Setting and patients
We performed a retrospective analysis mostly using the COCOREVAP cohort patients and some more patients of the Vannes and Saint–Brieuc centers. The COCOREVAP cohort is a multicenter retrospective observational study in 15 ICUs from 11 centers in western France. All adults admitted with COVID-19 from February 1st 2020 until December 31th 2021 who required mechanical ventilation were eligible. Additional patients in the Vannes and Saint–Brieuc centers were included between June the 1st and December 31th 2021. Patients under liberty deprivation (i.e., are under individual protection measure, such as tutorship and curatorship), pregnant women and patients younger than 18 years were excluded from the study. In addition to standard care (SC), three ICUs used a multiple-site decontamination regimen (MSD) for the prevention of acquired infections in intubated patients. MSD was used in all patients in one center (Rennes) and since May 5, 2021 in the two others (Saint–Brieuc and Vannes). Multiple-site decontamination is a variant of selective digestive decontamination, which consists of the administration of topical antibiotics including an aminoglycoside (tobramycin, 300 mg per day, in Rennes or gentamicin, 543 mg per day, in the two others centers), colistin sulfate (400 mg per day) and amphotericin B (2 g per day), four times daily in the oropharynx and the gastric tube, chlorhexidine body washing once daily and a 5-day nasal mupirocin course in patients who had an expected intubation duration of 24 h or more throughout the duration of intubation. Full details about the MSD regimen have been reported elsewhere [12]. Patients in the others ICUs received standard care alone. Patients who required intubation for an expected duration greater than 2 days were eligible for study and divided into two groups: MSD group and SC group.
Each center had a nosocomial infection committee for the prevention and prospective census of acquired infections and applied the recommendations of the French Society for Hospital Hygiene for the prevention and treatment of infection (available at https://sf2h.net/publications/actualisation-precautions-standard-2017).
The study protocol received approval from the ethical committee of the French Intensive Care Society (CE 21–56). Patients or closest relative were informed of the anonymous prospective collection of the data and had the possibility not to participate in the study. In case of refusal, the data were not collected accordingly. This manuscript follows the STROBE statement for reporting cohort studies.
Definition
Infection was considered acquired in the ICU when it was diagnosed 48 h after admission and was not incubating on admission. BSI was defined as a positive blood culture occurring 48 h or more after admission. Regarding common skin contaminants, 2 positives blood cultures drawn on separate occasions were required [4]. The diagnosis of VAP was considered in patients ventilated for 48 h or more and was based on clinical signs (fever, purulent sputum, hypoxia), radiological findings (new infiltrate on chest-X-ray or CT scan), and leukocytosis [13]. Microorganisms responsible for infection were considered as multi-drug resistant (MDR) according to the European Society of Clinical Microbiology and Infectious Disease definition [14]. Respiratory samples used for VAP diagnosis were performed either with broncho-alveolar lavage, endotracheal aspiration or distally protected samples according with local protocols. To take into account the diagnosis heterogeneity of VAP among centers, the variable “Strategy for VAP diagnoses in center of admission” was created. It corresponds to the more frequently used pulmonary sample for VAP diagnosis in the center in which the patients was admitted. Of note, 7 centers mainly used endotracheal aspiration, 4 performed a majority of distally protected samples and the others performed broncho-alveolar lavage.
Primary and secondary endpoints
The primary endpoint was the incidence of ICU-acquired infections, and secondary endpoints were specific VAP and BSI incidences as well as in hospital mortality.
Statistical analysis
Statistical analysis was performed with the statistical software R 4.1.1. Categorical variables were expressed as percentages and continuous variables as median and interquartile range (IQR). The chi-square test and Fisher exact test were used to compare categorical variables and the Mann–Whitney U test or the Wilcoxon for continuous variables. Overall, 6.1% of the data were missing (192 patients had at least one missing data). For the purpose of the multivariable analysis, missing data were considered as missing at random and were handled using chained equation, using “MICE” R package to create an imputed data set.
Incidence rate and risk factors for acquired infections were analyzed using a univariate and multivariable Poisson regression model. Survival analysis were conducted with Kaplan–Meier survival curves with log-rank test and logistic regression with a stepwise backward regression using Akaike criteria as a stopping rule. Non-redundant variables associated with event (acquired infection or death) with a p value < 0.2 in the univariate analysis were included in the multivariable analysis.
To draw unbiased marginal estimates of exposure effect, a propensity-score matched analysis was performed. Propensity score was calculated using a non-parsimonious model (including all available baseline characteristics: age, male sex, body mass index, comorbidities, period of admission, inter-hospital transport, localization before admission, simplified acute physiology score II, bacterial co-infection at admission, biological parameters at admission, strategy for VAP diagnoses in center of admission and early management) and correspond for each patient to his probability to be admitted in an ICU, where MSD is implemented. Because of the non-parsimonious design, interaction effects between variables were not taken into account (e.g., between age and SAPS II scores). Using the “MatchIt” package, a k-nearest neighbor algorithm was used for propensity-score matching with a 1:1 ratio. The balance between matched groups was evaluated by the analysis of the standardized mean differences after weighting.
All tests were two-sided, and p < 0.05 was considered statistically significant.