were obtained from 24 ICU patients during the fifth day of piperacillin treatment and assayed by HPLC-UV. Population pharmacokinetic modelling was conducted using Pmetrics. Empiric dose of 4 g IV 6- and 8-hourly were simulated for 50 and 100% fT > MIC and the probabil-ity of target attainment (PTA) and the fractional target attainment (FTA) determined. Results: A two-compartment model was designed to describe the pharmacokinetics of critically ill Brazillian patients. Clearance and volume of distribution were (mean ± SD) 3.33 ± 1.24 L h−1 and 10.69 ± 4.50 L, respectively. Creatinine clearance was positively correlated with piperacillin clearance and a high creatinine clearance was associated with lower values of PTA and FTA. An external vali-dation was performed using data from two different ethnic ICU populations (n = 30), resulting in acceptable bias and precision. Conclusion: The primary pharmacokinetic parameters obtained from critically ill Brazilian patients were similar to those observed in studies performed in critically ill patients of other ethnicities. Based on our results, the use of dose adjustment based on creati-nine clearance is required in Brazilian patients.
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Reducing the volume of blood sampled from neonatal or paediatric patients is important to facilitate research in a group that is under-represented in clinical studies. Not all patients have a cannula available for blood sampling, meaning there are real advantages in obtaining a blood microsample by skin prick. In this study, the results obtained from both capillary microsamples (CMS) and a microfluidic (MF)-CMS by skin prick are compared to conventional plasma sampled from an arterial catheter in a clinical bridging study. Six critically ill patients receiving meropenem were included with the incurred sample reanalysis test meeting the acceptance criteria for both CMS (n = 24 samples) and MF-CMS (n = 20 samples). Bland-Altman plots comparing MF-CMS to conventional arterial blood sampling revealed a difference of - 12.7 ± 22.1% (mean ± standard deviation (SD), and comparing CMS to conventional arterial blood sampling a difference of - 3.4 ± 17.0%. At - 12.7%, the bias between MF-CMS and conventional sampling is greater than the bias found with CMS, although within the limit of acceptability for analytical accuracy (that being ± 15%). Samples collected by skin prick and using CMS produced meropenem concentrations that were comparable to those obtained from conventional arterial catheter sampling. CMS samples were found to be stable when stored in the capillary tube for 24 h at 5 °C or for 4 h at room temperature.
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Recolección de Muestras de Sangre , Manejo de Especímenes , Recolección de Muestras de Sangre/métodos , Niño , Humanos , Recién Nacido , Meropenem , PlasmaAsunto(s)
Antibacterianos/análisis , Antibacterianos/uso terapéutico , Monitoreo de Drogas/normas , Gentamicinas/análisis , Gentamicinas/uso terapéutico , Tamizaje Masivo/normas , Sepsis/tratamiento farmacológico , Monitoreo de Drogas/métodos , Femenino , Humanos , Lactante , Recién Nacido , Enfermedades del Recién Nacido/tratamiento farmacológico , Masculino , Tamizaje Masivo/métodos , Guías de Práctica Clínica como AsuntoRESUMEN
BACKGROUND: Conventional sampling for pharmacokinetic clinical studies requires removal of large blood volumes from patients. This can result in a physiological/emotional burden for children. Microsampling to support pharmacokinetic clinical studies in pediatrics may reduce this burden. METHODS: Parents/guardians and bedside nurses completed a questionnaire describing their perception of the use of microsampling compared to conventional sampling to collect blood samples, based on their child's participation or their own role within a paired-sample pharmacokinetic clinical study. Responses were based on a seven-point Likert scale and were analyzed using frequency distributions. RESULTS: Fifty-one parents/guardians and seven bedside nurses completed a questionnaire. Parents/guardians (96%) and bedside nurses (100%) indicated that microsampling was highly acceptable and recommended as a method for collecting blood samples for pediatric patients. Responding to a question about the child indicating pain during the blood sampling procedure, 61% of parent/guardians reported no pain in their children, 14% remained neutral, and 26% reported that their child indicated pain; 71% of the bedside nurses slightly agreed that the children indicated pain. CONCLUSIONS: This study strongly suggests that parents/guardians and bedside nurses prefer microsampling to conventional sampling to conduct pediatric pharmacokinetic clinical studies. Employing microsampling may support increased participation by children in these studies. IMPACT: Pharmacokinetic clinical studies require the withdrawal of blood samples at multiple times during a dosing interval. This can result in a physiological or emotional burden, particularly for neonates or pediatric patients. Microsampling offers an important opportunity for pharmacokinetic clinical studies in vulnerable patient populations, where smaller sample volumes can be collected. However, microsampling is not commonly used in clinical studies. Understanding the perceptions of parents/guardians and bedside nurses about microsampling may ascertain if this technique offers an improvement to conventional blood sample collection to perform pharmacokinetic clinical studies for pediatric patients.
