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About ZERBAXA® (ceftolozane/tazobactam)

Updated on 07/10/2019

ANTIBIOTICS
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For your critically ill adult patients who have ventilator-associated pneumonia due to confirmed or suspected Pseudomonas aeruginosa**

*ZERBAXA is indicated for the treatment of hospital-acquired pneumonia (HAP), including ventilator‑associated pneumonia (VAP) in adults.

**To be used in combination with an antibacterial agent active against Gram-positive pathogens when these are known or suspected to be contributing to the infectious process.

Consideration should be given to official guidance on the appropriate use of antibacterial agents. Please refer to SPC for a full list of indications, and before prescribing.

Patient
Penetration and dosing
Study design
Results
Safety

ZERBAXA: now indicated for the treatment of adults with HAP, including VAP1

 

Studied in critically ill ventilated patients with HAP, or VAP1,2

 

Clinical deterioration or no response to initial antibiotic treatment2

 

Confirmed P. aeruginosa before susceptibilities or highly suspected P. aeruginosa before cultures1

 

Penetrate the lung to get to the site of infection3

The recommended intravenous infusion (IV) dose of ZERBAXA with patients with creatinine clearance >50 mL/min is 3 g (2 g ceftolozane / 1 g tazobactam) administered every 8 hours by IV infusion over 1 hour for treatment period of 8–14 days in patients 18 years or older with HAP (vHAP) including VAP.1***

***To be used in combination with an antibacterial agent active against Gram-positive pathogens when these are known or suspected to be contributing to the infectious process.

Various Pharmacokinetics (PK) factors are altered in critically ill patients and can have profound effects on the attainment of adequate antibiotic concentration4


Adapted from Xiao AJ et al. 2017;6 Onufrak NJ et al. 2016;7 Rizk ML et al. 2018.8

Antibacterial factors5
  • Drug concentration must exceed Minimum Inhibitory Concentration (MIC) of pathogen in infection site
  • Time dependent antibiotics need maximum time over the MIC
  • Hydrophilic drugs can diffuse slowly and partially into lung
Pathophysiology of critically ill patient5
  • Capillary leak
  • Increased cardiac output
  • Altered protein levels
Altered PK factors in critically ill4,5
  • Limited site penetration
  • Altered renal clearance
  • Increased volume of distribution

Attaining adequate concentration4

Patients may not attain MIC of pathogen and maximum bacterial killing, impacting outcomes.

Lung penetration and pharmacokinetic/pharmacodynamic (PK/PD) attainment in pulmonary epithelial lining fluid (ELF) following administration of 3 g ceftolozane and tazobactam to ventilated, critically ill patients3


Adapted from Caro et al. 2018.3

Preliminary Phase 1 open label non-comparative PK study aimed to evaluate lung penetration of ceftolozane and tazobactam of 26 ventilated, critically ill patients* shows:

  • Mean ceftolozane and tazobactam ELF concentrations remained above MIC for 100% of dosing interval
  • Both ceftolozane and tazobactam achieved good lung penetration, estimated at 50% and 62% respectively

* Patients received 4–6 doses of ceftolozane/tazobactam. Blood concentrations were obtained after the first and last dose; ELF concentrations were obtained 1, 2, 4, 6 or 8 hours after the last dose.

ZERBAXA was studied in critically ill patients in the ICU as part of assessment of the safety profile and efficacy of ceftolozane-tazobactam-nosocomial pneumonia (ASPECT-NP)

Studied in a Phase 3, double–blind, multinational non–inferiority study

Study analysed intent-to-treat population which included all randomised patients.

European Medicines Agency (EMA) primary objective and endpoint2

  • To demonstrate the non-inferiority of ZERBAXA versus meropenem in adult subjects with VNP based on the difference in clinical response rates in the intent-to-treat (ITT) population at the test-of-cure (TOC) visit (7 to 14 days after the end of therapy (EOT) visit), using a non‑inferiority margin of 12.5%

Key secondary objective and endpoint2

  • To compare the Day 28 all-cause mortality rates of subjects in the ZERBAXA versus meropenem arms in the ITT population using a non‑inferiority margin of 12.5%

Based on select baseline characteristics including:


 

High risk and critically ill patients

All patients were ventilated (N=726), with median Acute Physiology and Chronic Health Evaluation (APACHE) II score of 172

 

Patients with bacteraemia

Bacteraemia was present in 14.5% of patients2

 

Failing current antibiotic Nosocomial Pneumonia (NP) therapy

12.8% of patients2

 

Augmented renal clearance

Greater than 15% of patients (creatinine clearance ≥150 mL/min)2

Adapted from Kollef et al. 2019.2

Key inclusion and exclusion criteria

 

Key inclusion criteria2

  • Males or females 18 years or older
  • Intubated and on mechanical ventilation diagnosed with VAP or ventilated HAP
  • Chest radiograph obtained within 24 hours prior to the first dose of study drug showing presence of new or progressive infiltrate(s) suggestive of bacterial pneumonia
  • Purulent tracheal secretions with at least 1 other clinical criterion (i.e. documented fever [≥38°C], hypothermia [≤35°C], white blood cells ≥10,000 cells/mm3 or ≤4,500 cells/mm3, or ≥15% immature neutrophils)
  • A baseline lower respiratory tract specimen obtained for Gram stain and quantitative culture within 36 hours prior to the first dose of study drug
 

Key exclusion criteria2

  • Only Gram-positive pathogens detected on Gram stain
  • Gram-negative pathogens resistant to either study drug identified from a respiratory or blood culture ≤15 days before first dose
  • More than 24 hours active Gram-negative antibacterials for NP ≤72 hours before first dose (exception: persistent/worsening or new NP despite ≥48 hours of active Gram-negative therapy)
  • Conditions potentially interfering with outcome assessment/interpretation including cystic fibrosis
  • Active immunosuppression or severe neutropenia (absolute neutrophil count <500/mm 3 )
  • Continuous renal replacement therapy or end-stage renal disease requiring haemodialysis

Adapted from Kollef et al. 2019.2

ZERBAXA achieved non-inferiority in clinical cure at TOC and 28-day all-cause mortality2

Results for primary and secondary endpoints and VAP and vHAP diagnosis within the non‑inferiority margin for EMA.

Clinical cure rates at TOC in the ITT population

Intent–to–treat population

Adapted from Kollef et al. 2019.2

*Pre-specified subgroup analyses gave exploratory endpoints for patients with VAP and vHAP, as well as individual baseline characteristics. No statistical conclusions can be drawn from exploratory endpoints.

Safety and tolerability profile for HAP and VAP indications only

ZERBAXA was evaluated in a Phase 3 comparator-controlled clinical trial of hospital-acquired pneumonia, including ventilator-associated pneumonia, which included a total of 361 patients, treated with ZERBAXA (2 g/1 g intravenously every 8 hours, adjusted to match renal function where appropriate) for up to 14 days.1

The most common adverse reactions (≥5% in a Phase 3 trial of hospital-acquired pneumonia, including ventilator-associated pneumonia) occurring in patients receiving ZERBAXA were diarrhoea, alanine aminotransferase increased, and aspartate aminotransferase increased and were generally mild or moderate in severity.1

Adverse reactions identified during clinical trials with ceftolozane/tazobactam1


System organ class Common (≥1/100 to <1/10 ) Uncommon (≥1/1,000 to <1/100 )
Infections and infestations Clostridioides difficile colitis* Clostridioides difficile infection*
Gastrointestinal disorders Diarrhoea, vomiting**
Investigations Alanine aminotransferase increased,** aspartate aminotransferase increased,** transaminases increased, liver function test abnormal,* blood alkaline phosphatase increased,* gamma‑glutamyltransferase increased* Coombs test positive,** Clostridioides test positive*

Limitations of the clinical data: Patients who were immunocompromised, and patients with severe neutropenia, and patients with end‑stage renal disease on haemodialysis were excluded from clinical trials.

Please see ZERBAXA Summary of Product Characteristics for full details of adverse reactions identified during clinical trials with ceftolozane/tazobactam including those of other indications.

*Specific for the hospital-acquired pneumonia, including ventilator-associated pneumonia indication treated with ZERBAXA (2 g / 1 g intravenously every 8 hours) for up to 14 days (n=361).

**Applies across all indications: complicated intra-abdominal infections, acute pyelonephritis, complicated urinary tract infections, and hospital-acquired pneumonia, including ventilator-associated pneumonia (n=1376).

Abbreviations

APACHE = Acute Physiology and Chronic Health Evaluation; ASPECT-NP = Assessment of the Safety Profile and Efficacy of Ceftolozane-Tazobactam-Nosocomial Pneumonia; ELF = Epithelial Lining Fluid; EMA = European Medicines Agency; EOT = End of Therapy; FDA = Food and Drug Administration; HAP = Hospital-Acquired Pneumonia; ITT = Intent-To-Treat; MIC = Minimum Inhibitory Concentration; NP = Nosocomial Pneumonia; PD = Pharmacodynamic; PK = Pharmacokinetics; TOC = Test-Of-Cure; VAP = Ventilator-Associated Pneumonia; vHAP = Ventilated Hospital-Acquired Pneumonia; VNP = Ventilated Nosocomial Pneumonia.

References

  1. ZERBAXA Summary of Product Characteristics.
  2. Kollef M H et al. Ceftolozane-tazobactam versus meropenem for treatment of nosocomial pneumonia (ASPECT-NP): a randomised, controlled, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis 2019, published online September 25, 2019 https://doi.org/10.1016/S1473-3099(19)30403-7.
  3. Caro L. et al. Lung Penetration and Pharmacokinetic/Pharmacodynamic (PK/PD) Attainment in Pulmonary Epithelial Lining Fluid (ELF) Following Administration of 3 g Ceftolozane/Tazobactam to Ventilated, Critically Ill Patients. ECCMID 2018 Poster P2225.
  4. Vincent et al. Advances in antibiotic therapy in the critically ill. Critical Care 2016;20:133.
  5. Shah S et al. Pharmacokinetic considerations and dosing strategies of antibiotics in the critically ill patient. Journal of the Intensive Care Society 2015;16(2):147–153.
  6. Xiao AJ et al. J Clin Pharmacol. 2017;56(1):56–66.
  7. Onufrak NJ et al. Clin Ther. 2016;38(9):1930–1947.
  8. Rizk ML et al. Antimicrob Agents Chemother. 2018;62(3):e01411–17.
  9. Meropenem Summary of Product Characteristics.

Supporting documentation

Prescribing Information | Summary of Product Characteristics | Patient Information Leaflet

ZERBAXA (ceftolozane/tazobactam 1 g/0.5 g) is indicated for the treatment of the following infections in adults: Hospital-acquired pneumonia (HAP), including ventilator-associated pneumonia (VAP). Contraindications: Hypersensitivity to active substances, excipients, to any cephalosporin antibacterial agent, severe hypersensitivity (e.g. anaphylactic reaction, severe skin reaction) to any other type of beta-lactam antibacterial agent (e.g. penicillins or carbapenems). Considerations of renal function and C. diff diagnosis prior to, during, and after treatment is important. Please consult SPC before prescribing and consideration should be given to official guidance on the appropriate use of antibacterial agents.

GB-ZER-00092 | Date of Preparation: October 2019