RESUMEN
OBJECTIVES: WCK 4282 is a novel combination of cefepime 2â g and tazobactam 2â g being developed for the treatment of infections caused by piperacillin/tazobactam-resistant ESBL infections. The dosing regimen for cefepime/tazobactam needs to be optimized to generate adequate exposures to treat infections caused by ESBL-producing pathogens resistant to both cefepime and piperacillin/tazobactam. METHODS: We developed pharmacokinetic population models of cefepime and tazobactam to evaluate the optimal dose adjustments in patients, including those with augmented renal clearance as well as various degrees of renal impairment, and also for those on intermittent haemodialysis. Optimal doses for various degrees of renal function were identified by determining the PTA for a range of MICs. To cover ESBL-producing pathogens with an cefepime/tazobactam MIC of 16â mg/L, a dosing regimen of 2â g q8h infused over 1.5â h resulted in a combined PTA of 99% for the mean murine 1â log10-kill target for the cefepime/tazobactam combination. RESULTS: We found that to adjust for renal function, doses need to be reduced to 1â g q8h, 500â mg q8h and 500â mg q12h for patients with CLCR of 30-59, 15-29 and 8-14â mL/min (as well as patients with intermittent haemodialysis), respectively. In patients with high to augmented CLR (estimated CLCR 120-180â mL/min), a prolonged 4â h infusion of standard dose is required. CONCLUSIONS: The suggested dosing regimens will result in exposures of cefepime and tazobactam that would be adequate for infections caused by ESBL-producing pathogens with a cefepime/tazobactam MICs up to 16â mg/L.
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Antibacterianos , Cefepima , Cefalosporinas , Pruebas de Sensibilidad Microbiana , Combinación Piperacilina y Tazobactam , Diálisis Renal , Humanos , Cefepima/administración & dosificación , Cefepima/farmacocinética , Antibacterianos/administración & dosificación , Antibacterianos/farmacocinética , Antibacterianos/farmacología , Combinación Piperacilina y Tazobactam/administración & dosificación , Combinación Piperacilina y Tazobactam/farmacocinética , Cefalosporinas/administración & dosificación , Cefalosporinas/farmacocinética , Cefalosporinas/uso terapéutico , Masculino , Femenino , Tazobactam/administración & dosificación , Tazobactam/uso terapéutico , Persona de Mediana Edad , beta-Lactamasas , Adulto , Ácido Penicilánico/análogos & derivados , Ácido Penicilánico/administración & dosificación , Ácido Penicilánico/farmacocinética , Voluntarios Sanos , Adulto Joven , Piperacilina/administración & dosificación , Piperacilina/farmacocinética , Piperacilina/farmacología , AnimalesRESUMEN
Piperacillin/tazobactam (TZP) is administered intravenously in a fixed ratio (8:1) with the potential for inadequate tazobactam exposure to ensure piperacillin activity against Enterobacterales. Adult patients receiving continuous infusion (CI) of TZP and therapeutic drug monitoring (TDM) of both agents were evaluated. Demographic variables and other pertinent laboratory data were collected retrospectively. A population pharmacokinetic approach was used to select the best kidney function model predictive of TZP clearance (CL). The probability of target attainment (PTA), cumulative fraction of response (CFR) and the ratio between piperacillin and tazobactam were computed to identify optimal dosage regimens by continuous infusion across kidney function. This study included 257 critically ill patients (79.3% male) with intra-abdominal, bloodstream, and hospital-acquired pneumonia infections in 89.5% as the primary indication. The median (min-max range) age, body weight, and estimated glomerular filtration rate (eGFR) were 66 (23-93) years, 75 (39-310) kg, and 79.2 (6.4-234) mL/min, respectively. Doses of up to 22.5 g/day were used to optimize TZP based on TDM. The 2021 chronic kidney disease epidemiology equation in mL/min best modeled TZP CL. The ratio of piperacillin:tazobactam increased from 6:1 to 10:1 between an eGFR of <20 mL/min and >120 mL/min. At conventional doses, the PTA is below 90% when eGFR is ≥100 mL/min. Daily doses of 18 g/day and 22.5 g/day by CI are expected to achieve a >80% CFR when eGFR is 100-120 mL/min and >120-160 mL/min, respectively. Inadequate piperacillin and tazobactam exposure is likely in patients with eGFR ≥ 100 mL/min. Dose regimen adjustments informed by TDM should be evaluated in this specific population.
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Gammaproteobacteria , Inhibidores de beta-Lactamasas , Adulto , Humanos , Masculino , Anciano , Anciano de 80 o más Años , Femenino , Inhibidores de beta-Lactamasas/farmacocinética , Antibacterianos/farmacocinética , beta-Lactamas , Estudios Retrospectivos , Ácido Penicilánico/uso terapéutico , Ácido Penicilánico/farmacocinética , Combinación Piperacilina y Tazobactam/farmacocinética , Piperacilina/farmacocinética , Tazobactam , beta-Lactamasas , Pruebas de Sensibilidad MicrobianaRESUMEN
BACKGROUND: Pathophysiological changes in severely burned patients alter the pharmacokinetics (PK) of anti-infective agents, potentially leading to subtherapeutic concentrations at the target site. Albumin supplementation, to support fluid resuscitation, may affect pharmacokinetic properties by binding drugs. This study aimed to investigate the PK of piperacillin/tazobactam in burn patients admitted to the ICU before and after albumin substitution as total and unbound concentrations in plasma. PATIENTS AND METHODS: Patients admitted to the ICU and scheduled for 4.5 g piperacillin/tazobactam administration and 200 mL of 20% albumin substitution as part of clinical routine were included. Patients underwent IV microdialysis, and simultaneous arterial plasma sampling, at baseline and multiple timepoints after drug administration. PK analysis of total and unbound drug concentrations under steady-state conditions was performed before and after albumin supplementation. RESULTS: A total of seven patients with second- to third-degree burns involving 20%-60% of the total body surface were enrolled. Mean (SD) AUC0-8 (h·mg/L) of total piperacillin/tazobactam before and after albumin substitution were 402.1 (242)/53.2 (27) and 521.8 (363)/59.7 (32), respectively. Unbound mean AUC0-8 before and after albumin supplementation were 398.9 (204)/54.5 (25) and 456.4 (439)/64.5 (82), respectively. CONCLUSIONS: Albumin supplementation had little impact on the PK of piperacillin/tazobactam. After albumin supplementation, there was a numerical increase in mean AUC0-8 of total and unbound piperacillin/tazobactam, whereas similar Cmax values were observed. Future studies may investigate the effect of albumin supplementation on drugs with a higher plasma protein binding.
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Antibacterianos , Quemaduras , Humanos , Antibacterianos/uso terapéutico , Piperacilina/farmacocinética , Ácido Penicilánico/farmacocinética , Combinación Piperacilina y Tazobactam/farmacocinética , Quemaduras/complicaciones , Quemaduras/tratamiento farmacológico , Unidades de Cuidados IntensivosRESUMEN
Optimizing the entire therapeutic regimen in septic critically ill patients should be based not only on improving antibiotic use but also on optimizing the entire therapeutic regimen by considering possible drug-drug or drug-nutrient interactions. The aim of this narrative review is to provide a comprehensive overview on recent advances to optimize the therapeutic regimen in septic critically ill patients based on a pharmacokinetics and pharmacodynamic approach. Studies on recent advances on TDM-guided drug therapy optimization based on PK and/or PD results were included. Studies on patients <18 years old or with classical TDM-guided therapy were excluded. New approaches in TDM-guided therapy in septic critically ill patients based on PK and/or PD parameters are presented for cefiderocol, carbapenems, combinations beta-lactams/beta-lactamase inhibitors (piperacillin/tazobactam, ceftolozane/tazobactam, ceftazidime/avibactam), plazomicin, oxazolidinones and polymyxins. Increased midazolam toxicity in combination with fluconazole, nephrotoxic synergism between furosemide and aminoglycosides, life-threatening hypoglycemia after fluoroquinolone and insulin, prolonged muscle weakness and/or paralysis after neuromuscular blocking agents and high-dose corticosteroids combinations are of interest in critically ill patients. In the real-world practice, the use of probiotics with antibiotics is common; even data about the risk and benefits of probiotics are currently spares and inconclusive. According to current legislation, probiotic use does not require safety monitoring, but there are reports of endocarditis, meningitis, peritonitis, or pneumonia associated with probiotics in critically ill patients. In addition, probiotics are associated with risk of the spread of antimicrobial resistance. The TDM-guided method ensures a true optimization of antibiotic therapy, and particular efforts should be applied globally. In addition, multidrug and drug-nutrient interactions in critically ill patients may increase the likelihood of adverse events and risk of death; therefore, the PK and PD particularities of the critically ill patient require a multidisciplinary approach in which knowledge of clinical pharmacology is essential.
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Antibacterianos , Enfermedad Crítica , Humanos , Adolescente , Enfermedad Crítica/terapia , Antibacterianos/efectos adversos , Tazobactam , Combinación Piperacilina y Tazobactam/farmacocinéticaRESUMEN
INTRODUCTION: To determine appropriate dosing of piperacillin-tazobactam in critically ill patients receiving continuous renal replacement therapy (CRRT). METHODS: The databases of PubMed, Embase, and ScienceDirect were searched. We used the Medical Subject Headings of "piperacillin-tazobactam," "CRRT," and "pharmacokinetics" or related terms or synonym to identify the studies for reviews. A one-compartment pharmacokinetic model was conducted to predict piperacillin levels for the initial 48 h of therapy. The pharmacodynamic target was 50% of free drug level above the minimum inhibitory concentration (MIC) and 4 times of the MIC. The dose that achieved at least 90% of the probability of target attainment was defined as an optimal dose. RESULTS: Our simulation study reveals that the dosing regimen of piperacillin-tazobactam 12 g/day is appropriate for treating Pseudomonal infection with KDIGO recommended effluent rate of 25-35 mL/kg/h. The MIC values of each setting were an important factor to design piperacillin-tazobactam dosing regimens. CONCLUSION: The Monte Carlo simulation can be a useful tool to evaluate drug dosing in critically ill acute kidney injury patients receiving CRRT when limited pharmacokinetic data are a concern. Clinical validation of these results is needed.
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Lesión Renal Aguda , Terapia de Reemplazo Renal Continuo , Humanos , Antibacterianos , Enfermedad Crítica/terapia , Diálisis Renal , Combinación Piperacilina y Tazobactam/farmacocinética , Piperacilina/farmacocinética , Lesión Renal Aguda/terapia , Pruebas de Sensibilidad Microbiana , Terapia de Reemplazo RenalRESUMEN
OBJECTIVES: To explore extracorporeal membrane oxygenation (ECMO)-related alterations of the pharmacokinetics (PK) of piperacillin/tazobactam and determine an optimal dosage regimen for critically ill adult patients. METHODS: Population PK models for piperacillin/tazobactam were developed using a non-linear mixed effect modelling approach. The percentage of time within 24â h for which the free concentration exceeded the MIC at a steady-state (50%fT>MIC, 100%fT>MIC, and 100%fT>4×MIC) for various combinations of dosage regimens and renal function were explored using Monte-Carlo simulation. RESULTS: A total of 226 plasma samples from 38 patients were used to develop a population PK model. Piperacillin/tazobactam PK was best described by two-compartment models, in which estimated glomerular filtration rate (eGFR), calculated using CKD-EPI equation based on cystatin C level, was a significant covariate for total clearance of each piperacillin and tazobactam. ECMO use decreased the central volume of distribution of both piperacillin and tazobactam in critically ill patients. Patients with Escherichia coli or Klebsiella pneumoniae infection, but not those with Pseudomonas aeruginosa infection, exhibited a PK/pharmacodynamic target attainment >90% when the target is 50%fT>MIC, as a result of applying the currently recommended dosage regimen. Prolonged or continuous infusion of 16â g/day was required when the treatment goal was 100%fT>MIC or 100%fT>4×MIC, and patients had an eGFR of 130-170â mL/min/1.73â m2. CONCLUSIONS: ECMO use decreases piperacillin/tazobactam exposure. Prolonged or continuous infusion can achieve the treatment target in critically ill patients, particularly when MIC is above 8â mg/L or when patients have an eGFR of 130-170â mL/min/1.73â m2.
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Enfermedad Crítica , Oxigenación por Membrana Extracorpórea , Adulto , Antibacterianos/farmacología , Enfermedad Crítica/terapia , Humanos , Pruebas de Sensibilidad Microbiana , Ácido Penicilánico/farmacocinética , Piperacilina/farmacocinética , Combinación Piperacilina y Tazobactam/farmacocinética , República de Corea , Tazobactam/farmacocinéticaRESUMEN
BACKGROUND: Children with febrile neutropenia commonly exhibit alterations of pharmacokinetic (PK) parameters, leading to decreased ß-lactam concentrations. AIMS: This study evaluated piperacillin PK and probability of target attainment (PTA) with continuous infusion of piperacillin-tazobactam, in order to optimize the dosing regimen. METHODS: This prospective PK study included children with cancer, aged 1-17 years, who were treated with piperacillin-tazobactam for suspected or verified infection. A piperacillin-tazobactam loading dose (100 mg/kg) was administered followed by continuous infusion (300 mg/kg/day). The unbound fraction of piperacillin was quantified by high-performance liquid chromatography and PK were described using population PK modeling. PK data was used to update and extend a previous PK model built on data following intermittent administration. Monte Carlo simulations were performed to assess PTA for targets of 100% time above the minimum inhibitory concentration (100% fT > MIC) and 50% fT > 4xMIC. RESULTS: We included 68 fever episodes among 38 children with a median (IQR) age of 6.5 years and body weight of 27.4 kg (15.1-54.0). A three-compartment model adequately described the concentration-time data. Median (95% confidence interval) estimates for clearance and piperacillin concentration at steady state were 14.2 L/h/70 kg (13.0; 15.3) and 47.6 mg/L (17.2; 129.5), respectively. Body weight or lean body weight was significantly associated with the PK parameters, and body weight was integrated in the final PK model. Based on piperacillin exposure, continuous infusion was the only dosing regimen to achieve optimal PTA for the P. aeruginosa breakpoint (16 mg/L) with the target of 100% fT > MIC, and a daily dose of 300 mg/kg reached optimal PTA. The strict target of 50% fT > 4xMIC (64 mg/L) was not feasibly attained by any dosing regimen at recommended doses. CONCLUSION: Unlike conventional piperacillin intermittent administration and extended infusion regimens, continuous infusion allows the target of 100% fT > MIC to be reached for children with febrile neutropenia.
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Neutropenia Febril , Neoplasias , Antibacterianos , Peso Corporal , Niño , Neutropenia Febril/tratamiento farmacológico , Fiebre/tratamiento farmacológico , Fiebre/etiología , Humanos , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , Piperacilina/farmacocinética , Piperacilina/uso terapéutico , Combinación Piperacilina y Tazobactam/farmacocinética , Combinación Piperacilina y Tazobactam/uso terapéutico , Estudios ProspectivosRESUMEN
Methicillin-resistant Staphylococcus aureus (MRSA) infections of surgically implanted subcutaneous vascular catheters (SISVCs) cause serious morbidity in patients with chronic illnesses. Previous in vitro and murine models demonstrated the synergistic interaction of equimolar concentrations of meropenem/piperacillin/tazobactam (MPT) (VIO-001) against MRSA infection. We investigated the pharmacokinetics (PK) and efficacy of VIO-001 for the treatment of MRSA bacteremia in immunocompetent rabbits with SISVCs. In PK studies, we determined that optimal dosing to achieve a time above 4× MIC (T>4×MIC) of a duration of 3 to 3.30 h required a 1-h infusion with every-4-h (Q4h) dosing. Study groups in efficacy experiments consisted of MPT combinations of 100/150/100 mg/kg of body weight (MPT100), 200/300/200 mg/kg (MPT200), and 400/600/400 mg/kg (MPT400); vancomycin (VAN) at 15 mg/kg; and untreated controls (UC). The inoculum of MRSA isolate USA300-TCH1516 (1 × 103 organisms) was administered via the SISCV on day 1 and locked for 24 h. The 8-day therapy started at 24 h postinoculation. There was a significant reduction of MRSA in blood cultures from the SISVCs in all treatment groups, with full clearance on day 4, versus UCs (P < 0.05). Consistent with the clearance of SISVC-related infection, full eradication of MRSA was achieved in lungs, heart, liver, spleen, and kidneys at the end of the study versus UC (P < 0.01). These results strongly correlated with time-kill data, where MPT in the range of 4/6/4 µg/ml to 32/48/32 µg/ml demonstrated a significant 6-log decrease in the bacterial burden versus UC (P < 0.01). In summary, VIO-001 demonstrated a favorable PK/pharmacodynamic (PD) profile and activity against SISCV MRSA infection, bacteremia, and disseminated infection. This rabbit model provides a new system for understanding new antimicrobial agents against MRSA SISVC-related infection, and these data provide a basis for future clinical investigation.
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Antibacterianos/farmacocinética , Bacteriemia , Staphylococcus aureus Resistente a Meticilina , Infecciones Estafilocócicas , Dispositivos de Acceso Vascular , Animales , Antibacterianos/uso terapéutico , Bacteriemia/tratamiento farmacológico , Meropenem , Pruebas de Sensibilidad Microbiana , Combinación Piperacilina y Tazobactam/farmacocinética , Combinación Piperacilina y Tazobactam/uso terapéutico , Conejos , Infecciones Estafilocócicas/tratamiento farmacológico , Distribución TisularRESUMEN
Continuous infusion (CI) piperacillin/tazobactam is frequently used to treat infections in very elderly patients. This study aimed to conduct a population pharmacokinetic analysis of CI piperacillin/tazobactam, and to identify optimal dosages for safe and effective probability of target attainment (PTA) against Enterobacterales and Pseudomonas aeruginosa. Non-linear mixed-effects modelling was performed with Pmetrics. Monte Carlo simulations assessed the steady-state concentration (Css) of increasing piperacillin/tazobactam regimens (from 2.25 to 18 g daily by continuous infusion). Permissible doses were defined as those associated with <10% probability of Css >157.2 mg/L. PTA at the pharmacodynamic targets of free plasma steady-state concentration (fCss)/minimum inhibitory concentration (MIC) ≥1 and ≥4 and cumulative fraction of response (CFR) against EUCAST MIC distribution were also calculated. A total of 141 patients (median age 85 years) provided 217 plasma piperacillin Css. Most patients (55.2%) had hospital-acquired pneumonia and intra-abdominal infections. A one-compartment pharmacokinetic model with parallel linear and Michaelis-Menten elimination best described piperacillin data. Creatinine clearance (CLCR) was the covariate retained by the model. Pharmacokinetic estimates were 6.05 L/h for clearance and 3.39 mg/L for the Michaelis-Menten constant. Permissible doses were up to 4.5, 9, 11.25 and 13.5 g daily by continuous infusion for patients with CLCR of 0-19, 20-39, 40-59 and 60-79 mL/min/1.73 m2, respectively. At the clinical breakpoint of 8 mg/L, the permissible doses only achieved optimal PTA for fCss/MIC ≥1 in patients with CLCR 20-79 mL/min/1.73 m2. Optimal CFRs with the permissible doses were only attained against Escherichia coli and Proteus mirabilis. Permissible dosages and CLCR should be considered for prescribing CI piperacillin/tazobactam in very elderly patients.