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Recolección de Muestras de Sangre , Pediatría , Recolección de Muestras de Sangre/métodos , Niño , Humanos , Recién Nacido , Dolor , Proyectos de InvestigaciónRESUMEN
BACKGROUND: Tuberculosis (TB) patients admitted to intensive care units (ICU) have high mortality rates. It is uncertain whether the pharmacokinetics of first-line TB drugs in ICU patients are different from outpatients. This study aims to compare the pharmacokinetics of oral ethambutol in TB patients in ICU versus TB outpatients and to determine whether contemporary dosing regimens achieve therapeutic exposures. METHODS: A prospective population pharmacokinetic study of ethambutol was performed in Amazonas State, Brazil. Probability of target attainment was determined using AUC/MIC > 11.9 and Cmax/MIC > 0.48 values. Optimized dosing regimens were simulated at steady state. RESULTS: Ten ICU patients and 20 outpatients were recruited. Ethambutol pharmacokinetics were best described using a two-compartment model with first-order oral absorption. Neither ICU patients nor outpatients consistently achieved optimal ethambutol exposures. The absorption rate for ethambutol was 2-times higher in ICU patients (p < 0.05). Mean bioavailability for ICU patients was >5-times higher than outpatients (p < 0.0001). Clearance and volume of distribution were 93% (p < 0.0001) and 53% (p = 0.002) lower in ICU patients, respectively. CONCLUSIONS: ICU patients displayed significantly different pharmacokinetics for an oral fixed-dose combination administration of ethambutol compared to outpatients, and neither patient group consistently achieved pre-defined therapeutic exposures.
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Recent advances suggest that miniaturised mid-infrared (MIR) devices could replace more time-consuming, laboratory-based techniques for clinical diagnostics. This work uses Fourier transform infrared spectroscopy to show that the MIR complex refractive index of whole blood varies across a range of haematocrit. This indicates that the use of an evanescent measurement is not sufficient to optically exclude the cellular content of blood in the MIR, as previously assumed. Here, spectral refractive index data is presented in two ways. First, it is given as whole blood with varying haematocrit. Second, it is given as the percentage error that haematocrit introduces to plasma. The maximum error in the effective plasma refractive index due to the haematocrit of healthy adults was 0.25% for the real part n and 11% for the imaginary part k. This implies that calibration measurements of haematocrit can be used to account for errors introduced by the cellular content, enabling plasma spectra and analyte concentrations to be indirectly calculated from a whole blood sample. This methodological advance is of clinical importance as plasma concentration of analytes such as drugs can be determined using MIR without the preprocessing of whole blood.
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Hematócrito , Refractometría , Espectroscopía Infrarroja por Transformada de Fourier , Humanos , Preparaciones Farmacéuticas , PlasmaRESUMEN
Critical illness has been shown to affect the pharmacokinetics of antibiotics, which can lead to ineffective antibiotic exposure and the potential emergence of resistant bacteria. The lack of studies describing antibiotic pharmacokinetics in critically ill children has led to significant off-label dosing. This is, in part, due to the ethical and physiological challenges of removing frequent, large-volume samples from children. Capillary microsampling facilitates the collection of small volumes of blood samples to conduct clinical pharmacokinetic studies. A sensitive, rapid, and accurate ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) bioanalytical method to measure cefotaxime and desacetylcefotaxime in 2.8 µL of plasma was developed and validated. Plasma samples were treated with acetonitrile and analytes were separated using a Kinetex C8 (100 × 2.1 mm) column. The chromatographic separation was established using a gradient method, with the mobile phases consisting of acetonitrile and ammonium acetate. An electrospray ionization source interface operated in a positive mode for the multiple reaction monitoring MS/MS analysis of cefotaxime, desacetylcefotaxime, and deuterated cefotaxime (internal standard). The bioanalytical method using microsample volumes met requirements for method validation for both analytes. Cefotaxime had precision within ± 7.3% and accuracy within ± 5% (concentration range of 0.5 to 500 mg/L). Desacetylcefotaxime had precision within ± 9.5% and accuracy within ± 3.5% (concentration range of 0.2 to 10 mg/L). The bioanalytical method was applied for the quantification of cefotaxime and its metabolite to 20 capillary microsamples collected at five time points in one dosing interval from five critically ill children.
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Antibacterianos/sangre , Cefotaxima/análogos & derivados , Cefotaxima/sangre , Niño , Cromatografía Líquida de Alta Presión/métodos , Enfermedad Crítica/terapia , Monitoreo de Drogas/métodos , Humanos , Límite de Detección , Proyectos Piloto , Reproducibilidad de los Resultados , Espectrometría de Masas en Tándem/métodosRESUMEN
OBJECTIVES: Novel treatment options for some carbapenem-resistant Gram-negative pathogens have been identified by the World Health Organization as being of the highest priority. Ceftolozane-tazobactam is a novel cephalosporin-beta-lactamase inhibitor combination antibiotic with potent bactericidal activity against the most difficult-to-treat multi-drug resistant and extensively drug resistant Gram-negative pathogens. This study aimed to develop and validate a liquid chromatography - tandem mass spectrometry method for the simultaneous quantification of ceftolozane and tazobactam in plasma (total and unbound), renal replacement therapy effluent (RRTE), cerebrospinal fluid (CSF) and urine. METHODS: Analytes were separated using mixed-mode chromatography with an intrinsically base-deactivated C18 column and a gradient mobile phase consisting of 0.1% formic acid, 10 mM ammonium formate and acetonitrile. The analytes and internal standards were detected using rapid ionisation switching between positive and negative modes with simultaneous selected reaction monitoring. RESULTS: A quadratic calibration was obtained for plasma (total and unbound), RRTE and CSF over the concentration range of 1-200 mg/L for ceftolozane and 0.5-100 mg/L for tazobactam, and for urine the concentration range of 10-2,000 mg/L for ceftolozane and 5-1,000 mg/L for tazobactam. For both ceftolozane and tazobactam, validation testing for matrix effects, precision and accuracy, specificity and stability were all within the acceptance criteria of ±15%. CONCLUSIONS: This methodology was successfully applied to one pilot pharmacokinetic study in infected critically ill patients, including patients receiving renal replacement therapy, and one case study of a patient with ventriculitis, where all patients received ceftolozane-tazobactam.