Tazobactam In Plasma Research Articles

Pharmacokinetics of intravenous piperacillin/tazobactam among patients with peritoneal dialysis-associated peritonitis.

Currently, pharmacokinetic information on intravenous (IV) piperacillin/tazobactam in patients with peritoneal dialysis-associated peritonitis (PD peritonitis) is limited. This study employed a prospective single-dose pharmacokinetic design to assess the pharmacokinetics of IV piperacillin/tazobactam in these patients. Four patients with PD peritonitis who received an IV loading dose of 4000 mg/500 mg piperacillin/tazobactam were enrolled in this study. The concentrations of piperacillin and tazobactam in plasma, peritoneal dialysis fluid (PDF) and urine were determined by high-performance liquid chromatography. Non-compartmental methods were used for pharmacokinetic analysis. During a 6-h dwell time for chronic ambulatory peritoneal dialysis (CAPD), 9.23 ± 4.01% of the piperacillin was recovered in the PDF. This result is greater than that observed in patients without peritonitis in prior research. Piperacillin's PD clearance (CLPD), steady-state volume of distribution (Vss) and terminal half-life (t 1/2) were 5.79 ± 2.55 mL/min, 24.35 ± 11.26 L and 5.74 ± 1.53 h, respectively. These values are also higher than those of patients without peritonitis in a prior study. Eight hours following the loading dosage, the plasma and PDF piperacillin concentrations of all patients (98.25 ± 26.03 and 52.70 ± 22.99 mg/L, respectively) surpassed the Pseudomonas aeruginosa and Enterobacterales Clinical and Laboratory Standards Institute susceptible breakpoints. In summary, the CLPD, Vss and t 1/2 for piperacillin were found to be greater in patients with PD peritonitis than in CAPD patients without peritonitis when compared with the results of a previous study. The IV loading dose of 4000 mg/500 mg piperacillin/tazobactam is sufficient to treat peritonitis caused by susceptible P. aeruginosa and Enterobacterales. The multiple-dose pharmacokinetics of IV piperacillin and tazobactam in this specific patient group should be further investigated.

Ceftolozane/Tazobactam Probability of Target Attainment in Patients With Hospital-Acquired or Ventilator-Associated Bacterial Pneumonia.

Probability of target attainment (PTA) analyses were conducted to support the recommended ceftolozane/tazobactam dosing regimens, adjusted for renal function, in patients with hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP). Previously published population pharmacokinetic models describing the disposition of ceftolozane and tazobactam in plasma and epithelial lining fluid (ELF) in patients with HABP/VABP were used to simulate ceftolozane and tazobactam concentration-time profiles in plasma and ELF over the course of 14days. The simulations were conducted for patients with normal renal function and for patients receiving adjusted doses for mild, moderate, and severe renal impairment. PTA was calculated using established pharmacokinetic/pharmacodynamic targets for ceftolozane and tazobactam. Across renal function groups, plasma PTA was 100% for ceftolozane and >99% for tazobactam; ELF PTA was >99% for ceftolozane and >87% for tazobactam. These results provided support for the currently recommended ceftolozane/tazobactam dosing regimens for HABP/VABP, which were efficacious and well tolerated in the Ceftolozane-Tazobactam Versus Meropenem for Treatment of Nosocomial Pneumonia (ASPECT-NP) trial.

An Integral Pharmacokinetic Analysis of Piperacillin and Tazobactam in Plasma and Urine in Critically Ill Patients.

Background and ObjectivesAlthough dose optimization studies have been performed for piperacillin and tazobactam separately, a combined integral analysis is not yet reported. As piperacillin and tazobactam pharmacokinetics are likely to show correlation, a combined pharmacokinetic model should be preferred to account for this correlation when predicting the exposure. Therefore, the aim of this study was to describe the pharmacokinetics and evaluate different dosing regimens of piperacillin and tazobactam in critically ill patients using an integral population pharmacokinetic model in plasma and urine.MethodsIn this observational study, a total of 39 adult intensive care unit patients receiving piperacillin–tazobactam as part of routine clinical care were included. Piperacillin and tazobactam concentrations in plasma and urine were measured and analyzed using non-linear mixed-effects modeling. Monte Carlo simulations were performed to predict the concentrations for different dosing strategies and different categories of renal function.ResultsA combined two-compartment linear pharmacokinetic model for both piperacillin and tazobactam was developed, with an output compartment for the renally excreted fraction. The addition of 24-h urine creatinine clearance significantly improved the model fit. A dose of 12/1.5 g/24 h as a continuous infusion is sufficient to reach a tazobactam concentration above the target (2.89 mg/L) and a piperacillin concentration above the target of 100% f T>1×MIC (minimum inhibitory concentration [MIC] ≤ 16 mg/L). To reach a target of 100% f T>5×MIC with an MIC of 16 mg/L, piperacillin doses of up to 20 g/24 h are inadequate. Potential toxic piperacillin levels were reached in 19.6% and 47.8% of the population with a dose of 12 g/24 h and 20 g/24 h, respectively.ConclusionsA regular dose of 12/1.5 g/24 h is sufficient in > 90% of the critically ill population to treat infections caused by Escherichia coli and Klebsiella pneumoniae with MICs ≤ 8 mg/L. In case of infections caused by Pseudomonas aeruginosa with an MIC of 16 mg/L, there is a fine line between therapeutic and toxic exposure. Dosing guided by renal function and therapeutic drug monitoring could enhance target attainment in such cases.ClinicalTrials.gov identifierNCT03738683.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40262-022-01113-6.

A validated LC-MS/MS method for the simultaneous quantification of the novel combination antibiotic, ceftolozane-tazobactam, in plasma (total and unbound), CSF, urine and renal replacement therapy effluent: application to pilot pharmacokinetic studies.

Novel treatment options for some carbapenem-resistant Gram-negative pathogens have been identified by the World Health Organization as being of the highest priority. Ceftolozane-tazobactam is a novel cephalosporin-beta-lactamase inhibitor combination antibiotic with potent bactericidal activity against the most difficult-to-treat multi-drug resistant and extensively drug resistant Gram-negative pathogens. This study aimed to develop and validate a liquid chromatography- tandem mass spectrometry method for the simultaneous quantification of ceftolozane and tazobactam in plasma (total and unbound), renal replacement therapy effluent (RRTE), cerebrospinal fluid (CSF) and urine. Analytes were separated using mixed-mode chromatography with an intrinsically base-deactivated C18 column and a gradient mobile phase consisting of 0.1% formic acid, 10mM ammonium formate and acetonitrile. The analytes and internal standards were detected using rapid ionisation switching between positive and negative modes with simultaneous selected reaction monitoring. A quadratic calibration was obtained for plasma (total and unbound), RRTE and CSF over the concentration range of 1-200mg/L for ceftolozane and 0.5-100mg/L for tazobactam, and for urine the concentration range of 10-2,000mg/L for ceftolozane and 5-1,000mg/L for tazobactam. For both ceftolozane and tazobactam, validation testing for matrix effects, precision and accuracy, specificity and stability were all within the acceptance criteria of ±15%. This methodology was successfully applied to one pilot pharmacokinetic study in infected critically ill patients, including patients receiving renal replacement therapy, and one case study of a patient with ventriculitis, where all patients received ceftolozane-tazobactam.

Validation of a simple and economic HPLC-UV method for the simultaneous determination of vancomycin, meropenem, piperacillin and tazobactam in plasma samples

Critically ill patients are often affected by several pathophysiological conditions requiring antibiotic administration and, frequently, extracorporeal therapy that significantly alter the normal pharmacokinetics of drugs. Therapeutic drug monitoring (TDM) may assist to establish the correct antibiotic dosage, but a TDM service is usually available only for some aminoglycosides and glycopeptides. The aim of this study is the validation of an HPLC-UV method for the simultaneous quantification of meropenem, vancomycin, piperacillin and tazobactam in human plasma samples.The analytes were extracted from 250 μL of human plasma by the addition of acetonitrile for protein precipitation. After evaporation to dryness of the solvent, samples were reconstituted with 250 μL of mobile phase, and 100 μL were injected in HPLC. Chromatographic analysis was performed using a Kinetex C18 column and an UV/Vis detector set at 220 and 298 nm. The mobile phase was a mixture of phosphate buffer 0.1 M pH 3.15 and methanol in gradient, delivered at 1 mL/min.The method was validated over clinical concentration ranges. For all the analytes, the lower limit of quantification was 1 μg/mL, and the calibration curves were linear between 1 and 100 μg/mL, with coefficients of determination ≥ 0.999. Intra-day precision was < 4%, while inter-day precision was < 7% for each analyte.The applicability of the method has been evaluated by analysing plasma samples collected from 4 critically ill patients undergoing continuous renal replacement therapy. Moreover, the analysis of vancomycin with VANC Flex® confirmed a good correlation between the results of HPLC-UV and commercially available kits usually used by TDM service.The method we developed only requires a small volume of plasma and uses the same sample preparation protocol, stationary phase and elution conditions for all analytes. This method offers the additional advantages of simple and rather inexpensive sample preparation and instrumentation, features that make this method an easy implementation for a general TDM laboratory.

Determination of total and free ceftolozane and tazobactam in human plasma and interstitial fluid by HPLC-UV

Ceftolozane/tazobactam is a new cephalosporin/beta-lactamase inhibitor combination. An HPLC-UV method is described for the determination of total and free ceftolozane and tazobactam in human plasma and in microdialysate of subcutaneous tissue, respectively. Separation was performed using a reversed-phase column with phosphate buffer/acetonitrile as eluent and photometric detection at 260 nm (ceftolozane) or 220 nm (tazobactam). Linearity has been shown down to ceftolozane/tazobactam 0.1/0.05 mg/L in plasma and 0.03/0.015 mg/L in saline, respectively. The plasma protein binding of both drugs as determined by ultrafiltration was less than 10%. Temperature, pH or relative centrifugation force (up to 3000 x g) had no significant impact on the protein binding. The method was applied to the determination of ceftolozane and tazobactam in plasma and interstitial fluid of healthy volunteers following intravenous infusion of ceftolozane/tazobactam 1.0/0.5 g.

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

A simple, rapid, economical and sensitive HPLC-UV method was developed for the simultaneous quantification of ceftolozane and tazobactam in plasma samples. After deproteinization followed by a liquid-liquid back-extraction, the compounds were separated on a C18 column (150mm×4.6mm, 5μm) with UV-visible detection at 220nm. 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 1.0ml/min and at a column oven temperature of 30°C. Cefepime was used as an internal standard. Linearity was achieved in the concentration range of 0.50-100.00μg/ml for ceftolozane and 0.25-50.00μg/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. 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.

OAT1 and OAT3 also mediate the drug-drug interaction between piperacillin and tazobactam

This study aimed to demonstrate that organic anion transporters (OATs) mediate the drug-drug interaction (DDI) between piperacillin and tazobactam. After co-administration with piperacillin in rats, the AUC of tazobactam in plasma was significantly increased, and t1/2β was prolonged with significant reduction in plasma clearance, renal clearance and cumulative urinary excretion. In rat and human kidney slices, probenecid, p-aminohippurate and benzylpenicillin inhibited the uptake of piperacillin and tazobactam. Piperacillin significantly inhibited the uptake of tazobactam. Moreover, the uptakes of piperacillin, tazobactam and sulbactam in hOAT1/3-HEK293 cells were significantly higher compared with mock-HEK293 cells, respectively. Piperacillin significantly inhibited the uptake of tazobactam in hOAT1/3-HEK293 cells. The Km values of tazobactam (431 ± 67 μM for hOAT1, 377 ± 63 μM for hOAT3) were significantly higher than those of piperacillin (37 ± 5 μM for hOAT1, 172 ± 28 μM for hOAT3). This suggested that piperacillin has a stronger affinity to hOAT1/3 than tazobactam. Meanwhile, the Km values of tazobactam were increased in the presence of piperacillin with unchanged Vmax. This indicated that piperacillin inhibited the uptake of tazobactam in a competitive manner. In conclusion, piperacillin and tazobactam are the substrates of hOAT1/3, and OAT1/3 mediate the DDI between piperacillin and tazobactam.

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 of piperacillin and tazobactam in plasma and subcutaneous interstitial fluid in critically ill patients receiving continuous venovenous haemodiafiltration

This prospective pharmacokinetic study aimed to describe plasma and interstitial fluid (ISF) pharmacokinetics of piperacillin and tazobactam in critically ill patients on continuous venovenous haemodiafiltration (CVVHDF). Piperacillin/tazobactam (4g/0.5g) was administered every 8h and CVVHDF was performed as a 3–3.5L/h exchange using a polyacrylonitrile filter with a surface area of 1.05m2. Serial blood (pre- and post-filter), filtrate/dialysate, urine and ISF concentrations were measured. Subcutaneous tissue ISF concentrations were determined using microdialysis. A total of 407 samples were collected. Median peak plasma concentrations were 210.5 (interquartile range=161.5–229.0) and 29.4 (27.9–32.0) mg/L and median trough plasma concentrations were 64.3 (49.0–68.9) and 12.3 (7.7–13.7) mg/L for piperacillin and tazobactam, respectively. The plasma elimination half-life was 6.4 (4.6–8.7) and 7.3 (4.6–11.8) h, volume of distribution 0.42 (0.29–0.49) and 0.32 (0.24–0.36) L/kg, total clearance 5.1 (4.2–6.2) and 3.8 (3.3–4.2) L/h and CVVHDF clearance 2.5 (2.3–3.1) and 2.5 (2.3–3.2) L/h for piperacillin and tazobactam, respectively. The tissue penetration ratio or ratio of area under the concentration–time curve of the unbound drug in ISF to plasma (unbound AUCISF/AUCplasma) was ca. 1 for both piperacillin and tazobactam. This is the first report of concurrent plasma and ISF concentrations of piperacillin and tazobactam during CVVHDF. For the CVVHDF settings used in this study, a dose of 4.5g piperacillin/tazobactam administered evry 8h resulted in piperacillin concentrations in plasma and ISF >32mg/L throughout most of the dosing interval.

Determination of Free and Total Piperacillin–Tazobactam in Plasma by HPLC–MS–MS: An Adapted Method for Neonates

A sensitive and specific liquid chromatography electrospray ionization-tandem mass spectrometry method for determination of total and free piperacillin–tazobactam in human plasma has been developed and validated. Plasma deproteinization was achieved with Amicon® Ultra-0.5 mL centrifugal filter device (Millipore, Bedford, USA). Chromatography was performed on a Capcell Pak C18 MG column (ID 2 mm × 100 mm, 5 μm, Shiseido, Kyoto, Japan) with isocratic elution using a mobile phase containing water and acetonitrile with an addition of 0.02% of formic acid. Detection was achieved by an Applied Biosystems API 3000 triple quadrupole mass spectrometer (ABI-SCIEX, Toronto, Canada). Electrospray ionization (ESI) was used for ion production. The limits of quantification were 100 ng mL−1 for piperacillin and 30 ng mL−1 for tazobactam. The precision and accuracy for both intra- and inter-day determination of piperacillin ranged from 2.8 to 9.1% and from 94.9 to 104.4%. The precision and accuracy for intra- and inter-day determination of tazobactam ranged from 2.9 to 9.3% and from 88.9 to 99.8%. The precision and accuracy for intra- and inter-day determination of free piperacillin ranged from 4.4 to 14.7% and from 89.0 to 109.6%. The precision and accuracy for intra- and inter-day determination of free tazobactam ranged from 2.8 to 14.4% and from 93.9 to 108.0%. Fifty and 150 μL plasma were used for total and free piperacillin–tazobactam analysis, respectively. The validation results of this analytical method made it feasible for being used in a further pilot study of population pharmacokinetics of piperacillin–tazobactam in neonates.

Quantitation and stability of piperacillin and tazobactam in plasma and ultrafiltrate from patients undergoing continuous venovenous hemofiltration by HPLC

Simple and reproducible HPLC methods for the determination of piperacillin and tazobactam have been developed and a complete stability study carried out. The method for piperacillin plasma samples consisted of protein precipitation with methanol using penicillin G as internal standard. No sample preparation was needed for ultrafiltrate samples. Tazobactam sample preparation involved protein precipitation with acetonitrile and the removal of lipids with dichloromethane. Piperacillin separation was performed on a microBondapack C(18) column (300 x 3.9, 10 microm) and tazobactam on a Novapack C(18) column (150 x 3.9, 4 microm) with UV detection set at 229 and 225 nm, respectively. The mobile phase consisted of phosphate buffer-acetonitrile, delivered at 1.5 mL[sol ]min. Calibration curves determination coefficients were >or=0.999 and response factors CV% < 5%. Intra- and inter-assay precision and accuracy of the quality control and limit of quantification were satisfactory. Plasma and ultrafiltrate samples were stable at -20 and -80 degrees C for 2 months and after three freeze-thaw cycles. In the chromatographic rack, tazobactam ultrafiltrate samples were stable for 24 h and plasma samples for 12 h, piperacillin ultrafiltrate samples for 8 h, but plasma samples for only 4 h. Storage of piperacillin samples at 4 degrees C until analysis is recommended. Piperacillin was stable in the presence of tazobactam.

Determination of free interstitial concentrations of piperacillin-tazobactam combinations by microdialysis.

The investigation of tissue penetration and distribution of antibiotics is of great importance, since infections occur mostly in the tissues. The aim of this study was to investigate the pharmacokinetics of piperacillin and tazobactam, alone and in combination, by measuring total plasma and free interstitial concentrations, and to examine the relationship between free levels of both drugs in blood and those in the extracellular space. Piperacillin and tazobactam were administered, alone and in combination, to anaesthetized rats as a single iv bolus dose. Total plasma concentrations and free extracellular concentrations were quantified by HPLC. In-vivo microdialysis sampling was used to study the free tissue distribution patterns of both drugs. The pharmacokinetics of piperacillin and tazobactam in plasma were consistent with a two-compartment body model. Piperacillin pharmacokinetics were not influenced by co-administration of tazobactam. Tazobactam's volumes of distribution and clearance were decreased by the co-administration of piperacillin and the area under the curve was significantly increased. Comparisons between calculated free concentrations in the peripheral compartment for both drugs and measured free extracellular concentrations revealed excellent agreement. For piperacillin and tazobactam, alone and in combination, predictions of the concentration-time profiles of free drug in the peripheral compartment can be made on the basis of plasma data.

Penetration of Piperacillin/Tazobactam Into Gynecologic Tissues Following a Single Loading Dose Prior toHysterectomy

Objective: This study was undertaken to determine plasma and pelvic tissue concentrations of piperacillin/tazobactam following a single intravenous administration. Methods: Plasma and tissue samples were obtained following administration of 3 g of piperacillin and 0.375 g of tazobactam. Concentrations of these agents were determined by chromatography. Results: Plasma concentrations (mean ±SD) for piperacillin/tazobactam were 208 ± 87/27 ± 8 and 95 ± 53/14 ± 2, respectively, at 30 and 60 min after the start of the infusion. The 8:1 ratio between piperacillin and tazobactam in plasma remained constant for up to 96 min. Tissue concentrations yielded a broader range, but each agent achieved significant penetration in each of the tissues studied. Conclusions: Piperacillin/tazobactam demonstrates favorable penetration in female genital tract tissues and Should be considered a potentially effective agent for female pelvic infections.

Pharmacokinetics and tissue penetration of tazobactam and piperacillin in patients undergoing colorectal surgery.

The pharmacokinetics of tazobactam and piperacillin in plasma and different tissues after a 30-min intravenous infusion of 4 g of piperacillin and 0.5 g of tazobactam were investigated in 18 patients who underwent elective colorectal surgery. Serial blood samples were collected for up to 6 h after the initiation of the infusion. The types of tissue collected were fatty tissue, muscle, skin, appendix, and intestinal mucosa (proximal and distal). On the basis of concentrations in plasma, the following pharmacokinetic parameter values were obtained (values are means +/- standard deviations): maximum concentration of drug in serum, tazobactam, 27.9 +/- 7.67 micrograms/ml; piperacillin, 259 +/- 81.8 micrograms/ml; time to maximum concentration of drug in serum, tazobactam, 0.51 +/- 0.03 h; piperacillin, 0.51 +/- 0.03 h; area under the concentration-time curve, tazobactam, 47.6 +/- 13.3 micrograms.h/ml; piperacillin, 361 +/- 80.3 micrograms.h/ml; clearance, tazobactam, 188 +/- 52.3 ml/min; piperacillin, 194 +/- 42.9 ml/min; half-life, tazobactam, 1.42 +/- 0.32 h; piperacillin, 1.27 +/- 0.24 h; apparent volume of distribution, tazobactam, 0.31 +/- 0.07 liter/kg of body weight; piperacillin, 0.29 +/- 0.06 liter/kg; volume of distribution at steady state, tazobactam, 0.28 +/- 0.04 liter/kg; piperacillin, 0.25 +/- 0.05 liter/kg. The concentrations of tazobactam and piperacillin in fatty tissue and muscle tissue were 10 to 13 and 18 to 30% of the levels in plasma, respectively. In skin, the concentrations of piperacillin were 60 to 95% of the levels in plasma, whereas the concentrations of tazobactam in plasma were 49 to 93% of the levels in skin tissue. The mean concentration of tazobactam in the investigated gastrointestinal tissues (appendix, proximal and distal mucosa) exceeded levels in plasma after 1 h, while piperacillin showed a mean penetration into these tissues of 43 and 53%. The mechanisms that can be used to explain the extent of penetration of piperacillin and tazobactam are discussed. Simple diffusion may take place in fatty and muscle tissue, while penetration into skin and gastrointestinal tissue is governed by more complex mechanisms which lead to differences in penetration between piperacillin and tazobactam. For all tissues investigated (except fatty tissue), the time course of the concentrations of both compounds was similar, with a peak in concentration at between 1 and 2 h after the start of infusion followed by a decline of concentrations that were almost parallel to the curves of the drug concentrations in plasma. In plasma and in all investigated tissues, piperacillin as well as tazobactam reached or exceeded the concentrations found to be effective in vitro.