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Antibacterianos/uso terapéutico , Infecciones por Enterobacteriaceae/tratamiento farmacológico , Combinación Piperacilina y Tazobactam/farmacocinética , Combinación Piperacilina y Tazobactam/uso terapéutico , Infecciones por Pseudomonas/tratamiento farmacológico , Inhibidores de beta-Lactamasas/uso terapéutico , Anciano de 80 o más Años , Antibacterianos/farmacocinética , Enterobacteriaceae/efectos de los fármacos , Femenino , Humanos , Infusiones Intravenosas , Italia , Masculino , Pruebas de Sensibilidad Microbiana , Método de Montecarlo , Pseudomonas aeruginosa/efectos de los fármacos , Estudios Retrospectivos , Inhibidores de beta-Lactamasas/farmacocinéticaRESUMEN
BACKGROUND AND OBJECTIVES: Morbidity and mortality from serious infections are common in intensive care units (ICUs). The appropriateness of the antibiotic treatment is essential to combat sepsis. We aimed to evaluate pharmacokinetic/pharmacodynamic target attainment of meropenem and piperacillin/tazobactam administered at standard total daily dose as continuous infusion in critically ill patients without renal dysfunction and to identify risk factors of non-pharmacokinetic/pharmacodynamic target attainment. RESULTS: We included 118 patients (149 concentrations), 47% had microorganism isolation. Minimum inhibitory concentration (MIC) [median (interquartile range, IQR) values in isolated pathogens were: meropenem: 0.05 (0.02-0.12) mg/l; piperacillin: 3 (1-4) mg/l]. Pharmacokinetic/pharmacodynamic target attainments (100%fCss≥1xMIC, 100%fCss≥4xMIC and 100%fCss ≥ 8xMIC, respectively) were: 100%, 96.15%, 96.15% (meropenem) and 95.56%, 91.11%, 62.22% (piperacillin) for actual MIC; 98.11%, 71.70%, 47.17% (meropenem, MIC 2 mg/l), 95.83%, 44.79%, 6.25% (piperacillin, MIC 8 mg/l), 83.33%, 6.25%, 1.04% (piperacillin, MIC 16 mg/l) for EUCAST breakpoint of Enterobacteriaceae spp. and Pseudomonas spp. Multivariable linear analysis identified creatinine clearance (CrCL) as a predictive factor of free antibiotic concentrations (fCss) of both therapies (meropenem [ß = - 0.01 (95% CI - 0.02 to - 0.0; p = 0.043)] and piperacillin [ß = - 0.01 (95% CI - 0.02 to 0.01, p < 0.001)]). Neurocritical status was associated with lower piperacillin fCss [ß = - 0.36 (95% CI - 0.61 to - 0.11; p = 0.005)]. CONCLUSION: Standard total daily dose of meropenem allowed achieving pharmacokinetic/pharmacodynamic target attainments in ICU patients without renal dysfunction. Higher doses of piperacillin/tazobactam would be needed to cover microorganisms with MIC > 8 mg/l. CrCL was the most powerful factor predictive of fCss in both therapies.
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Antibacterianos/administración & dosificación , Meropenem/administración & dosificación , Combinación Piperacilina y Tazobactam/administración & dosificación , Sepsis/tratamiento farmacológico , Anciano , Antibacterianos/farmacocinética , Antibacterianos/farmacología , Enfermedad Crítica , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Infusiones Intravenosas , Unidades de Cuidados Intensivos , Masculino , Meropenem/farmacocinética , Meropenem/farmacología , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Combinación Piperacilina y Tazobactam/farmacocinética , Combinación Piperacilina y Tazobactam/farmacología , Estudios Prospectivos , Factores de Riesgo , Sepsis/microbiologíaRESUMEN
BACKGROUND AND OBJECTIVE: Standard piperacillin-tazobactam (P-T) dosing may be suboptimal in obesity, but high-dose regimens have not been studied. We prospectively evaluated the pharmacokinetics and pharmacodynamics of standard- and high-dose P-T in obese adult inpatients. METHODS: Those receiving standard-dose P-T with BMI ≥ 30 kg/m2 weighing 105-139 kg or ≥ 140 kg were given up to 6.75 g or 9 g every 6 h, respectively. Patients were monitored closely for safety. Elimination phase blood samples were drawn for 28 patients on standard and high doses to calculate the pharmacokinetic values using a one-compartment model. The likelihood of pharmacodynamic target attainment (100% fT > 16/4 mg/L) on various P-T regimens was calculated using each patient's own pharmacokinetic values. RESULTS: Piperacillin and tazobactam half-lives ranged from 0.5-10.6 to 0.9-15.0 h, while volumes of distribution ranged from 13.6-54.8 to 11.5-60.1 L, respectively. Predicted dose requirements for target attainment ranged from 2.25 g every 6 h in hemodialysis patients to a 27 g/24-h continuous infusion in a patient with a short P-T half-life. An amount of 4.5 g every 6 h would have met the target for only 1/12 (8%) patients with creatinine clearance ≥ 80 mL/min and 13/28 (46%) for all enrolled patients. One patient (3%) experienced an adverse event deemed probably related to high-dose P-T. CONCLUSION: Some patients required high P-T doses for target attainment, but dosing requirements were highly variable. Doses up to 6.75 g or 9 g every 6 h may be tolerable; however, studies are needed to see if high dosing, prolonged infusions, or real-time therapeutic drug monitoring improves outcomes in obese patients. CLINICAL TRIAL REGISTRATION (CLINICALTRIALS.GOV): NCT01923363.
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Antibacterianos/administración & dosificación , Modelos Biológicos , Obesidad/epidemiología , Combinación Piperacilina y Tazobactam/administración & dosificación , Adulto , Anciano , Antibacterianos/farmacocinética , Antibacterianos/farmacología , Creatinina/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Semivida , Humanos , Persona de Mediana Edad , Combinación Piperacilina y Tazobactam/farmacocinética , Combinación Piperacilina y Tazobactam/farmacología , Estudios Prospectivos , Diálisis Renal , Distribución Tisular , Adulto JovenAsunto(s)
Lesión Renal Aguda/inducido químicamente , Antibacterianos/efectos adversos , Neutropenia Febril/prevención & control , Neoplasias Hematológicas/epidemiología , Combinación Piperacilina y Tazobactam/efectos adversos , Vancomicina/efectos adversos , Anciano , Anciano de 80 o más Años , Antibacterianos/administración & dosificación , Antibacterianos/farmacocinética , Quimioterapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Combinación Piperacilina y Tazobactam/administración & dosificación , Combinación Piperacilina y Tazobactam/farmacocinética , Estudios Retrospectivos , Vancomicina/administración & dosificación , Vancomicina/farmacocinéticaRESUMEN
OBJECTIVES: Piperacillin is a ß-lactam antimicrobial frequently used in critically ill patients with acute kidney injury treated with continuous renal replacement therapy (CRRT). However, data regarding piperacillin tissue concentrations in this patient population are limited. A prospective observational study was conducted of free piperacillin concentrations during a single 8-h dosing interval in plasma (8 samples) and subcutaneous tissue (SCT) (13 samples), in 10 patients treated with CRRT following piperacillin 4 g given every 8 h as intermittent administration over 3 min. METHODS: A population pharmacokinetic model was developed using NONMEM 7.4.3, to simulate alternative administration modes and dosing regimens. SCT concentrations were obtained using microdialysis. Piperacillin concentrations were compared to the clinical breakpoint minimum inhibitory concentration (MIC) for Pseudomonas aeruginosa (16 mg/l), with evaluation of the following pharmacokinetic/pharmacodynamics targets: 50% fT > 1 × MIC, 100% fT > 1 × MIC, and 100% fT > 4 × MIC. RESULTS: SCT concentrations were generally lower than plasma concentrations. For the target of 50% free time (fT) > 1 × MIC and 100% fT > 1 × MIC, piperacillin 4 g every 8 h resulted in probability of target attainment (PTA) >90% in both plasma and SCT. PTA > 90% for the target of 100% fT > 4 × MIC was only achieved for continuous infusion. CONCLUSIONS: Piperacillin 4 g every 8 h is likely to provide sufficient exposure in both plasma and SCT to treat P.aeruginosa infections in critically ill patients on CRRT, given that targets of 50% fT > 1 × MIC or 100% fT > 1 × MIC are adequate. However, if a more aggressive target of 100% fT > 4 × MIC is adopted, continuous infusion is needed.
Asunto(s)
Antibacterianos/farmacocinética , Infecciones Bacterianas/tratamiento farmacológico , Terapia de Reemplazo Renal Continuo , Combinación Piperacilina y Tazobactam/farmacocinética , Tejido Subcutáneo/metabolismo , Anciano , Anciano de 80 o más Años , Antibacterianos/uso terapéutico , Infecciones Bacterianas/microbiología , Simulación por Computador , Femenino , Humanos , Masculino , Modelos Biológicos , Combinación Piperacilina y Tazobactam/sangre , Combinación Piperacilina y Tazobactam/uso terapéutico , Estudios Prospectivos , Infecciones por Pseudomonas/tratamiento farmacológico , Pseudomonas aeruginosa/efectos de los fármacosRESUMEN
The percentage of the time that the free drug concentration remains above a concentration threshold (%fT > concentration threshold) has frequently been identified to be the optimal pharmacokinetic (PK)-pharmacodynamic (PD) target of interest for tazobactam using in vitro infection models. Similar in vitro models suggested that an 85% fT > concentration threshold of 2 µg/ml for tazobactam is required to demonstrate a 2-log10-unit decrease in the number of CFU per milliliter from that at the baseline at 24 h for high-level ß-lactamase-producing Escherichia coli strains. The objective of this study was to characterize the tazobactam concentrations in a cohort of critically ill patients with Gram-negative bacterial infections, determine if traditional dosing regimens achieve a prespecified PK/PD target of an 80% fT > concentration threshold of 2 µg/ml, and propose alternative dosing regimens. Hospitalized critically ill adult patients receiving piperacillin-tazobactam (TZP) for a culture-positive Gram-negative bacterial infection were eligible to consent for study inclusion. Two blood samples were drawn, one during the midpoint of the dosing interval and one at the time of the trough concentration once the patient achieved PK steady state. A population PK model was developed using Phoenix NLME (v8.1) software to characterize the observed concentration-time profile of tazobactam, explore potential covariates to explain the variability in the clearance and volume parameters, and to simulate potential dosing regimens that would achieve the PK/PD target. The PK of tazobactam were adequately described by a one-compartment model with first-order elimination in 18 patients who provided consent. The final model incorporated creatinine clearance as a covariate on clearance. Simulations demonstrated target attainments of less than 50% for tazobactam using traditional dosing regimens (4/0.5 g over 30 min every 6 h). Target attainments of greater than 75% were achieved when using extended infusion times of 4 to 6 h or when administering TZP as a continuous infusion (16/2 g over 24 h). Traditional tazobactam dosing regimens fail to achieve conservative PK/PD targets in critically ill patients. Increases in the tazobactam dose or prolongation of the infusion rate may be warranted to achieve activity against ß-lactamase-producing Gram-negative bacteria.
