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OBJECTIVES: An increased risk of mortality and postoperative side effects led to aprotinin (Trasylol®) withdrawal from the market in 2008, but since 2018 aprotinin has again been used in France. The French retrospective multicentre APACHE study (AProtinin versus tranexamic Acid in Cardiac surgery patients with High-risk for Excessive bleeding) compared the efficacy of tranexamic acid versus half-dose aprotinin. The aim of this study, ancillary to the APACHE study, is to carry out a medico-economic analysis of the use of these two antifibrinolytics on an APACHE subpopulation. METHODS: Economic data on reimbursement by the French health insurance system were extracted from the program for the data processing of medical information, and quantitative data on the cost of healthcare products were obtained from the hospital pharmacy software. RESULTS: The main analysis of costs for the population shows that the global valuation was not significantly different between the two treatment groups (P=0.60), but the costs of blood products included in the related hospital stay group (Groupe Homogène de séjour [GHS]) (whole blood, platelets and plasma) were higher for the tranexamic acid group (P=0.007). In a sub-analysis of patients alive at discharge, the costs of blood products in addition to GHS (blood-derived medicines) and the costs of blood products in the GHS were higher for the tranexamic acid group (P=0.04 and 0.001, respectively). CONCLUSIONS: The additional cost of aprotinin at the time of purchase is offset by the additional costs of blood products in the tranexamic acid group.
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Our objective was to calculate an immunosuppressant possession ratio (IPR) to diagnose non-adherence at the time of antibody-mediated rejection (ABMR). IPR was defined as the ratio of number of pills collected at the pharmacy to the number of pills prescribed over a defined period. In a first cohort of 91 kidney transplant recipients (KTRs), those with an IPR < 90% had more frequently a tacrolimus through level coefficient of variation >30% than patients with an IPR = 100% (66.7% vs. 29.4%, p = 0.05). In a case-control study, 26 KTRs with ABMR had lower 6 months IPRs than 26 controls (76% vs. 99%, p < 0.001). In KTRs with ABMR, non-adherence was more often diagnosed by a 6 months IPR < 90% than by clinical suspicion (73.1% vs 30.8%, p = 0.02). In the multivariable analysis, only de novo DSA and 6 months IPR < 90% were independently associated with ABMR, whereas clinical suspicion was not (odds ratio, 4.73; 95% CI, 1.17-21.88; p = 0.03; and odds ratio, 6.34; 95% CI, 1.73-25.59; p = 0.007, respectively). In summary, IPR < 90% is a quantifiable tool to measure immunosuppressant non-adherence. It is better associated with ABMR than clinical suspicion of non-adherence.
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Imunossupressores , Transplante de Rim , Humanos , Imunossupressores/uso terapêutico , Estudos de Casos e Controles , Farmacêuticos , Anticorpos , Rejeição de Enxerto/prevenção & controle , Rejeição de Enxerto/diagnóstico , IsoanticorposRESUMO
The objective of the present study was to determine whether augmented renal clearance (ARC) impacts negatively on ceftriaxone pharmacokinetic (PK)/pharmacodynamic (PD) target attainment in critically ill patients. Over a 9-month period, all critically ill patients treated with ceftriaxone were eligible. During the first 3 days of antimicrobial therapy, every patient underwent 24-h creatinine clearance (CLCR) measurements and therapeutic drug monitoring of unbound ceftriaxone. ARC was defined by a CLCR of ≥150 ml/min. Empirical underdosing was defined by a trough unbound ceftriaxone concentration under 2 mg/liter (percentage of the time that the concentration of the free fraction of drug remained greater than the MIC [fT>MIC], 100%). Monte Carlo simulation (MCS) was performed to determine the probability of target attainment (PTA) of different dosing regimens for various MICs and three groups of CLCR (<150, 150 to 200, and >200 ml/min). Twenty-one patients were included. The rate of empirical ceftriaxone underdosing was 62% (39/63). A CLCR of ≥150 ml/min was associated with empirical target underdosing with an odds ratio (OR) of 8.8 (95% confidence interval [CI] = 2.5 to 30.7; P < 0.01). Ceftriaxone PK concentrations were best described by a two-compartment model. CLCR was associated with unbound ceftriaxone clearance (P = 0.02). In the MCS, the proportion of patients who would have failed to achieve a 100% fT>MIC was significantly higher in ARC patients for each dosage regimen (OR = 2.96; 95% CI = 2.74 to 3.19; P < 0.01). A dose of 2 g twice a day was best suited to achieve a 100% fT>MIC When targeting a 100% fT>MIC for the less susceptible pathogens, patients with a CLCR of ≥150 ml/min remained at risk of empirical ceftriaxone underdosing. These data emphasize the need for therapeutic drug monitoring in ARC patients.
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Antibacterianos/farmacocinética , Ceftriaxona/farmacocinética , Creatinina/urina , Monitoramento de Medicamentos/métodos , Taxa de Depuração Metabólica/fisiologia , Adulto , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Ceftriaxona/administração & dosagem , Ceftriaxona/uso terapêutico , Cuidados Críticos , Estado Terminal , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-IdadeRESUMO
AIM: To date, neither the benefit of mycophenolic acid (MPA) therapeutic drug monitoring (TDM), the prodrug of mycophenolate mofetil (MMF), nor the optimal monitoring technique have been established in autoimmune diseases. This study was undertaken to confirm, in a cohort of new patients, the plasma MPA thresholds previously published in patients with systemic lupus erythematosus (SLE) or vasculitis. METHODS: MPA areas under the concentration-time curves between 0 and 12 h, 12 h trough concentrations and pre-dose concentrations (C0 ) were determined for 23 patients with SLE and 21 with systemic vasculitis. The relationship between patients' pharmacokinetic (PK) variables and their clinical outcomes during follow-up were analyzed. RESULTS: In both autoimmune diseases, at PK assessment, median MPA C0 for patients with uncontrolled disease was significantly lower than that of patients with stable disease or in remission, 1.6 mg l(-1) (IQR 0.9-2.1 mg l(-1)) vs. 2.95 mg l(-1) (IQR 1.38-3.73 mg l(-1)) for SLE (P = 0.048) and 1.55 mg l(-1) (IQR 0.98-2.18 mg l(-1)) vs. 3 mg l(-1) (IQR 2.2-4.4 mg l(-1)) for vasculitis (P = 0.016). According to our receiver operating characteristics curve analysis, a C0 threshold of 2.5-3 mg l(-1) was best able to discriminate a flare (SLE: 88% sensitivity, 80% specificity; vasculitis: 100% sensitivity, 90% specificity). Patients with C0 ≥ 2.5-3 mg l(-1) at inclusion had better clinical outcomes during the 12 months following PK assessment. CONCLUSION: Provided that the benefit of TDM in patients with autoimmune diseases could be confirmed by randomized, controlled trials, it might be based on the C0 measured approximately 12 h post-dose.
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Monitoramento de Medicamentos , Imunossupressores/sangue , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Ácido Micofenólico/análogos & derivados , Adulto , Idoso , Área Sob a Curva , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/sangueRESUMO
OBJECTIVES: Patients with bone and joint infections (BJI) are involved in a complex care pathway and require prolonged antimicrobial treatment. Some studies have suggested that a pharmacist-led telehealth intervention (TI) could help to ensure better follow-up of chronic diseases. To our knowledge, there are no data on the effects of pharmacist-led TI on patients with BJI. The aim of this study is to assess the impact of a TI on patients treated for BJIs at three weeks after hospital discharge. PATIENTS AND METHODS: Patients encountered during hospitalization and receiving standardized care including TI were included in the study. All adverse events (AE) reported by patients during TI were evaluated. Impact of pharmaceutical interventions (PIs) provided by a clinical pharmacist following TI was evaluated by CLEO© (CLinical, Economic and Organizational) scale. Patient satisfaction concerning TI was assessed by an anonymous questionnaire following medical consultation at the end of antimicrobial treatment. RESULTS: Over a 4-month period, 36 patients received TI. Fifty-two AEs were identified in 21 patients (58%). Two patients were hospitalized due to an AE. Clinical pharmacists provided 34 pharmaceutical interventions (PIs) for 23 patients (64%). According to CLEO scale, 11 PIs had a major clinical impact (32%), 6 PIs (18%) had a favorable impact on the direct cost of treatment and 27 PIs (79%) had positive organizational impact. Concerning TI process, patients were satisfied or very satisfied, with an average score of 9.6/10. CONCLUSION: TI led to a high number of pharmaceutical interventions (PIs), with a meaningful clinical, organizational, and economic impact. Patients were also highly satisfied with this intervention.
