Hematologic NeoplasmsNCT06422533
Ceftolozane/Tazobactam vs. Piperacillin/Tazobactam for the Treatment of Bacteremia in Hemato-oncological Patients
A study testing Ceftolozane/tazobactam and Piperacillin/tazobactam in people with Hematologic Neoplasms and Neutropenia, run by Instituto Nacional de Cancerologia de Mexico at 1 site in Mexico.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Hematologic Neoplasms, Neutropenia
- What is being tested?
- Ceftolozane/tazobactam and Piperacillin/tazobactam
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 226 participants
- Where
- 1 siteMexico
- Study dates
- 7 Nov 2023to 30 Aug 2025
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
Mexico1 site, 1 recruiting
- Recruiting
Instituto Nacional de Cancerologia
Mexico City, Tlalpan, 14080
Diana Vilar Compte, M.D., M.Sc., +52 56280400 ext. 12110, diana_vilar@yahoo.com.mx
Patricia Volkow, M.D., +52 56280400 ext. 12120, pvolkowf@gmail.com
About this study
Official title: Ceftolozane/Tazobactam vs. Piperacillin/Tazobactam for the Treatment of Bacteremia Due to Enterobacteriaceae and Pseudomonas Aeruginosa in Hemato-oncological Patients With Severe Neutropenia and Fever: Non-inferiority Study
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.
Read more
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.
Read the detailed description
At a global level, a very significant increase in multidrug-resistant (MDR) Gram-negative microorganisms has been described during the last decade, particularly Enterobacteriaceae producing extended-spectrum beta-lactamases (ESBL) and MDR Pseudomonas aeruginosa. This is directly related to the use of broad-spectrum antimicrobials, particularly carbapenems. Among the strategies to reduce bacterial resistance, using ceftolozane/tazobactam (C/T) as a "carbapenem-sparing" antibiotic is proposed. C/T has been administered in hemato-oncological patients with severe neutropenia, colonized by resistant strains in centers with a high prevalence of Enterobacteriaceae-ESBL and P. aeruginosa MDR.
The study's purpose is to demonstrate non-inferiority between ceftolozane/tazobactam vs. piperacillin/tazobactam for patients with hematological malignancies who present severe neutropenia and fever, including those patients who have bacteremia due to Enterobacteriaceae and Pseudomonas aeruginosa. 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.
At the National Cancer Institute, Gram-negative bacilli have been identified for more than 20 years as the pathogens most frequently associated with bacteremia, with Escherichia coli occupying first place at 25% (41% ESBL), followed by Klebsiella sp. in 5.6% (11.2% ESBL), and P. aeruginosa in 5.6% (11.2% MDR). The protocol for approaching and treating hemato-oncological patients with severe neutropenia and fever is to initiate an antimicrobial regimen with piperacillin/tazobactam (P/T) if they are hemodynamically stable. 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 a carbapenem (usually meropenem).
A randomized, open, non-inferiority clinical trial comparing 1:1 two antibiotics, P/T vs. C/T, for the treatment of severe neutropenia and fever and/or developing Enterobacteriaceae or P. aeruginosa bacteremia in patients with hematologic malignancies
Methodological strategies All patients who come to the National Cancer Institute with signs of severe neutropenia (polymorphonuclear cells <500 cells/mm3) and fever (≥38.3 degrees Celsius in one measure or ≥38 degrees Celsius in at least two measures) will be considered for inclusion. Blood cultures will be taken upon admission (catheter and peripheral in those with the same), or two peripherals with a difference of 15 minutes between each one. Blood cultures will be requested before signing the informed consent since they are part of the initial approach to these patients, regardless of whether they enter the study. They will be taken before the administration of antimicrobials.
Medical staff from the infectious disease department will evaluate the inclusion and exclusion criteria and invite the candidate to the study.
If the patient accepts, they will be provided informed consent to review it in detail, explaining any doubts. If they agree to participate, the corresponding signatures will be made.
Randomization will be done based on a stratified method in two groups: Group 1, patients with leukemia, and Group 2, patients with other hemato-oncological pathologies. They will be randomized into ten blocks and divided into the two groups above.
The administration of the P/T or C/T antimicrobial regimen will begin depending on the group to which they have been assigned, following the manufacturer's instructions and according to the administration standards at INCan.
The clinical and microbiological response will be evaluated in the first 72-96 hours (taking randomization as day +1), defined as patient survival plus resolution of fever plus sterilization of blood cultures (taken within the first 72-96 hours).
If patients have been fever-free for at least 48 hours and have no growth in blood cultures, they will receive at least five days of antibiotic treatment.
The administration time will be at least seven days in patients with P. aeruginosa or Enterobacteriaceae growth in blood cultures.
Patients whose blood cultures report growth of bacteria different from the previous ones, yeast, or polymicrobial growth will be excluded from the study.
Treatment failure will be considered, and the following will be included in the intention-to-treat analysis:
- If the growth in the blood culture is Enterobacteriaceae or P. aeruginosa, resistant to the antibiotic assigned.
- There is growth of the same bacteria in control blood cultures taken 72-96 hours after starting antibiotics.
- If, during treatment, the patient presents signs of hemodynamic instability, respiratory failure, clinical deterioration, or septic shock, changing the antimicrobial regimen will be considered.
The following will be considered a relapse and will be included in the intention-to-treat analysis:
- When the same microorganism is isolated at the beginning, it grows in blood cultures after having negative blood cultures.
- Or in the first 30 days after completing the antibiotic regimen, considering the resolution of the primary infectious focus.
During treatment, they will not be able to receive any other Gram-negative antibiotic except prophylaxis against P. jirovecii (400/80 mg/day TMP/SMX or 800/160 mg every 48 h).
The number of days of antibiotics will be counted. It will be documented when an antibiotic is modified and the reason for the change (microbiological failure, clinical deterioration, drug-related adverse events, and others). The appearance of diarrhea will be monitored, and Glutamate dehydrogenase (GDH) and toxin for Clostridiodes difficile will be requested.
Patients will be evaluated daily until fever resolution and until hospital discharge (if this occurs in the first 14 days), recording fever and adverse events, including diarrhea, leukocytes, and neutrophils. Follow-up will be carried out until day +30 from the patient's inclusion in the study. If the patient is discharged before this date, a telephone call will be made on day +30 to verify the clinical status.
The evolution will be classified as alive without infection, alive with clinical or microbiological data of infection, also considering C. difficile infection, dead from infection without neutropenia, dead from infection with neutropenia, dead from terminal illness, or dead from another cause.
- Conditions
- Hematologic Neoplasms, Neutropenia
- Being tested
- Ceftolozane/tazobactam, Piperacillin/tazobactam
- Keywords
- ceftolozane/tazobactam, piperacillin/tazobactam, neutropenia, hematologic neoplasms
- Medical subject headings
- Hematologic Neoplasms, Neutropenia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Ceftolozane/tazobactamDrug
Also called Zerbaxa
Ceftolozane/tazobactam 1.5 g tid IV infusion for 1 hour during 5 to 7 days
Piperacillin/tazobactamDrug
Also called Tazocin, Pipertazo, Tazonam, Tazovak
Piperacillin/tazobactam 4.5 g qid IV infusion for 30 minutes during 5 to 7 days
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Drug: Piperacillin/tazobactam |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Day 30
Secondary outcomes (2)
Microbiological response through the sterilization of repeated blood cultures take
Number of patients that will have repeated blood cultures sterilized (no growth of the same bacteria isolated in the first set of blood cultures taken in day 1).
Measured: Day 3 to day 4
Clinical response measured through fever resolution
The presence of fever (>38 Celsius degree) will be evaluated according to nursing records that are carried out three times a day (morning, afternoon, and night shifts). Clinical failure will be considered when the patient persists with fever (>38 Celsius degrees) on day four after starting the antimicrobial regimen. Clinical success will be considered when the fever resolves between day 1 and day 3 of starting antibiotics.
Measured: Day 4
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 May 2024
- Study start7 Nov 2023
- Primary completion31 Jul 2025 (estimated)
- Study completion30 Aug 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (14)Papers the sponsor has linked to this study.
- Other trials for Hematologic NeoplasmsStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Randomized, open, non-inferiority clinical trial comparing 1:1 two antibiotics, piperacillin/tazobactam vs. ceftolozane/tazobactam
- Masking
- None (open label)
- Enrolment
- 226 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Instituto Nacional de Cancerologia de Mexico
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Patricia Cornejo Juarez, Instituto Nacional de Cancerologia de Mexico
- Investigators
- Patricia Cornejo-Juarez, M.D.,M.Sc., Principal investigator, Instituto Nacional de Cancerología, Mexico
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06422533
- Sponsor's protocol ID
- CI0565-2023
- Status last verified
- Jun 2024
- First submitted
- 25 Apr 2024
- Last updated
- 4 Jun 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Individual participant data (IPD) could be shared with other researchers.
Publications
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.
PubMed 32033322Xie 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.
PubMed 33256752Giacobbe 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.
PubMed 29493397Shortridge 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.
PubMed 29039729Pfaller 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.
PubMed 28165526Livermore 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.
PubMed 28520867Pfaller 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.
