Pseudomonas aeruginosa Ventilator-Associated Pneumonia: Comparison of Episodes Due to Piperacillin-Resistant versus Piperacillin-Susceptible Organisms

Clinical Infectious Diseases, Apr 2002

We sought to determine the epidemiological characteristics of patients in an intensive care unit (ICU) who developed ventilator-associated pneumonia (VAP) caused by piperacillin-resistant Pseudomonas aeruginosa (PRPA; n = 34) or piperacillin-susceptible P. aeruginosa (PSPA; n = 101). According to univariate analysis, the factors associated with the development of PRPA VAP were presence of an underlying fatal medical condition, immunocompromised status, longer previous hospital stay, less-severe illness at the time of ICU admission, duration of mechanical ventilation before onset of VAP, number of classes of antibiotic received, and previous exposure to imipenem or fluoroquinolone. Multivariate logistic regression analysis identified the following significant independent factors: presence of an underlying fatal medical condition (odds ratio [OR], 5.6), previous fluoroquinolone use (OR, 4.6), and initial disease severity (OR, 0.8). We concluded that the clinical characteristics of patients who develop PRPA VAP differ from those of patients who develop PSPA VAP. Restricted fluoroquinolone use is the sole independent risk factor for PRPA VAP that is open to medical intervention.

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Pseudomonas aeruginosa Ventilator-Associated Pneumonia: Comparison of Episodes Due to Piperacillin-Resistant versus Piperacillin-Susceptible Organisms

J. L. Trouillet 0 A. Vuagnat 0 A. Combes 0 N. Kassis 0 J. Chastre 0 C. Gibert 0 Service de Reanimation Medicale 0 Laboratoire de Bacteriologie 0 Hopital Bichat Assitance Publique-Hopitaux de Paris 0 Paris 0 France 0 0 Received 19 July 2001; revised 26 November 2001; electronically published 15 March 2002. 47-83 Boulevard de l'Hopital, 75651 Paris Cedex 13, France (jean-louis We sought to determine the epidemiological characteristics of patients in an intensive care unit (ICU) who developed ventilator-associated pneumonia (VAP) caused by piperacillin-resistant Pseudomonas aeruginosa (PRPA; n p 34) or piperacillin-susceptible P. aeruginosa (PSPA; n p 101). According to univariate analysis, the factors associated with the development of PRPA VAP were presence of an underlying fatal medical condition, immunocompromised status, longer previous hospital stay, less-severe illness at the time of ICU admission, duration of mechanical ventilation before onset of VAP, number of classes of antibiotic received, and previous exposure to imipenem or fluoroquinolone. Multivariate logistic regression analysis identified the following significant independent factors: presence of an underlying fatal medical condition (odds ratio [OR], 5.6), previous fluoroquinolone use (OR, 4.6), and initial disease severity (OR, 0.8). We concluded that the clinical characteristics of patients who develop PRPA VAP differ from those of patients who develop PSPA VAP. Restricted fluoroquinolone use is the sole independent risk factor for PRPA VAP that is open to medical intervention. - Pseudomonas aeruginosa, one of the main pathogenic agents responsible for nosocomial pneumonia (especially among patients who have undergone intubation and have been hospitalized in intensive care units [ICUs]), ranks second among all pathogens reported to the National Nosocomial Infection Surveillance System or evidenced in the European Prevalence of Infections in Intensive Care Study [1, 2]. Ventilatorassociated pneumonia (VAP) caused by this microorganism remains a severe and dreaded complication [37]. Compared with community-acquired strains, nosocomially acquired P. aeruginosa isolates tend to be more resistant (often, to multiple classes of antibiotics). Thus, infection with multidrug-resistant P. aeruginosa has been a growing problem in medical facilities, and the occurrence of infections due to strains that are resistant to almost all commercially available antibacterial drugs has become a not-uncommon event [8]. Although a substantial proportion of cases of nosocomial infection are caused by multidrug-resistant P. aeruginosa, there have been few published studies of this topic, with the exception of studies of patients with cystic fibrosis. The few published investigations usually have involved small numbers of patients with mostly extrapulmonary infections, have lacked adequate control subjects, or both [8, 9]. The aim of the present study was to compare the epidemiological characteristics, risk factors, and outcomes of patients who received mechanical ventilation (MV) and developed antipseudomonal penicillinresistant P. aeruginosa (PRPA) VAP with those who developed penicillin-susceptible P. aeruginosa (PSPA) VAP. Historically, carbenicillin was the first penicillin found to be active against P. aeruginosa, but, because piperacillin has become the reference drug, the piperacillin susceptibility of the P. aeruginosa strain is used as a marker of multidrug resistance. PATIENTS, MATERIALS, AND METHODS Study population. The study was conducted from January 1994 through August 1999 in one ICU in a 1200-bed Parisian university hospital (Ho pital Bichat) that serves as both a referral center and a first-line treatment facility. The only remarkable characteristic of this 17-bed ICU is its recruitment of a large number of patients who experience multiple-organ failure following cardiac surgery (20% of all patients admitted to the ICU). All hospitalized patients who received mechanical ventilation (MV) for 148 h were eligible for the study, if pneumonia was suggested on the basis of clinical criteria. All the data were prospectively collected and stored in a specially designed database. It should be noted that, during the study period, no systemic antibiotic regimen was prescribed for nosocomial pneumonia prophylaxis or selective decontamination of the digestive tract. The antimicrobial prescription policy, which was systematically applied by medical staff, was to prescribe the narrowest-spectrum antibiotic as soon as the susceptibility of the causative bacteria became known. For all patients, a heat-moisture exchanger was positioned between the Y-piece and the patient and was changed every 48 h [10]. The oropharyngeal cavity was carefully cleaned with antiseptic solution (hexamedine) 4 times daily. To prevent nosocomial infection, other measures were also applied systematically, including effective surveillance, staff education, identification of high-risk patients, proper isolation techniques, and such practices as handwashing and wearing gloves for each patient contact. Diagnosis of VAP. VAP was defined as any lower respiratory tract infection that developed after a patient received MV for 2 days. The criteria for clinical suspicion of pneumonia were presence of a new or persistent lung opacity on chest radiographs plus 2 of the following findings: presence of either fever (temperature, 38.3 C) or hypothermia (temperature, !36 C), a WBC count of 110,000 cells/mm3 or !5000 cells/mm3, and purulent endotracheal aspirate. Every patient suspected of having pneumonia underwent fiberoptic bronchoscopy so that protected specimen brush (PSB) and bronchoalveolar lavage (BAL) fluid samples could be obtained. Specimens were collected and processed according to procedures extensively described elsewhere [11, 12]. Nonbronchoscopic BAL was performed only in rare cases, and its results were taken into account to confirm VAP [13]. Thus, VAP was diagnosed on the basis of microbiological findings from analysis of PSB and BAL samples, according to the following thresholds for significance (i.e., significant thresholds): PSB culture yielding 103 cfu/mL, 2% of recovered cells containing intracellular bacteria on direct examination of BAL fluid samples, and/or BAL culture yielding 104 cfu/mL. For nonbronchoscopic BAL, only the last 2 criteria were taken into account. The presence of 2 of the aforementioned criteria was always required for the diagnosis of VAP. VAP was considered to be caused by P. aeruginosa when PSB and/or BAL specimens yielded significant concentrations of this pathogen. If microorganisms other than P. aeruginosa grew at rates above the significant threshold, or if 2 different strains of P. aeruginosa grew to concentrations greater than the significant thresholds, then the episode was categorized as a polymicrobial VAP episode. Microbiologic methods. P. aeruginosa was identified by standard microbiological methods. Piperacillin susceptibility was determined by the disk-diffusion test. According to the criteria of the Antibiogram Committee of the French Society for Microbiology, the organism was considered susceptible when the inhibition diameter was 18 mm, intermediate (denoting intermediately susceptible) when the diameter was 1217 mm, and resistant when the diameter was !12 mm, all for a disk content of 75 mg of antimicrobial agent [14]. Intermediate susceptibility to piperacillin was considered to be resistance, because piperacillin was never prescribed for intermediate strains in such cases. Susceptibilities to ticarcillin, ticarcillin-clavulanic acid, piperacillin-tazobactam, ceftazidime, imipenem, amikacin, or ciprofloxacin were systematically evaluated by use of the disk-diffusion test [14]. For polymicrobial VAP episodes, bacterial identification and susceptibility tests were systematically performed, and their results were taken into account in the choice of antimicrobial therapy. Risk factors associated with PRPA VAP. Patients with PRPA VAP were compared with patients with PSPA VAP to determine the risk factors for developing PRPA VAP. For the purpose of the study, only the first episode of P. aeruginosa VAP was taken into account. If 2 different P. aeruginosa strains (1 piperacillin-susceptible strain and 1 piperacillin-resistant strain) were isolated during the same episode, and if they grew to concentrations greater than the previously defined significant thresholds, the episode was classified as having been caused by the piperacillin-resistant strain. For purposes of comparison, the following information on each patient was collected within the first 24 h after admission to the ICU: age; sex; severity of the underlying medical condition (stratified, according to the criteria of McCabe and Jackson, as rapidly fatal, ultimately fatal, or not fatal [15]); immunocompromised status (defined according to criteria used in the determination of the Acute Physiology and Chronic Health Evaluation [APACHE] II score [16]). For HIV-positive Characteristic or finding At the time of ICU admission Age, mean years SD Male sex Underlying medical condition (ultimately or rapidly fatal) Chronic obstructive pulmonary disease Immunocompromised status Direct admission to the ICU Duration of hospitalization before ICU admission, mean days APACHE II score, mean SD Reason for MV Postoperative respiratory failure Other ARDS at admission ODIN score, mean SD At the time of diagnosis of VAP Duration of MV before onset of VAP, mean days SD Temperature, mean C SD WBCs 103/mL, mean no. SD Pao2/Fio2, mean mm Hg SD Radiological score, mean SD No. (%) of polymicrobial VAP episodes Associated with multidrug-resistant microorganismsa No (%) associated with bacteremia Received previous antibiotic therapy No. of antibiotic classes received,b mean no. SD Patients with PSPA VAP (n p 101) NOTE. Data are no. (%) of patients, unless indicated otherwise. APACHE, Acute Physiology and Chronic Health Evaluation; ARDS, acute respiratory distress syndrome; MV, mechanical ventilation; ODIN, organ dysfunction and/ or infection; Pao2/Fio2, partial pressure of oxygen in the alveoli/fraction of inspiried oxygen; PRPA, piperacillin-resistant P. aeruginosa; PSPA, piperacillin-susceptible P. aeruginosa. a Methicillin-resistant Staphylococcus aureus, Acinetobacter baumannii, and Stenotrophomonas maltophilia. b See table 2 for details. patients, AIDS was defined according to criteria used in the Simplified Acute Physiology Score (SAPS) II [17]. Corticosteroid treatment was considered long term if it was 11 month in duration, and it was considered high-dose treatment if the dosage was 1 bolus of 5 mg/kg given daily. Also collected was information on referral from another hospital or direct admission from our emergency department (i.e., direct ICU admission); prior duration of hospital stay; indications for receiving MV (on the basis of the classification described by Zwillich et al. [18]); presence of pneumonia at admission; presence of chronic obstructive pulmonary disease and acute respiratory distress syndrome [19]; APACHE II score [16]; and organ dysfunction and/or infection (ODIN) score [20]. The parameters recorded at the time of each episode of P. aeruginosa VAP were temperature; WBC count; partial pressure of oxygen in the alveoli (Pao2)/fraction of inspiried oxygen (Fio2); radiological score (according to the definition of Fagon et al. [21]); associated bacteremia; duration of MV before the diagnosis of VAP (day of the fiberoptic bronchoscopy; recorded as a continuous variable); presence of other causative organisms; and use of any antimicrobial agent for 124 h during the 15 days preceding diagnosis of VAP (day of the fiberoptic bronchoscopy). In addition, we recorded for each patient the use of any of the following 5 antibiotic classes during the 15 days preceding the diagnosis of VAP: imipenem, third-generation cephalosporin, aminoglycoside, fluoroquinolone, and/or other antibiotics (defined by exclusion). Outcome. A recurrent episode of P. aeruginosa VAP was defined by (1) occurrence of an episode at least 72 h after clinical resolution of a prior episode, (2) presence of the criteria for clinical suspicion of pneumonia, as defined in the Diagnosis of VAP subsection above, (3) a quantitative bronchoscopic specimen culture that was positive for P. aeruginosa, and (4) absence of evidence of a new extrapulmonary source of infection. Finally, the duration of MV, measured from the day of VAP diagnosis, and the mortality rate among patients in the ICU were recorded. Statistical analyses. Potential risk factorsthat is, all the Antibiotic class received Imipenem Third-generation Aminoglycoside Fluoroquinolone Other No. (%) of patients with PRPA VAP (n p 34) PSPA VAP (n p 101) parameters listed abovewere subjected to univariate