piperacillin--tazobactam-drug-combination and Body-Weight

Although survival of children with hematological diseases and cancer has increased dramatically, febrile neutropenia (FN) is a frequently observed complication and is sometimes life-threatening in pediatric cancer patients. A prospective, randomized study was performed to clarify the usefulness of meropenem (MEPM) and piperacillin/tazobactam (PIPC/TAZ) for pediatric patients with FN. Ninety-nine patients with 394 episodes were randomly assigned to receive MEPM or PIPC/TAZ. MEPM was administered at 120 mg/kg/day as a 1-h drip infusion 3 times a day. On the other hand, PIPC/TAZ was administered at 360 mg/kg/day as a 1-h drip infusion 4 times a day. MEPM was effective in 69.5% of the 200 episodes, and PIPC/TAZ was effective in 77.2% of the 193 episodes. Compared with our previous study of MEPM 120 mg/kg/day as a 1-h drip infusion 3 times a day versus PIPC/TAZ 337.5 mg/kg/day as a 1-h drip infusion 3 times a day, the success rate of the MEPM group was not different. However, the success rate of the PIPC/TAZ group was higher than in the previous study (p = 0.001). In particular, the success rate in patients ≥ 15 years of age was improved in the PIPC/TAZ group of the present study compared with the previous study (p = 0.005).

Topics: Adolescent; Adult; Anti-Bacterial Agents; Bacteremia; Body Weight; Child; Child, Preschool; Drug Administration Schedule; Drug Therapy, Combination; Febrile Neutropenia; Historically Controlled Study; Humans; Immunologic Deficiency Syndromes; Infant; Infant, Newborn; Infusions, Intravenous; Maximum Tolerated Dose; Meropenem; Neoplasms; Piperacillin, Tazobactam Drug Combination; Stem Cell Transplantation; Young Adult

To develop population pharmacokinetic (PK) models for piperacillin/tazobactam in neonates and infants of less than 2 months of age in order to determine the appropriate dosing regimen and provide a rational basis for the development of preliminary dosing guidelines suitable for this population.. A two-stage, open-label study was conducted in neonates and infants less than 2 months of age in the neonatal intensive care unit (NICU). A total of 207 piperacillin and 204 tazobactam concentration-time data sets from 71 patients were analyzed using a nonlinear mixed-effect modeling approach (NONMEM VII). PK models were developed for piperacillin and tazobactam. The final models were evaluated using both bootstrap and visual predictive checks. External model evaluations were made in 20 additional patients.. For neonates and young infants less than 2 months of age, the median central clearance was 0.133 and 0.149 L/h/kg for piperacillin and tazobactam, respectively. Postmenstrual age (PMA) was identified as the most significant covariate on central clearance of piperacillin and tazobactam. However, the combination of current bodyweight (BW) and postnatal age proved to be superior to PMA alone. BW was the most important covariate for apparent central volume of distribution. Both internal and external evaluations supported the prediction of the final piperacillin and tazobactam PK models. The dosing strategy 44.44/5.56 mg/kg/dose piperacillin/tazobactam every 8 or 12 h evaluated in this study achieved the pharmacodynamic target (free piperacillin concentrations >4 mg/L for more than 50 % of the dosing interval) in about 67 % of infants.. Population PK models accurately described the PK profiles of piperacillin/tazobactam in infants less than 2 months of age. The results indicated that higher doses or more frequent dosing regimens may be required for controlling infection in this population in NICU.

Topics: Age Factors; Anti-Bacterial Agents; Body Weight; China; Computer Simulation; Drug Dosage Calculations; Drug Monitoring; Female; Humans; Infant; Infant, Newborn; Intensive Care Units, Neonatal; Male; Models, Biological; Nonlinear Dynamics; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination

Children with febrile neutropenia commonly exhibit alterations of pharmacokinetic (PK) parameters, leading to decreased β-lactam concentrations.. This study evaluated piperacillin PK and probability of target attainment (PTA) with continuous infusion of piperacillin-tazobactam, in order to optimize the dosing regimen.. 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.. 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.. 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.

Topics: Anti-Bacterial Agents; Body Weight; Child; Febrile Neutropenia; Fever; Humans; Neoplasms; Piperacillin; Piperacillin, Tazobactam Drug Combination; Prospective Studies

The average body weight is smaller in Asian patients compared with Western patients, but influence of body weight in antibiotic dosing is unknown. This study was to predict the optimal ceftazidime, cefepime, meropenem, piperacillin/tazobactam doses in Asian patients undergoing continuous venovenous hemofiltration (CVVH).. Monte Carlo simulations (MCS) were performed using published Asian demographics and pharmacokinetics parameters in 5000 virtual patients at three CVVH effluent rates (Qeff; 20, 30, 40 mL/kg/h). Various dosing regimens were assessed for the probability of target attainments using 60% fT > 1 × MIC or 4xMIC and neurotoxicity risk at 48-h using suggested neurotoxicity thresholds.. Ceftazidime 1 g q12h, meropenem 1 g q12h, and piperacillin/tazobactam 3.375 g q6h were optimal for all Qeff settings against fT > 1 × MIC. Cefepime 2 g q24h and 2 g q12h were optimal at 20 and 30-40 mL/kg/h respectively. For the aggressive PD target (4 × MIC), optimal ceftazidime regimens were 1.25 g q8h (20-30 mL/kg/h) and 1.5 g q8h (40 mL/kg/h). Cefepime 2 g q8h and meropenem 1 g q8h were optimal at all Qeff settings. No simulated piperacillin doses attained the aggressive PD target. Increased neurotoxicity risk was predicted with ceftazidime and cefepime doses attaining the efficacy.. MCS enabled the prediction of optimal β-lactam dosing regimens for Asian patients receiving CVVH at varying Qeff. Clinical validation is warranted.

Topics: Anti-Bacterial Agents; Body Weight; Cefepime; Ceftazidime; Critical Illness; Humans; Lactams; Meropenem; Microbial Sensitivity Tests; Piperacillin; Piperacillin, Tazobactam Drug Combination

The β-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.. 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% fT > 1×MIC and 50% fT > 4×MIC) and resultant exposure, across body weights.. 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.. 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% fT > 4×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% fT > 1×MIC due to the rapid piperacillin elimination.. 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% fT > 1×MIC) or prolonged infusions (50% fT > 4×MIC).

Topics: Adolescent; Anti-Bacterial Agents; Bacterial Infections; Body Weight; Child; Child, Preschool; Female; Fever; Glomerular Filtration Rate; Humans; Infant; Male; Microbial Sensitivity Tests; Neoplasms; Piperacillin; Piperacillin, Tazobactam Drug Combination; Tazobactam

Results of a study to determine whether obesity is associated with acute kidney injury (AKI) among patients receiving combination therapy with piperacillin-tazobactam and vancomycin are reported.. A retrospective, single-center cohort study of patients who received combination therapy for at least 48 hours was conducted using data from the University of Kentucky Center for Clinical and Translational Science's Enterprise Data Trust. Patients with chronic kidney disease, baseline creatinine clearance of less than 30 mL/min, cystic fibrosis, or missing height or weight information were excluded.. A total of 8,125 patients were included in the cohort. Among the variables evaluated, total body weight of 91 kg or more was the variable most predictive of AKI. Patients with a weight of 91 kg or higher were more likely than lower-weight patients to have diabetes (39% versus 21%, p < 0.00001), hypertension (64% versus 47%, p < 0.00001), and heart failure (15% versus 13%, p = 0.007). The median daily vancomcyin dose was lower in patients with a weight of less than 91 kg (2,000 mg versus 3,000 mg, p < 0.00001); however, weight-based doses were lower in patients weighing 91 kg or more (25.5 mg/kg/day versus 27.9 mg/kg/day, p < 0.00001). AKI was more common in patients weighing 91 kg or more (24% versus 18%, p < 0.00001; adjusted odds ratio, 1.46 [95% confidence interval, 1.28-1.66]).. Increased total body weight increased the rate of AKI among patients concurrently treated with piperacillin-tazobactam and vancomycin independent of clinically important confounders, with an important breakpoint occurring at 91 kg.

Topics: Acute Kidney Injury; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Body Weight; Drug Therapy, Combination; Female; Humans; Kentucky; Male; Middle Aged; Obesity; Piperacillin, Tazobactam Drug Combination; Retrospective Studies; Risk Factors; Vancomycin; Young Adult

The study was to establish a population pharmacokinetic (PPK) model of piperacillin (PIP) and tazobactam (TAZ) that explain pharmacokinetic variability and to propose optimized dosage regimens in patients with nosocomial infections.. In total, 310 PIP and 280 TAZ concentration-time points were collected at steady state over multiple dosing intervals from 50 patients who received PIP/TAZ infused within 30 min or over 3 h. Drug analysis was performed by high-performance liquid chromatography (HPLC). Nonlinear mixed effects modeling was employed to develop PPK model and 1000 Monte Carlo simulation was used to predict the probability of target attainment (PTA) with a target time of non-protein-bound concentration above MIC > 50 % of the dosing interval.. A model with one-compartment model had the best predictive performance for the PPK model. The population estimates of PIP were 13.8 L/h (31.1 %) for clearance (CL) and 21.7 L (38 %) for volume of distribution (V). The population estimates of TAZ were 9.3 L/h (29.1 %) for CL and 16 L (35.3 %) for V. Influence of creatinine clearance (CLcr) and body weight were identified as important covariates for PIP/TAZ CL and V, respectively. A 30-min infusion of 4 g every 6 h achieved robust (≥90 %) PTAs for MIC ≤ 16 mg/L. As an alternative mode of administration, a 3-h infusion of 4 g every 6 h achieved robust PTAs for Pseudomonas aeruginosa and Klebsiella pneumoniae.. Prolonged infusions achieved better PTAs compared with shorter infusions at similar daily doses. This benefit was most pronounced for MICs between 16 and 40 mg/L.

Topics: Anti-Bacterial Agents; Body Weight; Cross Infection; Female; Humans; Infusions, Intravenous; Male; Microbial Sensitivity Tests; Middle Aged; Models, Biological; Monte Carlo Method; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Tazobactam

This multicentre study aimed to describe the pharmacokinetics (PK) of piperacillin in critically ill patients with multiple organ dysfunction syndrome (MODS) receiving continuous venovenous haemodiafiltration (CVVHDF), to identify the sources of PK variability and evaluate different dosing regimens to develop recommendations based on clinical parameters.. Nineteen patients with MODS and CVVHDF receiving piperacillin/tazobactam were enrolled from three tertiary hospitals (95 plasma samples). Population PK modelling and Monte Carlo simulations were performed using NONMEM v7.3(®).. Patients' median age was 70 years (range 39-82), median weight was 80 kg (45-129), median APACHE II score at admission was 21 (13-33) and median SOFA score on the day of study was 11 (8-21). The final population PK model was characterized by CL (L/h) = 6.11 * [weight (kg)/80](1.39) * CLMEMB. If membrane = 1.5 m(2) AN69ST, CLMEMB = 1; if membrane = 0.9 m(2) AN69, CLMEMB = 0.51. Monte Carlo simulations showed that: (i) to maintain unbound piperacillin concentrations above the MIC for the bacteria for 100% of dosing interval T (100%fuT>MIC), patients receiving CVVHDF with 1.5 m(2) AN69ST membranes required doses of 4000 mg q8h for the treatment of bacteria with a susceptibility to piperacillin close to the clinical breakpoint (MIC = 8-16 mg/L) (2000 mg q8h was sufficient for patients with CVVHDF using 0.9 m(2) AN69 membranes); and (ii) for the treatment of bacteria with high susceptibility to piperacillin (MIC <4 mg/L) or for the attainment of a more traditional pharmacodynamic target (50%fuT>MIC), 2000 mg q8h sufficed regardless of type of membrane and body weight.. Our results suggest that type of membrane and body weight should be considered for piperacillin dose titration in critically ill patients with MODS and CVVHDF requirement.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Body Weight; Chromatography, Liquid; Critical Illness; Female; Hemodiafiltration; Humans; Infusions, Intravenous; Male; Mass Spectrometry; Microbial Sensitivity Tests; Middle Aged; Multiple Organ Failure; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Plasma; Prospective Studies; Tertiary Care Centers; Young Adult

Piperacillin/tazobactam, an intravenous antibacterial combination product, has recently been approved for paediatric (age 2 months to 17 years) use in the USA. The purpose of this analysis is to describe the basis for the dosing recommendations in this age group. Pharmacokinetic (PK) parameters and demographic covariates from 53 children enrolled in two paediatric studies were used in the analysis. Individual drug clearance (CL) values calculated by non-compartmental methods were available. The influence of demographic covariates on CL was investigated by non-linear regression. The analysis identified CL to be dependent on body weight. CL was also found to be influenced by age in paediatric patientsor=9 months, a dose of 100/12.5 mg/kg every 8h showed exposures similar to adults; for paediatric patients aged 2-9 months, the dose of 100/12.5 mg/kg should be reduced by a factor of 0.8 (i.e. 80/10 mg/kg), likely due to immature renal function. Based upon this analysis, dosing recommendations for paediatric patients down to 2 months of age were incorporated in the labelling. No data were available to allow additional recommendations for paediatric patients<2 months of age to be made.

Topics: Age Factors; Anti-Bacterial Agents; Body Weight; Child; Child, Preschool; Computer Simulation; Demography; Drug Labeling; Humans; Infant; Metabolic Clearance Rate; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Regression Analysis; Tissue Distribution