PubMed 28735046Pfaller 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.
PubMed 28941394Seifert 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.
PubMed 28705666Fernandez-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.
PubMed 30530598Bergas 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.
PubMed 35475683Criscuolo 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.
PubMed 32028615Marchesi 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.
PubMed 32952976Clerici 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.
PubMed 33838223
Study at a glance
From the registry record, last updated by the sponsor on 4 Jun 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Ceftolozane/Tazobactam vs. Piperacillin/Tazobactam for the Treatment of Bacteremia Due to Enterobacteriaceae and Pseudomonas Aeruginosa in Hemato-oncological Patients With Severe Neutropenia and Fever: Non-inferiority Study
- ClinicalTrials.gov ID
- NCT06422533
- Acronym / sponsor ID
- CI0565-2023
- Conditions
- Hematologic Neoplasms, Neutropenia
- Keywords
- ceftolozane/tazobactam, piperacillin/tazobactam, neutropenia, hematologic neoplasms
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 226 participants (estimated)
- Lead sponsor
- Instituto Nacional de Cancerologia de MexicoUniversity, hospital or other
- Study start
- 7 Nov 2023 (actual)
- Primary completion
- 31 Jul 2025 (estimated)
- Study completion
- 30 Aug 2025 (estimated)
- First posted
- 21 May 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
At a global level, a very significant increase in multidrug-resistant (MDR) Gram-negative microorganisms has been described during the last decade, particularly Enterobacteriaceae producing extended-spectrum beta-lactamases (ESBL) and MDR Pseudomonas aeruginosa. This is directly related to the use of broad-spectrum antimicrobials, particularly carbapenems. Among the strategies to reduce bacterial resistance, using ceftolozane/tazobactam (C/T) as a "carbapenem-sparing" antibiotic is proposed. C/T has been administered in hemato-oncological patients with severe neutropenia, colonized by resistant strains in centers with a high prevalence of Enterobacteriaceae-ESBL and P. aeruginosa MDR.
The study's purpose is to demonstrate non-inferiority between ceftolozane/tazobactam vs. piperacillin/tazobactam for patients with hematological malignancies who present severe neutropenia and fever, including those patients who have bacteremia due to Enterobacteriaceae and Pseudomonas aeruginosa. 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.
At the National Cancer Institute, Gram-negative bacilli have been identified for more than 20 years as the pathogens most frequently associated with bacteremia, with Escherichia coli occupying first place at 25% (41% ESBL), followed by Klebsiella sp. in 5.6% (11.2% ESBL), and P. aeruginosa in 5.6% (11.2% MDR). The protocol for approaching and treating hemato-oncological patients with severe neutropenia and fever is to initiate an antimicrobial regimen with piperacillin/tazobactam (P/T) if they are hemodynamically stable. 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 a carbapenem (usually meropenem).
A randomized, open, non-inferiority clinical trial comparing 1:1 two antibiotics, P/T vs. C/T, for the treatment of severe neutropenia and fever and/or developing Enterobacteriaceae or P. aeruginosa bacteremia in patients with hematologic malignancies
Methodological strategies All patients who come to the National Cancer Institute with signs of severe neutropenia (polymorphonuclear cells <500 cells/mm3) and fever (≥38.3 degrees Celsius in one measure or ≥38 degrees Celsius in at least two measures) will be considered for inclusion. Blood cultures will be taken upon admission (catheter and peripheral in those with the same), or two peripherals with a difference of 15 minutes between each one. Blood cultures will be requested before signing the informed consent since they are part of the initial approach to these patients, regardless of whether they enter the study. They will be taken before the administration of antimicrobials.
Medical staff from the infectious disease department will evaluate the inclusion and exclusion criteria and invite the candidate to the study.
If the patient accepts, they will be provided informed consent to review it in detail, explaining any doubts. If they agree to participate, the corresponding signatures will be made.
Randomization will be done based on a stratified method in two groups: Group 1, patients with leukemia, and Group 2, patients with other hemato-oncological pathologies. They will be randomized into ten blocks and divided into the two groups above.
The administration of the P/T or C/T antimicrobial regimen will begin depending on the group to which they have been assigned, following the manufacturer's instructions and according to the administration standards at INCan.
The clinical and microbiological response will be evaluated in the first 72-96 hours (taking randomization as day +1), defined as patient survival plus resolution of fever plus sterilization of blood cultures (taken within the first 72-96 hours).
If patients have been fever-free for at least 48 hours and have no growth in blood cultures, they will receive at least five days of antibiotic treatment.
The administration time will be at least seven days in patients with P. aeruginosa or Enterobacteriaceae growth in blood cultures.
