An interventional study of Ceftolozane/tazobactam and Piperacillin/tazobactam in Hematologic Neoplasms and Neutropenia, sponsored by Instituto Nacional de Cancerologia de Mexico. Recruiting at 1 site in Mexico. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2024-06-04.
Sponsored by Instituto Nacional de Cancerologia de Mexico · Not applicable, Interventional, and Treatment
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.
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:
The following will be considered a relapse and will be included in the intention-to-treat analysis:
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.
1,444 studies on the registry are indexed under Hematologic Neoplasms; 420 are open to participants now.
This study's planned enrollment of 226 is above the median of 46 across 1,044 interventional studies indexed under Hematologic Neoplasms.
Browse Hematologic Neoplasms studies →Instituto Nacional de Cancerologia de Mexico is the lead sponsor of 41 studies on the registry; 13 are open to participants now.
Counted across the registry records on this site, refreshed daily.
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Malignancy means cancer. Criteria about another or earlier malignancy ask whether you have had a different cancer, usually within a set number of years.
Some are commonly allowed, such as treated skin cancers other than melanoma and early cancers removed completely — check the exceptions this study lists.
The study doctor’s estimate of how long someone is likely to live. Criteria use it so that people can stay in the study long enough for it to answer its question.
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
How quickly the kidneys clear creatinine, a waste product, from the blood. A study may estimate it from a blood test with age, weight and sex (often by the Cockcroft–Gault formula), or measure it using blood and urine collected over a set time. Given in mL/min; higher is better.
Cancer (malignancy)
Malignancy means cancer. Criteria about another or earlier malignancy ask whether you have had a different cancer, usually within a set number of years.
Some are commonly allowed, such as treated skin cancers other than melanoma and early cancers removed completely — check the exceptions this study lists.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Life expectancy
The study doctor’s estimate of how long someone is likely to live. Criteria use it so that people can stay in the study long enough for it to answer its question.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hypersensitivity
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Creatinine clearance (CrCl)
How quickly the kidneys clear creatinine, a waste product, from the blood. A study may estimate it from a blood test with age, weight and sex (often by the Cockcroft–Gault formula), or measure it using blood and urine collected over a set time. Given in mL/min; higher is better.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
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
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
Drug page: Ceftolozane
Ceftolozane/tazobactam 1.5 g tid IV infusion for 1 hour during 5 to 7 days
Also known as: Zerbaxa
Piperacillin/tazobactam 4.5 g qid IV infusion for 30 minutes during 5 to 7 days
Also known as: Tazocin, Pipertazo, Tazonam, Tazovak
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.
Time frame: Day 30
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).
Time frame: 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.
Time frame: Day 4
Clostridioides difficile infection documented through toxin/GDH C. difficile test in those patients who develop diarrhea, abdominal pain and/or distended abdomen.
Number of patients who develop diarrhea or abdominal pain or distended abdomen, with a test positive for C. difficile (toxin/GDH C. difficile test).
Time frame: Day 1 to day 30
Plan to share: Yes — Individual participant data (IPD) could be shared with other researchers.
Supporting information: Study protocol, Informed consent form
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.
Started Nov 2023 (actual). Primary completion is estimated for Jul 2025, 20 months after the start.
Of 185 non-industry interventional studies with no phase under Hematologic Neoplasms, half reached primary completion within 40 months of starting (the median), counting those still running; a quarter within 21 and three quarters within 125. This study's planned 20 months is below that.
Counting every sponsor, half of 191 studies reached it within 40 months; a quarter within 21 and three quarters within 125.
How these figures are worked out, and which studies are left out of them.
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Studies of the drug tested here: Ceftolozane
Instituto Nacional de Cancerologia de Mexico