analysis (comparison of means) to identify those that had a significant association with PRPA VAP. Continuous variables were compared using Students t test; when that was not appropriate, the Mann-Whitney U test was used. The x 2 test was used for categorical variables; when they were not appropriate, Fishers exact test was used. Differences between groups were considered to be significant for variables for which P ! .05. Only those variables for which a p 0.05 were entered into the model of logistic regression analysis to determine independent risk factors for developing PRPA VAP. The discriminating ability of the model was assessed by use of the area under the receiver operating characteristic (ROC) curve. Mortality rates, duration of MV, and susceptibility of strains to other antibiotics, according to piperacillin resistance, were also determined. For 135 (34.4%) of the 393 consecutive patients who developed 1 episode of VAP, cultures of BAL fluid and/or PSB samples yielded P. aeruginosa at concentrations above the significant thresholds. PRPA isolates were recovered from 34 patients (25.2%) and PSPA isolates from 101 patients (74.8%). The epidemiological characteristics of VAP caused by the 2 types of Pseudomonas strains are reported in tables 1 and 2. For 127 patients, diagnosis of Pseudomonas VAP was established on the basis of culture results for PSB and BAL samples obtained during fiberoptic bronchoscopy; for the remaining 8 patients, it was established with BAL fluid samples obtained blindly. In 48 episodes (35.6%), 1 other pathogen was isolated at a significant concentration. Details regarding the species of the other pathogens are indicated in table 3. The incidence of polymicrobial VAP episodes was higher in the PSPA group (39.6%) than in the PRPA group (23.5%), but the difference was not statistically significant (P p .10). Distributions of PRPA and PSPA VAP episodes, according to year of diagnosis, are shown in figure 1; no significant trend was observed (P p .37). Moreover, throughout the entire study, no period in which there was a peak in the number of P. aeruginosa VAP episodes was observed, no epidemic strain was identified, and no temporal-spatial aggregation of cases was found. Risk Factors for Developing PRPA VAP Univariate analysis. According to a univariate analysis comparison of means, the factors that were significantly associated with PRPA VAP were the presence of an underlying fatal medical condition (P p .03), immunocompromised status (P p .004), longer previous stay in the hospital ICU (P p .009), lower APACHE II score (P ! .0002), lower ODIN score at the time of admission to the ICU (P p .03), longer duration of MV at the time of VAP diagnosis (P p .05), more different classes of antibiotics administered before VAP (P p .01), and prior antimicrobial therapy with imipenem (P p .04) or a fluoroquinolone (P p .007). A third-generation cephalosporin had been prescribed more frequently to the PRPA group, but the difference between groups did not reach statistical significance (P p .08). Multivariate analysis. When all the variables that were significantly different in univariate analysis were subjected to logistic regression multivariate analysis, 3 remained in the final model: presence of an underlying fatal medical condition, prior use of a fluoroquinolone, and APACHE II score (table 4). The odds ratio associated with the APACHE II score is expressed Miscellaneousc No. of microorganisms In PRPA In PSPA groupa groupb 2 0 0 0 4 2 6 6 20 NOTE. MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-susceptible S. aureus. a Eight polymicrobial VAP episodes. b Forty polymicrobial VAP episodes. c Neisseria species, Haemophilus species, and diphtheroids. d The total values are greater than values listed in footnotes a and b because 11 microorganism was associated with individual episodes. Figure 1. Distribution of episodes of Pseudomonas aeruginosa ventilator-associated pneumonia, according to year of diagnosis. Only episodes that occurred during the first 8 months of 1999 were included. PRPA, piperacillin-resistant P. aeruginosa; PSPA, piperacillin-susceptible P. aeruginosa. per point accorded and indicates that this parameter is a risk factor when lower values are recorded at admission. The overall discriminating value of this multiple regression model to predict the probability of developing PRPA VAP, as assessed by ROC analysis, was 0.82. Table 5 shows the percentages of PRPA VAP episodes, according to the presence or absence of a fatal underlying disease and previous exposure to a fluoroquinolone. Outcome Ten patients (7 in the PSPA group and 3 in the PRPA group) had recurrence of P. aeruginosa VAP (i.e., relapse with the previous strain or infection with a new one). The second episode developed at a median of 17.4 days (range, 636 days) after the initial episode. For 6 patients, the antibiotic-resistance patterns of strains isolated during this second episode differed from those of strains isolated during the first episode. The mean duration of MV (SD), measured from the day of diagnosis of VAP, was 17.3 17.4 days for the PRPA group and 21.0 26.0 days for the PSPA group (P value not significant). A total of 20 patients (58.8%) in the PRPA group died versus 50 patients (49.5%) in the PSPA group (P value not significant). Susceptibility to Other Antibiotics with Antipseudomonal Activity, According to Piperacillin Resistance A significant relationship was found between piperacillin resistance and cross-resistance to other antibiotics active against P. aeruginosa infections (table 6). When P. aeruginosa strains were susceptible to piperacillin, they were !20% resistant to other antibiotics, except for ciprofloxacin. Piperacillin-resistant strains were 50% resistant to each drug tested. Thirteen strains (9.6%) were resistant to piperacillin-tazobactam plus ceftazidime plus imipenem, and 8 strains were resistant to these 3 antibiotics and amikacin. All strains were susceptible to colistin. The resistance of strains to imipenem, ceftazidime, or ciprofloxacin, according to previous administration of imipenem, a third-generation cephalosporin, or a fluoroquinolone, is reported in table 7. As expected, patients who had received 1 of these 3 antibiotics had a higher probability of becoming infected with a strain resistant to the given antibiotic class. Moreover, VAP episodes due to imipenem-resistant strains were more frequently associated with prior fluoroquinolone administration than were VAP episodes due to imipenem-susceptible strains (P p .05). DISCUSSION We analyzed 135 consecutive patients who developed an episode of P. aeruginosa VAP, using strict criteria to define pneumonia. PRPA VAP episodes (25% of all P. aeruginosa VAP episodes) were significantly associated with 9 factors. According to multivariate analysis, a fatal underlying medical condition, prior use of a fluoroquinolone, and APACHE II score remained independently associated with PRPA VAP. The high percentage of VAP episodes due to P. aeruginosa (34.4%) confirms findings reported elsewhere [22]. This high percentage can be explained by the fact that the ICU is an area of endemicity for P. aeruginosa colonization [23] and, also, by the characteristics of the studied populations. Most of our patients were transferred from another ICU or ward after a mean hospital stay of 12 weeks. All but 1 episode of P. aeruginosa VAP occurred 17 days after initiation of MV, and all were classified as late-onset VAP [7]. We observed a high rate of increased resistance among the Pseudomonas strains isolated from the patients with VAP seen at our ICU. This finding has been noted at other European ICUs, as was shown by Hanberger et al. [24] in their study comparing the antibiotic susceptibilities of aerobic gram-negative bacilli in 5 European countries. Except in Sweden, the percentage of Pseu domonas strains resistant to piperacillin was 114%, reaching 22% in Portugal and 26% in France [24], which is similar to our findings. The percentage of strains resistant to other antibiotics (e.g., imipenem and ciprofloxacin) was also high (in France, 24% were resistant to imipenem and 35% were resistant to ciproRisk factor Underlying medical condition that is rapidly or ultimately fatal Previous exposure to fluoroquinolone APACHE II score, per point accorded OR (95% CI) 5.6 (2.016.2) 4.6 (1.712.7) 0.8 (0.70.9) NOTE. APACHE, acute physiology and chronic health evaluation. Risk factor No prior exposure to fluoroquinolone No fatal underlying medical condition Fatal underlying medical condition Prior exposure to fluoroquinolone No fatal underlying medical condition Fatal underlying medical condition No. of PRPA VAP episodes/total no. of patients PRPA VAP episodes, % floxacin). Similar results have been observed for Pseudomonas strains in the United States [1], even if strict comparison of the studies is made difficult because standards provided by the National Center for Clinical Laboratory Standards are defined using a disk content of 100 mg of piperacillin for the same threshold diameter of 18 mm. Moreover, our data confirm that PRPA isolates are more likely to be resistant to other antipseudomonal agents than are PSPA isolates (table 6). The specific objective of our study was to determine independent risk factors that lead to the emergence of PRPA VAP. The results of our multivariate analysis indicate that exposure to antibiotics appears to be a crucial factor in the emergence of multidrug-resistant bacteria and confirms previously reported data for other resistant pathogens [25, 26]. Finally, the results of the present study highlighted the major role of fluoroquinolones in the emergence of multidrug-resistant P. aeruginosa responsible for VAP. These findings are in accordance with the results of Harris et al. [8], who found multidrug and lengthy antipseudomonal antibiotic exposures to be factors that predispose for the development of an infection with multidrugresistant P. aeruginosa. One pertinent finding is that recent exposure to a fluoroquinolone was also found to be an independent risk factor for carriage of and persistent colonization with methicillin-resistant Staphylococcus aureus [2729]. This information could provide an extremely simple way to identify subgroups of patients from whom PRPA are likely to be isolated. Our multivariate analysis identified 2 other independent risk for PRPA: less-severe disease at the time of admission to the ICU, as assessed by APACHE II score, and presence of an underlying medical condition that is rapidly or ultimately fatal. It is unclear why the presence of more-severe disease at admission to the ICU protects patients from infection with multidrug-resistant P. aeruginosa strains. This finding may indicate a subgroup of patients who carry this marker, rather than reflect a direct causal relationship. The major limitations of interpreting the marker accurately are the observational nature of the data and the relatively small number of episodes that may lower the power of this study. The other major predisposing factor associated with PRPA pneumonia was the presence of an underlying medical condition, as assessed by the MacCabe and Jackson score. This factor might reflect a lower degree of immune function that leads to infections caused by less virulent strains, as has been claimed for multidrug-resistant strains of P. aeruginosa [4]. Two other factors identified in the case-control study by Arruda et al. [9] were confirmed by our univariate analysis but were eliminated in the multivariate analysis: immunocompromised status and prolonged length of hospital stay before the occurrence of nosocomial infection. In the case-control study, the occurrence of nosocomial infections due to P. aeruginosa resistant to all antimicrobials commercially available in Spain was associated with the use of immunosuppressants, neutropenia, or prolonged prior hospitalization. Prolonged length of hospital stay before infection was also reported by Harris et al. [8], but their study did not include any control population. In our study, immunocompromised patients were few in number and low in proportion, precluding a powerful analysis of this point. Percentage of isolates Ticarcillin Piperacillin-tazobactam Ceftazidime Imipenem Ciprofloxacin Amikacin PRPA NOTE. PRPA, piperacillin-resistant P. aeruginosa; PSPA, piperacillin-susceptible P. aeruginosa. Strain resistance To ceftazidime To ciprofloxacin No. (%) of patients, by previous drug therapy received Third-generation cephalosporin Fluoroquinolone No 11 (52.4)a 18 (29.0)b 12 (34.3)d 20 (57.1)c Finally, inclusion of polymicrobial VAP episodes could introduce another limitation in our result, but the rate of polymicrobial episodes was not statistically different between the 2 groups. Concerning outcome, mortality rates were similar in the monomicrobial and polymicrobial groups (50.6% versus 54.2%, respectively, without trend, as found by Crouch Brewer et al. [5]). In addition, the proportion of associated multidrugresistant microorganisms, a factor usually associated with a poorer prognosis, was not statistically different between the PRPA and PSPA groups (table 1). In summary, the results of the present study showed that (1) PRPA VAP episodes frequently occurred in this type of ICU population, (2) piperacillin-resistant strains were clearly more resistant to other antipseudomonal drugs than were piperacillin-susceptible strains, and (3) the mortality rate among patients with PRPA VAP was 150%. Statistical analyses suggested that the clinical characteristics of patients who subsequently develop PRPA VAP differ from those of patients with PSPA VAP episodes. Because previous use of a fluoroquinolone was the only independent factor open to medical intervention that was identified in the present study, these data support the recommendation that in-hospital prescription of broad-spectrum antibiotics, especially fluoroquinolones, should be restricted. Acknowledgment We thank Nathalie Desruelle for manuscript preparation. References


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J. L. Trouillet, A. Vuagnat, A. Combes, N. Kassis, J. Chastre, C. Gibert. Pseudomonas aeruginosa Ventilator-Associated Pneumonia: Comparison of Episodes Due to Piperacillin-Resistant versus Piperacillin-Susceptible Organisms, Clinical Infectious Diseases, 2002, 1047-1054, DOI: 10.1086/339488