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Satisfação do Paciente , Farmacêuticos , Telemedicina , Humanos , Feminino , Masculino , Idoso , Pessoa de Meia-Idade , Inquéritos e Questionários , Adulto , Artrite Infecciosa/tratamento farmacológico , Artrite Infecciosa/terapia , Idoso de 80 Anos ou mais , Hospitalização/estatística & dados numéricos , Antibacterianos/uso terapêuticoRESUMO
In the context of essential drug shortages, this article reports a proof of concept for the hospital preparation of a 2% propofol injectable nanoemulsion. Two processes for propofol were assessed: mixing propofol with the commercial Intralipid® 20% emulsion and a "de novo" process performed using separate raw materials (i.e., oil, water, and surfactant) and optimized for droplet size reduction with a high-pressure homogenizer. A propofol HPLC-UV stability-indicating method was developed for process validation and short-term stability. In addition, free propofol in the aqueous phase was quantified by dialysis. To envision routine production, sterility and endotoxin tests were validated. Only the "de novo" process using high-pressure homogenization gave satisfactory physical results similar to commercialized Diprivan® 2%. Both terminal heat sterilization processes (121 °C, 15 min and 0.22 µm filtration) were validated, but an additional pH adjustment was required prior to heat sterilization. The propofol nanoemulsion was monodisperse with a 160 nm mean droplet size, and no droplets were larger than 5µm. We confirmed that free propofol in the aqueous phase of the emulsion was similar to Diprivan 2%, and the chemical stability of propofol was validated. In conclusion, the proof of concept for the in-house 2% propofol nanoemulsion preparation was successfully demonstrated, opening the field for the possible production of the nanoemulsion in hospital pharmacies.
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OBJECTIVES: This study aimed to determine the steady-state serum and alveolar concentrations of linezolid administered by continuous infusion to critically ill patients with ventilator-associated pneumonia (VAP). PATIENTS AND METHODS: This was a prospective, open-label study performed in an intensive care unit and research ward in a university hospital. Twelve critically ill adult patients with VAP received 600 mg of linezolid as a loading dose followed by 1200 mg/day by continuous infusion. After 2 days of therapy, the steady-state serum and alveolar (collected by a mini-bronchoalveolar procedure) concentrations of linezolid were determined by HPLC. RESULTS: The median (IQR) serum and epithelial lining fluid (ELF) linezolid concentrations at steady state (C(ss)) were 7.1 (6.1-9.8) and 6.9 (5.8-8.6) mg/L, respectively, and the median (IQR) AUC (AUC(0-24)) values were 169 (146-235) and 164 (139-202) mg · h/L, respectively, corresponding to a median (IQR) linezolid alveolar diffusion of 97% (80%-108%). CONCLUSIONS: Our study shows that the continuous infusion of 1200 mg of linezolid daily in critically ill patients with VAP provides satisfactory pharmacokinetic results, with a linezolid alveolar diffusion of 100% and concentrations exceeding almost twice the susceptibility breakpoint for Staphylococcus aureus (4 mg/L) in both serum and ELF for 100% of the time. However, the clinical benefit of continuous infusion in comparison with standard intermittent infusion is still to be determined.
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Acetamidas/farmacocinética , Antibacterianos/farmacocinética , Oxazolidinonas/farmacocinética , Pneumonia Associada à Ventilação Mecânica/tratamento farmacológico , Alvéolos Pulmonares/química , Acetamidas/administração & dosagem , Adulto , Antibacterianos/administração & dosagem , Estado Terminal , Feminino , Humanos , Infusões Intravenosas , Linezolida , Masculino , Pessoa de Meia-Idade , Oxazolidinonas/administração & dosagem , Pneumonia Estafilocócica/tratamento farmacológico , Estudos Prospectivos , Soro/química , Staphylococcus aureus/efeitos dos fármacosRESUMO
The extended use of protein drugs in therapeutics has created the need for their quantification in human plasma. A methodology using the therapeutic protein itself as internal standard for quantitative analysis by multiple reaction monitoring (MRM) has been designed and applied to epoetin beta, a recombinant human erythropoietin (rhEPO). After depletion of major proteins, plasma samples were desalted and enriched in rhEPO by reversed phase liquid chromatography prior to tryptic cleavage. Differential isotopic labeling of peptides was performed by derivatization with 2-methoxy-4,5-dehydro-imidazole. A light version (four hydrogen atoms) of this reagent was used for plasma peptides. Tryptic peptides obtained from pure rhEPO were derivatized with a heavy version (four deuterium atoms) of the same reagent and used as internal standards. Two rhEPO tryptic peptides with three MRM transitions per peptide were selected for quantification. This strategy provided a quantification limit close to 50 amol of epoetin beta per microliter of plasma (equivalent to 1.7 ng/mL), i.e., well below the expected therapeutic concentrations in plasma (around 100-500 amol/µL).
