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

Summary

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.

Timeline

Start

2025-03-26

Primary completion

2026-12

Completion

2026-12

Publications

• Background 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.
• Background 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.
• Background 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.
• Background 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. 2015 Feb;50(2):282-8. doi: 10.1038/bmt.2014.231. Epub 2014 Oct 13.
• Background 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 Hematol. 2018 Sep;97(9):1717-1726. doi: 10.1007/s00277-018-3341-6. Epub 2018 Apr 28.
• Background 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.
• Background 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.2020.07.011. Epub 2020 Jul 17.
• Background 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.
• Background Gomis-Font MA, Cabot G, Lopez-Arguello S, Zamorano L, Juan C, Moya B, Oliver A. Comparative analysis of in vitro dynamics and mechanisms of ceftolozane/tazobactam and imipenem/relebactam resistance development in Pseudomonas aeruginosa XDR high-risk clones. J Antimicrob Chemother. 2022 Mar 31;77(4):957-968. doi: 10.1093/jac/dkab496.
• Background Bitar I, Salloum T, Merhi G, Hrabak J, Araj GF, Tokajian S. Genomic Characterization of Mutli-Drug Resistant Pseudomonas aeruginosa Clinical Isolates: Evaluation and Determination of Ceftolozane/Tazobactam Activity and Resistance Mechanisms. Front Cell Infect Microbiol. 2022 Jun 15;12:922976. doi: 10.3389/fcimb.2022.922976. eCollection 2022.
• Background Timsit JF, Huntington JA, Wunderink RG, Shime N, Kollef MH, Kivistik U, Novacek M, Rea-Neto A, Martin-Loeches I, Yu B, Jensen EH, Butterton JR, Wolf DJ, Rhee EG, Bruno CJ. Ceftolozane/tazobactam versus meropenem in patients with ventilated hospital-acquired bacterial pneumonia: subset analysis of the ASPECT-NP randomized, controlled phase 3 trial. Crit Care. 2021 Aug 11;25(1):290. doi: 10.1186/s13054-021-03694-3.
• Background Solomkin J, Hershberger E, Miller B, Popejoy M, Friedland I, Steenbergen J, Yoon M, Collins S, Yuan G, Barie PS, Eckmann C. 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). Clin Infect Dis. 2015 May 15;60(10):1462-71. doi: 10.1093/cid/civ097. Epub 2015 Feb 10.
• Background Wagenlehner FM, Umeh O, Steenbergen J, Yuan G, Darouiche RO. Ceftolozane-tazobactam compared with levofloxacin in the treatment of complicated urinary-tract infections, including pyelonephritis: a randomised, double-blind, phase 3 trial (ASPECT-cUTI). Lancet. 2015 May 16;385(9981):1949-56. doi: 10.1016/S0140-6736(14)62220-0. Epub 2015 Apr 27.
• Background Chaftari AM, Hachem R, Malek AE, Mulanovich VE, Szvalb AD, Jiang Y, Yuan Y, Ali S, Deeba R, Chaftari P, Raad I. A Prospective Randomized Study Comparing Ceftolozane/Tazobactam to Standard of Care in the Management of Neutropenia and Fever in Patients With Hematological Malignancies. Open Forum Infect Dis. 2022 Feb 14;9(6):ofac079. doi: 10.1093/ofid/ofac079. eCollection 2022 Jun.
• 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.
• 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.

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