Gram Negative InfectionPACCOFNCT06651047
PK/PD Analysis of Ceftazidime/Avibactam or Cefiderocol With or Without Fosfomycin for the Treatment of Difficult To-treat Gram-negative Infections
An observational study of Gram Negative Infection and Antimicrobial Resistance (AMR), run by University of Bologna at 11 sites in Italy.
Trial summary
A multicenter, national, prospective, observational pharmacological study of patients with difficult-to-treat Gram-negative infections treated with ceftazidime/avibactam (CAZ/AVI) or cefiderocol (CEF) monotherapy or combination therapy with ceftazidime/avibactam associated with fosfomycin (FOS) or cefiderocol… Read more about this study
- Who is it for?
- Any ageHealthy volunteers can take part
- Conditions the study is for
- Gram Negative Infection, Antimicrobial Resistance (AMR)
- How many people
- 120 participants
- Where
- 11 sitesItaly
- Study dates
- 9 Jul 2024to 30 Sep 2025
- Phase
- Observational
- 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 Any age
- All sexes
- Healthy volunteers accepted
- Child, Adult, Older adult
Study population: Patients with infection due to a difficult-to-treat Gram-negative bacteria, treated with CAZ/AVI alone, CEF alone, CAZ/AVI plus FOS, or CEF plus FOS (any age), hospitalized during the study period in the participating centers, will be screened for inclusion
Who may be able to join
- Patients with infection due to a difficult-to-treat Gram-negative bacteria treated with CAZ/AVI alone, CEF alone, CAZ/AVI plus FOS, or CEF plus FOS (any age)
- Signature of the informed consent (for pediatric patients: parents or guardians able to provide consent)
- Age ≥18 years
- Signature of the informed consent
Who cannot join
- Premature newborns
- Polymicrobial/mixed infections with the exception of cases with multiple Gram-negative bacteria susceptible to study drugs
- Continuous renal replacement therapy (CRRT) applications
- Any known clinically relevant health problems
Trial locations and contacts
11 sites in 1 country.
11 sites in 1 country
Italy11 sites, 11 recruiting
- Recruiting
Irccs Aoubo
Bologna, 40138
Maddalena Giannella, MD PhD, +39 0512143199, maddalena.giannella@unibo.it
Natascia Caroccia, PhD, natascia.caroccia@unibo.it
- Not yet recruiting
Azienda Ospedaliera di Rilievo Nazionale e di Alta Specializzazione (ARNAS) Garibaldi
Catania, 95124
Bruno Cacopardo, MD, +39 0957598453, bruno.cacopardo@unict.it
- Not yet recruiting
ASST-FBF-Sacco
Milan, 20157
Andrea Gori, MD, +39 02503 19632, andrea.gori@unimi.it
- Not yet recruiting
Azienda Ospedale - Università Padova
Padova, 35128
Daniele Donà, MD, +39 0498213563, daniele.dona@unipd.it
- Not yet recruiting
Istituto mediterraneo per i trapianti e terapie ad alta specializzazione (ISMETT)
Palermo, 90127
Alessandra Mularoni, MD, +390912192111, amularoni@ismett.edu
- Not yet recruiting
Policlinico Umberto I
Rome, 00100
Alessandra Oliva, MD, +39 0649971, alessandra.oliva@uniroma1.it
- Not yet recruiting
Policlinico Universitario Campus Bio-Medico
Rome, 00128
Silvia Angeletti, MD, +39 06 225411138, s.angeletti@policlinicocampus.it
- Not yet recruiting
Ospedale Pediatrico Bambin Gesù
Rome, 00165
Maia De Luca, MD, +39 06 68592947, maia.deluca@opbg.net
- Not yet recruiting
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Rome, 00168
Massimo Antonelli, MD, +39 063311434, massimo.antonelli@unicatt.it
- Not yet recruiting
Azienda Ospedaliero Universitaria Senese
Siena, 53100
Mario Tumbarello, MD, +39 0577585111, mario.tumbarello@unisi.it
- Not yet recruiting
Città della salute e della Scienza, Molinette
Turin, 10126
Silvia Corcione, MD, +39 011 633 1633, silvia.corcione@unito.it
About this study
Official title: Pharmacokinetic/Pharmacodynamic Analysis of Ceftazidime/Avibactam or Cefiderocol With or Without Fosfomycin for the Treatment of Difficult To-treat Gram-negative Infections
A multicenter, national, prospective, observational pharmacological study of patients with difficult-to-treat Gram-negative infections treated with ceftazidime/avibactam (CAZ/AVI) or cefiderocol (CEF) monotherapy or combination therapy with ceftazidime/avibactam associated with fosfomycin (FOS) or cefiderocol associated with fosfomycin.
Read the detailed description
Gram-negative infections, particularly those caused by Carbapenem-resistant Enterobacterales (CRE), have a dramatic impact on patient survival. Despite the introduction of new drugs in the last years have improved the outcome of patients with difficult-to-treat gram-negative infections, mortality and relapse rates are still relevant, especially in patients with high-risk sources such as pneumonia, and those in which the attainment of optimal exposure could be reduced by underlying renal disease. The use of a combination regimen in these scenarios has been proposed. However, a standardized approach to therapeutic management is still missing. To overcome this unmet clinical need, this study aims to investigate the pharmacokinetic/pharmacodynamics (PK/PD) optimization of antibiotic dosing regimens in patients with difficult-to-treat Gram-negative infections, using Therapeutic Drug Monitoring (TDM). A prompt implementation of an appropriate targeted antibiotic therapy could represent a valuable approach to improve clinical outcomes in patients with difficult-to-treat Gram-negative infections. Moreover, more information is needed in pediatric populations where ceftazidime/avibactam (CAZ/AVI) is approved only for children aged > 3 months (with the same indications as adults) and cefiderocol (CEF) is not approved. Indeed, cefiderocol is currently off-label administered in pediatric population using case-by-case dosages based on encouraging case reports.
Since several in vitro studies have highlighted the synergistic effect of fosfomycin (FOS) with different antibiotic classes, including cephalosporins such drug could be an appealing option in combination therapy for the management of difficult-to-treat gram-negative infections, both with CAZ/AVI and CEF. However, real-life prospective studies are needed to investigate the potential benefit of combination therapy on clinical outcomes and the occurrence of further resistance. Thus, the correct dose of FOS along with the type of administration (i.e., intermittent, extended, or continuous infusion) are issues to establish.
In particular, the primary aim of the study is to evaluate the probability of achieving pre-determined pharmacokinetic/pharmacodynamic (PK/PD) efficacy targets for CAZ/AVI, CEF and FOS.
Secondary objectives are:
- to evaluate the relationship between the achievement of the PK/PD target of CAZ/AVI, CEF and FOS and microbiological eradication;
- to evaluate the trend of clinical biomarkers in response to antibiotic therapy;
- to investigate the diagnostic and prognostic value of protein biomarkers.
This research is supported by EU funding within the Next Generation EU-MUR PNRR Extended Partnership initiative on Emerging Infectious Diseases (Project no. PE00000007, INF-ACT).
- Keywords
- Gram-negative infection, Ceftazidime/Avibactam, Cefiderocol, Fosfomycin, Pharmacokinetics/Pharmacodynamics targets, Carbapenem-resistant Enterobacterales (CRE)
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| Patients with difficult-to-treat gram-negative infection treated with CAZ/AVI or CEF, ± FOS | All patients (any age) with infection due to a difficult-to-treat Gram-negative bacteria treated with CAZ/AVI alone, CEF alone, CAZ/AVI plus FOS, or CEF plus FOS |
What is being measured
The primary outcome is the main question the study is designed to answer.
