Validated HPLC-UV detection method for the simultaneous determination of ceftolozane and tazobactam in human plasma.

AIM: A simple, rapid, economical and sensitive HPLC-UV method was developed for the simultaneous quantification of ceftolozane and tazobactam in plasma samples. METHODOLOGY: After deproteinization followed by a liquid-liquid back-extraction, the compounds were separated on a C18 column (150 mm × 4.6 mm, 5 µm) with UV-visible detection at 220 nm. The mobile phase consisted of acetonitrile and potassium dihydrogenphosphate buffer at pH 3.0 (8:92, v/v), delivered isocratically at a flow rate of 1.0 ml/min and at a column oven temperature of 30°C. Cefepime was used as an internal standard. RESULTS: Linearity was achieved in the concentration range of 0.50-100.00 µg/ml for ceftolozane and 0.25-50.00 µg/ml for tazobactam. The intra- and interday precision showed good reproducibility with coefficients of variation of less than 9.26% for ceftolozane and 9.62% for tazobactam. CONCLUSION: The sample preparation procedure avoids expensive or time-consuming steps used by other previously published methods. The methodology was validated according to standard guidelines and was used for quantification of ceftolozane and tazobactam in plasma samples from critically ill patients.

A rapid, LC-MS/MS assay for quantification of piperacillin and tazobactam in human plasma and pleural fluid; application to a clinical pharmacokinetic study.

Piperacillin, in combination with tazobactam is a common first-line antibiotic used for the treatment of pleural infection, however its pleural pharmacokinetics and penetration has not previously been reported. The objective of this work was to develop and validate a rapid and sensitive liquid chromatography with tandem mass spectrometry (LC-MS/MS) assay for quantification of piperacillin (PIP) and tazobactam (TAZ). PIP and TAZ were extracted from both human plasma and pleural fluid samples by protein precipitation in methanol containing the internal standards (IS) piperacillin-d5 (PIP-d5) and sulbactam (SUL). Briefly, 5 µL of sample was mixed with 125 µL of methanol containing IS, vortexed and centrifuged. Supernatant (50 µL) was diluted into 500 µL of mobile phase containing 10 mM of ammonium bicarbonate in LCMS grade water and transferred to the autosampler tray. Electrospray ionization in positive mode and multiple reaction monitoring (MRM) were used for PIP and PIP-d5 at the transitions m/z 518.2 → 143.2 and m/z 523.2 → 148.2 respectively, and electrospray ionization in negative mode and MRM were used for TAZ and SUL at the transitions m/z 299.1 → 138.1 and m/z 232.4 → 140.1. The chromatographic separation was achieved using an Acquity BEH C-18 column with gradient elution of mobile phase containing 10 mmol/L ammonium bicarbonate in water and methanol. A linear range was observed over the concentration range of 0.25-352 mg/L and 0.25-50.5 mg/L for PIP and TAZ respectively. Complete method validation was performed according to US FDA guidelines for selectivity, specificity, precision and accuracy, LLOQ, matrix effects, recovery and stability, with all results within acceptable limits. This method was successfully applied to two patients with pleural infection and is suitable for further pharmacokinetic studies and therapeutic drug monitoring.

Considerable variation of trough ß-lactam concentrations in older adults hospitalized with infection-a prospective observational study.

In older adults, few studies confirm that adequate concentrations of antibiotics are achieved using current dosage regimens of intravenous ß-lactam antibiotics. Our objective was to investigate trough concentrations of cefotaxime, meropenem, and piperacillin in older adults hospitalized with infection. We included 102 patients above 70 years of age. Total trough antibiotic concentrations were measured and related to suggested target intervals. Information on antibiotic dose, patient characteristics, and 28-day outcomes were collected from medical records and regression models were fitted. Trough concentrations for all three antibiotics exhibited considerable variation. Mean total trough concentrations for cefotaxime, meropenem, and piperacillin were 6.5 mg/L (range 0-44), 3.4 mg/L (range 0-11), and 30.2 mg/L (range 1.2-131), respectively. When a target range of non-species-related breakpoint - 5× non-species-related breakpoint was applied, only 36% of patients had both values within the target range. Regression models revealed that severe sepsis was associated with varying concentration levels and increasing age and diminishing kidney function with high concentration levels. The study was not powered to demonstrate consequences in clinical outcomes. Conclusively, in older adults treated with cefotaxime, meropenem, or piperacillin-tazobactam, trough antibiotic concentrations varied considerably. Better predictors to guide dosing regimens of ß-lactam antibiotics or increased use of therapeutic drug monitoring are potential ways to address such variations.

A UHPLC-MS/MS method for the simultaneous determination of piperacillin and tazobactam in plasma (total and unbound), urine and renal replacement therapy effluent.

Piperacillin-tazobactam is a beta-lactam/beta-lactamase combination antibiotic used in patients with moderate to severe infection. Dosing of piperacillin-tazobactam requires an understanding of this patient group to maximise the effectiveness of this antibiotic and limit a further emergence of resistant pathogens. This is the first method that measures piperacillin and tazobactam simultaneously, across this range of clinically-relevant biological matrices. The calibration line was linear across the concentration range of 0.5-500µg/mL for piperacillin and 0.625-62.5µg/mL for tazobactam. All validation testing for matrix effects, precision and accuracy, specificity and stability were within 15%. A calibration equivalence study was performed to investigate the suitability of applying calibration curves prepared in an alternative matrix, with a mean bias of -10.8% identified for the application of a calibration line prepared for tazobactam in plasma only. Bias for all other calibration lines prepared in alternate matrices was within the 5% acceptance criteria. The method was successfully applied to a pharmacokinetic study of a critically ill patient receiving renal replacement therapy, with the results included.

Pharmacokinetics and Tissue Penetration of Ceftolozane-Tazobactam in Diabetic Patients with Lower Limb Infections and Healthy Adult Volunteers.

Ceftolozane-tazobactam displays potent activity against Gram-negative bacteria that can cause diabetic foot infections (DFI), making it an attractive treatment option when few alternatives exist. The pharmacokinetics and tissue penetration of ceftolozane-tazobactam at 1.5 g every 8 h (q8h) in patients (n = 10) with DFI were compared with those in healthy volunteers (n = 6) using in vivo microdialysis. In the patient participants, the median values of the pharmacokinetic parameters for ceftolozane in total plasma were as follows: maximum concentration (Cmax), 55.2 µg/ml (range, 40.9 to 169.3 µg/ml); half-life (t1/2), 3.5 h (range, 2.3 to 4.7 h); and area under the concentration-time curve (AUC) from time zero to 8 h (AUC0-8), 191.6 µg · h/ml (range, 147.1 to 286.6 µg · h/ml). The median AUC for tissue (AUCtissue; where AUCtissue was the AUC0-8 for tissue for ceftolozane)/AUC for plasma for each antibiotic corrected by the fraction of free drug (fAUCplasma) was 0.75 (range, 0.35 to 1.00), resulting in a mean free time above 4 µg/ml (the Pseudomonas aeruginosa susceptibility breakpoint) in tissue of 99.8% (range, 87.5 to 100%). In the patient participants, the median values of the pharmacokinetic parameters for tazobactam in total plasma were as follows: Cmax, 14.2 µg/ml (range, 7.6 to 64.2 µg/ml); t1/2, 2.0 h (range, 0.7 to 2.4 h); and AUC0-8, 27.1 µg · h/ml (range, 15.0 to 70.0 µg · h/ml). The AUCtissue (where AUCtissue was the AUC from time zero to the time of the last measureable concentration in tissue for tazobactam)/fAUCplasma for tazobactam was 1.18 (range, 0.54 to 1.44). In the healthy volunteers, the median values of the pharmacokinetic parameters for ceftolozane in total plasma were as follows: Cmax, 91.5 µg/ml (range, 65.7 to 110.7 µg/ml); t1/2, 1.9 h (range, 1.6 to 2.1 h); and AUC0-8, 191.3 µg · h/ml (range, 118.1 to 274.3 µg · h/ml). The median AUCtissue/fAUCplasma was 0.87 (range, 0.54 to 2.20), resulting in a mean free time above 4 µg/ml in tissue of 93.8% (range, 87.5 to 100%). In the healthy volunteers, the median values of the pharmacokinetic parameters for tazobactam in total plasma were as follows: Cmax, 17.5 µg/ml (range, 15.4 to 27.3 µg/ml); t1/2, 0.7 h (range, 0.6 to 0.8 h); and AUC0-8, 22.2 µg · h/ml (range, 19.2 to 36.4 µg · h/ml). The AUCtissue/fAUCplasma for tazobactam was 0.85 (range, 0.63 to 2.10). Both ceftolozane and tazobactam penetrated into subcutaneous tissue with exposures similar to those of free drug in plasma in both patients with DFI and healthy volunteers. These data suggest that ceftolozane-tazobactam at 1.5 g q8h can achieve the optimal exposure with activity against susceptible Gram-negative pathogens in the tissue of patients with DFI. (This study has been registered at ClinicalTrials.gov under identifier NCT02620774.).

Antibiotic Dosing in Continuous Renal Replacement Therapy.

Appropriate antibiotic dosing is critical to improve outcomes in critically ill patients with sepsis. The addition of continuous renal replacement therapy makes achieving appropriate antibiotic dosing more difficult. The lack of continuous renal replacement therapy standardization results in treatment variability between patients and may influence whether appropriate antibiotic exposure is achieved. The aim of this study was to determine if continuous renal replacement therapy effluent flow rate impacts attaining appropriate antibiotic concentrations when conventional continuous renal replacement therapy antibiotic doses were used. This study used Monte Carlo simulations to evaluate the effect of effluent flow rate variance on pharmacodynamic target attainment for cefepime, ceftazidime, levofloxacin, meropenem, piperacillin, and tazobactam. Published demographic and pharmacokinetic parameters for each antibiotic were used to develop a pharmacokinetic model. Monte Carlo simulations of 5000 patients were evaluated for each antibiotic dosing regimen at the extremes of Kidney Disease: Improving Global Outcomes guidelines recommended effluent flow rates (20 and 35 mL/kg/h). The probability of target attainment was calculated using antibiotic-specific pharmacodynamic targets assessed over the first 72 hours of therapy. Most conventional published antibiotic dosing recommendations, except for levofloxacin, reach acceptable probability of target attainment rates when effluent rates of 20 or 35 mL/kg/h are used.

Dose optimization of piperacillin/tazobactam in critically ill children.

Objectives: To characterize the population pharmacokinetics of piperacillin and tazobactam in critically ill infants and children, in order to develop an evidence-based dosing regimen. Patients and methods: This pharmacokinetic study enrolled patients admitted to the paediatric ICU for whom intravenous piperacillin/tazobactam (8:1 ratio) was indicated (75 mg/kg every 6 h based on piperacillin). Piperacillin/tazobactam concentrations were measured by an LC-MS/MS method. Pharmacokinetic data were analysed using non-linear mixed effects modelling. Results: Piperacillin and tazobactam blood samples were collected from 47 patients (median age 2.83 years; range 2 months to 15 years). Piperacillin and tazobactam disposition was best described by a two-compartment model that included allometric scaling and a maturation function to account for the effect of growth and age. Mean clearance estimates for piperacillin and tazobactam were 4.00 and 3.01 L/h for a child of 14 kg. Monte Carlo simulations showed that an intermittent infusion of 75 mg/kg (based on piperacillin) every 4 h over 2 h, 100 mg/kg every 4 h given over 1 h or a loading dose of 75 mg/kg followed by a continuous infusion of 300 mg/kg/24 h were the minimal requirements to achieve the therapeutic targets for piperacillin (60% f T >MIC >16 mg/L). Conclusions: Standard intermittent dosing regimens do not ensure optimal piperacillin/tazobactam exposure in critically ill patients, thereby risking treatment failure. The use of a loading dose followed by a continuous infusion is recommended for treatment of severe infections in children >2 months of age.

Population Pharmacokinetics of Piperacillin in Nonobese, Obese, and Morbidly Obese Critically Ill Patients.

The treatment of infections in critically ill obese and morbidly obese patients is challenging because of the combined physiological changes that result from obesity and critical illness. The aim of this study was to describe the population pharmacokinetics of piperacillin in a cohort of critically ill patients, including obese and morbidly obese patients. Critically ill patients who received piperacillin-tazobactam were classified according to their body mass index (BMI) as nonobese, obese, and morbidly obese. Plasma samples were collected, and piperacillin concentrations were determined by a validated chromatographic method. Population pharmacokinetic analysis and Monte Carlo dosing simulations were performed using Pmetrics software. Thirty-seven critically ill patients (including 12 obese patients and 12 morbidly obese patients) were enrolled. The patients' mean ± standard deviation age, weight, and BMI were 50 ± 15 years, 104 ± 35 kg, and 38.0 ± 15.0 kg/m2, respectively. The concentration-time data were best described by a two-compartment linear model. The mean ± SD parameter estimates for the final covariate model were a clearance of 14.0 ± 7.1 liters/h, a volume of distribution of the central compartment of 49.0 ± 19.0 liters, an intercompartmental clearance from the central compartment to the peripheral compartment of 0.9 ± 0.6 liters · h-1, and an intercompartmental clearance from the peripheral compartment to the central compartment of 2.3 ± 2.8 liters · h-1 A higher measured creatinine clearance and shorter-duration infusions were associated with a lower likelihood of achieving therapeutic piperacillin exposures in patients in all BMI categories. Piperacillin pharmacokinetics are altered in the presence of obesity and critical illness. As with nonobese patients, prolonged infusions increase the likelihood of achieving therapeutic concentrations.

Standard dosing of piperacillin and meropenem fail to achieve adequate plasma concentrations in ICU patients.

BACKGROUND: Controversies remain regarding optimal dosing and the need for plasma concentration measurements when treating intensive care patients with beta-lactam antibiotics. METHODS: We studied ICU patients treated with either antibiotic, excluding patients on renal replacement therapy. Antibiotic concentrations were measured at the mid and end of the dosing interval, and repeated after 2-3 days when feasible. Glomerular filtration rate (GFR) was estimated from plasma creatinine and cystatin C, GFR calculated from cystatin C (eGFR) and measured creatinine clearance (CrCl). Measured concentrations were compared to the clinical susceptible breakpoints for Pseudomonas aeruginosa, 16 and 2 mg/l for piperacillin and meropenem respectively. RESULTS: We analysed 33 and 31 paired samples from 20 and 19 patients treated with piperacillin-tazobactam and meropenem respectively. Antibiotic concentrations at the mid and end of the dosing interval were for piperacillin, 27.0 (14.7-52.9) and 8.6 (2.7-30.3); and for meropenem, 7.5 (4.7-10.2) and 2.4 (1.0-3.5). All values median (interquartile range) and concentrations in mg/l. The percentage of measured concentrations below the breakpoint at the mid and end of the dosing interval were for piperacillin, 27% and 61%; and for meropenem, 6% and 48%. Lower estimates of GFR were associated with higher concentrations but concentrations varied greatly between patients with similar GFR. The correlation with terminal concentration half-life was similar for eGFR and CrCl. CONCLUSIONS: With standard doses of meropenem and piperacillin-tazobactam, plasma concentrations in ICU patients vary > 10-fold and are suboptimal in a significant percentage of patients. The variation is large also between patients with similar renal function.

Target attainment analysis and optimal sampling designs for population pharmacokinetic study on piperacillin/tazobactam in neonates and young infants.

OBJECTIVES: Population pharmacokinetic (popPK) analyses for piperacillin/tazobactam in neonates and infants of less than 2 months of age have been performed by our group previously. The results indicate that a dose of 44.44/5.56 mg/kg piperacillin/tazobactam every 8 or 12 h may not be enough for controlling infection in this population. In order to determine the appropriate dosing regimen and to provide a rationale for the development of dosing guidelines suitable for this population, further popPK studies of piperacillin/tazobactam would need to be conducted. The aim of the present study was to determine the appropriate dosing regimen and optimal sampling schedules in neonates and infants of less than 2 months of age. METHODS: Pharmacodynamic profiling of piperacillin using Monte Carlo simulation was performed to explore the target attainment probability of different dosing regimens for infections caused by different isolated pathogens. D-optimal designs for piperacillin and tazobactam were conducted separately, and the times that overlapped were chosen as the final sampling scheme for future popPK studies in neonates and young infants of less than 2 months of age. RESULTS: Our findings revealed that compared to the current empirical piperacillin/tazobactam dose regimen (50 mg/kg every 12 h by 5-min infusion in our hospital), the clinical outcome could be improved by increasing doses, increasing administration frequency, and prolonging intravenous infusion in neonates and infants of less than 2 months of age. The following optimal sampling windows were chosen as the final sampling scheme: 0.1-0.11, 0.26-0.29, 0.97-2.62, and 7.95-11.9 h administered every 12 h with 5-min infusion; 0.1-0.12, 0.39-0.56, 2.86-4.95, and 8.91-11.8 h administered every 12 h with 3-h infusion; 0.1-0.11, 0.22-0.29, 0.91-1.96, and 5.56-7.93 h administered every 8 h with 5-min infusion; 0.1-0.11, 0.38-0.48, 2.54-3.82, and 6.86-7.93 h administered every 8 h with 3-h infusion; 0.1-0.11, 0.25-0.28, 0.84-1.69, and 4.55-5.94 h administered every 6 h with 5-min infusion; and 0.1-0.11, 0.37-0.54, 3.13-3.72, and 5.57-5.99 h administered every 6 h with 3-h infusion. CONCLUSIONS: The dosing regimen and sampling schedules proposed in this study should be evaluated in future popPK studies of piperacillin/tazobactam in neonates and infants. To the best of our knowledge, this is the first study that combined optimal sampling design with Monte Carlo simulation for designing popPK studies of piperacillin/tazobactam.

A simple and rapid RP-HPLC method for the simultaneous determination of piperacillin and tazobactam in human plasma.

A rapid and sensitive reverse phase HPLC (RP-HPLC) method for the simultaneous quantitation of piperacillin and tazobactam in human plasma has been developed and validated. The method utilizes a novel, simple and rapid solid phase extraction step, which results in an improved extraction yield of analytes from human plasma, as well as significantly reduced interference from serum components at low UV wavelength detection compared to previously published liquid-liquid extraction methods. Chromatographic separation was carried out on a Hypersil ODS C18, 3µm column using an acetonitrile-trifluoroacetic acid-water gradient elution with dual wavelength quantitation at 254nm for piperacillin and 218nm for tazobactam. Linear relationships between peak area and drug concentration were obtained in the range of 1.0-200µg/mL for piperacillin and 0.78-50µg/mL for tazobactam, with r2=0.9997 and 0.9994 respectively. The assay proved to be sensitive (with a lower limit of quantitation of 1µg/mL for piperacillin and 0.78µg/mL for tazobactam), specific (no interference from plasma components at either 218nm or 254nm), and reproducible (both intra- and inter- day coefficients of variation were ≤6%). With a total process/assay time of less than 30min, the method provides a simple, precise and reproducible assay for monitoring piperacillin and tazobactam plasma levels that can be readily adapted for routine clinical use.

Population Pharmacokinetics and Safety of Ceftolozane-Tazobactam in Adult Cystic Fibrosis Patients Admitted with Acute Pulmonary Exacerbation.

Ceftolozane-tazobactam has potent activity against Pseudomonas aeruginosa, a pathogen associated with cystic fibrosis (CF) acute pulmonary exacerbations (APE). Due to the rapid elimination of many antibiotics, CF patients frequently have altered pharmacokinetics. In this multicenter, open-label study, we described the population pharmacokinetics and safety of ceftolozane-tazobactam at 3 g every 8 h (q8h) in 20 adult CF patients admitted with APE. Population pharmacokinetics were determined using the nonparametric adaptive grid program in Pmetrics for R. A 5,000-patient Monte Carlo simulation was performed to determine the probability of target attainment (PTA) for the ceftolozane component at 1.5 g and 3 g of ceftolozane-tazobactam q8h across a range of MICs using a primary threshold exposure of 60% free time above the MIC (fT>MIC). In these 20 adult CF patients, ceftolozane and tazobactam concentration data were best described by 2-compartment models, and ceftolozane clearance (CL) was significantly correlated with creatinine clearance (r = 0.71, P < 0.001). These data suggest that ceftolozane and tazobactam clearance estimates in CF patients are similar to those in adults without CF (ceftolozane CF CL, 4.76 ± 1.13 liter/h; tazobactam CF CL, 20.51 ± 4.41 liter/h). However, estimates of the volume of the central compartment (Vc) were lower than those for adults without CF (ceftolozane CF Vc, 7.51 ± 2.05 liters; tazobactam CF Vc, 7.85 ± 2.66 liters). Using a threshold of 60% fT>MIC, ceftolozane-tazobactam regimens of 1.5 g and 3 g q8h should achieve PTAs of ≥90% at MICs up to 4 and 8 µg/ml, respectively. Ceftolozane-tazobactam at 3 g q8h was well tolerated. These observations support additional studies of ceftolozane-tazobactam for Pseudomonas aeruginosa APE in CF patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02421120.).

Pharmacokinetics and Pharmacodynamics of Extended Infusion Versus Short Infusion Piperacillin-Tazobactam in Critically Ill Patients Undergoing CRRT.

BACKGROUND AND OBJECTIVES: Infection is the most common cause of death in severe AKI, but many patients receiving continuous RRT do not reach target antibiotic concentrations in plasma. Extended infusion of ß-lactams is associated with improved target attainment in critically ill patients; thus, we hypothesized that extended infusion piperacillin-tazobactam would improve piperacillin target attainment compared with short infusion in patients receiving continuous RRT. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted an institutional review board-approved observational cohort study of piperacillin-tazobactam pharmacokinetics and pharmacodynamics in critically ill patients receiving continuous venovenous hemodialysis and hemodiafiltration at three tertiary care hospitals between 2007 and 2015. Antibiotic concentrations in blood and/or dialysate samples were measured by liquid chromatography, and one- and two-compartment pharmacokinetic models were fitted to the data using nonlinear mixed effects regression. Target attainment for piperacillin was defined as achieving four times the minimum inhibitory concentration of 16 µg/ml for >50% of the dosing cycle. The probabilities of target attainment for a range of doses, frequencies, and infusion durations were estimated using a Monte Carlo simulation method. Target attainment was also examined as a function of patient weight and continuous RRT effluent rate. RESULTS: Sixty-eight participants had data for analysis. Regardless of infusion duration, 6 g/d piperacillin was associated with ≤45% target attainment, whereas 12 g/d was associated with ≥95% target attainment. For 8 and 9 g/d, target attainment ranged between 68% and 85%. The probability of target attainment was lower at higher effluent rates and patient weights. For all doses, frequencies, patient weights, and continuous RRT effluent rates, extended infusion was associated with higher probability of target attainment compared with short infusion. CONCLUSIONS: Extended infusions of piperacillin-tazobactam are associated with greater probability of target attainment in patients receiving continuous RRT.

Development of an HPLC Method for the Determination of Ceftolozane/Tazobactam in Biological and Aqueous Matrixes.

Herein, we report the development and validation of an HPLC method to analyze ceftolozane and tazobactam simultaneously in human plasma, human serum, swine serum and saline matrixes. A reversed-phase column was used with a UV detector set at 260 nm and switched to 218 nm. The mobile phase consisted of methanol and sodium phosphate buffer at a flow rate of 1.1 mL/min. Cefepime was used as the internal standard. The standard curves were linear over a range of 0.4-50 µg/mL. This methodology represents a simple, reproducible approach to the determination of drug concentrations with sufficient accuracy and precision for pharmacokinetic studies undertaken with this recently FDA-approved antimicrobial therapy.

Population Pharmacokinetics and Pharmacodynamics of Extended-Infusion Piperacillin and Tazobactam in Critically Ill Children.

The study objective was to evaluate the population pharmacokinetics and pharmacodynamics of extended-infusion piperacillin-tazobactam in children hospitalized in an intensive care unit. Seventy-two serum samples were collected at steady state from 12 patients who received piperacillin-tazobactam at 100/12.5 mg/kg of body weight every 8 h infused over 4 h. Population pharmacokinetic analyses were performed using NONMEM, and Monte Carlo simulations were performed to estimate the piperacillin pharmacokinetic profiles for dosing regimens of 80 to 100 mg/kg of the piperacillin component given every 6 to 8 h and infused over 0.5, 3, or 4 h. The probability of target attainment (PTA) for a cumulative percentage of the dosing interval that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (TMIC) of ≥50% was calculated at MICs ranging from 0.25 to 64 mg/liter. The mean ± standard deviation (SD) age, weight, and estimated glomerular filtration rate were 5 ± 3 years, 17 ± 6.2 kg, and 118 ± 41 ml/min/1.73 m(2), respectively. A one-compartment model with zero-order input and first-order elimination best fit the pharmacokinetic data for both drugs. Weight was significantly associated with piperacillin clearance, and weight and sex were significantly associated with tazobactam clearance. Pharmacokinetic parameters (mean ± SD) for piperacillin and tazobactam were as follows: clearance, 0.22 ± 0.07 and 0.19 ± 0.07 liter/h/kg, respectively; volume of distribution, 0.43 ± 0.16 and 0.37 ± 0.14 liter/kg, respectively. All extended-infusion regimens achieved PTAs of >90% at MICs of ≤16 mg/liter. Only the 3-h infusion regimens given every 6 h achieved PTAs of >90% at an MIC of 32 mg/liter. For susceptible bacterial pathogens, piperacillin-tazobactam doses of ≥80/10 mg/kg given every 8 h and infused over 4 h achieve adequate pharmacodynamic exposures in critically ill children.

Ceftolozane/tazobactam pharmacokinetic/pharmacodynamic-derived dose justification for phase 3 studies in patients with nosocomial pneumonia.

Ceftolozane/tazobactam is an antipseudomonal antibacterial approved for the treatment of complicated urinary tract infections (cUTIs) and complicated intra-abdominal infections (cIAIs) and in phase 3 clinical development for treatment of nosocomial pneumonia. A population pharmacokinetic (PK) model with the plasma-to-epithelial lining fluid (ELF) kinetics of ceftolozane/tazobactam was used to justify dosing regimens for patients with nosocomial pneumonia in phase 3 studies. Monte Carlo simulations were performed to determine ceftolozane/tazobactam dosing regimens with a > 90% probability of target attainment (PTA) for a range of pharmacokinetic/pharmacodynamic targets at relevant minimum inhibitory concentrations (MICs) for key pathogens in nosocomial pneumonia. With a plasma-to-ELF penetration ratio of approximately 50%, as observed from an ELF PK study, a doubling of the current dose regimens for different renal functions that are approved for cUTIs and cIAIs is needed to achieve > 90% PTA for nosocomial pneumonia. For example, a 3-g dose of ceftolozane/tazobactam for nosocomial pneumonia patients with normal renal function is needed to achieve a > 90% PTA (actual 98%) for the 1-log kill target against pathogens with an MIC of ≤ 8 mg/L in ELF, compared with the 1.5-g dose approved for cIAIs and cUTIs.

Population pharmacokinetics of piperacillin in the early phase of septic shock: does standard dosing result in therapeutic plasma concentrations?

Antibiotic dosing in septic shock patients poses a challenge for clinicians due to the pharmacokinetic (PK) variability seen in this patient population. Piperacillin-tazobactam is often used for empirical treatment, and initial appropriate dosing is crucial for reducing mortality. Accordingly, we determined the pharmacokinetic profile of piperacillin (4 g) every 8 h, during the third consecutive dosing interval, in 15 patients treated empirically for septic shock. We developed a population pharmacokinetic model to assess empirical dosing and to simulate alternative dosing regimens and modes of administration. Time above the MIC (T>MIC) predicted for each patient was evaluated against clinical breakpoint MIC for Pseudomonas aeruginosa (16 mg/liter). Pharmacokinetic-pharmacodynamic (PK/PD) targets evaluated were 50% fT>4×MIC and 100% fT>MIC. A population PK model was developed using NONMEM, and data were best described by a two-compartment model. Central and intercompartmental clearances were 3.6 liters/h (relative standard error [RSE], 15.7%) and 6.58 liters/h (RSE, 16.4%), respectively, and central and peripheral volumes were 7.3 liters (RSE, 11.8%) and 3.9 liters (RSE, 9.7%), respectively. Piperacillin plasma concentrations varied considerably between patients and were associated with levels of plasma creatinine. Patients with impaired renal function were more likely to achieve predefined PK/PD targets than were patients with preserved or augmented renal function. Simulations of alternative dosing regimens showed that frequent intermittent bolus dosing as well as dosing by extended and continuous infusion increases the probability of attaining therapeutic plasma concentrations. For septic shock patients with preserved or augmented renal function, dose increment or prolonged infusion of the drug needs to be considered. (This study has been registered at ClinicalTrials.gov under registration no. NCT02306928.).

High-risk febrile neutropenia and its management in children with solid tumors and lymphoma.

BACKGROUND/AIM: The clinical characteristics and treatment results of febrile neutropenia attacks that occurred in patients with lymphoma and solid tumors were analyzed. MATERIALS AND METHODS: A total of 50 patients with 94 high-risk attacks were evaluated for malignant diseases in this study. RESULTS: The fever etiology was determined as clinical (50%), microbiological (5.31%), clinical-microbiological (5.31%), or unknown (39.3%). A few of the attacks (21.3%) were observed in lymphoma cases and 77.7% were observed in patients with solid tumors. Patients who were in remission had 59.6% of the attacks, and 39.4% occurred in patients not in remission. Among the groups tested, 73% (the imipenem/amikacin group) and 47.9% (the piperacillin-tazobactam/amikacin group) of patients were in remission. Glycopeptide addition rates in these groups were 22.2% and 40.8% and antifungal addition rates were 8.8% and 18.3%, respectively. CONCLUSION: Clinical progress was more problematic in patients who were not in remission during the attacks. This was due to the fact that some patients had other factors that placed them in the high-risk group, as well as increased C reactive protein and procalcitonin values on the first day. Therefore, it may not be accurate to associate the success achieved in the different treatment regimens with antibiotics alone.

Extracorporeal Elimination of Piperacillin/Tazobactam during Molecular Adsorbent Recirculating System Therapy.

Use of the Molecular Adsorbent Recirculating System (MARS) as a liver support device continues to grow worldwide. Various components of the MARS circuit remove both protein-bound and water-soluble molecules. Little is known about the extent of the enhanced clearance mechanisms used in MARS therapy on drug elimination. Of particular interest to acute care practitioners is the impact of MARS on antibiotic clearance, as suboptimal concentrations of such drugs can negatively impact patient outcomes. The properties of piperacillin/tazobactam suggest that elimination may be enhanced in the setting of MARS therapy. We describe two cases in which this was studied. Piperacillin concentrations were determined at various points within the MARS circuit, and patient serum concentrations were reported throughout the dosing interval while receiving MARS therapy. Piperacillin concentrations in both cases were in excess of the desired goal minimum inhibitory concentrations for treatment of gram-negative infections. Use of an extended-infusion strategy of piperacillin/tazobactam 3.375 or 4.5 g given every 8 hours maintained desired serum levels throughout the dosing interval. To our knowledge, this is the second published report on the use of piperacillin/tazobactam during MARS therapy. These case reports reveal successful dosing strategies for patients requiring piperacillin/tazobactam while receiving MARS therapy, as well as quantify the influence of individual MARS elements on drug extraction.

A green capillary zone electrophoresis method for the simultaneous determination of piperacillin, tazobactam and cefepime in pharmaceutical formulations and human plasma.

A green, novel, rapid, accurate and reliable capillary zone electrophoresis method was developed and validated for the simultaneous determination of piperacillin, tazobactam and cefepime in pharmaceutical preparations. Separation was carried out using fused silica capillary (50 µm i.d. × 48.6 cm and 40.2 cm detection length) and applied potential of 20 kV (positive polarity) and a running buffer containing 15 m m sodium borate buffer adjusted to pH 9.3 with UV detection at 215 nm. Amoxicillin was used as an internal standard. The method was suitably validated according to International Conference on Harmonization guidelines. The method showed good linearity in the ranges of 10-100, 20-400 and 10-400 µg/mL with limits of quantitation of 1.87, 3.17 and 6.97 µg/mL and limits of detection of 0.56, 0.95 and 2.09 µg/mL for tazobactam, piperacillin and cefepime, respectively. The proposed method was successfully applied for the analysis of these drugs in their synthetic mixtures and co-formulated injection vials. The method was extended to the in vitro determination of the two drugs in spiked human plasma. It is considered a 'green' method as it consumes no organic solvents.