Patients whose blood cultures report growth of bacteria different from the previous ones, yeast, or polymicrobial growth will be excluded from the study.
Treatment failure will be considered, and the following will be included in the intention-to-treat analysis:
- If the growth in the blood culture is Enterobacteriaceae or P. aeruginosa, resistant to the antibiotic assigned.
- There is growth of the same bacteria in control blood cultures taken 72-96 hours after starting antibiotics.
- If, during treatment, the patient presents signs of hemodynamic instability, respiratory failure, clinical deterioration, or septic shock, changing the antimicrobial regimen will be considered.
The following will be considered a relapse and will be included in the intention-to-treat analysis:
- When the same microorganism is isolated at the beginning, it grows in blood cultures after having negative blood cultures.
- Or in the first 30 days after completing the antibiotic regimen, considering the resolution of the primary infectious focus.
During treatment, they will not be able to receive any other Gram-negative antibiotic except prophylaxis against P. jirovecii (400/80 mg/day TMP/SMX or 800/160 mg every 48 h).
The number of days of antibiotics will be counted. It will be documented when an antibiotic is modified and the reason for the change (microbiological failure, clinical deterioration, drug-related adverse events, and others). The appearance of diarrhea will be monitored, and Glutamate dehydrogenase (GDH) and toxin for Clostridiodes difficile will be requested.
Patients will be evaluated daily until fever resolution and until hospital discharge (if this occurs in the first 14 days), recording fever and adverse events, including diarrhea, leukocytes, and neutrophils. Follow-up will be carried out until day +30 from the patient's inclusion in the study. If the patient is discharged before this date, a telephone call will be made on day +30 to verify the clinical status.
The evolution will be classified as alive without infection, alive with clinical or microbiological data of infection, also considering C. difficile infection, dead from infection without neutropenia, dead from infection with neutropenia, dead from terminal illness, or dead from another cause.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- Randomized, open, non-inferiority clinical trial comparing 1:1 two antibiotics, piperacillin/tazobactam vs. ceftolozane/tazobactam
| Arm | Type | Receives |
|---|---|---|
| Ceftolozane/tazobactam | Experimental | Drug: Ceftolozane/tazobactamCeftozolane/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. |
| Piperacillin/tazobactam | Active comparator | Drug: Piperacillin/tazobactamAt 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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
Key exclusion criteria (5 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Ceftolozane/tazobactamAlso: ZerbaxaCeftolozane/tazobactam 1.5 g tid IV infusion for 1 hour during 5 to 7 days | Drug | Ceftolozane/tazobactam |
| Piperacillin/tazobactamAlso: Tazocin, Pipertazo, Tazonam, TazovakPiperacillin/tazobactam 4.5 g qid IV infusion for 30 minutes during 5 to 7 days | Drug | Piperacillin/tazobactam |
Primary outcome
Mortality of all patients at day 30
Time frame: 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.
2 secondary outcomes
Microbiological response through the sterilization of repeated blood cultures take
Time frame: Day 3 to day 4
Clinical response measured through fever resolution
Time frame: Day 4
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Jun 2024.
- Background: PubMed 32033322Karaiskos I, Giamarellou H. Carbapenem-Sparing Strategies for ESBL Producers: When and How. Antibiotics (Basel). 2020 Feb 5;9(2):61. doi: 10.3390/antibiotics9020061.
- Background: PubMed 33256752Xie 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.
- Background: PubMed 29493397Giacobbe 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.
- Background: PubMed 29039729Shortridge 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.
- Background: PubMed 28165526Pfaller 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.
- Background: PubMed 28520867Livermore 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.
- Background: PubMed 28735046Pfaller 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.
- Background: PubMed 28941394Pfaller 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.
- Background: PubMed 28705666Seifert 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.
- Background: PubMed 30530598Fernandez-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.
- Background: PubMed 35475683Bergas 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.
- Background: PubMed 32028615Criscuolo 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.
- Individual participant dataSharing planned: Yes. Individual participant data (IPD) could be shared with other researchers.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Patricia Cornejo-Juarez, M.D.,M.Sc. principal investigator
Instituto Nacional de Cancerología, Mexico
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Ceftolozane/tazobactam and Piperacillin/tazobactam in people with Hematologic Neoplasms and Neutropenia, run by Instituto Nacional de Cancerologia de Mexico at 1 site in Mexico.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 4 Jun 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Mexico. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Diana Vilar Compte, M.D.,M.Sc. (+52 5628 0400 ext. 12110, diana_vilar@yahoo.com.mx), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Mortality of all patients at day 30 (time frame: Day 30). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06422533, which also lists 14 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Jun 2024.