Ceftolozane-Tazobactam for Directed Treatment of Pseudomonas Aeruginosa Bacteremia and Pneumonia in Patients With Hematological Malignancies and Hematopoietic Stem Cell Transplantation

A Pilot Study of Ceftolozane-Tazobactam in Conjunction With Rapid Molecular Diagnosis for Directed Treatment of Pseudomonas Aeruginosa Bacteremia and Pneumonia in Patients With Hematological Malignancies and Hematopoietic Stem Cell Transplantation

This is an open-label study, where participants will be given ceftolozane-tazobactam as the primary treatment for Pseudomonas aeruginosa infections. Open-label means both the investigator and the participant will known what drug will be given. Participants will be followed for approximately 60 days. Ceftolozane-tazobactam is approved by the Food and Drug Administration (FDA) for treatment of serious bacterial infection and the investigator hypothesizes that ceftolozane/tazobactam may be effective as the primary antibiotic treatment for Pseudomonas aeruginosa infections.

Study Overview

• Status: Recruiting
• Conditions: Pneumonia; Hematologic Malignancy; Pseudomonas Aeruginosa
• Intervention / Treatment: Drug: Ceftolozane / Tazobactam Injection

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Anna Gwak, BA; Phone Number: 2127464089; Email: ang4021@med.cornell.edu
• Study Contact Backup: Name: Elizabeth Salsgiver, MPH; Phone Number: 2127464089; Email: els7021@med.cornell.edu

Study Locations

• United States
  • New York
    • New York, New York, United States, 10065
      • Recruiting
      • Weill Cornell Medicine
      • Contact: Anna Gwak, BA; Phone Number: 202-746-4089; Email: ang4021@med.cornell.edu
      • Contact: Elizabeth Salsgiver, MPH; Phone Number: 212-746-4089; Email: els7021@med.cornell.edu
      • Principal Investigator: Markus Plate, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• At least 18 years old
• Presence of hematologic malignancy or Hematopoietic Stem Cell Transplantation

Exclusion Criteria:

• Under the age of 18 years old
• Anaphylactic hypersensitivity or allergic reaction to cephalosporins
• Participants with expected mortality within 48 hours
• Hemodialysis or continuous renal replacement therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ceftolozane-Tazobactam; Participants receive ceftolozane-tazobactam by injection directly into the vein (intravenously, IV) every 8 hours for 10-14 days.	Drug: Ceftolozane / Tazobactam Injection; Zerbaxa (ceftolozane/tazobactam) for injection is supplied as a white to yellow sterile powder for reconstitution in single-use vials; each vial contains 1 g ceftolozane (equivalent to 1.147 g of ceftolozane sulfate) and 0.5 g tazobactam (equivalent to 0.537 g of tazobactam sodium).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Global response at end of therapy	The proportion of subjects with a complete or partial Global Response (GR). Complete response is defined as "Survival within the prespecified period of observation, resolution of all attributable symptoms and signs of disease and radiological abnormalities, and microbiological evidence of eradication of disease." Partial response is defined as "Survival within the prespecified period of observation, improvement in attributable symptoms and signs of disease and radiological abnormalities, and evidence of clearance of cultures."	Day 60

