Ceftolozane/Tazobactam Versus Meropenem for Febrile Neutropenia on Patients Colonized With or at Risk for Infection With Extended Spectrum Beta Lactamase - Producing Pathogens

Official title

Ceftolozane/Tazobactam Versus Meropenem for Febrile Neutropenia on Patients Colonized With or at Risk for Infection With Extended Spectrum Beta Lactamase (ESBL)-Producing Pathogens: a Randomized Double-blind Non-inferiority Trial.

Overview

The study proposes a planned, double-blind, non-inferiority clinical trial involving patients with febrile neutropenia and risk of extended-spectrum beta-lactamase (ESBL) infection. The goal is: \- Analyze the efficacy and tolerability of Ceftolozane/tazobactam (CEF/TAZ) compared to the current standard of care (meropenem) in patients with febrile neutropenia and risk of ESBL infection. Patients will be randomly assigned to receive CEF/TAZ or meropenem, with assessment of clinical response, toxicity and microbiological evolution. Stool samples will be collected before, during and after treatment for intestinal microbiota analysis and intestinal microbiome analysis to evaluate possible effects on GVHD. Analysis of the results will include the taxonomic classification of the organisms present. Data will be analyzed to assess non-inferiority in clinical response, incidence of GVHD, antimicrobial resistance and other outcomes.

Interventions

• Drug Ceftolozane-Tazobactam
  In the intervention arm 3g of ceftolozane-tazobactam are given intravenously every 8 hours. Duration of therapy should follow local guidelines and de-escalation is allowed after identification of causative pathogens.
• Drug Meropenem
  The comparator arm consists of 2g of meropenem given intravenously every 8 hours.Duration of therapy should follow local guidelines and de-escalation is allowed after identification of causative pathogens.

Primary outcome measures

• Percentage of Participants With Clinical Response of Clinical Cure at the End-of-Therapy (EOT) Visit in the Intent-to-Treat (ITT) Population [Time frame: Within 24 hours after last dose of study drug (Up to ~Day 15)]

Secondary outcome measures (10)

• Percentage of Participants With Clinical Response of Clinical Cure at the End-of-Therapy (EOT) Visit in the Microbiological Intent-to-Treat (mITT) Population [Time frame: 7 to 14 days after last dose of study drug (Up to ~Day 30)]
• Percentage of Participants With Clinical Response of Clinical Cure at the Test-of-Cure (TOC) Visit in the Intent-to-Treat (ITT) Population [Time frame: 7 to 14 days after last dose of study drug (Up to ~Day 30)]
• Incidence of microbiologically documented infections and identification of causative organisms in culture [Time frame: Up to 100 days]
• In-hospital mortality [Time frame: Until100 days after allogenic HSCT]
• Occurrence of graft versus host disease (GVHD) [Time frame: Until100 days after allogenic HSCT]
• Frequency of multidrug resistant-pathogen infections or colonization [Time frame: Until100 days after allogenic HSCT]
• Faecal microbiota analysis [Time frame: Up to 100 days]
• Percentage of Participants Who Report 1 or More Adverse Event (AE) [Time frame: Up to 35 days after last dose of study drug]
• Percentage of Participants With Any Serious Adverse Event (SAE) [Time frame: Up to 35 days after last dose of study drug (Up to ~Day 50) ]]
• Percentage of Participants Discontinuing Study Drug Due to an Adverse Event (AE) [Time frame: Up to 14 days after the first dose of study drug (Up to ~Day 15)]

Eligibility criteria

Inclusion criteria

\- Individuals who present with the onset of febrile neutropenia and at the same time present colonization with an ESBL-producing pathogen (identified through positive routine rectal swabs and/or positive culture of clinical specimen) or risk of infection with an ESBL-producing pathogen (use of 3rd/4th gen cephalosporin or piperacillin/tazobactam for at least 48 hours in the last 30 days).

Exclusion criteria

• Patients known to be colonized with carbapenem-resistant or CEF/TAZ-resistant pathogens
• Patients with previous use of carbapenems for at least 48h in the past 30 days are also excluded due to risk of resistance to the study drugs.
• Growth of a pathogen resistant to either study drug in a relevant clinical specimen during the intervention phase will be followed by adjustment of therapy according to local protocol, unblinding, and exclusion from the study.
• Patients that have received less than 72h of either study drug will also be excluded from the final analyses.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Brazil · 1 center

• A Beneficência Portuguesa de São Paulo — São Paulo

Publications

• Pillinger KE, Bouchard J, Withers ST, Mediwala K, McGee EU, Gibson GM, Bland CM, Bookstaver PB. Inpatient Antibiotic Stewardship Interventions in the Adult Oncology and Hematopoietic Stem Cell Transplant Population: A Review of the Literature. Ann Pharmacother. 2020 Jun;54(6):594-610. doi: 10.1177/1060028019890886. Epub 2019 Nov 26. PMID 31771337
• Coates ARM, Hu Y, Holt J, Yeh P. Antibiotic combination therapy against resistant bacterial infections: synergy, rejuvenation and resistance reduction. Expert Rev Anti Infect Ther. 2020 Jan;18(1):5-15. doi: 10.1080/14787210.2020.1705155. PMID 31847614
• Meletis G. Carbapenem resistance: overview of the problem and future perspectives. Ther Adv Infect Dis. 2016 Feb;3(1):15-21. doi: 10.1177/2049936115621709. PMID 26862399
• Girmenia C, Rossolini GM, Piciocchi A, Bertaina A, Pisapia G, Pastore D, Sica S, Severino A, Cudillo L, Ciceri F, Scime R, Lombardini L, Viscoli C, Rambaldi A; Gruppo Italiano Trapianto Midollo Osseo (GITMO); Gruppo Italiano Trapianto Midollo Osseo GITMO. Infections by carbapenem-resistant Klebsiella pneumoniae in SCT recipients: a nationwide retrospective survey from Italy. Bone Marrow Transplant PMID 25310302
• Cattaneo C, Di Blasi R, Skert C, Candoni A, Martino B, Di Renzo N, Delia M, Ballanti S, Marchesi F, Mancini V, Orciuolo E, Cesaro S, Prezioso L, Fanci R, Nadali G, Chierichini A, Facchini L, Picardi M, Malagola M, Orlando V, Trecarichi EM, Tumbarello M, Aversa F, Rossi G, Pagano L; SEIFEM Group. Bloodstream infections in haematological cancer patients colonized by multidrug-resistant bacteria. Ann PMID 29705860
• Camargo JF, Anderson AD, Natori Y, Natori A, Morris MI, Pereira D, Komanduri KV. Early antibiotic use is associated with CMV risk and outcomes following allogeneic hematopoietic cell transplantation. Blood Adv. 2020 Dec 22;4(24):6364-6367. doi: 10.1182/bloodadvances.2020003277. No abstract available. PMID 33351132
• Tanaka JS, Young RR, Heston SM, Jenkins K, Spees LP, Sung AD, Corbet K, Thompson JC, Bohannon L, Martin PL, Stokhuyzen A, Vinesett R, Ward DV, Bhattarai SK, Bucci V, Arshad M, Seed PC, Kelly MS. Anaerobic Antibiotics and the Risk of Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2020 Nov;26(11):2053-2060. doi: 10.1016/j.bbmt.2020.0 PMID 32682948
• van Duin D, Bonomo RA. Ceftazidime/Avibactam and Ceftolozane/Tazobactam: Second-generation beta-Lactam/beta-Lactamase Inhibitor Combinations. Clin Infect Dis. 2016 Jul 15;63(2):234-41. doi: 10.1093/cid/ciw243. Epub 2016 Apr 20. PMID 27098166

Identifiers

NCT: NCT06342115 · CLEMENT TRIAL

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