Asunto(s)
Enfermedad Crítica , Tazobactam/sangre , Tazobactam/farmacocinética , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Combinación Piperacilina y Tazobactam/sangre , Combinación Piperacilina y Tazobactam/farmacocinética , Estudios Prospectivos , Inhibidores de beta-Lactamasas/sangre , Inhibidores de beta-Lactamasas/farmacocinéticaRESUMEN
This exploratory study aimed to develop a risk prediction model of vancomycin-associated nephrotoxicity (VANT) in elderly patients. Clinical information of elderly patients who received vancomycin therapy from January 2016 to June 2018 was retrieved. A total of 255 patients were included in this study. Univariate analysis and multivariable logistic regression analysis revealed that vancomycin trough concentration ≥ 20 mg/L (odds ratio (OR) = 3.009; 95% confidence interval (CI) 1.345-6.732), surgery (OR = 3.357; 95% CI 1.309-8.605), the Charlson Comorbidities Index ≥ 4 points (OR = 2.604; 95% CI 1.172-5.787), concomitant use of cardiotonic drug (OR = 3.283; 95% CI 1.340-8.042), plasma volume expander (OR = 3.459; 95% CI 1.428-8.382), and piperacillin/tazobactam (OR = 2.547; 95% CI 1.680-6.007) were risk factors for VANT in elderly patients. Furthermore, a VANT risk prediction model was developed, which had good discriminative power and was well-calibrated.
Asunto(s)
Lesión Renal Aguda/epidemiología , Antibacterianos/efectos adversos , Combinación Piperacilina y Tazobactam/efectos adversos , Infecciones Estafilocócicas/tratamiento farmacológico , Vancomicina/efectos adversos , Lesión Renal Aguda/inducido químicamente , Factores de Edad , Anciano , Anciano de 80 o más Años , Antibacterianos/farmacocinética , Comorbilidad , Quimioterapia Combinada/efectos adversos , Quimioterapia Combinada/métodos , Quimioterapia Combinada/estadística & datos numéricos , Femenino , Humanos , Modelos Logísticos , Masculino , Staphylococcus aureus Resistente a Meticilina/aislamiento & purificación , Persona de Mediana Edad , Análisis Multivariante , Proyectos Piloto , Combinación Piperacilina y Tazobactam/farmacocinética , Estudios Retrospectivos , Medición de Riesgo/métodos , Factores de Riesgo , Infecciones Estafilocócicas/diagnóstico , Infecciones Estafilocócicas/epidemiología , Infecciones Estafilocócicas/microbiología , Vancomicina/farmacocinéticaRESUMEN
OBJECTIVE: We analysed the pharmacokinetics of meropenem and piperacillin-tazobactam in patients undergoing a standardised session of sustained low efficiency haemodiafiltration (SLED-HDF) to inform the dosing of these drugs in an acute setting. PARTICIPANTS: Six stable patients with end-stage kidney disease. METHODS: An open-label pilot pharmacokinetic study of meropenem and piperacillin-tazobactam. SLED-HDF was undertaken for 4 h. Plasma drug concentrations were measured pre- and post-filter and in the effluent at multiple time points. The pharmacokinetic data was analysed using non-compartmental methods. The fraction of time that individual plasma concentration profiles were predicted to remain above the MIC break-points for commonly isolated gram-negative pathogens during a prolonged SLED-HDF session was assessed using two targets; fT > MIC (fraction of time above the MIC) and the more aggressive fT > 4 × MIC (fraction of time above 4 × MIC). RESULTS: Meropenem total and SLED-HDF clearance ranged from 141 to 180 mL/min and 126-205 mL/min, respectively. Piperacillin total and SLED-HDF clearance values ranged from 131 to 252 mL/min and 135-162 mL/min, respectively. Our results suggest that prolonged SLED-HDF (12 h) will only maintain a sufficient meropenem and piperacillin-tazobactam plasma concentration to achieve a target of fT > MIC for gram-negative pathogens (MIC 2 mg/L-meropenem, 8 mg/L-piperacillin-tazobactam) for less than 40% of the time. Plasma concentrations would be inadequate to achieve the more aggressive target of 100 % fT > 4xMIC target recommended for critically unwell patients. CONCLUSIONS: The pharmacokinetic data obtained from this pilot study demonstrate significant quantities of meropenem and piperacillin are removed during a SLED-HDF session. This may lead to subtherapeutic concentrations of piperacillin and meropenem over the duration of HDF session. TRIAL REGISTRATION: Australasian Clinical Trials Registry Network (ACTRN12616000078459).
Asunto(s)
Antibacterianos/farmacocinética , Hemodiafiltración/métodos , Meropenem/farmacocinética , Combinación Piperacilina y Tazobactam/farmacocinética , Adulto , Anciano , Antibacterianos/administración & dosificación , Femenino , Humanos , Fallo Renal Crónico/terapia , Masculino , Meropenem/administración & dosificación , Persona de Mediana Edad , Proyectos Piloto , Combinación Piperacilina y Tazobactam/administración & dosificaciónRESUMEN
PURPOSE: Standard dosing and intermittent bolus application (IB) are important risk factors for pharmacokinetic (PK) target non-attainment during empirical treatment with ß-lactams in critically ill patients, particularly in those with sepsis and septic shock. We assessed the effect of therapeutic drug monitoring-guided (TDM), continuous infusion (CI) and individual dosing of piperacillin/tazobactam (PIP) on PK-target attainment in critically ill patients. METHODS: This is a retrospective, single-center analysis of a database including 484 patients [933 serum concentrations (SC)] with severe infections, sepsis and septic shock who received TDM-guided CI of PIP in the intensive care unit (ICU) of an academic teaching hospital. The PK-target was defined as a PIP SC between 33 and 64 mg/L [fT > 2-4 times the epidemiological cutoff value (ECOFF) of Pseudomonas aeruginosa (PSA)]. RESULTS: PK-target attainment with standard dosing (initial dose) was observed in 166 patients (34.3%), whereas only 49 patients (10.1%) demonstrated target non-attainment. The minimum PK-target of ≥ 33 mg/L was overall realized in 89.9% (n = 435/484) of patients after the first PIP dose including 146 patients (30.2%) with potentially harmful SCs ≥ 100 mg/L. Subsequent TDM-guided dose adjustments significantly enhanced PK-target attainment to 280 patients (62.4%) and significantly reduced the fraction of potentially overdosed (≥ 100 mg/L) patients to 4.5% (n = 20/449). Renal replacement therapy (RRT) resulted in a relevant reduction of PIP clearance (CLPIP): no RRT CLPIP 6.8/6.3 L/h (median/IQR) [SCs n = 752, patients n = 405], continuous veno-venous hemodialysis (CVVHD) CLPIP 4.3/2.6 L/h [SCs n = 160, n = 71 patients], intermittent hemodialysis (iHD) CLPIP 2.6/2.3 L/h [SCs n = 21, n = 8 patients]). A body mass index (BMI) of > 40 kg/m2 significantly increased CLPIP 9.6/7.7 L/h [SC n = 43, n = 18 patients] in these patients. Age was significantly associated with supratherapeutic PIP concentrations (p < 0.0005), whereas high CrCL led to non-target attainment (p < 0.0005). Patients with target attainment (33-64 mg/L) within the first 24 h exhibited the lowest hospital mortality rates (13.9% [n = 23/166], p < 0.005). Those with target non-attainment demonstrated higher mortality rates (≤ 32 mg/L; 20.8% [n = 10/49] ≥ 64 mg/L; 29.4% [n = 79/269]). CONCLUSION: TDM-guided CI of PIP is safe in critically ill patients and improves PK-target attainment. Exposure to defined PK-targets impacts patient mortality while lower and higher than intended SCs may influence the outcome of critically ill patients. Renal function and renal replacement therapy are main determinants of PK-target attainment. These results are only valid for CI of PIP and not for prolonged or intermittent bolus administration of PIP.
Asunto(s)
Antibacterianos/farmacocinética , Monitoreo de Drogas/estadística & datos numéricos , Infusiones Intravenosas/estadística & datos numéricos , Combinación Piperacilina y Tazobactam/farmacocinética , Infecciones por Pseudomonas/tratamiento farmacológico , Pseudomonas aeruginosa/efectos de los fármacos , Adolescente , Adulto , Anciano , Antibacterianos/uso terapéutico , Cuidados Críticos/estadística & datos numéricos , Enfermedad Crítica , Femenino , Alemania , Hospitales de Enseñanza , Humanos , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Combinación Piperacilina y Tazobactam/uso terapéutico , Estudios Retrospectivos , Adulto JovenRESUMEN
OBJECTIVE: To determine the percentage of patients given standard doses of piperacillin/tazobactam or meropenem by continuous infusion who achieved the target pharmacokinetic/pharmacodynamic (PK/PD) index, which was defined as free concentrations four times more than the minimum inhibitory concentration (CMI) for 100% of the dosing interval (100% fT≥ 4 x MIC). METHOD: Preliminary data from a larger prospective clinical study analysing the PK/PD behaviour of ß-lactams antibiotics continuous infusion (CI) in critical patients. The study was conducted in the intensive care units of a tertiary university hospital for adults (June 2015-May 2017). Inclusion criteria: normal renal function (glomerular renal function (GFR) CKD-EPI formula ≥ 60 mL/min/1.73 m2) and treatment with standard dose ß-lactams CI. Concentrations at steady state (Css) conditions were determined using UHPLC-MS/MS. We selected the highest susceptible MIC for all likely organisms according to European Commitee on Antimicrobial Susceptibility Testing's (i.e. piperacillin/tazobactam: 8 mg/L for enterobacteriaceae and 16 mg/L for Pseudomonas aeruginosa; meropenem: 2 mg/L for any microorganism). In addition, a subanalysis of patients was conducted using actual MIC values. RESULTS: 61 patients were enrolled (25 to meropenem and 36 to piperacillin/tazobactam). Average age was 59 (15) years and median GFR rate was 95 mL/min/1.73 m2 (83-115). Median meropenem and piperacillin free concentrations were 16 mg/L (11-29) and 40 mg/L (21- 51), respectively. 88% of patients treated with meropenem reached the PK/PD target, without differences between both microorganisms. For piperacillin/tazobactam, 61% and 11% of patients reached the target, with enterobacteriaceae and Pseudomonas as suspected microorganisms, respectively. The pathogen was isolated in 35 (57%) patients: 94% reached the target PK/PD, without differences between both antibiotic therapies. CONCLUSIONS: Standard doses of meropenem CI are sufficient to achieve a PK/PD target of 100% fT≥ 4 x MIC in suspected infections with high MICs (Pseudomonas aeruginosa or enterobacteriaceae). However, higher doses of piperacillin/tazobactam could be considered to achieve this goal. In patients with isolated microorganisms, a standard dose of both antibiotic therapies would be sufficient to achieve the target. Therapeutic drug monitoring is highly recommended for therapeutic optimization.
Objetivo: Determinar el porcentaje de pacientes, a los que se les administró dosis estándar de piperacilina/tazobactam o meropenem en perfusión continua, que alcanzaban el índice farmacocinético/farmacodinámico diana definido como el 100% del intervalo de administración en que las concentraciones de antibiótico libre fueron cuatro veces iguales o superiores a la concentración mínima inhibitoria (100% fT ≥ 4 x CMI).Método: Datos preliminares obtenidos de un estudio clínico prospectivo que analiza el comportamiento farmacocinético/farmacodinámico de los antibióticos betalactámicos administrados en perfusión continua en pacientes críticos. Se realizó en unidades de cuidados intensivos de un hospital universitario de tercer nivel, desde junio de 2015 a mayo de 2017. Criterios de inclusión: adultos con función renal correcta (filtrado glomerular según la fórmula CKD-EPI ≥ 60 ml/min/1,73 m2) y tratados con dosis estándar de antibióticos betalactámicos en perfusión continua. Las concentraciones en estado de equilibrio estacionario fueron determinadas mediante cromatografía líquida acoplada a espectrometría de masas (UHPLC- MS/MS). Se utilizaron valores de concentración mínima inhibitoria teóricos para microorganismos más resistentes (piperacilina/ tazobactam: 16 mg/l para Pseudomonas aeruginosa y 8 mg/l para Enterobacteriaceae; meropenem: 2 mg/l, independientemente del microorganismo). Además, se realizó un subanálisis de los pacientes con aislamiento microbiológico (concentraciones mínimas inhibitorias reales).Resultados: Se incluyeron 61 pacientes (25 meropenem y 36 piperacilina/ tazobactam). Edad media 59 años (15), mediana de filtrado glomerular 95 ml/min/1,73 m2 (83-115). Mediana de concentraciones en estado de equilibrio estacionario libre: 16 mg/l (11- 29) meropenem y 40 mg/l (21-51) piperacilina. El 88% de los pacientes tratados con meropenem alcanzaron el objetivo farmacocinético/farmacodinámico, sin diferencias entre Enterobacteriaceae y Pseudomonas. En el caso de piperacilina/tazobactam, el 61% y el 11% de los pacientes alcanzaron la diana, considerando Enterobacteriaceae y Pseudomonas como microorganismo sospechoso. Un total de 35 (57%) pacientes presentaron aislamiento microbiológico. El 94% de ellos alcanzaron la diana, sin diferencias entre los dos antibióticos.Conclusiones: Ante la sospecha de infecciones por microorganismos con concentraciones mínimas inhibitorias elevadas (Pseudomonas aeruginosa o enterobacterias), se observa que dosis convencionales de meropenem en perfusión continua son suficientes para lograr la diana 100% fT≥ 4 x MIC. Sin embargo, se requerirían dosis superiores de piperacilina/tazobactam. En casos de aislamiento microbiológico, dosis estándar de ambos antibióticos fueron suficientes para lograr la diana. La monitorización farmacocinética es altamente recomendable para la optimización terapéutica.
