Clinical trial NCT05566665: Nosocomial Infections in ECMO Patients
Official title: Nosocomial Infections in Patients Treated With Extracorporeal Membrane Oxygenation
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Acute Respiratory Distress Syndrome
Nosocomial Infection
Extracorporeal Membrane Oxygenation Complication
Lead sponsor: Policlinico Hospital
Sponsor class: OTHER
Collaborators: name: Pfizer
First posted: 2022-10-04
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: The study population for the Aim 1 study will comprise adult patients admitted to the aforementioned ICUs suffering from ARDS (as defined by the Berlin criteria) and treated with ECMO.

The study population for the Aim 2 study will comprise the subgroup of patients as per Aim 1, whose clinical course is complicated by VAP necessitating antibiotic treatment with ceftazidime/avibactam, meropenem/vaborbactam, ceftolozane/tazobactam, or cefiderocol

Brief summary: Nosocomial Infections (NI) are a common and dreadful complication for patients suffering from Acute Respiratory Distress Syndrome (ARDS) treated with Extracorporeal Membrane Oxygenation (ECMO). Unfortunately, no study has thoroughly evaluated NI in this fragile patient cohort. Newly developed antibiotics may help manage such infections, but their pharmacokinetics (PK) during ECMO has not been evaluated.

Objectives of this prospective observational multicenter pharmacological no-profit study are: 1) describe incidence, microbial etiology, and resistance patterns, and assess risk factors for NIs in a large prospective cohort of ARDS patients undergoing ECMO. 2) provide a PK analysis of ceftazidime/avibactam, meropenem/vaborbactam, ceftolozane/tazobactam, and cefiderocol in adult patients undergoing ECMO Incidence, microbial etiology, and antibiotic resistance patterns of confirmed NIs will be prospectively collected and analyzed. In the subgroup of patients treated with ceftazidime/avibactam, meropenem/vaborbactam, ceftolozane/tazobactam, or cefiderocol as per clinical practice, blood and bronchoalveolar concentration of the antibiotic will be measured, and PK modeling carried out.

Detailed description: The most severe acute respiratory distress syndrome (ARDS) cases require extracorporeal membrane oxygenation (ECMO). ECMO is a life-support technique utilized in patients with reversible refractory respiratory failure. Nosocomial infections (NI) are common complications in ECMO patients due to predisposing factors such as patients' comorbidities, immunocompromise associated with the critical illness, and invasiveness of ECMO and other life support procedures. Few studies have assessed the incidence, risk factors, microbial etiology, and antibiotic resistance of NIs during ECMO. In a monocentric retrospective observational analysis, a high incidence of NI was detected in ECMO patients. The most common NI was ventilation-associated pneumonia (VAP), frequently caused by multidrug-resistant (MDR) bacteria. Patients developing an infection had a longer duration of ECMO and mechanical ventilation and a more prolonged ICU stay. The rate of MDR bacterial isolates was very high, and the first NI episode caused by MDR germs was an independent risk factor for death. To date, no prospective study has studied the epidemiology and clinical significance of NIs during ECMO. Better knowledge of NIs epidemiology during ECMO may allow us to target possibly causative agents using more specific empirical antibiotic therapy, increase accuracy, and optimize the timing of antimicrobial treatment. In turn, this may lead to better treatment of NIs in patients undergoing ECMO, thus reducing the overall burden of infections in such a fragile population and allowing a significant decrease in the costs of treatment.

Several new antimicrobial agents utilized for the treatment of MDR infections (i.e., ceftazidime/avibactam, meropenem/vaborbactam, ceftolozane/tazobactam, cefiderocol) have been granted approval in Europe for the treatment of VAP. Antibiotic efficacy in pneumonia requires sufficient unbound drug concentrations at the pulmonary site of infection, and determination of the bronchopulmonary availability of antibiotics in epithelial lining fluid (ELF) allows penetration into the lung to be characterized. While population pharmacokinetic (PK) models have been carried out in healthy volunteers, no data is available relative to the PK of those antibiotics ECMO patients. In general, ECMO has been shown to impact PK in three primary ways: direct extraction by the circuit increased volume of distribution, and altered clearance5. Thus, knowledge of the PK of these newly introduced antibiotic agents in ECMO patients suffering from VAP due to MDR bacteria may be of great clinical impact.

Based on these premises, in a large cohort of ECMO patients with ARDS, the investigators will carry out a prospective multicenter observational study to describe NIs and their risk factors. Overall, with this study, the investigators will significantly broaden the data as regards to NIs during ECMO.

In addition, in a subgroup of patients treated with ceftazidime/avibactam, meropenem/vaborbactam, ceftolozane/tazobactam, or cefiderocol for VAP during ECMO treatment, the investigators will carry out a pharmacokinetic study.

Eligibility criteria: Inclusion Criteria:

* Age \> 18 years
* Diagnosis of ARDS (i.e., acute onset ( \< 7 days) from the known clinical insult of respiratory failure, with bilateral opacities - not explained by effusions, lung and lobar collapse, or nodules -, not fully explained by cardiac failure/fluid overload; with P/F ratio \<= 300 mmHg and continuous positive airway pressure \>= 5 cmH2O)
* Ongoing ECMO

Adjunctive Inclusion Criterium for the sole Secondary Objective:

- Antibiotic treatment with ceftazidime/avibactam, meropenem/vaborbactam, ceftolozane/tazobactam, or cefiderocol.

Exclusion Criteria:

* Pregnancy
* Expected survival \< 24 hours.

Primary outcomes:
measure: Incidence of NIs in a large prospective cohort of ARDS patients undergoing ECMO.
timeFrame: January 2023-December 2024
measure: Microbial etiology of NIs in a large prospective cohort of ARDS patients undergoing ECMO.
timeFrame: January 2023-December 2024
measure: Resistance patterns of NIs in a large prospective cohort of ARDS patients undergoing ECMO.
timeFrame: January 2023-December 2024
measure: Risk factors of NIs in a large prospective cohort of ARDS patients undergoing ECMO.
timeFrame: January 2023-December 2024
Secondary outcomes:
measure: Plasma concentration of ceftazidime/avibactam, meropenem/vaborbactam, ceftolozane/tazobactam, and cefiderocol in adult patients undergoing ECMO
timeFrame: January 2023-December 2024
measure: Bronchoalveolar lavage concentration of ceftazidime/avibactam, meropenem/vaborbactam, ceftolozane/tazobactam, and cefiderocol in adult patients undergoing ECMO
timeFrame: January 2023-December 2024
Other outcomes:
Locations:
city: Milan
country: Italy
facility: Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico
state: MI
city: Milan
country: Italy
facility: Fondazione IRCCS Ca'Granda - Ospedale Maggiore Policlinico
Study officials:
affiliation: University of Milan
name: Vittorio Scaravilli, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Milan
name: Giacomo Grasselli, MD
role: PRINCIPAL_INVESTIGATOR
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