Assistance Publique-Hôpitaux de Paris, France §The other members of the PneumA Trial Group are listed in the Appendix. Funding: The PNEUMA trial was supported by a research grant from the Délégation à la Recherche Clinique, Assistance Publique−Hopitaux de Paris (PHRC AOM 97147) and the "Diagnostic strategy" trial by grants from the Société de Réanimation de Langue Française and the Délégation à la Recherche Clinique, Assistance Publique−Hopitaux de Paris Running head: Impact of MRSA on VAP

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... me Descriptor: 11. Ventilator-associated pneumonia Text-only word count: 2766 This article has an Online Data Supplement, which is accessible from this issue's table of content online at www.thoracic.org ABSTRACT The impact of methicillin resistance on morbidity and mortality of patients suffering from severe Staphylococcus aureus infections remains highly controversial. We analyzed a retrospective cohort of 97 patients with methicillin-susceptible and 74 patients with methicillinresistant Staphylococcus aureus ventilator-associated pneumonia. Initial empiric antibiotic therapy was appropriate for every patient. Patients with methicillin-resistant Staphylococcus aureus ventilator-associated pneumonia were older, had higher disease-severity scores and had been on mechanical ventilation longer at ventilator-associated pneumonia onset. Factors associated with 28-day death retained by multivariate logistic regression analysis were: age (OR = 1.05, 95% CI, 1.02 1.08, p = 0.001) and day-1 ODIN score (OR = 1.90, 95% CI, 1.31 2.78, p = 0.001), but not methicillin resistance (OR = 1.72, 95% CI, 0.73 4.05, p = 0.22). The percentages of infection relapse or superinfection did not differ significantly between the 2 patient groups. In conclusion, after controlling for clinical and physiologic heterogeneity between groups, methicillin resistance did not significantly affect 28-day mortality of patients with Staphylococcus aureus ventilator-associated pneumonia receiving appropriate antibiotics. Abstract word count: 165 Multivariate Models. Combes et al 2 Methicillin-resistant Staphylococcus aureus (MRSA) was first described in 1961 (1). Since then, it has emerged as a major cause of nosocomial infections worldwide, with more than 50% of Staphylococcus aureus strains isolated in intensive care units being MRSA (2). To date, conflicting data have been published regarding the impact of methicillin resistance on the outcome of Staphylococcus aureus infections (2-15). One of the major confounders in studying MRSA and methicillin-susceptible Staphylococcus aureus (MSSA) pathogenicity might be higher rates of inappropriate empiric antimicrobial treatments prescribed to MRSA-infected patients, as they ranged from 8% to 55% in previous studies (5, 9, 11, 12, 16). Pertinently, inappropriate antimicrobial treatment of infections, including nosocomial pneumonia, was recently recognized as the most important independent determinant of hospital mortality in a large cohort of critically ill patients (17) . Staphylococcus aureus is also one of the most common bacteria isolated from patients with ventilator-associated pneumonia (VAP) (18) and, to date, only a few studies based on limited numbers of patients have evaluated the morbidity and the mortality associated with MRSA VAP (16, 19, 20). Therefore, the objective of this study was to analyze the impact of methicillin resistance on a large series of patients with Staphylococcus aureus VAP, for whom the initial antibiotic therapy was always appropriate. Some of the results of the present study have been previously reported in the form of an abstract (21). METHODS (Methods section word count: 697) Patients The charts of patients who had been hospitalized in our unit or had been included in 2 randomized controlled trials on VAP conducted by our group were retrospectively analyzed (22, 23). Patients meeting the following criteria were selected: mechanical ventilation (MV) duration 48 hours prior to VAP onset; clinical suspicion of VAP (22); Staphylococcus aureus was Combes et al 3 among the bacteria grown at significant concentrations from distal pulmonary samples obtained with a fiberoptic bronchoscope (22); and appropriate antibiotic therapy was instigated within the 24 hours following bronchoscopy (22). Additional details on the population of patients included in this study are provided in an online data supplement. Microbiologic Methods and Antibiotic Therapy Staphylococcus aureus was identified using standard laboratory procedures and methicillin resistance was detected as recommended by the French antibiogram committee (24). A double test was realized: incubation for -lactam (oxacillin) resistance at 30°C for 24 and 48 h and detection of methicillin resistance on saline Mueller Hinton agar at 37°C. All but -lactam antibiotics were incubated at 37°C for 24 h. MRSA infections were treated with vancomycin and 1 2 other antibiotics based on bacterial susceptibility. The recommended trough vancomycin concentration targeted to treat patients with MRSA VAP was 15-20 µg/ml. Antibiotic therapy for VAP lasted 15 days, except for patients randomly assigned to receive the 8-day regimen in the PNEUMA trial (22). Data Collection At ICU admission, the following data were recorded for each patient: age; sex; severity of underlying medical condition, according to the criteria of McCabe and Jackson (25); SAPS II (26); SOFA score (27) ; ODIN score (28); and the primary reason for initiating MV. On the day of bronchoscopy (day 1) were recorded: duration of prior MV; SAPS II, ODIN and SOFA scores; temperature; leukocyte count; PaO 2 /FIO 2 ratio; radiologic score (29); hemoculture positivity; presence of shock or the acute respiratory distress syndrome, defined by the presence for more than 24 hours of 3 criteria: 1) acute decrease in PaO 2 / FIO 2 to 200 mmHg or less whatever the level of PEEP; 2) bilateral pulmonary infiltrates or a chest radiograph consistent Combes et al 4 with edema; 3) pulmonary artery occlusion pressure of less than 18 mmHg or no clinical evidence of left atrial hypertension (30). Outcome Measures Outcome measures included: 28-day mortality; number of MV-free days from day 1 to day 28, and durations of MV and ICU stay after VAP onset. Additionally, the following data were recorded on days 3, 7, 14, 21 and 28 following VAP onset: temperature; leukocyte counts; PaO 2 /FIO 2 ; SOFA, radiologic and ODIN scores. Fiberoptic bronchoscopy was performed as soon VAP recurrence was suspected. Patients were considered to have recurrent pulmonary infection when at least 1 bacterial species grew at a significant concentration from samples collected during a second bronchoscopy. Recurrence was considered a relapse if at least 1 of the initial causative bacterial strains grew at a significant concentration from a second distal sample; otherwise, it was considered a superinfection. Statistical Analyses Continuous variables were compared with Student's t-test or the Mann Whitney U-test, as appropriate. Categorical variables were compared with chi-square tests. To examine the univariate effects of patients' clinical characteristics and initial ICU events on 28-day mortality, a logistic regression model was used to test each characteristic. Thereafter, multiple logistic regression using backward stepwise variable elimination (with variable exit threshold set at p > 0.05) was applied to the outcome of 28-day mortality. Factors with p 0.10 in our univariate analysis were entered into the model and methicillin resistance was forced into the final model as a covariate (31). We also repeated the analysis including in the final multivariate model for 28-day mortality variables that changed the odds ratio (OR) for mortality associated with methicillin resistance by 10% in a bivariate model, even when they were not associated with mortality in the univariate analysis (31). All potential explanatory variables included in the Combes et al 5 multivariate analyses were subjected to a correlation matrix for analysis of collinearity. Variables with association among each other were not included in the multivariate model.