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Impact of Methicillin Resistance on Outcome of Staphylococcus aureus Ventilator-associated Pneumonia

Service de Réanimation Médicale, Hôpital Pitié-Salpêtrière, Service de Réanimation Médicale, Hôpital Européen Georges-Pompidou, and Service de Réanimation Médicale, Hôpital Bichat-Claude-Bernard, Assistance Publique–Hôpitaux de Paris, Paris, France

Correspondence and requests for reprints should be addressed to Alain Combes, M.D., Ph.D., Service de Réanimation Médicale, Pr Gibert, Institut de Cardiologie, Groupe Hospitalier Pitié-Salpêtrière, 47, boulevard de l'Hôpital, 75651 Paris Cedex 13, France. E-mail: alain.combes{at}psl.ap-hop-paris.fr

	ABSTRACT

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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 methicillin-resistant Staphylococcus aureus ventilator-associated pneumonia (VAP). Initial empiric antibiotic therapy was appropriate for every patient. Patients with methicillin-resistant Staphylococcus aureus VAP were older, had higher disease-severity scores, and had been on mechanical ventilation longer at onset of VAP. Factors associated with 28-day mortality retained by multivariate logistic regression analysis were: age (odds ratio [OR] = 1.05, 95% confidence interval [CI], 1.02–1.08, p = 0.001) and Day 1 organ dysfunctions or infection (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 two 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 VAP receiving appropriate antibiotics.

Key Words: antibiotic-resistant bacteria • multivariate models • outcome assessment • respiration, artificial

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 S. 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 S. aureus infections (2–15). One of the major confounders in studying MRSA and methicillin-susceptible S. 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).

S. 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 S. 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

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Patients
The charts of patients who had been hospitalized in our unit or had been included in two 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 before VAP onset; clinical suspicion of VAP (22); S. aureus was among the bacteria grown at significant concentrations from distal pulmonary samples obtained with a fiberoptic bronchoscope (22); and appropriate antibiotic therapy was instigated within 24 hours after bronchoscopy (22). Additional details on the population of patients included in this study are provided in an online supplement.

Microbiologic Methods and Antibiotic Therapy
S. 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 ß-lactam (oxacillin) resistance at 30°C for 24 and 48 hours and detection of methicillin resistance on saline Mueller–Hinton agar at 37°C. All but ß-lactam antibiotics were incubated at 37°C for 24 hours. MRSA infections were treated with vancomycin and one to two other antibiotics based on bacterial susceptibility. The recommended trough vancomycin concentration targeted to treat patients with MRSA VAP was 15 to 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); Simplified Acute Physiology Score II (SAPS II) (26); Sepsis-related Organ Failure Assessment (SOFA) score (27); organ dysfunctions or infection (ODIN) score (28); and the primary reason for initiating MV.

On the day of bronchoscopy (Day 1) the following were recorded: duration of prior MV; SAPS II, ODIN, and SOFA scores; temperature; leukocyte count; Pa_O2/FI_O2 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 three criteria: (1) acute decrease in Pa_O2/FI_O2 to 200 mm Hg or less whatever the level of positive end-expiratory pressure (PEEP); (2) bilateral pulmonary infiltrates or a chest radiograph consistent with edema; (3) pulmonary artery occlusion pressure of less than 18 mm Hg or no clinical evidence of left atrial hypertension (30).

Outcome Measures
Outcome measures included: 28-day mortality; number of MV-free days from Days 1 to 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 after VAP onset: temperature; leukocyte counts; Pa_O2/FI_O2; and 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 one bacterial species grew at a significant concentration from samples collected during a second bronchoscopy. Recurrence was considered a relapse if at least one 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 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. Interactions were explored between the substantive variables that remained in multivariate analyses. Statistical significance was defined as p < 0.05. Analyses were performed using StatView 5.0 (SAS Institute Inc., Cary, NC) and SPSS 11.5 (SPSS Inc., Chicago, IL).

	RESULTS

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Study Population
We identified 171 patients with S. aureus VAP, MRSA being involved in 74 (43%) episodes. ICU admission and Day 1 clinical characteristics of patients with MRSA or MSSA infection are reported in Tables 1 and 2, respectively. Compared with patients with MSSA VAP, those with MRSA VAP were older, had longer MV duration before VAP onset, had higher ODIN scores at ICU admission and at VAP onset, and had signs of more severe pulmonary lesions as indicated by a higher percentage of patients with acute respiratory distress syndrome and higher radiologic scores. Polymicrobial infection (involving or not nonfermenting Gram-negative bacilli) rates did not differ statistically between the two groups. Empiric antibiotic therapy for MSSA VAP included an antistaphyloccocal ß-lactam agent for every patient—alone (54%) or in combination with vancomycin (43%)—except for three patients who received only vancomycin. Every patient in the MRSA group were initially treated with vancomycin, alone (22%) or in combination with an antistaphyloccocal ß-lactam agent (78%). Adapted antibiotics prescribed to MSSA and MRSA VAP are detailed in an online supplement (Table E1).

Finally, we evaluated risk factors for in-hospital mortality. As for 28-day mortality, methicillin resistance was not associated with hospital mortality, for the entire cohort of patients or when it was restricted to the patients selected from the PNEUMA cohort (see the online supplement, Tables E7 and E8).

Other Clinical Outcomes
As indicated in Table 3, patients with MSSA VAP had more MV-free days from Days 1 to 28. All the other outcomes evaluated—percentages of patients developing VAP recurrence, either a relapse (due to S. aureus or to another bacteria involved in the first episode) or a superinfection, or durations of ICU stay after VAP onset—did not differ significantly between groups.

Figure 1 shows the evolution of physiologic and functional scores from Days 1 to 28. Notably, clinical, biologic, and radiologic status improved in parallel, with the significant early MRSA-MSSA differences for ODIN, SOFA, and radiologic scores fading at later time points.

View larger version (28K): [in this window] [in a new window]   Figure 1. Physiologic and functional score changes from Day 1 (day of bronchoscopy) to Day 28. Data are expressed as means (90% confidence intervals). Open circles = methicillin-resistant Staphylococcus aureus (MRSA); filled circles = methicillin-susceptible Staphylococcus aureus (MSSA). SOFA = sepsis-related organ failure assessment; ODIN = organ dysfunctions and/or infection. * p < 0.05.

	DISCUSSION

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The impact of methillicin resistance on the outcomes of severe S. aureus infections has been the subject of highly controversial debates over the past decade. Most studies published to date have focused on the outcomes of S. aureus bacteremia and surgical site infections. Although some authors (3–7, 19, 32), including those of a recent meta-analysis of S. aureus bacteremia (8), found higher mortality rates for MRSA than MSSA infections, many analyses failed to identify a relationship between methicillin resistance and mortality (9–13, 15, 33). These results may reflect the endpoints chosen (crude versus infection-related mortality), major differences in patient populations, preexisting comorbidities, severity of S. aureus infection at the time of its diagnosis, sites of these infections and, above all, high rates of inappropriate empiric antibiotic regimens prescribed for MRSA infections. The outcomes of nosocomial S. aureus pneumonia were addressed much less often. According to an investigation of an outbreak of nosocomial pneumonia due to gentamicin–methicillin-resistant S. aureus, survival rates were comparable for the 17 patients with MRSA infection and the 12 patients with MSSA infection (20). In contrast, Rello and coworkers (19) compared 38 MSSA- and 11 MRSA-VAP episodes and demonstrated that unadjusted mortality attributed to pneumonia was 20 times higher for patients with MRSA. More recently, Gonzalez and colleagues (16) studied 32 cases of MRSA and 54 cases of MSSA bacteremic VAP; again mortality did not differ significantly between groups. Notably, more than 25% of the patients in that study did not receive appropriate antibiotic treatment (16); unfortunately, this information was not provided in the two other papers (19, 20). Indeed, the appropriateness of antibiotic therapy has recently been recognized as an independent and critical determinant of mortality of patients in the ICU. Based on their multivariate regression analysis, Kollef and coworkers (17) found that inappropriate antimicrobial treatment was the most important independent factor of hospital mortality among critically ill infected patients. In their cohort, inappropriate antibiotics had initially been administered to 60% of the patients in the MRSA group versus 9% of those in the MSSA group (62% of the infections studied were pneumonia). Similarly, inappropriate antimicrobial treatment was independently associated with hospital mortality in the largest investigation of S. aureus bacteremia yet published (11).

Our results are strengthened by several lines of evidence. First, our study is by far the largest to date to evaluate the impact of methicillin resistance in S. aureus VAP. Second, because of the major effect of inappropriate initial antibiotics on the mortality associated with ICU infections and to better estimate the true impact of methicillin resistance on VAP mortality, we selected only those patients for whom initial antibiotic therapy was appropriate (this element was among the inclusion criteria for patients evaluated in the PNEUMA trial [22]). Third, to control for the inherent biases due to patients' clinical and physiologic heterogeneity between MSSA and MRSA groups, we used multivariate logistic regression analysis to determine the factors associated with 28-day mortality. In agreement with one of the largest epidemiologic studies published (34), we found significant differences between patients with MRSA and MSSA infections that should be taken into account when the two populations are compared: older age and prolonged hospital stay have been associated with MRSA carriage. Patients with MRSA infection also tended to present signs of more severe disease at the infection's onset in two studies of S. aureus bacteremia (4, 11) and our data confirmed those observations. Specifically, ODIN scores and the severity of pulmonary damage (as expressed by radiologic score and the percentage of patients with acute respiratory distress syndrome) were significantly higher for patients with MRSA infection. Whether the increased severity associated with MRSA infection is related to host factors (altered immune response to S. aureus due to advanced age or debilitated premorbid condition) or to a putative increased virulence of MRSA strains remains unsettled. However, in vitro and in vivo experimental results do not support the latter hypothesis (14, 35–39).

One possible explanation for the higher morbidity and mortality associated with MRSA infections advanced in some studies could be the suboptimal antimicrobial action of vancomycin. It has been suggested that vancomycin may be less rapidly bactericidal than semisynthetic penicillin for the treatment of severe S. aureus infections, such as endocarditis (40, 41). Moreover, the penetration of vancomycin into lung tissue (42) and pulmonary lining fluid (43) has been reported to be relatively low (blood-to-tissue ratio: 3:1–6:1) and linearly correlated to the plasma concentration. In a previous study by our group, only trough plasma vancomycin levels of 15 to 20 µg/ml were associated with pulmonary lining fluid concentration exceeding the drug's minimal inhibitory concentrations for most Gram-positive cocci (43). It should be noted that this trough vancomycin concentration was targeted to treat patients with MRSA VAP in this study. New antibiotic classes broadly active against Gram-positive bacteria, such as linezolid, may offer attractive alternative options for treating MRSA VAP. Linezolid, the first commercially available member of the oxazolidinone class, showed excellent lung penetration, with the epithelial lining fluid concentration exceeding that of blood (44). Indeed, in their recent retrospective analysis of two double-blind studies of patients with MRSA pneumonia, Wunderink and colleagues (45) demonstrated that linezolid was associated with significantly better survival and clinical cure rate than vancomycin. However, linezolid and vancomycin showed similar cure rates in a randomized open-label trial of MRSA infections, 25% of which were pneumonia (46). Therefore, additional trials are warranted before linezolid becomes the standard treatment for MRSA VAP.

We recognize several limitations to the present study. First, it was a retrospective subgroup analysis combining data from three different cohorts. However, all the data had been collected prospectively, the diagnosis of S. aureus VAP was always ascertained using results of quantitative cultures of distal pulmonary secretion samples obtained during fiberoptic bronchoscopy and the patients were carefully followed until Day 28 (physiologic and functional scores were collected frequently and extreme vigilance for VAP recurrence was maintained throughout the study periods). Second, antibiotic treatment duration was not the same for all the patients (some patients were treated for 8 or 15 days in the PNEUMA trial). However, pertinently, treatment duration for S. aureus VAP was not associated with 28-day mortality or VAP recurrence in the present study, neither for the entire cohort of patients nor when it was restricted to patients with MRSA VAP or to PNEUMA trial participants (22). Third, we did not collect in our databases the exact time from bronchoscopy to prescription of appropriate antibiotics and trough vancomycin concentrations. Both factors might be associated with VAP outcome. Finally, we cannot exclude that increasing the power of the study by including more patients might have yielded different conclusions, even though our study is by far the largest to date to evaluate the impact of methicillin resistance on S. aureus VAP.

In summary, we conclude that after controlling for clinical and physiologic heterogeneity between groups, methicillin resistance is not significantly associated with either infection recurrence or 28-day mortality for patients with S. aureus VAP receiving appropriate initial empiric antibiotic therapy. Identification of patients with risk factors favoring MRSA infection, such as a history of multiple hospitalizations, prolonged duration of MV prior to VAP onset, or prior antibiotic use (47), should prompt the initiation of an empiric antibiotic regimen including vancomycin or linezolid, which can usually be deescalated 48 to 72 hours later when the results of distal pulmonary secretion cultures become available.

	FOOTNOTES

 
The PNEUMA trial was supported by a research grant from the Délégation à la Recherche Clinique, Assistance Publique–Hopitaux de Paris (PHRC AOM 97,147) 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

This article has an online supplement, which is accessible from this issue's table of contents online at www.thoracic.org

Conflict of Interest Statement: A.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; C-E.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; J-Y.F. received &euro;1,000 in 2003 for serving on an advisory board for Pfizer; M.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; J-L.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; C.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; J.C. received &euro;1,000 in 2003–2004 for serving on an advisory board for Intrabiotics and received &euro;460 in 2003 for speaking at conferences sponsored by Pfizer.

The PNEUMA Trial Group included the following investigators (French centers): A. Alvarez, C. Brun-Buisson, F. Stéphan (Hôpital Henri-Mondor, AP–HP), P. Alquier, P. Asfar (CHRU Angers), F. D'Athis (Hôpital Lapeyronnie, Montpellier), P. F. Perrigault, P. Colson, S. Aubas (Hôpital A.-de-Villeune, Montpellier), P. Corne, O. Jonquet (Hôpital Gui-de-Chauliac, Montpellier), J. P. Bedos (CHG de Versailles, Le Chesnay), F. Blot, G. Nitenberg (Institut Gustave-Roussy, Villejuif), J. Bocquet, P. E. Bollaert (Hôpital Général Nancy), F. Brivet, C. Legall, G. Simonneau (Hôpital de Clamart, AP–HP), R. Bronchard, J. Marty, H. Mal, M. Fournier (Hôpital Beaujon, AP–HP), M. Canonne (Hôpital Les Feugrais, Elbeuf), Y. Castaing (Hôpital Pellegrin Tripode, Bordeaux), J. Régnier, E. Clementi (Hôpital les Audaries, La-Roche-sur-Yon), J. M. Coulaud (CHI Montfermeil), Y. Domart (Centre Hospitalier, Compiègne), P. Gajdos, J Gonzalez (Hôpital R. Poincaré, AP–HP), B. Garo, J. M. Boles (Hôpital de la Cavale Blanche, Brest), R. Gauzit (Hôpital Jean-Verdier, AP–HP), C. Gervais, E. de la Coussaye (Hôpital Georges-Doumergue, Nîmes), S. Guyomarch, F. Zéni, (Hôpital Bellevue, Saint-Etienne), A. Jaeger (Hôpital Hautepierre, Strasbourg), P. Kalfon, F. Thomas (Hôpital des Diaconesses, Paris), J. Hayon, J. L. Ricome (CHG, St-Germain-en-Laye), G. Girault, G. Bonmarchand, D. Huchon, B. Veber, D Jusserand (Hôpital Charles-Nicolle, Rouen), J. C. Lacherade, H. Outin (CHI, Poissy), C. Lamer (Institut Montsouris, Paris), M. J. Laisné (Hôpital Lariboisière, AP–HP), A. Rabbat (Hôpital Hotel-Dieu, AP–HP), B. Schlemmer (Saint-Louis, AP–HP), E. Maury, G. Offenstadt (Hôpital Saint-Antoine, AP–HP), K. Nourdine, J. C. Ducreux (CHG, Roanne), J. L. Pallot (CHI, Montreuil), A. Tenaillon, D. Perrin (Hôpital Louise-Michel, Évry), E. Pigné, D. Dreyfuss (Hôpital Louis-Mourier, AP–HP), M. Pinsart (CH, Dieppe), C. Richard, D. Wermert (Hôpital du Kremlin–Bicêtre, AP–HP), A. Roch, J.P. Auffray (Hôpital Sainte-Marguerite, Marseille), M. Slama (Centre Hospitalier Sud, Amiens), J. P. Sollet, G. Bleichner (Hôpital V.-Dupouy, Argenteuil), F. Thaler, P. Loirat (Hôpital Foch, Suresnes), G. Trouillet (Centre Hospitalier, Pontoise), D. Villers (Hôtel-Dieu, Nantes), M. Wolff, B. Régnier, C. Paugam, J. M. Desmonts (Hôpital Bichat–Claude-Bernard, AP–HP), J. L. Diehl, A. Novara, J. Y. Fagon (HEGP, AP–HP), J. L. Trouillet, C. Gibert, J. Chastre (Hôpital de la Pitié–Salpêtrière, AP–HP).

^* The other members of the PNEUMA Trial Group are listed in the Appendix.

Received in original form March 16, 2004; accepted in final form July 7, 2004

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