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      Development of an HPLC–MS/MS method for the determination of ceftolozane/tazobactam in bronchoalveolar lavage fluid

      1 , 2 , * , 1 , 3
      Future Science OA
      Future Science Ltd
      BAL, ceftolozane, HPLC–MS, tazobactam

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          We describe the validation of an HPLC–MS/MS method to analyze ceftolozane and tazobactam simultaneously in saline matrixes.

          Materials & methods:

          An Agilent 1260 HPLC interfaced to an Agilent 6470 triple-quadrupole mass spectrometer was used for quantification. A reverse-phase column running a gradient of water and acetonitrile containing 0.1% formic acid mobile phase at a flow rate of 1.0 ml/min provided chromatographic fractionation. Tazobactam 15N 3 was used as the internal standard. The standard curves were linear over a range of 0.02–0.5 μg/ml.


          This methodology represents a simple, reproducible approach to the determination of drug concentrations with accuracy and precision for pharmacokinetic studies undertaken with this recently US FDA-approved antimicrobial therapy.

          Lay abstract

          We describe the validation of an assay to analyze ceftolozane and tazobactam simultaneously in saline matrixes. This methodology represents a simple, reproducible approach to the determination of drug concentrations. This method can be modified to determine human concentrations of this antibiotic, which would be important for doctors to determine appropriate patient dosing.

          Most cited references7

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          Intrapulmonary penetration of ceftolozane/tazobactam and piperacillin/tazobactam in healthy adult subjects.

          Appropriate antibiotic exposure at the site of infection is important for clinically effective therapy. This study compared the epithelial lining fluid (ELF) penetration of ceftolozane/tazobactam, which has potent in vitro activity against many Gram-negative pathogens causing nosocomial pneumonia, with that of piperacillin/tazobactam in healthy adult volunteers. In this Phase 1, open-label trial, 51 healthy adult subjects were randomized to receive three doses of either ceftolozane/tazobactam 1.5 g administered every 8 h via a 60 min infusion or piperacillin/tazobactam 4.5 g administered every 6 h via a 30 min infusion. Serial blood samples were obtained for determination of plasma drug concentrations. Bronchoscopy and bronchoalveolar lavage were performed at pre-specified timepoints in five subjects per timepoint in each treatment group to determine the ELF drug concentration. The penetration of individual analytes into the ELF was determined from the ratio of the area under the plasma concentration-time curve in ELF to that in plasma (AUC(ELF)/AUC(plasma)). Plasma and ELF concentrations of ceftolozane, piperacillin and tazobactam increased rapidly, reaching maximal concentrations at the end of the infusion. Mean maximum concentration and AUC from time 0 to the end of the dosing interval (AUC(0-τ)) for ceftolozane in ELF were 21.8 mg/L and 75.1 mg·h/L, respectively. Corresponding values for piperacillin were 58.8 mg/L and 94.5 mg·h/L. The ELF/plasma AUC ratio for ceftolozane was 0.48 compared with 0.26 for piperacillin. This study demonstrated that ceftolozane penetrated well into the ELF following parenteral administration of ceftolozane/tazobactam.
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            Pharmacokinetics and safety of intravenous ceftolozane-tazobactam in healthy adult subjects following single and multiple ascending doses.

            The pharmacokinetics and safety of ceftolozane, a novel cephalosporin, and tazobactam, a β-lactamase inhibitor, alone and in combination as a 2:1 ratio in single doses of up to 2,000 and 1,000 mg of ceftolozane and tazobactam, respectively, and multiple doses of up to 3,000 and 1,500 mg of ceftolozane and tazobactam, respectively, per day were evaluated in healthy adult subjects. In part 1, groups of six subjects each received single ascending doses of ceftolozane, tazobactam, and ceftolozane-tazobactam in a within-cohort crossover design. In part 2, groups of 5 or 10 subjects each received multiple doses of ceftolozane, tazobactam, or ceftolozane-tazobactam for 10 days. After a single dose of ceftolozane alone, the ranges of mean values for half-life (2.48 to 2.64 h), the total clearance (4.35 to 6.01 liters/h), and the volume of distribution at steady state (11.0 to 14.1 liters) were consistent across dose levels and similar to those observed when ceftolozane was coadministered with tazobactam. Mean values after multiple doses for ceftolozane alone and ceftolozane-tazobactam were similar to those seen following a single dose. The pharmacokinetics of the dosing regimens evaluated were dose proportional and linear. Ceftolozane-tazobactam was well tolerated and systemic adverse events were uncommon. Mild infusion-related adverse events were the most commonly observed following multiple-dose administration. Adverse events were not dose related, and no dose-limiting toxicity was identified.
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              Ceftolozane-tazobactam activity against Pseudomonas aeruginosa clinical isolates from US hospitals: Report from an antimicrobial surveillance program (PACTS, 2012-2015).

              The activity of ceftolozane-tazobactam was compared to the activity of 7 antimicrobials against 3,851 Pseudomonas aeruginosa isolates collected from 32 US hospitals in the Program to Assess Ceftolozane-Tazobactam Susceptibility from 2012-2015. Ceftolozane-tazobactam and comparator susceptibilities were determined using the CLSI broth microdilution method at a central monitoring laboratory. For ceftolozane-tazobactam, 97.0% of the isolates were susceptible. Susceptibilities of the other antibacterials tested were: amikacin, 96.9%; cefepime, 85.9%; ceftazidime, 85.1%; colistin, 99.2%; levofloxacin, 76.6%; meropenem, 81.8%; and piperacillin-tazobactam, 80.4%.Of the 699 (18.1%) meropenem nonsusceptible P. aeruginosa, 87.6% were susceptible to ceftolozane-tazobactam.Six hundred and seven isolates (15.8%) were classified as multidrug-resistant (MDR), and 363 (9.4%) were classified as extensively drug resistant. Only 1 isolate was considered pan-drug resistant, which was resistant to all tested agents, including colistin. Of the 607 MDR isolates, 84.9% were ceftolozane-tazobactam susceptible and 76.9% of XDR isolates were ceftolozane-tazobactam susceptible. In vitro activity against drug resistant P. aeruginosa indicates ceftolozane-tazobactam may be an important agent in treating serious bacterial infections.

                Author and article information

                Future Sci OA
                Future Sci OA
                Future Science OA
                Future Science Ltd (London, UK )
                January 2019
                15 November 2018
                : 5
                : 1
                : FSO352
                [1 ]Center for Anti-Infective Research & Development Hartford Hospital, Hartford, CT, 06102 USA
                [2 ]PureHoney Technologies, Inc., Billerica, MA, 01821 USA
                [3 ]Division of Infectious Diseases, Hartford Hospital, Hartford, CT, 06102 USA
                Author notes
                *Author for correspondence: Tel.: +1 860 972 3941; Fax: +1 860 545 3992; David.Nicolau@ 123456hhchealth.org
                © 2018 David P. Nicolau

                This work is licensed under a Creative Commons Attribution 4.0 License

                : 09 August 2018
                : 25 September 2018
                : 15 November 2018

                bal, ceftolozane, hplc–ms, tazobactam


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