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival at 30 days	Survival will be assessed by chart review or phone visit, as appropriate.	Day 30
Survival at 60 days	Survival will be assessed by chart review or phone visit, as appropriate.	Day 60
Time in days to resolution of bacteremia	This will be measured in days from the Subject's initial Pseudomonas aeruginosa blood culture, until the subject has two consecutive negative blood cultures for Pseudomonas aeruginosa , assessed by examining results from daily blood cultures obtained as standard of care.	Screen, Day 1, Day 2, Day 3, Day 4, Day 5, Day 6, Day 7, Day 8, Day 9, Day 10, Day 11, Day 12, Day 13, Day 14, Day 15, Day 16, Day 17, Day 18, Day 19, Day 20, Day 21, Day 22, Day 23, Day 24, Day 25, Day 26, Day 27, Day 28
Time in days of hospital stays	This will be obtained from Hospitalization Status Assessment.	Day 1, Day 2, Day 3, Day 4, Day 5, Day 6, Day 7, Day 8, Day 9, Day 10, Day 11, Day 12, Day 13, Day 14, Day 15, Day 16, Day 17, Day 18, Day 19, Day 20, Day 21, Day 22, Day 23, Day 24, Day 25, Day 26, Day 27, Day 28, Day 30, Day 60
Time in days of ICU stays	This will be obtained from Hospitalization Status Assessment.	Day 1, Day 2, Day 3, Day 4, Day 5, Day 6, Day 7, Day 8, Day 9, Day 10, Day 11, Day 12, Day 13, Day 14, Day 15, Day 16, Day 17, Day 18, Day 19, Day 20, Day 21, Day 22, Day 23, Day 24, Day 25, Day 26, Day 27, Day 28, Day 30, Day 60
Time in days to emergence of resistant isolates	This will be measured in days from the most recent microbiological isolate susceptibility testing to ceftolozane/tazobactam showing no resistance, to the first identification of resistance to ceftolozane/tazobactam.	Screen, Day 1, Day 2, Day 3, Day 4, Day 5, Day 6, Day 7, Day 8, Day 9, Day 10, Day 11, Day 12, Day 13, Day 14, Day 15, Day 16, Day 17, Day 18, Day 19, Day 20, Day 21, Day 22, Day 23, Day 24, Day 25, Day 26, Day 27, Day 28
Time in days to appropriate therapy	This will be measured in days from initial treatment for Pseudomonas aeruginosa infection until the Subject begins therapy for this infection that is efficacious, based on microbiologic isolate susceptibility testing and review of Subject's concomitant medications.	Screen, Day 1, Day 2, Day 3, Day 4, Day 5, Day 6, Day 7, Day 8, Day 9, Day 10, Day 11, Day 12, Day 13, Day 14, Day 15, Day 16, Day 17, Day 18, Day 19, Day 20, Day 21, Day 22, Day 23, Day 24, Day 25, Day 26, Day 27, Day 28, Day 30, Day 60
Change of microbiological eradication	Microbiological eradication will be defined by resolution of positive blood cultures, by repeat assessment of bronchoalveolar lavage, or in the absence of repeat respiratory tract specimen.	Screen, Day 1, Day 2, Day 3, Day 4, Day 5, Day 6, Day 7, Day 8, Day 9, Day 10, Day 11, Day 12, Day 13, Day 14, Day 15, Day 16, Day 17, Day 18, Day 19, Day 20, Day 21, Day 22, Day 23, Day 24, Day 25, Day 26, Day 27, Day 28
Incidence of abnormal and physical examinations findings - general appearance	A physical examination assessing and documenting changes from the previous examination, including any new abnormalities, will be conducted.	3 times weekly through treatment (Week 1, Week 2, Week 3, Week 4)
Incidence of abnormal and physical examinations findings - neurological	A physical examination assessing and documenting changes from the previous examination, including any new abnormalities, will be conducted.	3 times weekly through treatment (Week 1, Week 2, Week 3, Week 4)
Incidence of abnormal and physical examinations findings - heart/cardiovascular	A physical examination assessing and documenting changes from the previous examination, including any new abnormalities, will be conducted.	3 times weekly through treatment (Week 1, Week 2, Week 3, Week 4)
Incidence of abnormal and physical examinations findings - lungs	A physical examination assessing and documenting changes from the previous examination, including any new abnormalities, will be conducted.	3 times weekly through treatment (Week 1, Week 2, Week 3, Week 4)
Incidence of abnormal and physical examinations findings - abdomen	A physical examination assessing and documenting changes from the previous examination, including any new abnormalities, will be conducted.	3 times weekly through treatment (Week 1, Week 2, Week 3, Week 4)
Incidence of abnormal and physical examinations findings - endocrine	A physical examination assessing and documenting changes from the previous examination, including any new abnormalities, will be conducted.	3 times weekly through treatment (Week 1, Week 2, Week 3, Week 4)
Incidence of abnormal and physical examinations findings - extremities	A physical examination assessing and documenting changes from the previous examination, including any new abnormalities, will be conducted.	3 times weekly through treatment (Week 1, Week 2, Week 3, Week 4)
Incidence of abnormal and physical examinations findings - lymphatic	A physical examination assessing and documenting changes from the previous examination, including any new abnormalities, will be conducted.	3 times weekly through treatment (Week 1, Week 2, Week 3, Week 4)
Incidence of abnormal and physical examinations findings - skin	A physical examination assessing and documenting changes from the previous examination, including any new abnormalities, will be conducted.	3 times weekly through treatment (Week 1, Week 2, Week 3, Week 4)
Time in days until stabilization or resolution of pneumonic infiltrates	This will be measured in days from Subject's initial presentation of pneumonic infiltrates until Subject's pneumonic infiltrates stabilize or resolve, based on diagnostic imaging obtained as standard of care.	Screen, Day 1, Day 2, Day 3, Day 4, Day 5, Day 6, Day 7, Day 8, Day 9, Day 10, Day 11, Day 12, Day 13, Day 14, Day 15, Day 16, Day 17, Day 18, Day 19, Day 20, Day 21, Day 22, Day 23, Day 24, Day 25, Day 26, Day 27, Day 28
Time in days to initial antimicrobial therapy	This will be measured in days from initial diagnosis of Pseudomonas aeruginosa infection unit initiation of antimicrobial therapy for this infection, based on review of Subject's concomitant medications.	Screen, Day 1, Day 2, Day 3, Day 4, Day 5, Day 6, Day 7, Day 8, Day 9, Day 10, Day 11, Day 12, Day 13, Day 14, Day 15, Day 16, Day 17, Day 18, Day 19, Day 20, Day 21, Day 22, Day 23, Day 24, Day 25, Day 26, Day 27, Day 28, Day 30, Day 60
Change in days until emergence of other bacteria	This will be measured in days from initial diagnosis of Pseudomonas aeruginosa infection until identification of additional bacteria, assessed by examining results from daily blood cultures obtained as standard of care.	Screen, Day 1, Day 2, Day 3, Day 4, Day 5, Day 6, Day 7, Day 8, Day 9, Day 10, Day 11, Day 12, Day 13, Day 14, Day 15, Day 16, Day 17, Day 18, Day 19, Day 20, Day 21, Day 22, Day 23, Day 24, Day 25, Day 26, Day 27, Day 28
Number of days on ventilator, as measured by assessment of clinical status		Screen, Day 1, Day 2, Day 3, Day 4, Day 5, Day 6, Day 7, Day 8, Day 9, Day 10, Day 11, Day 12, Day 13, Day 14, Day 15, Day 16, Day 17, Day 18, Day 19, Day 20, Day 21, Day 22, Day 23, Day 24, Day 25, Day 26, Day 27, Day 28

Collaborators and Investigators

• Sponsor: Weill Medical College of Cornell University
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Markus Plate, MD, Weill Medical College of Cornell University

Publications and helpful links

General Publications

• Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, Raad II, Rolston KV, Young JA, Wingard JR; Infectious Diseases Society of America. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america. Clin Infect Dis. 2011 Feb 15;52(4):e56-93. doi: 10.1093/cid/cir073.
• Satlin MJ, Walsh TJ. Multidrug-resistant Enterobacteriaceae, Pseudomonas aeruginosa, and vancomycin-resistant Enterococcus: Three major threats to hematopoietic stem cell transplant recipients. Transpl Infect Dis. 2017 Dec;19(6):10.1111/tid.12762. doi: 10.1111/tid.12762. Epub 2017 Oct 25.
• Nguyen L, Garcia J, Gruenberg K, MacDougall C. Multidrug-Resistant Pseudomonas Infections: Hard to Treat, But Hope on the Horizon? Curr Infect Dis Rep. 2018 Jun 6;20(8):23. doi: 10.1007/s11908-018-0629-6.
• Kaye KS, Pogue JM. Infections Caused by Resistant Gram-Negative Bacteria: Epidemiology and Management. Pharmacotherapy. 2015 Oct;35(10):949-62. doi: 10.1002/phar.1636.
• Munita JM, Aitken SL, Miller WR, Perez F, Rosa R, Shimose LA, Lichtenberger PN, Abbo LM, Jain R, Nigo M, Wanger A, Araos R, Tran TT, Adachi J, Rakita R, Shelburne S, Bonomo RA, Arias CA. Multicenter Evaluation of Ceftolozane/Tazobactam for Serious Infections Caused by Carbapenem-Resistant Pseudomonas aeruginosa. Clin Infect Dis. 2017 Jul 1;65(1):158-161. doi: 10.1093/cid/cix014.
• Gallagher JC, Satlin MJ, Elabor A, Saraiya N, McCreary EK, Molnar E, El-Beyrouty C, Jones BM, Dixit D, Heil EL, Claeys KC, Hiles J, Vyas NM, Bland CM, Suh J, Biason K, McCoy D, King MA, Richards L, Harrington N, Guo Y, Chaudhry S, Lu X, Yu D. Ceftolozane-Tazobactam for the Treatment of Multidrug-Resistant Pseudomonas aeruginosa Infections: A Multicenter Study. Open Forum Infect Dis. 2018 Oct 31;5(11):ofy280. doi: 10.1093/ofid/ofy280. eCollection 2018 Nov.
• Petraitis V, Petraitiene R, Naing E, Aung T, Thi WP, Kavaliauskas P, Win Maung BB, Michel AO, Ricart Arbona RJ, DeRyke AC, Culshaw DL, Nicolau DP, Satlin MJ, Walsh TJ. Ceftolozane-Tazobactam in the Treatment of Experimental Pseudomonas aeruginosa Pneumonia in Persistently Neutropenic Rabbits: Impact on Strains with Genetically Defined Mechanisms of Resistance. Antimicrob Agents Chemother. 2019 Aug 23;63(9):e00344-19. doi: 10.1128/AAC.00344-19. Print 2019 Sep.

Study record dates

Study Major Dates

• Study Start (Actual): July 20, 2022
• Primary Completion (Estimated): March 1, 2024
• Study Completion (Estimated): May 1, 2024

Study Registration Dates

• First Submitted: December 4, 2020
• First Submitted That Met QC Criteria: December 11, 2020
• First Posted (Actual): December 17, 2020

Study Record Updates

• Last Update Posted (Actual): August 24, 2023
• Last Update Submitted That Met QC Criteria: August 22, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Pneumonia; Hematologic Malignancy; Pseudomonas Aeruginosa; Ceftolozane-Tazobactam; Zerbaxa
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Neoplasms by Site; Systemic Inflammatory Response Syndrome; Inflammation; Hematologic Diseases; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Sepsis; Neoplasms; Hematologic Neoplasms; Pneumonia; Bacteremia; Pseudomonas Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; beta-Lactamase Inhibitors; Anti-Infective Agents, Urinary; Tazobactam; Ceftolozane; Ceftolozane, tazobactam drug combination
• Other Study ID Numbers: 19-11021048

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes