Nosocomial Infections in ECMO Patients

NCT05566665 | Recruiting DMC

• 1 other identifier: INF-ECMO
• Study Type: observational
• Target: 200
• Locations: 1 country
• Sites: 2

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.

Conditions

Acute Respiratory Distress Syndrome; Nosocomial Infection; Extracorporeal Membrane Oxygenation Complication

Outcome Measures

Primary Outcomes (4)

• Incidence of NIs in a large prospective cohort of ARDS patients undergoing ECMO.

  Only microbiologically-confirmed infections will be considered. Accordingly, the composite outcome (i.e., infected patient) will be composed of the following NIs: ventilator-associated pneumonia (VAP), catheter-associated urinary tract infection (UTI), bloodstream infection (BSI), and catheter-related bloodstream infection (CRBSI). Incidence of pulmonary aspergillosis and clostridium difficile colitis will be collected but not included in the composite outcome (i.e., infected patient). To carry out this aim, a supervisor for each participating center will be in charge of patients' follow-up. For each center, a critical care specialist and an infectious disease specialist will review the available clinical and laboratory data. Incidence will be expressed as: 1) percentage of patients who will develop a NI/total of patients; 2) rate of incidence: number of infection/total time at risk of NIs.

  January 2023-December 2024

• Microbial etiology of NIs in a large prospective cohort of ARDS patients undergoing ECMO.

  Only microbiologically-confirmed infections will be considered. Accordingly, the composite outcome (i.e., infected patient) will be composed of the following NIs: ventilator-associated pneumonia (VAP), catheter-associated urinary tract infection (UTI), bloodstream infection (BSI), and catheter-related bloodstream infection (CRBSI). Incidence of pulmonary aspergillosis and clostridium difficile colitis will be collected but not included in the composite outcome (i.e., infected patient). To carry out this aim, a supervisor for each participating center will be in charge of patients' follow-up. For each center, a critical care specialist and an infectious disease specialist will review the available clinical and laboratory data. Different microbial etiology will be described according to simple descriptive statistics methods.

  January 2023-December 2024

• Resistance patterns of NIs in a large prospective cohort of ARDS patients undergoing ECMO.

  Only microbiologically-confirmed infections will be considered. Accordingly, the composite outcome (i.e., infected patient) will be composed of the following NIs: ventilator-associated pneumonia (VAP), catheter-associated urinary tract infection (UTI), bloodstream infection (BSI), and catheter-related bloodstream infection (CRBSI). Incidence of pulmonary aspergillosis and clostridium difficile colitis will be collected but not included in the composite outcome (i.e., infected patient). To carry out this aim, a supervisor for each participating center will be in charge of patients' follow-up. For each center, a critical care specialist and an infectious disease specialist will review the available clinical and laboratory data. Resistance patterns of NIs' microbes will be described according to simple descriptive statistics methods.

  January 2023-December 2024

• Risk factors of NIs in a large prospective cohort of ARDS patients undergoing ECMO.

  Only microbiologically-confirmed infections will be considered. Accordingly, the composite outcome (i.e., infected patient) will be composed of the following NIs: ventilator-associated pneumonia (VAP), catheter-associated urinary tract infection (UTI), bloodstream infection (BSI), and catheter-related bloodstream infection (CRBSI). Incidence of pulmonary aspergillosis and clostridium difficile colitis will be collected but not included in the composite outcome (i.e., infected patient). To carry out this aim, a supervisor for each participating center will be in charge of patients' follow-up. For each center, a critical care specialist and an infectious disease specialist will review the available clinical and laboratory data. Multivariate analysis will be conducted to evaluate risk factors of NIs. For each risk factor identified Odds Ratio with 95% Confidence Interval will be reported.

  January 2023-December 2024

Secondary Outcomes (2)

• Plasma concentration of ceftazidime/avibactam, meropenem/vaborbactam, ceftolozane/tazobactam, and cefiderocol in adult patients undergoing ECMO

  January 2023-December 2024

• Bronchoalveolar lavage concentration of ceftazidime/avibactam, meropenem/vaborbactam, ceftolozane/tazobactam, and cefiderocol in adult patients undergoing ECMO

  January 2023-December 2024

Study Arms (2)

ECMO requiring ARDS patients

The study population for the Aim 1 study will comprise adult patients admitted to the participating 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.

Antibiotic treated ECMO requiring ARDS patients.

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.

Diagnostic Test: Collection of blood and bronchoalveolar samples to study Pharmacokinetics of ceftazidime/avibactam, meropenem/varbobactam, ceftolozane/tazobactam, or cefiderocol

Interventions

Collection of blood and bronchoalveolar samples to study Pharmacokinetics of ceftazidime/avibactam, meropenem/varbobactam, ceftolozane/tazobactam, or cefiderocol DIAGNOSTIC_TEST

The antibiotic treatment with ceftazidime/avibactam, meropenem/vaborbactam, ceftolozane/tazobactam, or cefiderocol will follow the standard clinical practice. The concentration of ceftazidime/avibactam, meropenem/vaborbactam, ceftolozane/tazobactam, or cefiderocol will be measured at specific timepoints in plasma samples and bronchoalveolar lavage samples, and a PK analysis and modeling will be carried out .

Antibiotic treated ECMO requiring ARDS patients.

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• 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

You may qualify if:

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

You may not qualify if:

• Pregnancy
• Expected survival \< 24 hours.

Sponsors & Collaborators

• Policlinico Hospital: lead
• Pfizer: collaborator

Study Sites (2)

Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico

Milan, MI, 20122, Italy

RECRUITING

Fondazione IRCCS Ca'Granda - Ospedale Maggiore Policlinico

Milan, 20100, Italy

NOT YET RECRUITING

Related Publications (9)

• Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, Gattinoni L, van Haren F, Larsson A, McAuley DF, Ranieri M, Rubenfeld G, Thompson BT, Wrigge H, Slutsky AS, Pesenti A; LUNG SAFE Investigators; ESICM Trials Group. Epidemiology, Patterns of Care, and Mortality for Patients With Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries. JAMA. 2016 Feb 23;315(8):788-800. doi: 10.1001/jama.2016.0291.

  PMID: 26903337 BACKGROUND

• Schmidt M, Hajage D, Lebreton G, Monsel A, Voiriot G, Levy D, Baron E, Beurton A, Chommeloux J, Meng P, Nemlaghi S, Bay P, Leprince P, Demoule A, Guidet B, Constantin JM, Fartoukh M, Dres M, Combes A; Groupe de Recherche Clinique en REanimation et Soins intensifs du Patient en Insuffisance Respiratoire aiguE (GRC-RESPIRE) Sorbonne Universite; Paris-Sorbonne ECMO-COVID investigators. Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome associated with COVID-19: a retrospective cohort study. Lancet Respir Med. 2020 Nov;8(11):1121-1131. doi: 10.1016/S2213-2600(20)30328-3. Epub 2020 Aug 13.

  PMID: 32798468 BACKGROUND

• Grasselli G, Scaravilli V, Di Bella S, Biffi S, Bombino M, Patroniti N, Bisi L, Peri AM, Pesenti A, Gori A, Alagna L. Nosocomial Infections During Extracorporeal Membrane Oxygenation: Incidence, Etiology, and Impact on Patients' Outcome. Crit Care Med. 2017 Oct;45(10):1726-1733. doi: 10.1097/CCM.0000000000002652.

  PMID: 28777198 BACKGROUND

• Yusuf E, Bax HI, Verkaik NJ, van Westreenen M. An Update on Eight "New" Antibiotics against Multidrug-Resistant Gram-Negative Bacteria. J Clin Med. 2021 Mar 4;10(5):1068. doi: 10.3390/jcm10051068.

  PMID: 33806604 BACKGROUND

• Sherwin J, Heath T, Watt K. Pharmacokinetics and Dosing of Anti-infective Drugs in Patients on Extracorporeal Membrane Oxygenation: A Review of the Current Literature. Clin Ther. 2016 Sep;38(9):1976-94. doi: 10.1016/j.clinthera.2016.07.169. Epub 2016 Aug 21.

  PMID: 27553752 BACKGROUND

• ARDS Definition Task Force; Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, Camporota L, Slutsky AS. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012 Jun 20;307(23):2526-33. doi: 10.1001/jama.2012.5669.

  PMID: 22797452 BACKGROUND

• Falcone M, Menichetti F, Cattaneo D, Tiseo G, Baldelli S, Galfo V, Leonildi A, Tagliaferri E, Di Paolo A, Pai MP. Pragmatic options for dose optimization of ceftazidime/avibactam with aztreonam in complex patients. J Antimicrob Chemother. 2021 Mar 12;76(4):1025-1031. doi: 10.1093/jac/dkaa549.

  PMID: 33378458 BACKGROUND

• Castagnola E, Cangemi G, Mesini A, Castellani C, Martelli A, Cattaneo D, Mattioli F. Pharmacokinetics and pharmacodynamics of antibiotics in cystic fibrosis: a narrative review. Int J Antimicrob Agents. 2021 Sep;58(3):106381. doi: 10.1016/j.ijantimicag.2021.106381. Epub 2021 Jun 19.

  PMID: 34157401 BACKGROUND

• Grasselli G, Scaravilli V, Mangioni D, Scudeller L, Alagna L, Bartoletti M, Bellani G, Biagioni E, Bonfanti P, Bottino N, Coloretti I, Cutuli SL, De Pascale G, Ferlicca D, Fior G, Forastieri A, Franzetti M, Greco M, Guzzardella A, Linguadoca S, Meschiari M, Messina A, Monti G, Morelli P, Muscatello A, Redaelli S, Stefanini F, Tonetti T, Antonelli M, Cecconi M, Foti G, Fumagalli R, Girardis M, Ranieri M, Viale P, Raviglione M, Pesenti A, Gori A, Bandera A. Hospital-Acquired Infections in Critically Ill Patients With COVID-19. Chest. 2021 Aug;160(2):454-465. doi: 10.1016/j.chest.2021.04.002. Epub 2021 Apr 20.

  PMID: 33857475 BACKGROUND

Biospecimen

Retention: SAMPLES WITHOUT DNA

Blood and bronchoalveolar lavage (BAL) samples will be collected. Blood samples collection timepoint: just prior to administration of the fifth dose of antibiotic (i.e., after 48 hours of therapy) (t0); at 1 hour after the end of the infusion (t1); 2 hours after the infusion (t2); 4 hours after the infusion (t3). They will be centrifuged, and plasma samples stored at -20°c until analysis. BAL samples will be collected only at t0. BAL will be carried out following standard procedure. The sample will be fresh-frozen and cryopreserved at -80°C. Cryopreserved samples will be shipped to the collaborating center (ASST Fatebenefratelli Sacco, Milan, Italy) at the end of the recruitment period, and thus tests will be performed.

MeSH Terms

Conditions

Respiratory Distress Syndrome; Cross Infection

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Respiration Disorders; Infections; Iatrogenic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Vittorio Scaravilli, MD

  University of Milan

  PRINCIPAL INVESTIGATOR

• Giacomo Grasselli, MD

  University of Milan

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Giacomo Grasselli, MD

CONTACT

+390255033285; giacomo.grasselli@unimi.it

Study Design

• Study Type: observational
• Observational Model: CASE ONLY
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Full Professor of Anesthesiology and Intensive Care Medicine, Director of General Intensive Care Unit, Principal Investigator

Study Record Dates

• First Submitted: September 13, 2022
• First Posted: October 4, 2022
• Study Start: January 1, 2023
• Primary Completion: December 31, 2025
• Study Completion (Estimated): December 31, 2026
• Last Updated: July 10, 2024

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Available online already
• Access Criteria: Open access

Locations

IT (2)