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

  • 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
    Clinical Chemistry and Laboratory Medicine, 2020
    Co-Authors: Suzanne L Parker, Fekade B Sime, Janine Stuart, Saurabh Pandey, Jeffrey Lipman, Jason A Roberts, Steven C Wallis
    Abstract:

    ObjectivesNovel 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.MethodsAnalytes were separated using mixed-mode chromatography with an intrinsically base-deactivated C18 column and a gradient mobile phase consisting of 0.1% formic acid, 10 mM 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.ResultsA quadratic calibration was obtained for plasma (total and unbound), RRTE and CSF over the concentration range of 1–200 mg/L for Ceftolozane and 0.5–100 mg/L for tazobactam, and for urine the concentration range of 10–2,000 mg/L for Ceftolozane and 5–1,000 mg/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%.ConclusionsThis 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.

  • cerebrospinal fluid penetration of Ceftolozane tazobactam in critically ill patients with an indwelling external ventricular drain
    Antimicrobial Agents and Chemotherapy, 2020
    Co-Authors: Fekade B Sime, Melissa Lassigsmith, Therese Starr, Janine Stuart, Saurabh Pandey, Suzanne L Parker, Steven C Wallis, Jeffrey Lipman
    Abstract:

    The aim of this study was to describe the pharmacokinetics of Ceftolozane/tazobactam in plasma and cerebrospinal fluid (CSF) of infected critically ill patients. In a prospective observational study, critically ill patients (≥ 18 years) with an indwelling external ventricular drain received a single intravenous dose of 3.0g Ceftolozane/tazobactam. Serial plasma and CSF samples were collected for measurement of unbound Ceftolozane and tazobactam concentration by liquid chromatography. Unbound concentration-time data were modelled in R using Pmetrics. Dosing simulations were performed using the final model. A three-compartment model adequately described the data from 10 patients. For Ceftolozane, the median (Inter quartile range, IQR) area under the unbound concentration-time curve from time zero to infinity (fAUC0-inf) in the CSF and plasma were 30 (19-128) h*mg/L, and 323 (183-414) h*mg/L respectively. For tazobactam, these values were 5.6 (2-24) h*mg/L and 52 (36-80) h*mg/L, respectively. Mean ± standard deviation (SD) CSF penetration ratios were 0.2 ± 0.2 and 0.2±0.26 for Ceftolozane and tazobactam respectively. With the 3.0 g 8-houly regimen, ≥ 0.9 probability of target attainment (PTA) for 40% fT>MIC in the CSF was possible only when MICs were ≤ 0.25 mg/L. The CSF cumulative fractional response for P. aeruginosa susceptible MIC distribution was 73%. The tazobactam PTA for the minimal suggested exposure of 20% fT>1mg/L was 12%. The current maximal dose of Ceftolozane/tazobactam (3.0 g 8-hourly) does not provide adequate CSF exposure for treatment of Gram-negative meningitis or ventriculitis unless the MIC for the causative pathogen is very low (≤0.25 mg/L).

  • a population pharmacokinetic model guided evaluation of Ceftolozane tazobactam dosing in critically ill patients undergoing continuous venovenous hemodiafiltration
    Antimicrobial Agents and Chemotherapy, 2019
    Co-Authors: Fekade B Sime, Melissa Lassigsmith, Therese Starr, Janine Stuart, Saurabh Pandey, Suzanne L Parker, Steven C Wallis, Jeffrey Lipman
    Abstract:

    The aim of this work was to describe optimised dosing regimens of Ceftolozane/tazobactam for critically ill patients receiving continuous venovenous hemodiafiltration (CVVHDF). We conducted a prospective observational pharmacokinetic study in adult critically ill patients with clinical indications for Ceftolozane/tazobactam and CVVHDF. Unbound drug concentrations were measured from serial pre-filter blood, post-filter blood and ultrafiltrate samples by a chromatographic assay. Population pharmacokinetic modelling and dosing simulations were preformed using Pmetrics®. A four compartment pharmacokinetic model adequately described the data from six patients. The mean (± standard deviation [SD]) extraction ratio for Ceftolozane and tazobactam were 0.76 ± 0.08 and 0.73 ± 0.1, respectively. The mean ± SD sieving coefficients were 0.94 ± 0.24 and 1.08 ± 0.30 respectively. Model estimated CVVHDF clearances were 2.7 ± 0.8 and 3.0 ± 0.6 L/h respectively. Residual non-CVVHDF clearances were 0.6 ± 0.5 and 3.3 ±0.9 L/h, respectively. In the initial 24 h, doses as low as 0.75g 8-hourly enable fractional target attainment of ≥ 85% for empiric coverage against considering 40 % T target. For 100 % T, at least 1.5 g 8-hourly is required. The median (interquartile range) steady state trough Ceftolozane concentrations for simulated 1.5g and 3.0g 8-hourly regimens were 28 (21-42) and 56 (42-84) mg/L, respectively. The corresponding tazobactam concentrations were 6.1 (5.5-6.7) and 12.1 (11.0-13.4) mg/L, respectively. We suggest a front-loaded regimen with a single 3.0 g loading dose followed by 0.75 g 8-hourly for critically ill patients undergoing CVVHDF with study blood and dialysate flow rates.

Robert K Flamm - One of the best experts on this subject based on the ideXlab platform.

Michael A Pfaller - One of the best experts on this subject based on the ideXlab platform.

Steven C Wallis - One of the best experts on this subject based on the ideXlab platform.

  • 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
    Clinical Chemistry and Laboratory Medicine, 2020
    Co-Authors: Suzanne L Parker, Fekade B Sime, Janine Stuart, Saurabh Pandey, Jeffrey Lipman, Jason A Roberts, Steven C Wallis
    Abstract:

    ObjectivesNovel 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.MethodsAnalytes were separated using mixed-mode chromatography with an intrinsically base-deactivated C18 column and a gradient mobile phase consisting of 0.1% formic acid, 10 mM 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.ResultsA quadratic calibration was obtained for plasma (total and unbound), RRTE and CSF over the concentration range of 1–200 mg/L for Ceftolozane and 0.5–100 mg/L for tazobactam, and for urine the concentration range of 10–2,000 mg/L for Ceftolozane and 5–1,000 mg/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%.ConclusionsThis 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.

  • cerebrospinal fluid penetration of Ceftolozane tazobactam in critically ill patients with an indwelling external ventricular drain
    Antimicrobial Agents and Chemotherapy, 2020
    Co-Authors: Fekade B Sime, Melissa Lassigsmith, Therese Starr, Janine Stuart, Saurabh Pandey, Suzanne L Parker, Steven C Wallis, Jeffrey Lipman
    Abstract:

    The aim of this study was to describe the pharmacokinetics of Ceftolozane/tazobactam in plasma and cerebrospinal fluid (CSF) of infected critically ill patients. In a prospective observational study, critically ill patients (≥ 18 years) with an indwelling external ventricular drain received a single intravenous dose of 3.0g Ceftolozane/tazobactam. Serial plasma and CSF samples were collected for measurement of unbound Ceftolozane and tazobactam concentration by liquid chromatography. Unbound concentration-time data were modelled in R using Pmetrics. Dosing simulations were performed using the final model. A three-compartment model adequately described the data from 10 patients. For Ceftolozane, the median (Inter quartile range, IQR) area under the unbound concentration-time curve from time zero to infinity (fAUC0-inf) in the CSF and plasma were 30 (19-128) h*mg/L, and 323 (183-414) h*mg/L respectively. For tazobactam, these values were 5.6 (2-24) h*mg/L and 52 (36-80) h*mg/L, respectively. Mean ± standard deviation (SD) CSF penetration ratios were 0.2 ± 0.2 and 0.2±0.26 for Ceftolozane and tazobactam respectively. With the 3.0 g 8-houly regimen, ≥ 0.9 probability of target attainment (PTA) for 40% fT>MIC in the CSF was possible only when MICs were ≤ 0.25 mg/L. The CSF cumulative fractional response for P. aeruginosa susceptible MIC distribution was 73%. The tazobactam PTA for the minimal suggested exposure of 20% fT>1mg/L was 12%. The current maximal dose of Ceftolozane/tazobactam (3.0 g 8-hourly) does not provide adequate CSF exposure for treatment of Gram-negative meningitis or ventriculitis unless the MIC for the causative pathogen is very low (≤0.25 mg/L).