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Eritropoetina/sangue , Espectrometria de Massas em Tandem/métodos , Cromatografia Líquida , Eritropoetina/química , Humanos , Mapeamento de Peptídeos , Proteínas Recombinantes , Padrões de Referência , Tripsina/químicaRESUMO
AIMS: To assess the effect of a pharmacist-led intervention, using Barrows cards method, during the first year after renal transplantation, on patient knowledge about their treatment, medication adherence and exposure to treatment in a French cohort. METHODS: We conducted a before-and-after comparative study between two groups of patients: those who benefited from a complementary pharmacist-led intervention [intervention group (IG), n = 44] versus those who did not [control group (CG), n = 48]. The pharmacist-led intervention consisted of a behavioral and educational interview at the first visit (visit 1). The intervention was assessed 4 months later at the second visit (visit 2), using the following endpoints: treatment knowledge, medication adherence [proportion of days covered (PDC) by immunosuppressive therapy] and tacrolimus exposure. RESULTS: At visit 2, IG patients achieved a significantly higher knowledge score than CG patients (83.3% versus 72.2%, p = 0.001). We did not find any differences in treatment exposure or medication adherence; however, the intervention tended to reduce the proportion of non-adherent patients with low knowledge scores. Using the PDC by immunosuppressive therapy, we identified 10 non-adherent patients (10.9%) at visit 1 and six at visit 2. CONCLUSIONS: Our intervention showed a positive effect on patient knowledge about their treatment. However, our results did not show any improvement in overall medication adherence, which was likely to be because of the initially high level of adherence in our study population. Nevertheless, the intervention appears to have improved adherence in non-adherent patients with low knowledge scores.
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PURPOSE: To date, how medication reconciliation (MR) could be prioritized in younger patients remains poorly evaluated. This study aimed at assessing whether a MR prioritization strategy based on the identification of high-risk medication at patients' admission treatment could be of interest in non-elderly patients. METHOD: This prospective study was conducted between July and September 2017 in an internal medicine unit at Bordeaux teaching hospital. All patients aged 16 to 74 years and receiving at least two long-term treatments at admission were considered eligible. High-risk medications were defined on the basis of a pharmacovigilance study, which identified the drugs most involved in serious adverse effects reported in the Nouvelle-Aquitaine region in non-elderly adults. They included antithrombotics, analgesics, antipsychotics and cardiac therapies. MR-induced treatment changes were compared according to the existence of high-risk medications at admission in study participants. RESULTS: Among the 92 study participants, 46 presented with high-risk medications at admission (median age 66 years, IQR 58-70) and 46 without such (median age 54 years, IQR 47-64). High risk-medications (HRM) existing at admission were antithrombotics (52.2%) and antipsychotics (22.4%). MR resulted in treatment changes in 37% of patients admitted with at-risk medications vs. 8.7% of those admitted without such (P=0.001). Overall, the mean number of treatment changes performed after MR was of 1 (95%CI 0.4-1.6) in patients with high-risk medication at admission and of 0.2 (95%CI 0-0.4) in patients without such. MR-induced treatment changes assessed as clinically major at least once by pharmacists or clinicians was greater in HRM group (43.5%) than in non-HRM group (31.6%). However, the consistency was low between clinicians and pharmacists, especially to distinguish the clinical importance of significant and minor interventions. CONCLUSION: Targeting high-risk medications at admission appeared efficient for the prioritization of MR in non-elderly patients hospitalised in internal medicine.
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Erros de Medicação , Reconciliação de Medicamentos , Adulto , Idoso , Humanos , Pessoa de Meia-Idade , Admissão do Paciente , Farmacêuticos , Estudos ProspectivosRESUMO
PURPOSE: To investigate the long-term chemical and physical stability of 5-mg/mL acyclovir solution in polypropylene bags stored at 5°C ± 3°C for 2 months in order to determine the feasibility of batch production by a centralized intravenous additive service. METHODS: Eight empty 100-mL polypropylene bags (bags A) and 8 empty 250-mL bags (bags B) were respectively filled with 60 mL and 200 mL of 5-mg/mL acyclovir and 0.9% sodium chloride injection (NaCl) under aseptic conditions through a semiautomated manufacturing process and vacuum packed before storage at 5°C ± 3°C. Four bags A and 4 bags B were tested for chemical stability via a stability-indicating high-performance liquid chromatography (HPLC) method immediately after preparation (time 0) and after 7, 14, 21, 28, 35, 42, and 63 days. Samples for microbiological assay were collected on days 0 and 63 from 4 bags A and 4 bags B immediately after breaking the vacuum. Osmolality, pH, and physical stability were assessed by visual examination, Subvisible particle counting was performed on 6 additional bags (3 each of bags A and B). RESULTS: Mean percentage loss of acyclovir relative to the mean experimental concentration at time 0 was below 5% over the 63-day study period.. No significant differences of pH, no change in color and no precipitate were observed during the study. Subvisible particle counts were compliant with European Pharmacopoeia requirements. Acyclovir solutions remained sterile over the 63 days of the study. CONCLUSION: Extemporaneously prepared acyclovir 5 mg/mL solutions in 0.9% NaCl stored in polypropylene bags were chemically and physically stable over 63 days when stored at 5°C ± 3°C.
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Embalagem de Medicamentos , Polipropilenos , Aciclovir , Cromatografia Líquida de Alta Pressão , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Hospitais , HumanosRESUMO
BACKGROUND: According to infliximab (IFX) license in Crohn's disease (CD), infusion doses are based on patient's body-weight. Dose banding providing standardized doses (SD) has been implemented in parenteral chemotherapy in order to optimize aseptic unit capacity and reduce drug expenditure, duration of hospital stay and costs without decreasing efficacy. MATERIAL AND METHOD: The first part was a single-center retrospective analysis of consecutive CD patients receiving IFX maintenance therapy to determine standardized doses covering more than 50% of infusions. The second part was a prospective cohort study assessing the impact of SD compared to body-weight doses (BWD) on admission duration and costs. RESULTS: Six IFX SD covering more than 90% of infusion doses were implemented for dose banding. According to the Monte-Carlo simulation, there was no significant difference between IFX SD and BWD maintenance regimens. When assessed prospectively in 116 patients (75 patients treated with SD and 41 with BWD) corresponding to 128 infusions, hospitalization duration was shortened by 70â¯min per patient (pâ¯<â¯0.001). CONCLUSION: According to a pharmacokinetic model, IFX SD has a pharmacokinetic profile close to BWD and is associated with reduced length of hospitalization in a cohort of patients with CD. IFX SD implementation could optimize infusion units functioning and, save time and costs without decreasing efficacy.
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Doença de Crohn/tratamento farmacológico , Custos de Medicamentos , Cálculos da Dosagem de Medicamento , Fármacos Gastrointestinais/administração & dosagem , Infliximab/administração & dosagem , Adulto , Redução de Custos , Doença de Crohn/economia , Relação Dose-Resposta a Droga , Feminino , França , Fármacos Gastrointestinais/economia , Fármacos Gastrointestinais/farmacocinética , Hospitalização/estatística & dados numéricos , Humanos , Infliximab/economia , Infliximab/farmacocinética , Infusões Intravenosas/normas , Masculino , Método de Monte Carlo , Estudos Prospectivos , Estudos RetrospectivosRESUMO
OBJECTIVES: To determine the steady-state serum and alveolar concentrations of piperacillin/tazobactam administered in continuous infusion to critically ill patients with ventilator-associated pneumonia and various degrees of renal failure. DESIGN: Prospective comparative study. SETTING: An intensive care unit and research ward in a university hospital. PATIENTS: Forty patients with microbiologically documented ventilator-associated pneumonia. INTERVENTIONS: Patients were randomized to receive piperacillin/tazobactam daily continuous infusions of 12/1.5 g or 16/2 g after a loading dose of 4/0.5 g. The serum and alveolar piperacillin/tazobactam concentrations were determined at steady-state with high performance liquid chromatography. MEASUREMENTS AND MAIN RESULTS: The median (interquartile) serum and alveolar piperacillin concentrations were respectively 25.3 mg/L (23.1-32.6) and 12.7 mg/L (6.7-18.0) for 12/1.5 g/day, and 38.9 mg/L (32.9-59.6) and 19.1 mg/L (14.0-21.5), respectively, for 16/2 g/day in patients with no/mild renal failure. In patients with moderate/advance renal failure, the median (interquartile) serum and alveolar piperacillin concentrations were 102.4 mg/L (97.4-112.6) and 44.1 mg/L (33.4-48.3), respectively, for 12/1.5 g/day, and 135.3 mg/L (119.5-146.2) and 54.9 mg/L (45.2-110.3), respectively, for 16/2 g/day. Our results show great variability in piperacillin/tazobactam concentrations, with an alveolar percentage penetration of 40-50% for piperacillin and 65-85% for tazobactam and a negative association between serum or alveolar concentrations and creatinine clearance. CONCLUSIONS: A target piperacillin serum concentration of at least 35-40 mg/L is probably required to provide alveolar concentrations exceeding the susceptibility breakpoint for gram-negative bacteria (16 mg/L) during ventilator-associated pneumonia. In patients with no/mild renal failure, a continuous daily dose of piperacillin/tazobactam 16/2 g allows reaching this target concentration, which might be not observed with 12/1.5 g/day. In patients with moderate/advanced renal failure, both dosages achieve serum concentrations far above the 35-40 mg/L threshold, suggesting that in that case, therapeutic drug monitoring should be performed in order to adjust the daily dose.
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Antibacterianos/farmacocinética , Ácido Penicilânico/análogos & derivados , Piperacilina/farmacocinética , Pneumonia Associada à Ventilação Mecânica/metabolismo , Alvéolos Pulmonares/metabolismo , Idoso , Antibacterianos/administração & dosagem , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Ácido Penicilânico/administração & dosagem , Ácido Penicilânico/farmacocinética , Piperacilina/administração & dosagem , Estudos Prospectivos , TazobactamRESUMO
PURPOSE: To determine whether augmented renal clearance (ARC) impacts negatively on piperacillin-tazobactam unbound concentrations in critically ill patients receiving 16â¯g/2â¯g/day administered continuously. MATERIAL AND METHODS: Fifty nine critically ill patients without renal impairment underwent 24-h creatinine clearance (CrCL) measurement and therapeutic drug monitoring during the first three days of antimicrobial therapy by piperacillin-tazobactam. The main outcome was the rate of piperacillin underexposure, defined by at least one of three samples under 16â¯mg/L. Monte Carlo simulation was performed to predict the distribution of piperacillin concentrations for various CrCL and minimal inhibitory concentration (MIC) values. RESULTS: The rate of piperacillin underexposure was 19%, significantly higher in ARC patients (0 vs. 31%, pâ¯=â¯.003). A threshold of CrCLâ¯≥â¯170â¯mL/min had a sensitivity and specificity of 1 (95%CI: 0.79-1) and 0.69 (95%CI: 0.61-0.76) to predict piperacillin underexposure. In ARC patients, a 20â¯g/2.5â¯g/24â¯h PTZ dosing regimen was associated with the highest probability to reach the 16â¯mg/L empirical target, without risk of excessive dosing. CONCLUSIONS: When targeting a theoretical MIC at the upper limit of the susceptibility range, the desirable target (100%fT>16) may not be achieved in patients with CrCLâ¯≥â¯170â¯mL/min receiving PTZ 16â¯g/2â¯g/day administered continuously.
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Antibacterianos/administração & dosagem , Combinação Piperacilina e Tazobactam/administração & dosagem , Sepse/tratamento farmacológico , Adulto , Idoso , Antibacterianos/farmacologia , Estado Terminal/terapia , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos , Feminino , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Combinação Piperacilina e Tazobactam/farmacologia , Estudos RetrospectivosRESUMO
OBJECTIVE: To evaluate the reliability of mini-bronchoalveolar lavage (mini-BAL) for the measurement of tobramycin concentrations in epithelial lining fluid (ELF) in comparison with conventional bronchoscopic bronchoalveolar lavage (BAL). DESIGN: Prospective, open-label study. SETTING: An intensive care unit and research ward in a university hospital. PATIENTS: Twelve critically ill adult patients with ventilator-associated pneumonia (VAP). INTERVENTIONS: All subjects received intravenous infusions of tobramycin 7-10 mg/kg once daily. After 2 days of therapy, the steady-state serum and ELF concentrations (obtained from BAL and mini-BAL) of tobramycin were determined by means of high-performance liquid chromatography. MEASUREMENTS AND RESULTS: We observed poor penetration of tobramycin in ELF of approximately approximately 12% with ELF peak concentrations of approximately approximately 3 mg/l with both methods. Good agreement in Bland-Altman analysis (mean +/- SD bias = 0.04 +/- 0.38 mg/l) was observed between the two methods of sampling. CONCLUSION: Our results suggest that tobramycin 7-10 mg/kg once daily in critically ill patients with VAP might provide insufficient lung concentrations in the case of difficult-to-treat pathogens. Besides, mini-BAL, which is simple, non-invasive and easily repeatable at the bedside, appears to be a reliable method for the measurement of antibiotic concentrations in ELF in comparison with bronchoscopic BAL in critically ill patients with VAP.
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Antibacterianos/farmacocinética , Lavagem Broncoalveolar , Estado Terminal , Mucosa Respiratória/metabolismo , Tobramicina/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/administração & dosagem , Antibacterianos/análise , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Infusões Intravenosas , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Pneumonia Associada à Ventilação Mecânica/tratamento farmacológico , Estudos Prospectivos , Reprodutibilidade dos Testes , Tobramicina/administração & dosagem , Tobramicina/análiseRESUMO
The quantification of monoclonal antibodies (mAbs) such as bevacizumab, a recombinant humanized immunoglobulin G1 (hIgG1), in biological fluids, is an essential prerequisite to any pharmacokinetic preclinical and clinical study. To date, reference techniques used to quantify mAbs rely on enzyme-linked immunosorbent assay (ELISA) lacking specificity. Furthermore, the commercially available ELISA kit to quantify bevacizumab in human plasma only assesses the free fraction of the drug. However, the conditions of storage and analysis of plasma samples could alter the physiological equilibrium between the free, bound and partially bound forms of bevacizumab and this could result in over- or underestimation of drug concentration. We developed a new assay for absolute quantification of total fraction of bevacizumab by liquid chromatography tandem mass spectrometry (LC-MS/MS) basing identification and quantification of bevacizumab on two specific peptides. In this report we compare our assay with two internal standard (IS) calibration approaches: one using a different human mAb (Trastuzumab) and the other using a stable isotope labeled specific peptide. After enrichment by affinity chromatography on protein A and concentration by ultrafiltration, human plasma samples were proteolyzed by trypsin. Linearity was established from 12.5 to 500µg/mL with an interday accuracy ranging from 101.7 to 110.6% and precision from 7.0% to 9.9%. This study demonstrates the importance of the choice of the IS in quantifying bevacizumab in human plasma and highlights the difficulty of reaching a reliable proteolysis with a sufficient recovery. We developed a reliable and cost-effective LC-MS/MS method to quantify total plasmatic fraction of bevacizumab in human plasma. Through our development we proposed a generic methodology easily transposable to quantify all IgG1 subclass very useful for clinical pharmacokinetics studies.
Assuntos
Bevacizumab/sangue , Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodos , Bevacizumab/química , Calibragem , Humanos , Modelos Lineares , Peptídeos/química , Padrões de Referência , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
OBJECTIVES: To assess the impact of HIV-1 protease mutations and intracellular and plasma lopinavir minimum concentrations (Cmin) on virological success or failure on lopinavir/ritonavir-containing highly active antiretroviral therapy (HAART). DESIGN: HIV-1-infected HAART-experienced patients included in an observational study, received lopinavir/ritonavir (400/100 mg twice a day) plus two to three nucleoside reverse transcriptase inhibitors (NRTI) or one NRTI plus one non-NRTI. A viral load less than 50 copies/ml at month 6 defined virological success. METHODS: Intracellular and plasma lopinavir concentrations were determined by high-pressure liquid chromatography with mass-spectrometry detection. Reverse transcriptase and protease genes were sequenced at baseline and the time of virological failure. RESULTS: When the 38 patients started the lopinavir/ritonavir-based regimen, baseline median (25-75th percentile) values were: CD4 cell count 218 cells/microl (133-477); plasma HIV-1-RNA load 5.3 log10 copies/ml (3.8-5.1); number of lopinavir mutations four per protease gene (two to six). Univariate analysis associated virological success or failure at month 6 (21/38 patients) with the number of baseline lopinavir mutations, intracellular and plasma lopinavir Cmin, and the genotype inhibitory quotient (GIQ) at months 1 and 6. Multivariate analysis showed that the number of baseline lopinavir mutations and intracellular and plasma lopinavir Cmin were independently associated with virological success or failure. We defined the most discriminating intracellular and plasma lopinavir Cmin efficacy thresholds (8 and 4 microg/ml, respectively) and GIQ thresholds (1 and 3, respectively). CONCLUSION: The monitoring of lopinavir/rironavir-based HAART efficacy should include the number of baseline lopinavir/ritonavir mutations, intracellular and plasma lopinavir Cmin and GIQ calculation.
Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , HIV-1/enzimologia , Pirimidinonas/uso terapêutico , Adulto , Terapia Antirretroviral de Alta Atividade , Distribuição de Qui-Quadrado , Cromatografia Líquida de Alta Pressão , Quimioterapia Combinada , Feminino , Infecções por HIV/sangue , Protease de HIV/genética , Inibidores da Protease de HIV/sangue , Inibidores da Protease de HIV/farmacocinética , Transcriptase Reversa do HIV/genética , Humanos , Líquido Intracelular/metabolismo , Lopinavir , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Mutação , Pirimidinonas/sangue , Pirimidinonas/farmacocinética , Inibidores da Transcriptase Reversa/uso terapêutico , Resultado do Tratamento , Carga ViralRESUMO
OBJECTIVE: To determine the steady-state plasma and epithelial lining fluid (ELF) concentrations of piperacillin/tazobactam (P/T) administered to critically ill patients with severe bacterial pneumonia. DESIGN: Prospective, open-label study. SETTING: An intensive care unit and research ward in a university hospital. PATIENTS: Ten adult patients with severe nosocomial bacterial pneumonia on mechanical ventilation. INTERVENTIONS: All subjects received a 30-min intravenous infusion of P/T 4 g/0.5 g every 8 h. The steady-state plasma and ELF concentrations of P/T were determined by high-performance liquid chromatography. MEASUREMENTS AND MAIN RESULTS: The mean+/-SD steady-state plasma trough, peak, and intermediate concentrations were 8.5+/-4.6 microg/ml, 55.9+/-21.6 microg/ml, and 24.0+/-13.8 microg/ml for piperacillin, and 2.1+/-1.0 microg/ml, 4.8+/-2.1 microg/ml, and 2.4+/-1.2 microg/ml for tazobactam, respectively. The mean+/-SD steady-state intermediate ELF concentrations were 13.6+/-9.4 microg/ml for piperacillin and 2.1+/-1.1 microg/ml for tazobactam, respectively, showing a mean percentage penetration of piperacillin and tazobactam into ELF of 56.8% and 91.3 %, respectively, with a P/T ratio of 6.5:1. CONCLUSION: Our results show that during the treatment of severe nosocomial pneumonia, a regimen of P/T 4 g/0.5 g every 8 h might provide insufficient concentrations into lung tissue to exceed the MIC of many causative pathogens. This suggests that higher doses of P/T should be administered in order to maximize the antibiotic concentration at the site of infection, or that a second antimicrobial agent should be used in association.
Assuntos
Infecção Hospitalar/tratamento farmacológico , Ácido Penicilânico/uso terapêutico , Piperacilina/uso terapêutico , Pneumonia Bacteriana/tratamento farmacológico , Respiração Artificial/efeitos adversos , Infecção Hospitalar/sangue , Células Epiteliais/metabolismo , Feminino , Humanos , Unidades de Terapia Intensiva , Pulmão/metabolismo , Masculino , Pessoa de Meia-Idade , Ácido Penicilânico/análogos & derivados , Ácido Penicilânico/sangue , Piperacilina/sangue , Combinação Piperacilina e Tazobactam , Pneumonia Bacteriana/sangue , Pneumonia Bacteriana/etiologia , Estudos ProspectivosRESUMO
The aim of this study was to develop a specific and sensitive high-performance liquid chromatographic assay for the determination of linezolid in human plasma, and bronchoalveolar lavage. The sample extraction was based on a fully automated solid-phase extraction with an OASIS HLB cartridge. The method used ultraviolet detection set at a wavelength of 254 nm and a separation with a Zorbax Eclipse XDB C8 column. The assay has been found linear over the concentration range 0.02-30 microg/ml and 0.04-30 microg/ml for linezolid, respectively, in plasma and bronchoalveolar lavage. It provided good validation data for accuracy and precision (CV <4.64% and 5.08%, accuracy in the range 96.93-102.67% and 97.33-105.67%, respectively, for intra- and inter-day). The assay will be applied to determine the penetration of linezolid in human bronchoalveolar lavage during pharmacokinetic steady-state.
Assuntos
Acetamidas/sangue , Antibacterianos/sangue , Líquido da Lavagem Broncoalveolar/química , Cromatografia Líquida de Alta Pressão/métodos , Oxazolidinonas/sangue , Espectrofotometria Ultravioleta/métodos , Acetamidas/farmacocinética , Antibacterianos/farmacocinética , Automação , Calibragem , Humanos , Linezolida , Oxazolidinonas/farmacocinética , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
A selective and accurate assay for the simultaneous quantitation of four protease inhibitors (PIs) (amprenavir (APV), lopinavir (LPV), ritonavir (RTV) and saquinavir (SQV)) and a non-nucleoside reverse transcriptase inhibitor (NNRTI) (efavirenz, EFV) in human peripheral blood mononuclear cells using high-performance liquid chromatography-mass chromatography (LC/MS) has been developed and validated. After liquid-liquid extraction, the antiretroviral agents were separated within 15 min. The calibration curves of each drug showed a good linearity in a range of concentration between 2 and 200 ng/3 x 10(6) cells for amprenavir, lopinavir, efavirenz, 1.60 and 128 ng/3 x 10(6) cells for ritonavir and saquinavir. Mean intra- and inter-assay coefficients of variation over the ranges of the standard curves were less than 15% and mean extraction recoveries ranged 88.7-112.1%. The limits of quantification were 2 ng/3 x 10(6) cells for amprenavir, lopinavir, efavirenz, 1 ng/3 x 10(6) cells for ritonavir and 1.6 ng/3 x 10(6) cells for saquinavir. This novel LC/MS assay, which provides an excellent method for simultaneous intra-cellular determination of amprenavir, lopinavir, ritonavir, saquinavir and efavirenz in human peripheral blood mononuclear cells, could be successfully applied for therapeutic drug monitoring and pharmacokinetic studies.