Trial Title:
Ceftolozane/Tazobactam vs. Piperacillin/Tazobactam for the Treatment of Bacteremia in Hemato-oncological Patients
NCT ID:
NCT06422533
Condition:
Hematologic Neoplasms
Neutropenia
Conditions: Official terms:
Bacteremia
Hematologic Neoplasms
Neutropenia
Tazobactam
Piperacillin
Piperacillin, Tazobactam Drug Combination
Ceftolozane
Ceftolozane, tazobactam drug combination
Conditions: Keywords:
ceftolozane/tazobactam
piperacillin/tazobactam
neutropenia
hematologic neoplasms
Study type:
Interventional
Study phase:
N/A
Overall status:
Recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Intervention model description:
Randomized, open, non-inferiority clinical trial comparing 1:1 two antibiotics,
piperacillin/tazobactam vs. ceftolozane/tazobactam
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Ceftolozane/tazobactam
Description:
Ceftolozane/tazobactam 1.5 g tid IV infusion for 1 hour during 5 to 7 days
Arm group label:
Ceftolozane/tazobactam
Other name:
Zerbaxa
Intervention type:
Drug
Intervention name:
Piperacillin/tazobactam
Description:
Piperacillin/tazobactam 4.5 g qid IV infusion for 30 minutes during 5 to 7 days
Arm group label:
Piperacillin/tazobactam
Other name:
Tazocin
Other name:
Pipertazo
Other name:
Tazonam
Other name:
Tazovak
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.
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.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- 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
Exclusion Criteria:
- 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
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Instituto Nacional de Cancerologia
Address:
City:
Mexico City
Zip:
14080
Country:
Mexico
Status:
Recruiting
Contact:
Last name:
Diana Vilar Compte, M.D., M.Sc.
Phone:
+52 56280400
Phone ext:
12110
Email:
diana_vilar@yahoo.com.mx
Contact backup:
Last name:
Patricia Volkow, M.D.
Phone:
+52 56280400
Phone ext:
12120
Email:
pvolkowf@gmail.com
Investigator:
Last name:
Beda D Islas-Muñoz, M.D., M.Sc
Email:
Sub-Investigator
Investigator:
Last name:
Pamela Alatorre-Fernández, M.D.
Email:
Sub-Investigator
Start date:
November 7, 2023
Completion date:
August 30, 2025
Lead sponsor:
Agency:
Instituto Nacional de Cancerologia de Mexico
Agency class:
Other
Source:
Instituto Nacional de Cancerologia de Mexico
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06422533