Asunto(s)
Antibacterianos/administración & dosificación , Enfermedad Crítica/terapia , Meropenem/administración & dosificación , Combinación Piperacilina y Tazobactam/administración & dosificación , Adulto , Anciano , Antibacterianos/sangre , Antibacterianos/farmacocinética , Antibacterianos/uso terapéutico , Estudios Clínicos como Asunto/estadística & datos numéricos , Infección Hospitalaria/tratamiento farmacológico , Infecciones por Enterobacteriaceae/tratamiento farmacológico , Femenino , Hospitales Universitarios , Humanos , Infusiones Intravenosas , Unidades de Cuidados Intensivos , Masculino , Meropenem/sangre , Meropenem/farmacocinética , Meropenem/uso terapéutico , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Combinación Piperacilina y Tazobactam/sangre , Combinación Piperacilina y Tazobactam/farmacocinética , Combinación Piperacilina y Tazobactam/uso terapéutico , Estudios Prospectivos , Infecciones por Pseudomonas/tratamiento farmacológico , Centros de Atención TerciariaRESUMEN
Piperacillin-tazobactam (TZP) is frequently used to treat severe hospital-acquired infections in children. We performed a single-center, pharmacokinetic (PK) trial of TZP in children ranging in age from 2 months to 6 years from various clinical subpopulations. Children who were on TZP per the standard of care were prospectively included and assigned to receive a dose of 80 mg/kg of body weight every 6 h infused over 2 h (ages 2 to 5 months) or a dose of 90 mg/kg every 8 h infused over 4 h (ages 6 months to 6 years). Separate population PK models were developed for piperacillin and tazobactam using nonlinear mixed-effects modeling. Optimal dosing was judged based on the ability to maintain free piperacillin concentrations above the piperacillin MIC for enterobacteria and Pseudomonas aeruginosa for ≥50% of the dosing interval. Any untoward event occurring during treatment was collected as an adverse event. A total of 79 children contributed 174 PK samples. The median (range) age and weight were 1.7 years (2 months to 6 years) and 11.4 kg (3.8 to 27.6 kg), respectively. A 2-compartment model with first-order elimination best described the piperacillin and tazobactam data. Both final population PK models included weight and concomitant furosemide administration on clearance and weight on the volume of distribution of the central compartment. The optimal dosing regimens in children with normal renal function, based on the piperacillin component, were 75 mg/kg/dose every 4 h infused over 0.5 h in infants ages 2 to ≤6 months and 130 mg/kg/dose every 8 h infused over 4 h in children ages >6 months to 6 years against bacteria with MICs up to 16 mg/liter. A total of 44 children (49%) had ≥1 adverse event, with 3 of these (site infiltrations) considered definitely associated with the extended infusions.
Asunto(s)
Combinación Piperacilina y Tazobactam/efectos adversos , Combinación Piperacilina y Tazobactam/farmacocinética , Piperacilina/efectos adversos , Piperacilina/farmacocinética , Tazobactam/efectos adversos , Tazobactam/farmacocinética , Antibacterianos/efectos adversos , Antibacterianos/farmacocinética , Antibacterianos/uso terapéutico , Niño , Preescolar , Infección Hospitalaria/tratamiento farmacológico , Femenino , Humanos , Lactante , Masculino , Pruebas de Sensibilidad Microbiana/métodos , Piperacilina/uso terapéutico , Combinación Piperacilina y Tazobactam/uso terapéutico , Estudios Prospectivos , Infecciones por Pseudomonas/tratamiento farmacológico , Pseudomonas aeruginosa/efectos de los fármacos , Tazobactam/uso terapéuticoRESUMEN
BACKGROUND: The ß-lactam antibiotic piperacillin (in combination with tazobactam) is commonly chosen for empirical treatment of suspected bacterial infections. However, pharmacokinetic variability among patient populations and across ages leads to uncertainty when selecting a dosing regimen to achieve an appropriate pharmacodynamic target. OBJECTIVES: To guide dosing by establishing a population pharmacokinetic model for unbound piperacillin in febrile children receiving cancer chemotherapy, and to assess pharmacokinetic/pharmacodynamic target attainment (100% fTâ>â1×MIC and 50% fTâ>â4×MIC) and resultant exposure, across body weights. METHODS: Forty-three children admitted for 89 febrile episodes contributed 482 samples to the pharmacokinetic analysis. The typical doses required for target attainment were compared for various dosing regimens, in particular prolonged infusions, across MICs and body weights. RESULTS: A two-compartment model with inter-fever-episode variability in CL, and body weight included through allometry, described the data. A high CL of 15.4 L/h (70 kg) combined with high glomerular filtration rate (GFR) values indicated rapid elimination and hyperfiltration. The target of 50% fTâ>â4×MIC was achieved for an MIC of 4.0 mg/L in a typical patient with extended infusions of 2-3 (q6h) or 3-4 (q8h) h, at or below the standard adult dose (75 and 100 mg/kg/dose for q6h and q8h, respectively). Higher doses or continuous infusion were needed to achieve 100% fTâ>â1×MIC due to the rapid piperacillin elimination. CONCLUSIONS: The licensed dose for children with febrile neutropenia (80 mg/kg q6h as a 30 min infusion) performs poorly for attainment of fT>MIC pharmacokinetic/pharmacodynamic targets. Given the population pharmacokinetic profile, feasible dosing regimens with reasonable exposure are continuous infusion (100% fTâ>â1×MIC) or prolonged infusions (50% fTâ>â4×MIC).