  • a population pharmacokinetic model guided evaluation of Ceftolozane tazobactam dosing in critically ill patients undergoing continuous venovenous hemodiafiltration
    Antimicrobial Agents and Chemotherapy, 2019
    Co-Authors: Fekade B Sime, Melissa Lassigsmith, Therese Starr, Janine Stuart, Saurabh Pandey, Suzanne L Parker, Steven C Wallis, Jeffrey Lipman
    Abstract:

    The aim of this work was to describe optimised dosing regimens of Ceftolozane/tazobactam for critically ill patients receiving continuous venovenous hemodiafiltration (CVVHDF). We conducted a prospective observational pharmacokinetic study in adult critically ill patients with clinical indications for Ceftolozane/tazobactam and CVVHDF. Unbound drug concentrations were measured from serial pre-filter blood, post-filter blood and ultrafiltrate samples by a chromatographic assay. Population pharmacokinetic modelling and dosing simulations were preformed using Pmetrics®. A four compartment pharmacokinetic model adequately described the data from six patients. The mean (± standard deviation [SD]) extraction ratio for Ceftolozane and tazobactam were 0.76 ± 0.08 and 0.73 ± 0.1, respectively. The mean ± SD sieving coefficients were 0.94 ± 0.24 and 1.08 ± 0.30 respectively. Model estimated CVVHDF clearances were 2.7 ± 0.8 and 3.0 ± 0.6 L/h respectively. Residual non-CVVHDF clearances were 0.6 ± 0.5 and 3.3 ±0.9 L/h, respectively. In the initial 24 h, doses as low as 0.75g 8-hourly enable fractional target attainment of ≥ 85% for empiric coverage against considering 40 % T target. For 100 % T, at least 1.5 g 8-hourly is required. The median (interquartile range) steady state trough Ceftolozane concentrations for simulated 1.5g and 3.0g 8-hourly regimens were 28 (21-42) and 56 (42-84) mg/L, respectively. The corresponding tazobactam concentrations were 6.1 (5.5-6.7) and 12.1 (11.0-13.4) mg/L, respectively. We suggest a front-loaded regimen with a single 3.0 g loading dose followed by 0.75 g 8-hourly for critically ill patients undergoing CVVHDF with study blood and dialysate flow rates.

Benjamin Miller - One of the best experts on this subject based on the ideXlab platform.

  • cost effectiveness of Ceftolozane tazobactam plus metronidazole versus piperacillin tazobactam as initial empiric therapy for the treatment of complicated intra abdominal infections based on pathogen distributions drawn from national surveillance data in the united states
    Antimicrobial Resistance and Infection Control, 2017
    Co-Authors: Vimalanand S Prabhu, Benjamin Miller, Joseph S Solomkin, Goran Medic, Jason Foo, Rebekah H Borse, Teresa L Kauf, Shuvayu S Sen, Anirban Basu
    Abstract:

    The prevalence of antimicrobial resistance among gram-negative pathogens in complicated intra-abdominal infections (cIAIs) has increased. In the absence of timely information on the infecting pathogens and their susceptibilities, local or regional epidemiology may guide initial empirical therapy and reduce treatment failure, length of stay and mortality. The objective of this study was to assess the cost-effectiveness of Ceftolozane/tazobactam + metronidazole compared with piperacillin/tazobactam in the treatment of hospitalized US patients with cIAI at risk of infection with resistant pathogens. We used a decision-analytic Monte Carlo simulation model to compare the costs and quality-adjusted life years (QALYs) of persons infected with nosocomial gram-negative cIAI treated empirically with either Ceftolozane/tazobactam + metronidazole or piperacillin/tazobactam. Pathogen isolates were randomly drawn from the Program to Assess Ceftolozane/Tazobactam Susceptibility (PACTS) database, a surveillance database of non-duplicate bacterial isolates collected from patients with cIAIs in medical centers in the USA from 2011 to 2013. Susceptibility to initial therapy was based on the measured susceptibilities reported in the PACTS database determined using standard broth micro-dilution methods as described by the Clinical and Laboratory Standards Institute (CLSI). Our model results, with baseline resistance levels from the PACTS database, indicated that Ceftolozane/tazobactam + metronidazole dominated piperacillin/tazobactam, with lower costs ($44,226/patient vs. $44,811/patient respectively) and higher QALYs (12.85/patient vs. 12.70/patient, respectively). Ceftolozane/tazobactam + metronidazole remained the dominant choice in one-way and probabilistic sensitivity analyses. Based on surveillance data, Ceftolozane/tazobactam is more likely to be an appropriate empiric therapy for cIAI in the US. Results from a decision-analytic simulation model indicate that use of Ceftolozane/tazobactam + metronidazole would result in cost savings and improves QALYs, compared with piperacillin/tazobactam.

  • cost effectiveness of Ceftolozane tazobactam compared with piperacillin tazobactam as empiric therapy based on the in vitro surveillance of bacterial isolates in the united states for the treatment of complicated urinary tract infections
    BMC Infectious Diseases, 2017
    Co-Authors: Teresa L Kauf, Benjamin Miller, Vimalanand S Prabhu, Goran Medic, Rebekah H Borse, Jennifer G Gaultney, Anirban Basu
    Abstract:

    A challenge in the empiric treatment of complicated urinary tract infection (cUTI) is identifying the initial appropriate antibiotic therapy (IAAT), which is associated with reduced length of stay and mortality compared with initial inappropriate antibiotic therapy (IIAT). We evaluated the cost-effectiveness of Ceftolozane/tazobactam compared with piperacillin/tazobactam (one of the standard of care antibiotics), for the treatment of hospitalized patients with cUTI. A decision-analytic Monte Carlo simulation model was developed to compare the costs and effectiveness of empiric treatment with either Ceftolozane/tazobactam or piperacillin/tazobactam in hospitalized adult patients with cUTI infected with Gram-negative pathogens in the US. The model applies the baseline prevalence of resistance as reported by national in-vitro surveillance data. In a cohort of 1000 patients, treatment with Ceftolozane/tazobactam resulted in higher total costs compared with piperacillin/tazobactam ($36,413 /patient vs. $36,028/patient, respectively), greater quality-adjusted life years (QALYs) (9.19/patient vs. 9.13/patient, respectively) and an incremental cost-effectiveness ratio (ICER) of $6128/QALY. Ceftolozane/tazobactam remained cost-effective at a willingness to pay of $100,000 per QALY compared to piperacillin/tazobactam over a range of input parameter values during one-way and probabilistic sensitivity analysis. Model results show that Ceftolozane/tazobactam is likely to be cost-effective compared with piperacillin/tazobactam for the empiric treatment of hospitalized cUTI patients in the United States.

  • Cost-effectiveness of Ceftolozane/tazobactam plus metronidazole versus piperacillin/tazobactam as initial empiric therapy for the treatment of complicated intra-abdominal infections based on pathogen distributions drawn from national surveillance data in the United States
    BMC, 2017
    Co-Authors: Vimalanand S Prabhu, Benjamin Miller, Joseph S Solomkin, Goran Medic, Jason Foo, Rebekah H Borse, Teresa L Kauf, Shuvayu S Sen, Anirban Basu
    Abstract:

    Abstract Background The prevalence of antimicrobial resistance among gram-negative pathogens in complicated intra-abdominal infections (cIAIs) has increased. In the absence of timely information on the infecting pathogens and their susceptibilities, local or regional epidemiology may guide initial empirical therapy and reduce treatment failure, length of stay and mortality. The objective of this study was to assess the cost-effectiveness of Ceftolozane/tazobactam + metronidazole compared with piperacillin/tazobactam in the treatment of hospitalized US patients with cIAI at risk of infection with resistant pathogens. Methods We used a decision-analytic Monte Carlo simulation model to compare the costs and quality-adjusted life years (QALYs) of persons infected with nosocomial gram-negative cIAI treated empirically with either Ceftolozane/tazobactam + metronidazole or piperacillin/tazobactam. Pathogen isolates were randomly drawn from the Program to Assess Ceftolozane/Tazobactam Susceptibility (PACTS) database, a surveillance database of non-duplicate bacterial isolates collected from patients with cIAIs in medical centers in the USA from 2011 to 2013. Susceptibility to initial therapy was based on the measured susceptibilities reported in the PACTS database determined using standard broth micro-dilution methods as described by the Clinical and Laboratory Standards Institute (CLSI). Results Our model results, with baseline resistance levels from the PACTS database, indicated that Ceftolozane/tazobactam + metronidazole dominated piperacillin/tazobactam, with lower costs ($44,226/patient vs. $44,811/patient respectively) and higher QALYs (12.85/patient vs. 12.70/patient, respectively). Ceftolozane/tazobactam + metronidazole remained the dominant choice in one-way and probabilistic sensitivity analyses. Conclusions Based on surveillance data, Ceftolozane/tazobactam is more likely to be an appropriate empiric therapy for cIAI in the US. Results from a decision-analytic simulation model indicate that use of Ceftolozane/tazobactam + metronidazole would result in cost savings and improves QALYs, compared with piperacillin/tazobactam

  • Ceftolozane tazobactam plus metronidazole for complicated intra abdominal infections in an era of multidrug resistance results from a randomized double blind phase 3 trial aspect ciai
    Clinical Infectious Diseases, 2015
    Co-Authors: Joseph S Solomkin, Guojun Yuan, Ellie Hershberger, Benjamin Miller, Judith N Steenbergen, Myra Popejoy, Ian Friedland, Minjung Yoon, Sylva H Collins, Philip S Barie
    Abstract:

    Complicated intra-abdominal infections (cIAIs) are tissue-invasive infections leading to abscess formation or generalized peritonitis. The management of cIAIs involves operative or percutaneous intervention to obtain surgical control of the source. Nonetheless, patients with cIAIs are at risk of sepsis and mortality [1–4]. Empiric antimicrobial therapy with appropriate agents is an important component of treatment [5, 6]. Initial empiric therapy that is not effective against infecting pathogens increases costs, treatment failure, and death [7–10]. Because of this, cIAIs are an important infection category for evaluation of the efficacy of investigational agents. The well-recognized appearance of antimicrobial resistance among gram-negative bacteria has stimulated the development of novel agents [11], particularly those targeting Enterobacteriaceae that produce extended-spectrum β-lactamases (ESBLs) [12], which confer resistance to most β-lactam antimicrobial agents [1]. Ceftolozane/tazobactam consists of a novel cephalosporin and an established β-lactamase inhibitor that is being developed to address antimicrobial resistance in serious infections caused by gram-negative pathogens, including cIAI, complicated urinary tract infection/pyelonephritis (cUTI), and ventilated nosocomial pneumonia. In vitro activity of Ceftolozane/tazobactam has been confirmed against ESBL-producing Enterobacteriaceae, drug-resistant Pseudomonas aeruginosa [13–16], and some Streptococcus species [17]. The results from a phase 2 study with Ceftolozane/tazobactam in combination with metronidazole in cIAI supported further development for this indication [18]. We now report the results from ASPECT-cIAI (Assessment of the Safety Profile and Efficacy of Ceftolozane/Tazobactam in Complicated Intra-abdominal Infections), a large global phase 3 clinical program that evaluated intravenous Ceftolozane/tazobactam plus metronidazole vs meropenem for the treatment of hospitalized adult patients with cIAI.

  • Impact of renal function on the pharmacokinetics and safety of Ceftolozane-tazobactam
    Antimicrobial Agents and Chemotherapy, 2014
    Co-Authors: Myra Wooley, Ellie Hershberger, Gopal Krishna, Benjamin Miller, Gurudatt Chandorkar
    Abstract:

    Ceftolozane-tazobactam is a novel antipseudomonal cephalosporin with a β-lactamase inhibitor. We investigated the pharmacokinetics (PK) and safety of Ceftolozane-tazobactam in subjects with various degrees of renal function. In two phase I, open-label studies, a single dose of Ceftolozane-tazobactam was administered as a 1-h intravenous infusion to 24 subjects with normal, mild, or moderate renal impairment (1,000/500 mg) and six subjects with severe renal impairment (500/250 mg). Six subjects with end-stage renal disease (ESRD) received two doses of Ceftolozane-tazobactam (500/250 mg each), pre- and posthemodialysis (post-HD). PK parameters were determined by noncompartmental methods. Plasma exposure to Ceftolozane-tazobactam increased as renal function declined with only slightly increased exposures in subjects with mild renal impairment; the median area under the concentration-time curve from time zero to infinity (AUC0-∞) for Ceftolozane and tazobactam increased 1.4- and 1.2-fold, respectively. In subjects with moderate renal impairment, the AUC0-∞ increased 2.5- and 2.2-fold for Ceftolozane and tazobactam, respectively. In subjects with severe renal impairment, the dose-normalized median AUC0-∞ for Ceftolozane and tazobactam increased 4.4- and 3.8-fold, respectively. In ESRD subjects, Ceftolozane and tazobactam concentrations declined rapidly following the start of HD, with approximately 66 and 56% reductions in overall exposure based on the AUC0-∞ before and after dialysis. Slight increases in exposure with mild renal impairment do not warrant a dose adjustment; however, subjects with moderate or severe renal impairment and those on HD require a decrease in the dose, a change in the frequency of administration, or both to achieve exposures within the established safety and efficacy margins of Ceftolozane-tazobactam. Ceftolozane-tazobactam was well tolerated by all renal impairment groups.