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Carl M J Kirkpatrick - One of the best experts on this subject based on the ideXlab platform.

  • Are standard doses of Piperacillin sufficient for critically ill patients with augmented creatinine clearance?
    Critical Care, 2015
    Co-Authors: Andrew A. Udy, PAUL JARRETT, Steven C. Wallis, Peter S. Kruger, Kashyap Patel, Kerenaftali Klein, David L Paterson, Jeffrey Lipman, Carl M J Kirkpatrick, Michael S. Roberts
    Abstract:

    INTRODUCTION: The aim of this study was to explore the impact of augmented creatinine clearance and differing minimum inhibitory concentrations (MIC) on Piperacillin pharmacokinetic/pharmacodynamic (PK/PD) target attainment (time above MIC (fT>MIC)) in critically ill patients with sepsis receiving intermittent dosing. METHODS: To be eligible for enrolment, critically ill patients with sepsis had to be receiving Piperacillin-tazobactam 4.5 g intravenously (IV) by intermittent infusion every 6 hours for presumed or confirmed nosocomial infection without significant renal impairment (defined by a plasma creatinine concentration greater than 171 μmol/L or the need for renal replacement therapy). Over a single dosing interval, blood samples were drawn to determine unbound plasma Piperacillin concentrations. Renal function was assessed by measuring creatinine clearance (CLCR). A population PK model was constructed, and the probability of target attainment (PTA) for 50% and 100% fT>MIC was calculated for varying MIC and CLCR values. RESULTS: In total, 48 patients provided data. Increasing CLCR values were associated with lower trough plasma Piperacillin concentrations (P < 0.01), such that with an MIC of 16 mg/L, 100% fT>MIC would be achieved in only one-third (n = 16) of patients. Mean Piperacillin clearance was approximately 1.5-fold higher than in healthy volunteers and correlated with CLCR (r = 0.58, P < 0.01). A reduced PTA for all MIC values, when targeting either 50% or 100% fT>MIC, was noted with increasing CLCR measures. CONCLUSIONS: Standard intermittent Piperacillin-tazobactam dosing is unlikely to achieve optimal Piperacillin exposures in a significant proportion of critically ill patients with sepsis, owing to elevated drug clearance. These data suggest that CLCR can be employed as a useful tool to determine whether Piperacillin PK/PD target attainment is likely with a range of MIC values.

  • pharmacokinetics of Piperacillin and tazobactam in plasma and subcutaneous interstitial fluid in critically ill patients receiving continuous venovenous haemodiafiltration
    International Journal of Antimicrobial Agents, 2014
    Co-Authors: Julie M. Varghese, PAUL JARRETT, Robert J. Boots, Jeffrey Lipman, Carl M J Kirkpatrick, Jason A Roberts
    Abstract:

    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 (4 g/0.5 g) was administered every 8 h and CVVHDF was performed as a 3–3.5 L/h exchange using a polyacrylonitrile filter with a surface area of 1.05 m2. 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 4.5 g Piperacillin/tazobactam administered evry 8 h resulted in Piperacillin concentrations in plasma and ISF >32 mg/L throughout most of the dosing interval.

  • Pharmacokinetics of Piperacillin and tazobactam in plasma and subcutaneous interstitial fluid in critically ill patients receiving continuous venovenous haemodiafiltration
    International Journal of Antimicrobial Agents, 2014
    Co-Authors: Julie M. Varghese, PAUL JARRETT, Robert J. Boots, Jeffrey Lipman, Carl M J Kirkpatrick, Jason A Roberts
    Abstract:

    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 (4 g/0.5 g) was administered every 8 h and CVVHDF was performed as a 3-3.5 L/h exchange using a polyacrylonitrile filter with a surface area of 1.05 m2. 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 4.5 g Piperacillin/tazobactam administered evry 8 h resulted in Piperacillin concentrations in plasma and ISF >32 mg/L throughout most of the dosing interval. © 2014 Elsevier B.V. and the International Society of Chemotherapy.

  • Inhibition of flucloxacillin tubular renal secretion by Piperacillin.
    British Journal of Clinical Pharmacology, 2008
    Co-Authors: Cornelia Barbara Landersdorfer, M. Kinzig, Carl M J Kirkpatrick, Jürgen B. Bulitta, Ulrike Holzgrabe, Fritz Sorgel
    Abstract:

    WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Most β-lactams are excreted by filtration and to a greater extent by tubular secretion, which is a capacity-limited saturable pathway. • Pharmacokinetic interactions between co-administered β-lactams have been frequently reported; however, their mechanism and possible clinical benefits are not well defined. • We are not aware of the interaction between Piperacillin and flucloxacillin being reported in the literature. WHAT THIS STUDY ADDS • Piperacillin inhibits the renal and nonrenal elimination of flucloxacillin to a clinically significant extent, but not vice versa. • Modelling suggests that the mechanism for the decrease of renal clearance of flucloxacillin is probably competitive inhibition of renal tubular secretion by Piperacillin. • Piperacillin has a 15-times higher affinity for the renal transporter than flucloxacillin based on the molar ratio. AIMS To explore the extent, time course, site(s), mechanism and possible clinical relevance of the pharmacokinetic (PK) interaction between Piperacillin and flucloxacillin. METHODS A single-dose, randomized, six-way crossover study in 10 healthy volunteers where all subjects received all of the following as 5-min intravenous infusions: (i) 1.5 g Piperacillin, (ii) 0.5 g flucloxacillin, (iii) 1.5 g Piperacillin + 0.5 g flucloxacillin, (iv) 3 g Piperacillin, (v) 1 g flucloxacillin, and (vi) 3 g Piperacillin + 1 g flucloxacillin. Drug concentrations in plasma and urine were determined by high-performance liquid chromatography. WinNonlin® was used for PK modelling and statistics. RESULTS Piperacillin significantly decreased the renal clearance of flucloxacillin from 5.44 to 2.29 l h−1 (medians, P 

  • Inhibition of flucloxacillin tubular renal secretion by Piperacillin
    British Journal of Clinical Pharmacology, 2008
    Co-Authors: Cornelia Barbara Landersdorfer, M. Kinzig, Carl M J Kirkpatrick, Jürgen B. Bulitta, Ulrike Holzgrabe, Fritz Sorgel
    Abstract:

    AIMS: To explore the extent, time course, site(s), mechanism and possible clinical relevance of the pharmacokinetic (PK) interaction between Piperacillin and flucloxacillin.\n\nMETHODS: A single-dose, randomized, six-way crossover study in 10 healthy volunteers where all subjects received all of the following as 5-min intravenous infusions: (i) 1.5 g Piperacillin, (ii) 0.5 g flucloxacillin, (iii) 1.5 g Piperacillin + 0.5 g flucloxacillin, (iv) 3 g Piperacillin, (v) 1 g flucloxacillin, and (vi) 3 g Piperacillin + 1 g flucloxacillin. Drug concentrations in plasma and urine were determined by high-performance liquid chromatography. WinNonlin was used for PK modelling and statistics.\n\nRESULTS: Piperacillin significantly decreased the renal clearance of flucloxacillin from 5.44 to 2.29 l h(-1) (medians, P < 0.01) and the nonrenal clearance of flucloxacillin from 2.67 to 1.80 l h(-1) (P < 0.01). The renal clearance of flucloxacillin was reduced to 45% (point estimate, 90% confidence interval 40 to 50%) and the nonrenal clearance to 66% (59, 73). The extent of interaction was larger at the higher doses. Competitive inhibition of tubular secretion by Piperacillin was identified as the most likely mechanism for the decreased renal clearance of flucloxacillin. Piperacillin had a 15-times higher affinity for the renal transporter than flucloxacillin based on the molar ratio. Piperacillin PK was only slightly affected by flucloxacillin.\n\nCONCLUSIONS: Piperacillin inhibits renal and nonrenal elimination of flucloxacillin. This interaction seems clinically significant, as total clearance was reduced by a factor of 1.5 for the lower and 2.1 for the higher doses. PK interactions, especially with Piperacillin, are likely to occur also with other beta-lactam combinations and might be useful to improve the effectiveness of antibacterial treatment.

Jason A Roberts - One of the best experts on this subject based on the ideXlab platform.

  • pharmacokinetics of Piperacillin and tazobactam in plasma and subcutaneous interstitial fluid in critically ill patients receiving continuous venovenous haemodiafiltration
    International Journal of Antimicrobial Agents, 2014
    Co-Authors: Julie M. Varghese, PAUL JARRETT, Robert J. Boots, Jeffrey Lipman, Carl M J Kirkpatrick, Jason A Roberts
    Abstract:

    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 (4 g/0.5 g) was administered every 8 h and CVVHDF was performed as a 3–3.5 L/h exchange using a polyacrylonitrile filter with a surface area of 1.05 m2. 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 4.5 g Piperacillin/tazobactam administered evry 8 h resulted in Piperacillin concentrations in plasma and ISF >32 mg/L throughout most of the dosing interval.

  • Pharmacokinetics of Piperacillin and tazobactam in plasma and subcutaneous interstitial fluid in critically ill patients receiving continuous venovenous haemodiafiltration
    International Journal of Antimicrobial Agents, 2014
    Co-Authors: Julie M. Varghese, PAUL JARRETT, Robert J. Boots, Jeffrey Lipman, Carl M J Kirkpatrick, Jason A Roberts
    Abstract:

    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 (4 g/0.5 g) was administered every 8 h and CVVHDF was performed as a 3-3.5 L/h exchange using a polyacrylonitrile filter with a surface area of 1.05 m2. 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 4.5 g Piperacillin/tazobactam administered evry 8 h resulted in Piperacillin concentrations in plasma and ISF >32 mg/L throughout most of the dosing interval. © 2014 Elsevier B.V. and the International Society of Chemotherapy.

Jeffrey Lipman - One of the best experts on this subject based on the ideXlab platform.

  • Is high-dose β-lactam therapy associated with excessive drug toxicity in critically ill patients?
    Minerva Anestesiologica, 2016
    Co-Authors: Craig Mcdonald, Brett C. Mcwhinney, Menino O.cotta Cotta, Jeffrey Lipman, Peter J Little, Jacobus P J Ungerer, Jason A. Robertserts
    Abstract:

    BACKGROUND: beta-lactam antibiotics may necessitate higher than licensed drug doses to achieve therapeutic exposures in critically ill patients. Therapeutic drug monitoring can be used to guide dosing so as to maximise therapeutic effect whilst reducing the likelihood of exposure-related toxicity., METHODS: A retrospective review of critically ill patients identified those that received higher than licensed doses of either meropenem (3-6 g/day) or Piperacillin-tazobactam (16 g-2 g/day) (i.e. high-dose group) guided by therapeutic drug monitoring. beta-lactam-associated toxicities were compared with a patient group of similar age, sex, body mass index and admission diagnosis that received licensed doses of either antibiotic., RESULTS: Mean daily doses were more than 40% higher in the high-dose groups for each antibiotic. There were no significant differences between the high-dose and licensed-dose groups in terms of hepatocellular derangement (17.9% vs. 31.8%, P=0.25 for meropenem and 17.4% vs. 16.0%, P=0.90 for Piperacillin-tazobactam), cholestasis (28.0% vs. 13.6%, P=0.32 for meropenem and 13.0% vs. 4.0%, P=0.26 for Piperacillin-tazobactam), need for continuous renal replacement therapy (0% vs. 9.1%, P=0.10 for meropenem and 0% vs. 8.0%, P=0.16 for Piperacillin-tazobactam), seizure incidence (7.1% vs. 4.5%, P=0.70 for meropenem and nil for either Piperacillin-tazobactam group), thrombocytopenia (9.1% vs. 10.7%, P=0.85 for meropenem and 4.0% vs. 4.3% for Piperacillin-tazobactam), or neutropenia (4.5% vs. 3.6%, P=0.95 for meropenem and 0.0% vs. 4.3% for Piperacillin-tazobactam)., CONCLUSIONS: Higher than licensed doses of meropenem and Piperacillin-tazobactam guided by therapeutic drug monitoring were not associated with additional toxicities. Larger prospective studies are required to confirm the clinical utility of higher than licensed dosing

  • Are standard doses of Piperacillin sufficient for critically ill patients with augmented creatinine clearance?
    Critical Care, 2015
    Co-Authors: Andrew A. Udy, PAUL JARRETT, Steven C. Wallis, Peter S. Kruger, Kashyap Patel, Kerenaftali Klein, David L Paterson, Jeffrey Lipman, Carl M J Kirkpatrick, Michael S. Roberts
    Abstract:

    INTRODUCTION: The aim of this study was to explore the impact of augmented creatinine clearance and differing minimum inhibitory concentrations (MIC) on Piperacillin pharmacokinetic/pharmacodynamic (PK/PD) target attainment (time above MIC (fT>MIC)) in critically ill patients with sepsis receiving intermittent dosing. METHODS: To be eligible for enrolment, critically ill patients with sepsis had to be receiving Piperacillin-tazobactam 4.5 g intravenously (IV) by intermittent infusion every 6 hours for presumed or confirmed nosocomial infection without significant renal impairment (defined by a plasma creatinine concentration greater than 171 μmol/L or the need for renal replacement therapy). Over a single dosing interval, blood samples were drawn to determine unbound plasma Piperacillin concentrations. Renal function was assessed by measuring creatinine clearance (CLCR). A population PK model was constructed, and the probability of target attainment (PTA) for 50% and 100% fT>MIC was calculated for varying MIC and CLCR values. RESULTS: In total, 48 patients provided data. Increasing CLCR values were associated with lower trough plasma Piperacillin concentrations (P < 0.01), such that with an MIC of 16 mg/L, 100% fT>MIC would be achieved in only one-third (n = 16) of patients. Mean Piperacillin clearance was approximately 1.5-fold higher than in healthy volunteers and correlated with CLCR (r = 0.58, P < 0.01). A reduced PTA for all MIC values, when targeting either 50% or 100% fT>MIC, was noted with increasing CLCR measures. CONCLUSIONS: Standard intermittent Piperacillin-tazobactam dosing is unlikely to achieve optimal Piperacillin exposures in a significant proportion of critically ill patients with sepsis, owing to elevated drug clearance. These data suggest that CLCR can be employed as a useful tool to determine whether Piperacillin PK/PD target attainment is likely with a range of MIC values.

  • pharmacokinetics of Piperacillin and tazobactam in plasma and subcutaneous interstitial fluid in critically ill patients receiving continuous venovenous haemodiafiltration
    International Journal of Antimicrobial Agents, 2014
    Co-Authors: Julie M. Varghese, PAUL JARRETT, Robert J. Boots, Jeffrey Lipman, Carl M J Kirkpatrick, Jason A Roberts
    Abstract:

    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 (4 g/0.5 g) was administered every 8 h and CVVHDF was performed as a 3–3.5 L/h exchange using a polyacrylonitrile filter with a surface area of 1.05 m2. 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 4.5 g Piperacillin/tazobactam administered evry 8 h resulted in Piperacillin concentrations in plasma and ISF >32 mg/L throughout most of the dosing interval.

  • Pharmacokinetics of Piperacillin and tazobactam in plasma and subcutaneous interstitial fluid in critically ill patients receiving continuous venovenous haemodiafiltration
    International Journal of Antimicrobial Agents, 2014
    Co-Authors: Julie M. Varghese, PAUL JARRETT, Robert J. Boots, Jeffrey Lipman, Carl M J Kirkpatrick, Jason A Roberts
    Abstract:

    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 (4 g/0.5 g) was administered every 8 h and CVVHDF was performed as a 3-3.5 L/h exchange using a polyacrylonitrile filter with a surface area of 1.05 m2. 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 4.5 g Piperacillin/tazobactam administered evry 8 h resulted in Piperacillin concentrations in plasma and ISF >32 mg/L throughout most of the dosing interval. © 2014 Elsevier B.V. and the International Society of Chemotherapy.

Vidmantas Petraitis - One of the best experts on this subject based on the ideXlab platform.

  • detection of galactomannan antigenemia in patients receiving Piperacillin tazobactam and correlations between in vitro in vivo and clinical properties of the drug antigen interaction
    Journal of Clinical Microbiology, 2004
    Co-Authors: Thomas J. Walsh, Shmuel Shoham, Amy M. Kelaher, Robert L. Schaufele, Ruta Petraitiene, Tin Sein, Heidi Murray, John D. Bacher, Christine Myasan, Vidmantas Petraitis
    Abstract:

    Recent case reports describe patients receiving Piperacillin-tazobactam who were found to have circulating galactomannan detected by the double sandwich enzyme-linked immunosorbent assay (ELISA) system, leading to the false presumption of invasive aspergillosis. Since this property of Piperacillin-tazobactam and galactomannan ELISA is not well understood, we investigated the in vitro, in vivo, and clinical properties of this interaction. Among the 12 reconstituted antibiotics representing four classes of antibacterial compounds that are commonly used in immunocompromised patients, Piperacillin-tazobactam expressed a distinctively high level of galactomannan antigen in vitro (P = 0.001). After intravenous infusion of Piperacillin-tazobactam into rabbits, the serum galactomannan index (GMI) in vivo changed significantly (P = 0.0007) from a preinfusion mean baseline value of 0.27 to a mean GMI of 0.83 by 30 min to slowly decline to a mean GMI of 0.44 24 h later. Repeated administration of Piperacillin-tazobactam over 7 days resulted in accumulation of circulating galactomannan to a mean peak GMI of 1.31 and a nadir of 0.53. Further studies revealed that the antigen reached a steady state by the third day of administration of Piperacillin-tazobactam. Twenty-six hospitalized patients with no evidence of invasive aspergillosis who were receiving antibiotics and ten healthy blood bank donors were studied for expression of circulating galactomannan. Patients (n = 13) receiving Piperacillin-tazobactam had significantly greater mean serum GMI values (0.74 ± 0.14) compared to patients (n = 13) receiving other antibiotics (0.14 ± 0.08) and compared to healthy blood bank donors (0.14 ± 0.06) (P 0.5 compared to none of thirteen subjects receiving other antibiotics (P = 0.039) and to none of ten healthy blood bank donors (P = 0.046). These data demonstrate that among antibiotics that are commonly used in immunocompromised patients, only Piperacillin-tazobactam contains significant amounts of galactomannan antigen in vitro, that in animals receiving Piperacillin-tazobactam circulating galactomannan antigen accumulates in vivo to significantly increased and sustained levels, and that some but not all patients receiving this antibiotic will demonstrate circulating galactomannan above the threshold considered positive for invasive aspergillosis by the recently licensed double sandwich ELISA.

  • Detection of galactomannan antigenemia in patients receiving Piperacillin-tazobactam and correlations between in vitro, in vivo, and clinical properties of the drug-antigen interaction
    Journal of Clinical Microbiology, 2004
    Co-Authors: Thomas J. Walsh, Shmuel Shoham, Amy M. Kelaher, Christine Mya-san, Robert L. Schaufele, Ruta Petraitiene, Tin Sein, Heidi Murray, John D. Bacher, Vidmantas Petraitis
    Abstract:

    Recent case reports describe patients receiving Piperacillin-tazobactam who were found to have circulating galactomannan detected by the double sandwich enzyme-linked immunosorbent assay (ELISA) system, leading to the false presumption of invasive aspergillosis. Since this property of Piperacillin-tazobactam and galactomannan ELISA is not well understood, we investigated the in vitro, in vivo, and clinical properties of this interaction. Among the 12 reconstituted antibiotics representing four classes of antibacterial compounds that are commonly used in immunocompromised patients, Piperacillin-tazobactam expressed a distinctively high level of galactomannan antigen in vitro (P = 0.001). After intravenous infusion of Piperacillin-tazobactam into rabbits, the serum galactomannan index (GMI) in vivo changed significantly (P = 0.0007) from a preinfusion mean baseline value of 0.27 to a mean GMI of 0.83 by 30 min to slowly decline to a mean GMI of 0.44 24 h later. Repeated administration of Piperacillin-tazobactam over 7 days resulted in accumulation of circulating galactomannan to a mean peak GMI of 1.31 and a nadir of 0.53. Further studies revealed that the antigen reached a steady state by the third day of administration of Piperacillin-tazobactam. Twenty-six hospitalized patients with no evidence of invasive aspergillosis who were receiving antibiotics and ten healthy blood bank donors were studied for expression of circulating galactomannan. Patients (n = 13) receiving Piperacillin-tazobactam had significantly greater mean serum GMI values (0.74 +/- 0.14) compared to patients (n = 13) receiving other antibiotics (0.14 +/- 0.08) and compared to healthy blood bank donors (0.14 +/- 0.06) (P < 0.001). Five (38.5%) of thirteen patients receiving Piperacillin-tazobactam had serum GMI values > 0.5 compared to none of thirteen subjects receiving other antibiotics (P = 0.039) and to none of ten healthy blood bank donors (P = 0.046). These data demonstrate that among antibiotics that are commonly used in immunocompromised patients, only Piperacillin-tazobactam contains significant amounts of galactomannan antigen in vitro, that in animals receiving Piperacillin-tazobactam circulating galactomannan antigen accumulates in vivo to significantly increased and sustained levels, and that some but not all patients receiving this antibiotic will demonstrate circulating galactomannan above the threshold considered positive for invasive aspergillosis by the recently licensed double sandwich ELISA.

PAUL JARRETT - One of the best experts on this subject based on the ideXlab platform.

  • Are standard doses of Piperacillin sufficient for critically ill patients with augmented creatinine clearance?
    Critical Care, 2015
    Co-Authors: Andrew A. Udy, PAUL JARRETT, Steven C. Wallis, Peter S. Kruger, Kashyap Patel, Kerenaftali Klein, David L Paterson, Jeffrey Lipman, Carl M J Kirkpatrick, Michael S. Roberts
    Abstract:

    INTRODUCTION: The aim of this study was to explore the impact of augmented creatinine clearance and differing minimum inhibitory concentrations (MIC) on Piperacillin pharmacokinetic/pharmacodynamic (PK/PD) target attainment (time above MIC (fT>MIC)) in critically ill patients with sepsis receiving intermittent dosing. METHODS: To be eligible for enrolment, critically ill patients with sepsis had to be receiving Piperacillin-tazobactam 4.5 g intravenously (IV) by intermittent infusion every 6 hours for presumed or confirmed nosocomial infection without significant renal impairment (defined by a plasma creatinine concentration greater than 171 μmol/L or the need for renal replacement therapy). Over a single dosing interval, blood samples were drawn to determine unbound plasma Piperacillin concentrations. Renal function was assessed by measuring creatinine clearance (CLCR). A population PK model was constructed, and the probability of target attainment (PTA) for 50% and 100% fT>MIC was calculated for varying MIC and CLCR values. RESULTS: In total, 48 patients provided data. Increasing CLCR values were associated with lower trough plasma Piperacillin concentrations (P < 0.01), such that with an MIC of 16 mg/L, 100% fT>MIC would be achieved in only one-third (n = 16) of patients. Mean Piperacillin clearance was approximately 1.5-fold higher than in healthy volunteers and correlated with CLCR (r = 0.58, P < 0.01). A reduced PTA for all MIC values, when targeting either 50% or 100% fT>MIC, was noted with increasing CLCR measures. CONCLUSIONS: Standard intermittent Piperacillin-tazobactam dosing is unlikely to achieve optimal Piperacillin exposures in a significant proportion of critically ill patients with sepsis, owing to elevated drug clearance. These data suggest that CLCR can be employed as a useful tool to determine whether Piperacillin PK/PD target attainment is likely with a range of MIC values.

  • pharmacokinetics of Piperacillin and tazobactam in plasma and subcutaneous interstitial fluid in critically ill patients receiving continuous venovenous haemodiafiltration
    International Journal of Antimicrobial Agents, 2014
    Co-Authors: Julie M. Varghese, PAUL JARRETT, Robert J. Boots, Jeffrey Lipman, Carl M J Kirkpatrick, Jason A Roberts
    Abstract:

    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 (4 g/0.5 g) was administered every 8 h and CVVHDF was performed as a 3–3.5 L/h exchange using a polyacrylonitrile filter with a surface area of 1.05 m2. 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 4.5 g Piperacillin/tazobactam administered evry 8 h resulted in Piperacillin concentrations in plasma and ISF >32 mg/L throughout most of the dosing interval.

  • Pharmacokinetics of Piperacillin and tazobactam in plasma and subcutaneous interstitial fluid in critically ill patients receiving continuous venovenous haemodiafiltration
    International Journal of Antimicrobial Agents, 2014
    Co-Authors: Julie M. Varghese, PAUL JARRETT, Robert J. Boots, Jeffrey Lipman, Carl M J Kirkpatrick, Jason A Roberts
    Abstract:

    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 (4 g/0.5 g) was administered every 8 h and CVVHDF was performed as a 3-3.5 L/h exchange using a polyacrylonitrile filter with a surface area of 1.05 m2. 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 4.5 g Piperacillin/tazobactam administered evry 8 h resulted in Piperacillin concentrations in plasma and ISF >32 mg/L throughout most of the dosing interval. © 2014 Elsevier B.V. and the International Society of Chemotherapy.