Study design and inclusion criteria
From January 2013 to December 2016, a retrospective observational study was performed in a 30-bed surgical ICU in a teaching hospital in Paris. Our department is particularly involved in the management of neurological failure, due to the high level of neurosurgery activity in our hospital, which participates in a regional network of stroke centers.
Since rectal swabs and respiratory samples were part of our daily practice and no intervention was tested, the Ethics Committee of Société Française d’Anesthésie-Réanimation approved the protocol and waived the requirement of written informed consent. Furthermore, a declaration to the Commission Nationale de l’Informatique et des Libertés (CNIL) was done (declaration number: 2214863).
During the study period, all patients with a positive respiratory specimen (endotracheal aspirate, bronchoalveolar lavage, protected distal sampling or sputum) were enrolled. Bacterial documentation, including oropharyngeal flora, was collected and ESBL-E/HLAC-E phenotypes were retrieved (see microbiology section). Respiratory samples were performed in case of pneumonia suspected by the physician in charge, with or without mechanical ventilation. Systemic endotracheal aspirate surveillance culture is not part of our daily practice.
In our institution, screening for ESBL-E intestinal carriage is routinely performed by rectal swabbing within the first 24 h after ICU admission and weekly thereafter. This approach is part of our institutional infection control policy to implement isolation measures in identified carriers.
Respiratory samples with culture results below the diagnostic threshold were excluded (see microbiology section). Redundant respiratory samples, i.e., at least two respiratory samples positive for the same pathogen within 5 days, were excluded. Respiratory specimens without rectal swab cultures within the previous 21 days were excluded. Patients with known intestinal carriage with carbapenemase-producing Enterobacterales were excluded.
Clinical characteristics of selected patients were collected to describe the population: age, gender, simplified acute physiology score II (SAPS II), ICU mortality rate, length of stay in ICU, duration of mechanical ventilation and main admission diagnosis.
Microbiology
Screening for ESBL-E and HLAC-E intestinal carriage
Rectal swabs were performed by nurses using ESwab® (COPAN Diagnostics, Italy). Transport medium was then inoculated using PREVI® Isola standardized inoculation system (BioMérieux, Marcy-L’Etoile, France) on selective chromogenic ChromID ® ESBL agar plates (BioMérieux, Marcy-L’Etoile, France). This medium is not specific of ESBL-E [16] and also detects HLAC-E. Growing colonies were identified after a 24-h aerobic incubation at 37 °C using mass spectrometry with MALDI™ Biotyper system (Bruker Daltonics, Germany). Results were expressed qualitatively, and no quantification or semi-quantification of growing colonies has been performed. Antimicrobial susceptibility was tested by the disk diffusion method with Mueller–Hinton agar plates (MH agar plates, BioMérieux, Marcy-L’Etoile, France) according to the EUCAST (European Committee on Antimicrobial Susceptibility Testing) and CA-SFM (Antibiogram Committee of the French Society of Microbiology) guidelines.
3GCR-E isolates showing a synergy zone between expanded-spectrum cephalosporins (ESC) and clavulanate were categorized as ESBL-E, while those without synergy and less than 5-mm increase in the ESC inhibition diameter on cloxacillin-supplemented Mueller–Hinton agar (250 mg/mL) were categorized as HLAC-E.
The following ESC and monobactams were used in our antimicrobial susceptibility testing: cefotaxime, ceftazidime, cefepime, and aztreonam.
Carbapenem-Producing Enterobacterales (CPE) were identified using the Xpert® Carba-R Assay (Cepheid, Sunnyvale, CA).
HLAC-E results were not transmitted to clinicians, as there is no recommendation to isolate patients carrying such bacteria, but were prospectively collected in our laboratory information system (Glims, version 8.11.14, MIPS, Gent, Belgium).
3GCR-E were defined as Enterobacterales expressing resistance to third-generation cephalosporins, whatever the mechanism (i.e. ESBL-E and/or ESBL).
Respiratory samples
Respiratory samples were sputum samples obtained by expectoration after oral care with the assistance of a physiotherapist when necessary, endotracheal aspirates (Unomedical, ConvaTec, Deeside, United Kingdom), bronchoalveolar lavages (BAL) during bronchoscopy by slowly injecting and retrieving from the lung area of interest 100 mL of isotonic saline, and protected distal sampling (Combicath, Plastimed, Le Plessis Bouchard, France) using a fiberoptic bronchoscope. Samples were isolated on agar plates using routine methods according to the French Society of Microbiology guidelines. Microbiological identification and antimicrobial susceptibility testing (AST) were obtained as described above. Respiratory samples were defined as positive when at least 107 CFU/mL were observed in sputum cultures, 106 CFU/mL in endotracheal aspirates, 104 CFU/mL in BAL, and 103 colony-forming units CFU/mL in protected distal sampling. Culture results with microbiological identification and resistance patterns were reported to the physicians within 2 days after sampling.
The potential impact of screening for ESBL-E and HLAC-E intestinal carriage on empirical antibiotic therapy
The potential impact of screening for ESBL-E and HLAC-E intestinal carriage on EAT was evaluated for episodes of respiratory infections.
Episodes of respiratory infection were defined as a positive respiratory culture associated with at least 5 consecutive days of antimicrobial therapy. Respiratory colonization was defined for patients with incomplete antimicrobial therapy (i.e., less than 5 days), or who did not receive antimicrobial therapy. Episodes of respiratory infection associated with extrapulmonary infections were excluded. Last, episodes of respiratory infection for which antimicrobial therapy was initiated after the AST result were excluded.
EAT was defined as antimicrobial therapy initiated after respiratory sampling and before culture and AST results. The choice of EAT is routinely guided by local protocol during a daily infectious disease consultation, according to the guidelines [4, 22]. EAT is prescribed by the physician in charge of the patient, considering the length of previous hospitalization, intestinal carriage status, presumed infection origin and hemodynamic status. EAT with carbapenem was recommended for patients with ESBL-E intestinal carriage, following international recommendations [23] and the results of our previous works [15].
EAT was compared to the status of intestinal carriage according to the 4 main resistance profiles reported in the intestinal carriage: ESBL-E(-)/HLAC-E(-), ESBL-E(-)/HLAC-E(+), ESBL-E(+)/HLAC-E(-), and ESBL-E(+)/HLAC-E(+). We defined a “Potential Carbapenem overuse” for patients with suspected pneumonia and without ESBL-E intestinal carriage, for which EAT with carbapenem should be carefully justified [15]. “Potential inappropriate EAT” was defined as an EAT which was not effective on the resistance pattern reported in intestinal carriage.
Statistical analyses
Quantitative variables were described using the median (interquartile range) and categorical variables using the number (percentage). Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and likelihood ratios (LR) were determined to assess if ESBL-E and HLAC-E intestinal carriage could predict their presence or absence in respiratory samples. All analyses were performed using R, version 3.5.3.