PK/PD efficacy targets for study drugs
Primary endpoint will be the proportion of patients achieving the PK/PD efficacy target. Since these drugs are widely used in clinical practice, safety is not evaluated in this study
Measured: From enrollment (treatment onset) to the end of treatment (up to 7 days)
Secondary outcomes (6)
Difference in SOFA score
Difference in SOFA score (pSOFA for pediatric patients) between day 0 (day of index positive cultures) and day 7
Measured: From day 0 (day of index positive culture) and day 7
Difference in C-Reactive Protein (CRP), Procalcitonin (PCT) and Interleukin-6 (IL-6)
Difference in C-Reactive Protein (CRP), Procalcitonin (PCT) and Interleukin-6 (IL-6) between day 0 and day 7
Measured: From day 0 (day of index positive culture) and day 7
Identification of new protein-based biomarkers
- Difference in protein-based biomarkers at day 0 between study patients and a group of healthy subjects
- Difference in protein-based biomarkers in study patients between different timepoints (from treatment onset to the end of treatment)
Measured: From enrollment to the end of treatment (up to 7 days)
Microbiological eradication
Microbiological eradication defined as bacteremia clearance or negativization of index diagnostic samples within 7 days from index BC
Measured: From day 0 (day of index positive culture) and day 7
Relapse and/or reinfection
Relapse (new infection with the same pathogen emerging after treatment) and/or reinfection (new infection with a different pathogen emerging after treatment) rates at day 90
Measured: From enrollment to the end of the follow-up at three months
All-cause mortality
All-cause mortality at day 30 and at day 90
Measured: From enrollment to the end of the follow-up at three months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Oct 2024
- Study start9 Jul 2024
- Primary completion30 Sep 2025 (estimated)
- Study completion30 Sep 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Gram Negative InfectionStudies 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
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 120 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Bologna
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Maddalena Giannella, University of Bologna
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06651047
- Sponsor's protocol ID
- PACCOF
- Other IDs
- NextGenerationEU
- Acronym
- PACCOF
- Status last verified
- Oct 2024
- First submitted
- 15 Oct 2024
- Last updated
- 21 Oct 2024
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 21 Oct 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pharmacokinetic/Pharmacodynamic Analysis of Ceftazidime/Avibactam or Cefiderocol With or Without Fosfomycin for the Treatment of Difficult To-treat Gram-negative Infections
- ClinicalTrials.gov ID
- NCT06651047
- Acronym / sponsor ID
- PACCOF / PACCOF
- Keywords
- Gram-negative infection, Ceftazidime/Avibactam, Cefiderocol, Fosfomycin, Pharmacokinetics/Pharmacodynamics targets, Carbapenem-resistant Enterobacterales (CRE)
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 120 participants (estimated)
- Lead sponsor
- University of BolognaUniversity, hospital or other
- Study start
- 9 Jul 2024 (actual)
- Primary completion
- 30 Sep 2025 (estimated)
- Study completion
- 30 Sep 2025 (estimated)
- First posted
- 21 Oct 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.
A multicenter, national, prospective, observational pharmacological study of patients with difficult-to-treat Gram-negative infections treated with ceftazidime/avibactam (CAZ/AVI) or cefiderocol (CEF) monotherapy or combination therapy with ceftazidime/avibactam associated with fosfomycin (FOS) or cefiderocol associated with fosfomycin.
Detailed description
Gram-negative infections, particularly those caused by Carbapenem-resistant Enterobacterales (CRE), have a dramatic impact on patient survival. Despite the introduction of new drugs in the last years have improved the outcome of patients with difficult-to-treat gram-negative infections, mortality and relapse rates are still relevant, especially in patients with high-risk sources such as pneumonia, and those in which the attainment of optimal exposure could be reduced by underlying renal disease. The use of a combination regimen in these scenarios has been proposed. However, a standardized approach to therapeutic management is still missing. To overcome this unmet clinical need, this study aims to investigate the pharmacokinetic/pharmacodynamics (PK/PD) optimization of antibiotic dosing regimens in patients with difficult-to-treat Gram-negative infections, using Therapeutic Drug Monitoring (TDM). A prompt implementation of an appropriate targeted antibiotic therapy could represent a valuable approach to improve clinical outcomes in patients with difficult-to-treat Gram-negative infections. Moreover, more information is needed in pediatric populations where ceftazidime/avibactam (CAZ/AVI) is approved only for children aged > 3 months (with the same indications as adults) and cefiderocol (CEF) is not approved. Indeed, cefiderocol is currently off-label administered in pediatric population using case-by-case dosages based on encouraging case reports.
Since several in vitro studies have highlighted the synergistic effect of fosfomycin (FOS) with different antibiotic classes, including cephalosporins such drug could be an appealing option in combination therapy for the management of difficult-to-treat gram-negative infections, both with CAZ/AVI and CEF. However, real-life prospective studies are needed to investigate the potential benefit of combination therapy on clinical outcomes and the occurrence of further resistance. Thus, the correct dose of FOS along with the type of administration (i.e., intermittent, extended, or continuous infusion) are issues to establish.
In particular, the primary aim of the study is to evaluate the probability of achieving pre-determined pharmacokinetic/pharmacodynamic (PK/PD) efficacy targets for CAZ/AVI, CEF and FOS.
Secondary objectives are:
- to evaluate the relationship between the achievement of the PK/PD target of CAZ/AVI, CEF and FOS and microbiological eradication;
- to evaluate the trend of clinical biomarkers in response to antibiotic therapy;
- to investigate the diagnostic and prognostic value of protein biomarkers.
This research is supported by EU funding within the Next Generation EU-MUR PNRR Extended Partnership initiative on Emerging Infectious Diseases (Project no. PE00000007, INF-ACT).
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Patients with difficult-to-treat gram-negative infection treated with CAZ/AVI or CEF, ± FOS | – | –All patients (any age) with infection due to a difficult-to-treat Gram-negative bacteria treated with CAZ/AVI alone, CEF alone, CAZ/AVI plus FOS, or CEF plus FOS |
Who may qualify
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult, Older adult
- Study population
- Patients with infection due to a difficult-to-treat Gram-negative bacteria, treated with CAZ/AVI alone, CEF alone, CAZ/AVI plus FOS, or CEF plus FOS (any age), hospitalized during the study period in the participating centers, will be screened for inclusion
Key inclusion criteria (4 listed)
- Patients with infection due to a difficult-to-treat Gram-negative bacteria treated with CAZ/AVI alone, CEF alone, CAZ/AVI plus FOS, or CEF plus FOS (any age)
- Signature of the informed consent (for pediatric patients: parents or guardians able to provide consent)
- Age ≥18 years
- Signature of the informed consent
Key exclusion criteria (4 listed)
- Premature newborns
- Polymicrobial/mixed infections with the exception of cases with multiple Gram-negative bacteria susceptible to study drugs
- Continuous renal replacement therapy (CRRT) applications
- Any known clinically relevant health problems
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
PK/PD efficacy targets for study drugs
Time frame: From enrollment (treatment onset) to the end of treatment (up to 7 days)
Primary endpoint will be the proportion of patients achieving the PK/PD efficacy target. Since these drugs are widely used in clinical practice, safety is not evaluated in this study
6 secondary outcomes
Difference in SOFA score
Time frame: From day 0 (day of index positive culture) and day 7
Difference in C-Reactive Protein (CRP), Procalcitonin (PCT) and Interleukin-6 (IL-6)
Time frame: From day 0 (day of index positive culture) and day 7
Identification of new protein-based biomarkers
Time frame: From enrollment to the end of treatment (up to 7 days)
Microbiological eradication
Time frame: From day 0 (day of index positive culture) and day 7
Relapse and/or reinfection
Time frame: From enrollment to the end of the follow-up at three months
All-cause mortality
Time frame: From enrollment to the end of the follow-up at three months
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Oct 2024.
- The study is enclosed in the INF-ACT research program that addresses pressing unmet needs of human emerging infectious diseases sith an One Health approachLink provided by the sponsor.
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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.
11 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Gram Negative Infection and Antimicrobial Resistance (AMR), run by University of Bologna at 11 sites in Italy.
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 4 inclusion and 4 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 21 Oct 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 11 sites in Italy. 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 Maddalena Giannella, MD PhD (+39 0512143199, maddalena.giannella@unibo.it), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
PK/PD efficacy targets for study drugs (time frame: From enrollment (treatment onset) to the end of treatment (up to 7 days)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 21 Oct 2024.