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Safety, Tolerability, And Pharmacokinetics Of 3 G Of Ceftolozane/Tazobactam In Healthy Adults: A Randomized, Placebo‐Controlled, Multiple‐Dose Study

B. Yu, A. Adedoyin, E. Hershberger, L. Caro, A. Xiao, Elizabeth G. Rhee, J. Huntington
Published 2018 · Medicine

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Ceftolozane/tazobactam is an antibacterial approved at 1.5 g (1g/0.5 g) every 8 hours (q8h); higher doses may provide additional benefits in difficult‐to‐treat infections. We conducted a phase I trial in healthy adults evaluating safety, tolerability, and pharmacokinetics of 3 g (2 g/1 g) ceftolozane/tazobactam administered q8h for 10 days. Sixteen participants were randomized (2:1:1) to 3 g ceftolozane/tazobactam, 1.5 g ceftolozane/tazobactam, or placebo. Participants underwent regular safety and plasma drug level assessments, with a follow‐up safety visit 7 days after completion. No adverse events (AEs) were reported with placebo; 75% of participants in the 1.5‐g and 50% in the 3‐g arm experienced AEs. AE types were similar between the ceftolozane/tazobactam groups; all AEs were mild. No participants experienced clinically meaningful laboratory assessment or electrocardiogram abnormalities. Both ceftolozane and tazobactam exhibited dose‐proportional pharmacokinetics without accumulation and without substantial differences in clearance and volume of distribution between groups. In the 3‐g group, mean ceftolozane parameters were: peak concentration 104 μg/mL (day 1), 112 μg/mL (day 10); half‐life 3 hours (day 10); area under the concentration‐time curve (AUC(0‐t)) 272 μg·h/mL (day 1), 300μg·h/mL (day 10). Mean tazobactam parameters were: peak concentration 28 μg/mL (day 1), 26 μg/mL (day 10); half‐life 1 hour (day 10); AUC(0‐t) 47μg·h/mL (day 1), 41μg·h/mL (day 10). Administration of 3 g ceftolozane/tazobactam q8h for 10 days was safe and well tolerated in healthy volunteers.
This paper references
Adverse reactions to beta-lactam antimicrobials
P Lagace Wiens (2012)
Impli - cations of augmented renal clearance on drug dosing in critically ill patients : afocus on antibiotics
Hobbs ALV (2015)
10.1517/14740338.2012.643866
Adverse reactions to β-lactam antimicrobials
P. Lagacé-Wiens (2012)
10.1093/cid/civ097
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)
J. Solomkin (2015)
Insufficient beta-lactam concentrations in the early phase of severe sepsis and septic shock
FS Taccone (2010)
10.1002/phar.1636
Infections Caused by Resistant Gram-Negative Bacteria: Epidemiology and Management.
K. Kaye (2015)
10.1016/j.ijantimicag.2014.01.032
Ceftolozane/tazobactam activity tested against Gram-negative bacterial isolates from hospitalised patients with pneumonia in US and European medical centres (2012).
D. Farrell (2014)
10.1111/fcp.12227
Pharmacokinetics, safety, and tolerability of ceftolozane/tazobactam in healthy Japanese, Chinese, and white subjects
Anthony Aiudi (2016)
tibiotic dosing in multiple organ dysfunction syndrome
M Ulldemolins (2011)
10.1002/jcph.566
Ceftolozane/tazobactam pharmacokinetic/pharmacodynamic‐derived dose justification for phase 3 studies in patients with nosocomial pneumonia
A. Xiao (2016)
10.1002/phar.1653
Implications of Augmented Renal Clearance on Drug Dosing in Critically Ill Patients: A Focus on Antibiotics.
Athena L. V. Hobbs (2015)
10.1097/CCM.0b013e318241e553
Variability of antibiotic concentrations in critically ill patients receiving continuous renal replacement therapy: A multicentre pharmacokinetic study*
D. Roberts (2012)
10.1093/jac/dku184
Antimicrobial activity of ceftolozane/tazobactam tested against Pseudomonas aeruginosa and Enterobacteriaceae with various resistance patterns isolated in European hospitals (2011-12).
H. Sader (2014)
10.1128/AAC.00049-14
Multicenter, Double-Blind, Randomized, Phase II Trial To Assess the Safety and Efficacy of Ceftolozane-Tazobactam plus Metronidazole Compared with Meropenem in Adult Patients with Complicated Intra-Abdominal Infections
C. Lucasti (2014)
10.1586/14787210.5.3.365
Piperacillin–tazobactam: a β-lactam/β-lactamase inhibitor combination
A. Gin (2007)
10.1378/chest.10-2371
Antibiotic dosing in multiple organ dysfunction syndrome.
M. Ulldemolins (2011)
10.1378/chest.11-1671
Subtherapeutic initial β-lactam concentrations in select critically ill patients: association between augmented renal clearance and low trough drug concentrations.
A. Udy (2012)
Piperacillin-tazobactam: a beta-lactam/beta-lactamase inhibitor combination.
A. Gin (2007)
Is high-dose β-lactam therapy associated with excessive drug toxicity in critically ill patients?
C. McDonald (2016)
10.2215/CJN.05690611
Pharmacokinetics of ampicillin/sulbactam in critically ill patients with acute kidney injury undergoing extended dialysis.
J. Lorenzen (2012)
10.1007/s40265-013-0168-2
Ceftolozane/Tazobactam: A Novel Cephalosporin/β-Lactamase Inhibitor Combination with Activity Against Multidrug-Resistant Gram-Negative Bacilli
G. Zhanel (2013)
10.1093/jac/dks246
Intrapulmonary penetration of ceftolozane/tazobactam and piperacillin/tazobactam in healthy adult subjects.
G. Chandorkar (2012)
Implications of augmented renal clearance on drug dosing in critically ill patients: afocus on antibiotics.Pharmacotherapy
ALV Hobbs (2015)
Pharmacokinetics of ampicillin/sulbactam in critically ill patients with Yu et al 391 acute kidney injury undergoing extended dialysis
JM Lorenzen (2012)
10.2165/11594090-000000000-00000
Penetration of Anti-Infective Agents into Pulmonary Epithelial Lining Fluid
K. Rodvold (2011)
10.1016/S0140-6736(14)62220-0
Ceftolozane-tazobactam compared with levofloxacin in the treatment of complicated urinary-tract infections, including pyelonephritis: a randomised, double-blind, phase 3 trial (ASPECT-cUTI)
F. Wagenlehner (2015)
10.1086/344653
Prevention of resistance: a goal for dose selection for antimicrobial agents.
G. Drusano (2003)
10.1128/AAC.01753-09
Pharmacokinetics and Safety of CXA-101, a New Antipseudomonal Cephalosporin, in Healthy Adult Male and Female Subjects Receiving Single- and Multiple-Dose Intravenous Infusions
Y. Ge (2010)
10.1089/mdr.2015.0220
Multidrug-Resistant Gram-Negative Bacterial Infections in the Hospital Setting: Overview, Implications for Clinical Practice, and Emerging Treatment Options.
Elizabeth A Cerceo (2016)
10.1128/AAC.05360-11
Dosing Regimen Matters: the Importance of Early Intervention and Rapid Attainment of the Pharmacokinetic/Pharmacodynamic Target
M. Martinez (2012)
10.1016/S1473-3099(13)70190-7
Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases.
L. S. Munoz-Price (2013)
10.5603/AIT.a2015.0082
A pilot study on pharmacokinetic/pharmacodynamic target attainment in critically ill patients receiving piperacillin/tazobactam.
J. Martínková (2016)
10.1186/cc9091
Insufficient β-lactam concentrations in the early phase of severe sepsis and septic shock
F. Taccone (2010)
10.1128/AAC.02310-13
Relationship between Ceftolozane-Tazobactam Exposure and Selection for Pseudomonas aeruginosa Resistance in a Hollow-Fiber Infection Model
B. Vanscoy (2014)
10.1038/nrmicro862
Antimicrobial pharmacodynamics: critical interactions of 'bug and drug'
G. Drusano (2004)
Safety study designed to study the effects of two different doses of CXA-101/tazobactam, a low dose and a high dose, on the QT/QTc intervals in healthy subjects
10.1016/j.jcrc.2009.02.014
Pharmacodynamic-based clinical pathway for empiric antibiotic choice in patients with ventilator-associated pneumonia.
Anthony M. Nicasio (2010)
10.1186/cc12705
Meropenem and piperacillin/tazobactam prescribing in critically ill patients: does augmented renal clearance affect pharmacokinetic/pharmacodynamic target attainment when extended infusions are used?
M. Carlier (2013)
10.1128/AAC.06349-11
Pharmacokinetics and Safety of Intravenous Ceftolozane-Tazobactam in Healthy Adult Subjects following Single and Multiple Ascending Doses
B. Miller (2012)
10.1378/chest.11-1671
Original ResearchCritical CareSubtherapeutic Initial β-Lactam Concentrations in Select Critically Ill Patients
A. Udy (2012)
10.1186/s13054-016-1255-z
Piperacillin concentration in relation to therapeutic range in critically ill patients – a prospective observational study
Johannes Zander (2016)
10.1002/jcph.395
Population Pharmacokinetics of Ceftolozane/Tazobactam in Healthy Volunteers, Subjects With Varying Degrees of Renal Function and Patients With Bacterial Infections
G. Chandorkar (2015)
10.1592/PHCO.22.8.569.33209
Pharmacokinetic and pharmacodynamic evaluation of two dosing regimens for piperacillin-tazobactam.
Myo-Kyoung Kim (2002)



This paper is referenced by
10.1016/S1473-3099(19)30403-7
Ceftolozane-tazobactam versus meropenem for treatment of nosocomial pneumonia (ASPECT-NP): a randomised, controlled, double-blind, phase 3, non-inferiority trial.
M. Kollef (2019)
10.1016/j.jiac.2018.11.005
Population pharmacokinetics of tazobactam/ceftolozane in Japanese patients with complicated urinary tract infection and complicated intra-abdominal infection.
Makoto Kakara (2019)
10.1080/14656566.2020.1739269
An overview of ceftolozane sulfate + tazobactam for treating hospital acquired pneumonia
I. Los-Arcos (2020)
10.1128/AAC.00344-19
Ceftolozane-Tazobactam in the Treatment of Experimental Pseudomonas aeruginosa Pneumonia in Persistently Neutropenic Rabbits: Impact on Strains with Genetically Defined Mechanisms of Resistance
V. Petraitis (2019)
10.1093/jac/dkaa049
Lung penetration, bronchopulmonary pharmacokinetic/pharmacodynamic profile and safety of 3 g of ceftolozane/tazobactam administered to ventilated, critically ill patients with pneumonia
L. Caro (2020)
10.1016/j.cca.2018.10.034
Measurement of ceftolozane and tazobactam concentrations in plasma by UHPLC-MS/MS. Clinical application in the management of difficult-to-treat osteoarticular infections.
Raúl Rigo-Bonnin (2019)
10.21037/atm.2018.10.29
New treatments of multidrug-resistant Gram-negative ventilator-associated pneumonia.
G. Poulakou (2018)
10.1128/AAC.02578-18
Ceftolozane-Tazobactam Population Pharmacokinetics and Dose Selection for Further Clinical Evaluation in Pediatric Patients with Complicated Urinary Tract or Complicated Intra-abdominal Infections
K. B. Larson (2019)
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