Ceftolozane/Tazobactam vs. Piperacillin/Tazobactam for the Treatment of Bacteremia in Hemato-oncological Patients

NCT06422533 | Recruiting DMC

• 1 other identifier: CI0565-2023
• Study Type: interventional
• Target: 226
• Locations: 1 country
• Sites: 1

Brief Summary

Patients with hematological malignancies receive highly myelotoxic chemotherapy regimens that cause periods of severe myelosuppression, which places them at high risk of developing bacteremia. At a global level, a very significant increase in multidrug-resistant (MDR) Gram-negative microorganisms, particularly Enterobacteriaceae producing extended-spectrum beta-lactamases (ESBL) and MDR P.aeruginosa, have been described during the last decade. Among the strategies to reduce bacterial resistance, ceftolozane/tazobactam (C/T) as a "carbapenem-sparing" antibiotic has been proposed. C/T has broad-spectrum activity since it has action against ESBL-producing Enterobacteriaceae and MDR P. aeruginosa. Studies carried out in the real world using this antibiotic in patients with hematological malignancies have demonstrated clinical success in reports and case series, considered a therapeutic option in patients with Enterobacteriaceae and P. aeruginosa infections, particularly in MDR pathogens. At the National Cancer Institute (in Spanish, Instituto Nacional de Cancerologia), Gram-negative bacilli have been identified for more than 20 years as the pathogens most frequently associated with bacteremia. Escherichia coli occupies the first place in 25% (41% ESBL), followed by Klebsiella spp. in 5.6% (11.2% ESBL) and P. aeruginosa in 5.6% (11.2% MDR). The protocol for approaching and treating hematological malignancy patients with severe neutropenia and fever is to initiate an antimicrobial regimen with piperacillin/tazobactam (P/T). In patients who persist with fever after 48 to 72 hours of starting antibiotics, who present with clinical deterioration, or in whom P/T-resistant bacteria are identified, this is escalated to carbapenem. Therefore, it is proposed to compare the clinical and microbiological response in patients with hematological malignancies who present with severe neutropenia and fever and who present clinical data of bacteremia, with empirical treatment with C/T vs. P/T, trying to reduce the use of carbapenems in this group of patients.

Conditions

Hematologic Neoplasms; Neutropenia

Keywords

ceftolozane/tazobactam; piperacillin/tazobactam; neutropenia; hematologic neoplasms

Outcome Measures

Primary Outcomes (1)

• Mortality of all patients at day 30

  To assess the number of patients who will be alive or dead in the first 30 days. On day 30, a physical visit will be made to the patient's bedside if the patient is hospitalized. If the patient is not hospitalized, the clinical record will be evaluated, and one of the investigators will make a phone call to ensure the patient's status for that date.

  Day 30

Secondary Outcomes (2)

• Microbiological response through the sterilization of repeated blood cultures take

  Day 3 to day 4

• Clinical response measured through fever resolution

  Day 4

Other Outcomes (1)

• Clostridioides difficile infection documented through toxin/GDH C. difficile test in those patients who develop diarrhea, abdominal pain and/or distended abdomen.

  Day 1 to day 30

Study Arms (2)

Ceftolozane/tazobactam

EXPERIMENTAL

Ceftozolane/tazobactam (C/T) is a combination antibiotic with a new cephalosporin, structurally similar to ceftazidime, plus tazobactam. The FDA approved This known beta-lactamase inhibitor in 2018 to treat intra-abdominal and complicated urinary infections. In 2019, its indication was expanded to nosocomial pneumonia and those associated with mechanical ventilation. In Mexico, it was approved for marketing in June 2019. C/T has broad-spectrum activity since it has action against ESBL-producing Enterobacteria and MDR P. aeruginosa. Studies carried out in the real world using this antibiotic in patients with hematological malignancies have demonstrated clinical success in reports and case series, considered a therapeutic option in patients with Enterobacteriaceae and P. aeruginosa infections, particularly in MDR pathogens.

Drug: Ceftolozane/tazobactam

Piperacillin/tazobactam

ACTIVE COMPARATOR

At our hospital, Piperacillin/tazobactam is the primary drug used as an empirical treatment in patients with severe neutropenia and fever, according to Clinical Practice Guidelines for the use of antimicrobial agents in neutropenic patients with cancer.

Drug: Piperacillin/tazobactam

Interventions

Ceftolozane/tazobactam DRUG

Ceftolozane/tazobactam 1.5 g tid IV infusion for 1 hour during 5 to 7 days

Also known as: Zerbaxa

Ceftolozane/tazobactam

Piperacillin/tazobactam DRUG

Piperacillin/tazobactam 4.5 g qid IV infusion for 30 minutes during 5 to 7 days

Also known as: Tazocin, Pipertazo, Tazonam, Tazovak

Piperacillin/tazobactam

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• All patients \>18 years old
• Diagnosis of any hematological malignancy
• Severe neutropenia (polymorphonuclear \<500 cells/mm3)
• Fever (≥38.3 degrees Celsius in one measure, or ≥38 degrees Celsius in at least two measures)
• Median arterial pressure ≥65 mmHg on admission
• A life expectancy ≥ 5 days
• Agree to participate in the study

You may not qualify if:

• Known hypersensitivity to cephalosporins or anaphylaxis with beta-lactams
• Clinical signs related to hemodynamic instability
• Concomitant use of another antibiotic with activity against Gram-negatives (except Trimethoprim/Sulfamethoxazole (TMP/SMX) as prophylaxis for P. jirovecii
• Patients with end-stage chronic renal failure (\<10 ml/min by creatinine clearance-ACCr) or on renal replacement therapy.
• Patients with grade IV mucositis

Sponsors & Collaborators

• Instituto Nacional de Cancerologia de Mexico: lead

Study Sites (1)

Instituto Nacional de Cancerologia

Mexico City, Tlalpan, 14080, Mexico

RECRUITING

Related Publications (14)

• Karaiskos I, Giamarellou H. Carbapenem-Sparing Strategies for ESBL Producers: When and How. Antibiotics (Basel). 2020 Feb 5;9(2):61. doi: 10.3390/antibiotics9020061.

  PMID: 32033322 BACKGROUND

• Xie O, Cisera K, Taylor L, Hughes C, Rogers B. Clinical syndromes and treatment location predict utility of carbapenem sparing therapies in ceftriaxone-non-susceptible Escherichia coli bloodstream infection. Ann Clin Microbiol Antimicrob. 2020 Nov 30;19(1):57. doi: 10.1186/s12941-020-00400-z.

  PMID: 33256752 BACKGROUND

• Giacobbe DR, Bassetti M, De Rosa FG, Del Bono V, Grossi PA, Menichetti F, Pea F, Rossolini GM, Tumbarello M, Viale P, Viscoli C; ISGRI-SITA (Italian Study Group on Resistant Infections of the Societa Italiana Terapia Antinfettiva). Ceftolozane/tazobactam: place in therapy. Expert Rev Anti Infect Ther. 2018 Apr;16(4):307-320. doi: 10.1080/14787210.2018.1447381. Epub 2018 Mar 9.

  PMID: 29493397 BACKGROUND

• Shortridge D, Pfaller MA, Castanheira M, Flamm RK. Antimicrobial Activity of Ceftolozane-Tazobactam Tested Against Enterobacteriaceae and Pseudomonas aeruginosa with Various Resistance Patterns Isolated in U.S. Hospitals (2013-2016) as Part of the Surveillance Program: Program to Assess Ceftolozane-Tazobactam Susceptibility. Microb Drug Resist. 2018 Jun;24(5):563-577. doi: 10.1089/mdr.2017.0266. Epub 2017 Oct 17.

  PMID: 29039729 BACKGROUND

• Pfaller MA, Bassetti M, Duncan LR, Castanheira M. Ceftolozane/tazobactam activity against drug-resistant Enterobacteriaceae and Pseudomonas aeruginosa causing urinary tract and intraabdominal infections in Europe: report from an antimicrobial surveillance programme (2012-15). J Antimicrob Chemother. 2017 May 1;72(5):1386-1395. doi: 10.1093/jac/dkx009.

  PMID: 28165526 BACKGROUND

• Livermore DM, Mushtaq S, Meunier D, Hopkins KL, Hill R, Adkin R, Chaudhry A, Pike R, Staves P, Woodford N; BSAC Resistance Surveillance Standing Committee. Activity of ceftolozane/tazobactam against surveillance and 'problem' Enterobacteriaceae, Pseudomonas aeruginosa and non-fermenters from the British Isles. J Antimicrob Chemother. 2017 Aug 1;72(8):2278-2289. doi: 10.1093/jac/dkx136.

  PMID: 28520867 BACKGROUND

• Pfaller MA, Shortridge D, Sader HS, Flamm RK, Castanheira M. Ceftolozane-tazobactam activity against drug-resistant Enterobacteriaceae and Pseudomonas aeruginosa causing healthcare-associated infections in Australia and New Zealand: Report from an Antimicrobial Surveillance Program (2013-2015). J Glob Antimicrob Resist. 2017 Sep;10:186-194. doi: 10.1016/j.jgar.2017.05.025. Epub 2017 Jul 19.

  PMID: 28735046 BACKGROUND

• Pfaller MA, Shortridge D, Sader HS, Gales A, Castanheira M, Flamm RK. Ceftolozane-tazobactam activity against drug-resistant Enterobacteriaceae and Pseudomonas aeruginosa causing healthcare-associated infections in Latin America: report from an antimicrobial surveillance program (2013-2015). Braz J Infect Dis. 2017 Nov-Dec;21(6):627-637. doi: 10.1016/j.bjid.2017.06.008. Epub 2017 Sep 21.

  PMID: 28941394 BACKGROUND

• Seifert H, Korber-Irrgang B, Kresken M; German Ceftolozane/Tazobactam Study Group. In-vitro activity of ceftolozane/tazobactam against Pseudomonas aeruginosa and Enterobacteriaceae isolates recovered from hospitalized patients in Germany. Int J Antimicrob Agents. 2018 Feb;51(2):227-234. doi: 10.1016/j.ijantimicag.2017.06.024. Epub 2017 Jul 10.

  PMID: 28705666 BACKGROUND

• Fernandez-Cruz A, Alba N, Semiglia-Chong MA, Padilla B, Rodriguez-Macias G, Kwon M, Cercenado E, Chamorro-de-Vega E, Machado M, Perez-Lago L, Garcia de Viedma D, Diez Martin JL, Munoz P. A Case-Control Study of Real-Life Experience with Ceftolozane-Tazobactam in Patients with Hematologic Malignancy and Pseudomonas aeruginosa Infection. Antimicrob Agents Chemother. 2019 Jan 29;63(2):e02340-18. doi: 10.1128/AAC.02340-18. Print 2019 Feb.

  PMID: 30530598 BACKGROUND

• Bergas A, Albasanz-Puig A, Fernandez-Cruz A, Machado M, Novo A, van Duin D, Garcia-Vidal C, Hakki M, Ruiz-Camps I, Del Pozo JL, Oltolini C, DeVoe C, Drgona L, Gasch O, Mikulska M, Martin-Davila P, Peghin M, Vazquez L, Laporte-Amargos J, Dura-Miralles X, Pallares N, Gonzalez-Barca E, Alvarez-Uria A, Puerta-Alcalde P, Aguilar-Company J, Carmona-Torre F, Clerici TD, Doernberg SB, Petrikova L, Capilla S, Magnasco L, Fortun J, Castaldo N, Carratala J, Gudiol C. Real-Life Use of Ceftolozane/Tazobactam for the Treatment of Bloodstream Infection Due to Pseudomonas aeruginosa in Neutropenic Hematologic Patients: a Matched Control Study (ZENITH Study). Microbiol Spectr. 2022 Jun 29;10(3):e0229221. doi: 10.1128/spectrum.02292-21. Epub 2022 Apr 27.

  PMID: 35475683 BACKGROUND

• Criscuolo M, Trecarichi EM. Ceftazidime/Avibactam and Ceftolozane/Tazobactam for Multidrug-Resistant Gram Negatives in Patients with Hematological Malignancies: Current Experiences. Antibiotics (Basel). 2020 Feb 3;9(2):58. doi: 10.3390/antibiotics9020058.

  PMID: 32028615 BACKGROUND

• Marchesi F, Toma L, Di Domenico EG, Cavallo I, Spadea A, Prignano G, Pimpinelli F, Papa E, Terrenato I, Ensoli F, Mengarelli A. Ceftolozane-Tazobactam for Febrile Neutropenia Treatment in Hematologic Malignancy Patients Colonized by Multi-Resistant Enterobacteriaceae: Preliminary Results from a Prospective Cohort Study. Mediterr J Hematol Infect Dis. 2020 Sep 1;12(1):e2020065. doi: 10.4084/MJHID.2020.065. eCollection 2020. No abstract available.

  PMID: 32952976 BACKGROUND

• Clerici D, Oltolini C, Greco R, Ripa M, Giglio F, Mastaglio S, Lorentino F, Pavesi F, Farina F, Liberatore C, Castiglion B, Tassan Din C, Bernardi M, Corti C, Peccatori J, Scarpellini P, Ciceri F, Castagna A. The place of ceftazidime/avibactam and ceftolozane/tazobactam for therapy of haematological patients with febrile neutropenia. Int J Antimicrob Agents. 2021 Jun;57(6):106335. doi: 10.1016/j.ijantimicag.2021.106335. Epub 2021 Apr 7.

  PMID: 33838223 BACKGROUND

MeSH Terms

Conditions

Hematologic Neoplasms; Neutropenia

Interventions

ceftolozane, tazobactam drug combination; Piperacillin, Tazobactam Drug Combination

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Agranulocytosis; Leukopenia; Cytopenia; Leukocyte Disorders

Intervention Hierarchy (Ancestors)

Tazobactam; Penicillanic Acid; Penicillins; beta-Lactams; Lactams; Amides; Organic Chemicals; Piperacillin; Ampicillin; Penicillin G; Sulfur Compounds; Sulfones; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Drug Combinations; Pharmaceutical Preparations

Study Officials

• Patricia Cornejo-Juarez, M.D.,M.Sc.

  Instituto Nacional de Cancerología, Mexico

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Diana Vilar Compte, M.D.,M.Sc.

CONTACT

+52 5628 0400; diana_vilar@yahoo.com.mx

Patricia Volkow, M.D.

CONTACT

+52 5628 0400; pvolkowf@gmail.com

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: Randomized, open, non-inferiority clinical trial comparing 1:1 two antibiotics, piperacillin/tazobactam vs. ceftolozane/tazobactam

Study Record Dates

• First Submitted: April 25, 2024
• First Posted: May 21, 2024
• Study Start: November 7, 2023
• Primary Completion: July 31, 2025
• Study Completion: August 30, 2025
• Last Updated: June 4, 2024

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF
• Time Frame: The data will become available at the end of the study. The plan is to finish the analysis and write the manuscript at the end of 2025.
• Access Criteria: The data requisition must be carried out with a solid foundation for which the information will be used. The investigators and sub-investigators will review the criteria.

Locations

ME (1)