Clinical trial NCT06833593: Antimicrobial Combination Therapy for Treatment of Enterococcus Faecalis Bacteremia
Official title: Efficacy of Optimized Antimicrobial Combination Therapy for Treatment of Enterococcus Faecalis Bacteremia and Identification of Intestinal Microbiota Signature
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Enterococcus Faecalis Infection
Blood Stream Infection
Gut Microbiomes
Keywords: Enterococcus faecalis bloodstream infection
Human tissue analysis in vitro
Gut microbiota analysis
Enterococcus faecalis genomic analysis
Lead sponsor: IRCCS Azienda Ospedaliero-Universitaria di Bologna
Sponsor class: OTHER
First posted: 2025-02-19
Enrollment: 510
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: All adult patients (≥ 18 years) with primary Enterococcus faecalis monomicrobial bloodstream infection

Brief summary: Prospective, multicenter, national, observational pharmacological study on the evaluation of efficacy of appropriate monotherapy vs combination treatment for non-complicated Enterococcus faecalis (EF) bloodstream infection (BSI) and identification of gut microbiota fingerprint of patients with EF-BSI correlated to antimicrobial treatment and clinical outcome

Detailed description: Enterococcus faecalis (EF) is a common commensal of human gastrointestinal tract that can act as opportunistic pathogen causing mild to severe clinical illness. Severe infections due to EF include bacteremia, endocarditis and catheter-related infections. EF is the fourth causative pathogen of bloodstream infection (BSI) in Europe after E. coli, S. aureus and S. pneumoniae. The incidence of infections caused by E. faecalis has increased over the last decades probably as a consequence of the global aging of the population. EF-BSI is associated to a high mortality rate (11-26% of cases).The main factors that may contribute to short-term mortality are the number of comorbidities, the need of admission in intensive care unit and the prompt administration of appropriate antibiotic treatment.

The optimal treatment of EF-BSI uncomplicated with endocarditis is still a matter of debate. Ampicillin is commonly considered the drug of choice, when active in vitro. However, several studies demonstrated the synergistic effect of the combination treatment with an aminoglycosides or ceftriaxone in case of life-threatening infections. To date the efficacy of the combination treatment in patients with EF-BSI was poorly evaluated in clinical studies and most of the data come from very old uncontrolled clinical observations. One strategy for overcoming this uncertainty is to assess the synergistic interaction of different antimicrobial molecules by in vitro tests and to validate in vitro synergisms with clinical studies. Indeed, in vitro evaluation of the drug combination effect has the potentiality for improving treatment by suggesting the possible synergistic or antagonistic interaction of antimicrobial associations. Although, different studies suggested the potential clinical utility of synergy testing, the real prognostic value of these methods is not defined yet. In this context, synergy testing could be used as strategy for improving antibiotic treatment of EF-BSI by suggesting the optimal antimicrobial combination therapy. Ceftaroline and ceftobiprole are two novel cephalosporins, which exhibit intrinsic activity against methicillin-resistant S. aureus. Both drugs seem to show a good level of affinity to penicillin binding protein (PBP) 5, a class B, commonly expressed by Enterococcus spp. The use of these drugs in association with ampicillin or daptomycin seems promising. However, clinical efficacy of these combinations is not well defined yet. Gut microbiota of healthy individual is composed by a consortium of bacteria balanced by symbiotic or antagonistic relationships. Antimicrobial treatments altered this equilibrium conferring competitive advantage for different species, including host pathogens. Disruption of the balance in the gut microbial composition has been associated to different pathological conditions (metabolic disease, type 2 diabetes, colorectal cancer or inflammatory bowel disease). Also, administration of antimicrobials contributes to increase resistome in the intestinal microbiota and diffusion of antimicrobialresistant pathogens through selective pressure. The central objective of this study is to identify the gut microbiota signature associated to different antimicrobial therapy of EF-BSI and to clinically validate novel diagnostic tools for optimizing antimicrobial therapy in critically ill patients.

The primary aim of the study is to compare efficacy of appropriate monotherapy vs combination treatment for EF-BSI and validate clinically the in vitro synergistic/antagonistic interaction of antimicrobial combinations by synergy tests.

Secondary objectives are:

* To define the prognostic and predictive value of EF genotypic and phenotypic traits on the basis of antimicrobial treatment and clinical outcome
* To compare gut microbiota fingerprint of patients with EF-BSI and correlate to antimicrobial treatment and clinical outcome

Eligibility criteria: Inclusion Criteria:

* Adult (≥18 years)
* Monomicrobial EF-BSI
* Receipt of ≥ 5 days of at least one in vitro active drug (ampicillin, amoxicillin/clavulanate, ampicillin/sulbactam, piperacillin, vancomycin, teicoplanin, daptomycin and linezolid) with or without a synergistic drug (ceftriaxone, gentamycin, streptomycin), at common suggested dosages for EF-BSI in empirical or definitive therapy
* Written informed consent

Exclusion Criteria:

* Short term (within 3 days from BSI) mortality
* Other concomitant infection

Primary outcomes:
measure: Evaluation of Clinical Cure and Improvement Rates for EF-BSI
timeFrame: Up to 6 weeks from patient enrollment, with bacterial strains isolated at baseline
measure: Comparison of Clinical Outcomes Between Mono Therapy and Combination Therapy
timeFrame: Up to 6 weeks from patient enrollment, with bacterial strains isolated at baseline
measure: Validation of In Vitro Synergy Tests
timeFrame: Up to 6 weeks from patient enrollment, with bacterial strains isolated at baseline
Secondary outcomes:
measure: Genotypic Analysis of E. faecalis
timeFrame: From enrollment to the end of the follow-up at three months
measure: Phylogenetic Relationship and Clonal Diversity
timeFrame: From enrollment to the end of the follow-up at three months
measure: Correlation Between Genotypic/Phenotypic Traits and Clinical Outcome
timeFrame: From enrollment to the end of the follow-up at three months
measure: Gut Microbiota Fingerprint Analysis in EF-BSI Patients
timeFrame: From enrollment to the end of the follow-up at three months
measure: Intestinal Microbiota Composition and Its Correlation with Treatment Outcomes
timeFrame: From enrollment to the end of the follow-up at three months
Other outcomes:
Locations:
city: Bologna
country: Italy
facility: Ospedale Maggiore "Carlo Alberto Pizzardi" di Bologna
city: Bologna
country: Italy
facility: IRCCS Azienda Ospedaliero-Universitaria di Bologna
city: Catanzaro
country: Italy
facility: Azienda Ospedaliero Universitaria di Catanzaro "Mater Domini"
city: Milano
country: Italy
facility: Humanitas Research Hospital
Study officials:
affiliation: IRCCS Azienda Ospedaliero-Universitaria di Bologna
name: Maddalena Giannella, MD PhD
role: PRINCIPAL_INVESTIGATOR
References: