Clinical trial NCT06651047: PK/PD Analysis of Ceftazidime/Avibactam or Cefiderocol With or Without Fosfomycin for the Treatment of Difficult To-treat Gram-negative Infections
Official title: Pharmacokinetic/Pharmacodynamic Analysis of Ceftazidime/Avibactam or Cefiderocol With or Without Fosfomycin for the Treatment of Difficult To-treat Gram-negative Infections
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Gram Negative Infection
Antimicrobial Resistance (AMR)
Keywords: Gram-negative infection
Ceftazidime/Avibactam
Cefiderocol
Fosfomycin
Pharmacokinetics/Pharmacodynamics targets
Carbapenem-resistant Enterobacterales (CRE)
Lead sponsor: University of Bologna
Sponsor class: OTHER
First posted: 2024-10-21
Enrollment: 120
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
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

Brief 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 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).

Eligibility criteria: 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

Primary outcomes:
measure: PK/PD efficacy targets for study drugs
timeFrame: From enrollment (treatment onset) to the end of treatment (up to 7 days)
Secondary outcomes:
measure: Difference in SOFA score
timeFrame: From day 0 (day of index positive culture) and day 7
measure: Difference in C-Reactive Protein (CRP), Procalcitonin (PCT) and Interleukin-6 (IL-6)
timeFrame: From day 0 (day of index positive culture) and day 7
measure: Identification of new protein-based biomarkers
timeFrame: From enrollment to the end of treatment (up to 7 days)
measure: Microbiological eradication
timeFrame: From day 0 (day of index positive culture) and day 7
measure: Relapse and/or reinfection
timeFrame: From enrollment to the end of the follow-up at three months
measure: All-cause mortality
timeFrame: From enrollment to the end of the follow-up at three months
Other outcomes:
Locations:
city: Bologna
country: Italy
facility: Irccs Aoubo
city: Catania
country: Italy
facility: Azienda Ospedaliera di Rilievo Nazionale e di Alta Specializzazione (ARNAS) Garibaldi
city: Milan
country: Italy
facility: ASST-FBF-Sacco
city: Padova
country: Italy
facility: Azienda Ospedale - Università Padova
city: Palermo
country: Italy
facility: Istituto mediterraneo per i trapianti e terapie ad alta specializzazione (ISMETT)
city: Rome
country: Italy
facility: Policlinico Umberto I
city: Rome
country: Italy
facility: Policlinico Universitario Campus Bio-Medico
city: Rome
country: Italy
facility: Ospedale Pediatrico Bambin Gesù
city: Rome
country: Italy
facility: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
city: Siena
country: Italy
facility: Azienda Ospedaliero Universitaria Senese
city: Turin
country: Italy
facility: Città della salute e della Scienza, Molinette
Study officials:
References: