PK/PD Analysis of Ceftazidime/Avibactam or Cefiderocol With or Without Fosfomycin for the Treatment of Difficult To-treat Gram-negative Infections (PACCOF)
Pharmacokinetic/Pharmacodynamic Analysis of Ceftazidime/Avibactam or Cefiderocol With or Without Fosfomycin for the Treatment of Difficult To-treat Gram-negative Infections
Study Overview
Status
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 Type
Enrollment (Estimated)
Contacts and Locations
Study Contact
- Name: Natascia Caroccia, PhD
- Phone Number: +39 0512143595
- Email: natascia.caroccia@unibo.it
Study Contact Backup
- Name: Maddalena Giannella, MD PhD
- Phone Number: +39 0512143199
- Email: maddalena.giannella@unibo.it
Study Locations
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Bologna, Italy, 40138
- Recruiting
- IRCCS AOUBO
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Contact:
- Natascia Caroccia, PhD
- Email: natascia.caroccia@unibo.it
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Contact:
- Maddalena Giannella, MD PhD
- Phone Number: +39 0512143199
- Email: maddalena.giannella@unibo.it
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Catania, Italy, 95124
- Not yet recruiting
- Azienda Ospedaliera di Rilievo Nazionale e di Alta Specializzazione (ARNAS) Garibaldi
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Contact:
- Bruno Cacopardo, MD
- Phone Number: +39 0957598453
- Email: bruno.cacopardo@unict.it
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Milan, Italy, 20157
- Not yet recruiting
- ASST-FBF-Sacco
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Contact:
- Andrea Gori, MD
- Phone Number: +39 02503 19632
- Email: andrea.gori@unimi.it
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Padova, Italy, 35128
- Not yet recruiting
- Azienda Ospedale - Università Padova
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Contact:
- Daniele Donà, MD
- Phone Number: +39 0498213563
- Email: daniele.dona@unipd.it
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Palermo, Italy, 90127
- Not yet recruiting
- Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione (ISMETT)
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Contact:
- Alessandra Mularoni, MD
- Phone Number: +390912192111
- Email: amularoni@ismett.edu
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Rome, Italy, 00168
- Not yet recruiting
- Fondazione Policlinico Universitario Agostino Gemelli IRCCS
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Contact:
- Massimo Antonelli, MD
- Phone Number: +39 063311434
- Email: massimo.antonelli@unicatt.it
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Rome, Italy, 00128
- Not yet recruiting
- Policlinico Universitario Campus Bio-Medico
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Contact:
- Silvia Angeletti, MD
- Phone Number: +39 06 225411138
- Email: s.angeletti@policlinicocampus.it
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Rome, Italy, 00100
- Not yet recruiting
- Policlinico Umberto I
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Contact:
- Alessandra Oliva, MD
- Phone Number: +39 0649971
- Email: alessandra.oliva@uniroma1.it
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Rome, Italy, 00165
- Not yet recruiting
- Ospedale Pediatrico Bambin Gesù
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Contact:
- Maia De Luca, MD
- Phone Number: +39 06 68592947
- Email: maia.deluca@opbg.net
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Siena, Italy, 53100
- Not yet recruiting
- Azienda Ospedaliero Universitaria Senese
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Contact:
- Mario Tumbarello, MD
- Phone Number: +39 0577585111
- Email: mario.tumbarello@unisi.it
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Turin, Italy, 10126
- Not yet recruiting
- Città della salute e della Scienza, Molinette
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Contact:
- Silvia Corcione, MD
- Phone Number: +39 011 633 1633
- Email: silvia.corcione@unito.it
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Child
- Adult
- Older Adult
Accepts Healthy Volunteers
Sampling Method
Study Population
Description
Inclusion Criteria:
- 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)
Exclusion Criteria:
- 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
Inclusion Criteria for Healthy Volunteer Subjects:
- Age ≥18 years
- Signature of the informed consent
Exclusion Criteria for Healthy Volunteer Subjects:
- Any known clinically relevant health problems
Study Plan
How is the study designed?
Design Details
Cohorts and Interventions
Group / Cohort |
|---|
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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 the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
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
|
From enrollment (treatment onset) to the end of treatment (up to 7 days)
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Difference in SOFA score
Time Frame: From day 0 (day of index positive culture) and day 7
|
Difference in SOFA score (pSOFA for pediatric patients) between day 0 (day of index positive cultures) and day 7
|
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
|
Difference in C-Reactive Protein (CRP), Procalcitonin (PCT) and Interleukin-6 (IL-6) between day 0 and day 7
|
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)
|
|
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
|
Microbiological eradication defined as bacteremia clearance or negativization of index diagnostic samples within 7 days from index BC
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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
|
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
|
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
|
All-cause mortality at day 30 and at day 90
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From enrollment to the end of the follow-up at three months
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Collaborators and Investigators
Sponsor
Publications and helpful links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- PACCOF
- NextGenerationEU (Other Grant/Funding Number: European Union)
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
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