Katherine E. Kollef; Richard M. Reichley, RPh; Scott T. Micek, PharmD; and Marin H. Kollef, MD, FCCP

Transcription

1 CHEST Original Research The Modified Score Outperforms Curb65 Pneumonia Severity Score as a Predictor of 30-Day Mortality in Patients With Methicillin- Resistant Staphylococcus aureus Pneumonia* Katherine E. Kollef; Richard M. Reichley, RPh; Scott T. Micek, PharmD; and Marin H. Kollef, MD, FCCP PNEUMONIA Objective: To compare the predictive accuracy for 30-day mortality of the CURB65 score adopted by the British Thoracic Society and the simpler CRB65 score to APACHE (acute physiology and chronic health evaluation) II in patients with methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. Design: A retrospective, single-center, observational cohort study. Setting: Barnes-Jewish Hospital, a 1,200-bed urban teaching hospital. Patients: Adult patients requiring hospitalization identified to have MRSA pneumonia. Interventions: Retrospective data collection from automated hospital, microbiology, and pharmacy databases. Measurements and main results: Two hundred eighteen patients with MRSA pneumonia were identified over a 3-year period. Forty-four patients (20.2%) died during hospitalization. All three prediction rules had high negative predictive values but relatively low positive predictive values at most cut-off points examined. had the greatest area under the receiver operating characteristic curve (0.805; 95% confidence interval [CI], to 0.866) compared to CURB65 (0.634; 95% CI, to 0.727) and CRB65 (0.643; 95% CI, to 0.739) [p < 0.05 for both comparisons]. Similar results were obtained when the subgroups of community-acquired MRSA pneumonia and health-care associated MRSA pneumonia were examined separately. Conclusions: outperformed CURB65 and CRB65 for initial prognostic assessment in MRSA pneumonia. (CHEST 2008; 133: ) Key words: ; CRB65; CURB65; methicillin-resistant Staphylococcus aureus; pneumonia Abbreviations: APACHE acute physiology and chronic health evaluation; BJC Barnes-Jewish-Christian; CAP community-acquired pneumonia; CI confidence interval; Fio 2 fraction of inspired oxygen; MRSA methicillinresistant Staphylococcus aureus; ROC receiver operating characteristic Pneumonia due to methicillin-resistant Staphylococcus aureus (MRSA) is becoming increasingly more common both in the health-care setting and in the community. 1 4 Hospital mortality associated with MRSA pneumonia has been reported to be between 20% and 40%. 1,5 9 Most patients with MRSA pneumonia will require hospitalization, frequently being admitted to the ICU settings and often requiring ventilatory support. 10 Given the increasing prevalence and importance of MRSA pneumonia, clinical trials are likely to be planned examining new treatment modalities, the changing epidemiology of For editorial comment see page 336 MRSA pneumonia, and prevention strategies. To date, a validated prediction tool for clinical outcomes in patients with MRSA pneumonia has not been identified. Several international organizations have developed guidelines or scoring systems in an attempt to stratify CHEST / 133 / 2/ FEBRUARY,

2 patients with community-acquired pneumonia (CAP) according to risk severity Unfortunately, the use of similar methods for patients with health-care associated pneumonia, including MRSA pneumonia, have not been developed. Given the increasing prevalence of MRSA pneumonia and the future need for new clinical research, we designed a study with two main goals. Our first goal was to compare the accuracy of three prediction rules (modified APACHE [acute physiology and chronic health evaluation] II, CURB65, CRB65) to predict 30-day mortality in patients with MRSA pneumonia. Our second goal was to compare these prediction tools in patients admitted to the hospital with the community-acquired MRSA pneumonia phenotype and those acquiring healthcare associated MRSA pneumonia. Study Location and Patients Materials and Methods This study was conducted at a university-affiliated, urban teaching hospital: Barnes-Jewish Hospital (1,200 beds). During a 3-year period (January 2003 to June 2005), all hospitalized patients with MRSA pneumonia, microbiologically confirmed by BAL cultures, and treated with either vancomycin or linezolid monotherapy were eligible for this investigation. Patients with polymicrobial infection demonstrated by BAL cultures, requiring other antimicrobial treatment, and those treated with either vancomycin or linezolid for 72 h were excluded from evaluation. This study was approved by the Washington University School of Medicine Human Studies Committee, and informed consent was waived. Study Design and Data Collection A retrospective cohort study design was employed with the main outcome measure being 30-day mortality. A computerized list of patients with MRSA pneumonia was generated by the Medical Informatics Department through retrospective query of the Microbiology Laboratory database at Barnes-Jewish Hospital (performed by R.M.R.), which allowed identification of potential study patients. Patients could not be entered into the study more than once. At Barnes-Jewish Hospital, patients with MRSA pneumonia can be treated with vancomycin (15 mg/kg body weight IV q12h) or linezolid (600 mg IV q12h). Patients treated *From the Division of Pulmonary and Critical Care Medicine (Dr. Kollef and Ms. Kollef), Washington University School of Medicine; Center for Quality and Effectiveness (Mr. Reichley), BJC Healthcare; and Department of Pharmacy Practice (Dr. Micek), St. Louis College of Pharmacy, St. Louis, MO. The authors have no conflicts of interest to report regarding this article. Manuscript received July 25, 2007; revision accepted September 24, Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( org/misc/reprints.shtml). Correspondence to: Marin H. Kollef, MD, FCCP, Campus Box 8052, Washington University School of Medicine, 660 South Euclid Ave, St. Louis, MO 63110; mkollef@im.wustl.edu DOI: /chest with vancomycin can have their dosing and interval of dosing adjusted based on their underlying renal function. Definitions and Outcome Scoring Systems All definitions were selected prospectively as part of the original study design. scores were calculated based on clinical data available on the day the BAL was performed confirming the diagnosis of MRSA pneumonia. 19 A modified score was employed in that assessment of the Glasgow coma score was not included. The CURB65 and CRB65 scores were calculated based on the criteria specified in the original articles. 16,17 The confusion variable employed in this study was not the same as in the original definition of CURB65. The definition of confusion for CURB 65 was an Abbreviated Mental Test Score 8 or new disorientation to person, place, or time. 16 We assessed confusion only as a report of new disorientation to person, place, or time as documented in the medical records. The, CURB65, and CRB65 scores were computed by one investigator (K.E.K.) to avoid interobserver variability. Thirty-day mortality was assessed from the time when the diagnostic BAL for MRSA pneumonia was performed. For patients discharged prior to the 30-day cutoff for mortality evaluation, a computerized medical records search was undertaken to determine if hospital readmission and death had occurred. All 11 hospitals in the Barnes-Jewish-Christian (BJC) Healthcare system have a common computerized medical records system allowing tracking of patients at all system hospitals. A clinical diagnosis of MRSA pneumonia was based on criteria modified from those established by the American College of Chest Physicians. 20 These criteria require the occurrence of new and persistent radiographic infiltrates in conjunction with two of the following: fever, leukocytosis, and purulent tracheal aspirate or sputum. In addition to the clinical criteria for MRSA pneumonia, BAL cultures with appropriate quantitative thresholds were obtained bronchoscopically to support the diagnosis of MRSA pneumonia. Quantitative thresholds of 10 4 cfu/ml for MRSA were considered positive for the diagnosis of MRSA pneumonia. The community-acquired phenotype of MRSA was defined as isolates resistant to methicillin but sensitive to three or more of the following antibiotics: gentamicin, ciprofloxacin, trimethopim-sulfamethoxazole, and clindamycin. For purposes of this study health-care associated MRSA pneumonia included all patients hospitalized for 2 days prior to obtaining a positive BAL culture result, and patients with a first positive BAL culture result within 2 days of hospital admission whose isolates did not meet the criteria for the community-acquired phenotype of MRSA and who possessed any of the following: admission from another health-care facility including nursing homes, use of long-term hemodialysis, immunosuppression, and prior hospitalization within 30 days. 21 Microbiological Data The microbiology laboratory performed antimicrobial susceptibility of clinical isolates by the Kirby-Bauer disk diffusion method according to guidelines and break points established by the Clinical Laboratory and Standards Institute, using 150-mm round plates of Mueller-Hinton agar (BBL; Becton-Dickinson; Cockeysville, MD). A technologist experienced in reading zones of inhibition with a ruler against a black background measured the zone diameters manually. Statistical Analysis All comparisons were unpaired and all tests of significance were two-tailed. Continuous variables were compared using the 364 Original Research

3 Table 1 Definition of Performance Characteristics* Performance Characteristics Definition Equation Sensitivity (how good is the test at identifying patients who will die?) Specificity (how good is the test at identifying patients who will not die?) Positive predictive value (in the event of a positive test result, the probability that the patient will die) Negative predictive value (in the event of a negative test result, the probability that the patient will not die) ROC True-positive results (ie, tested positive and died); all deaths True-negative results (ie, tested negative and lived); all alive True-positive results; all positives True-negatives results; all negatives A curve created by mapping sensitivity against 1 specificity. The AUC is a marker of performance with higher values indicating better diagnostic ability. An AUC 1 indicates perfect performance, whereas an AUC 0.5 indicates that there is a 50:50 chance that the test correctly identifies those who die *Sensitivity and specificity are useful when considering the performance of a test at the population level. In contrast, positive predictive value and negative predictive value are better when considering the performance of a test at the patient level (ie, in the event of a positive test result, what is the probability that the patient will or will not die?). AUC area under the curve. Student t test for normally distributed variables and the Mann- Whitney U test for nonnormally distributed variables. The 2 or Fisher exact test was used to compare categorical variables. The primary data analysis compared 30-day nonsurvivors with survivors. We performed multiple logistic-regression analysis using statistical software (SPSS, version 11.0 for Windows; SPSS; Chicago, IL). Multivariate analysis was performed using models that were judged a priori to be clinically sound. 22 This was prospectively determined to be necessary to avoid producing spuriously significant results with multiple comparisons. All potential risk factors significant at the 0.15 level in univariate analyses were entered into the model. Sensitivity, specificity, positive predictive value, negative predictive value, and the areas under the receiver operating characteristic (ROC) curves for predicting 30-day mortality in each prediction rule were compared using the definitions shown in Table 1. ROC curves were generated for the population as a whole and then for the patients with the community-acquired phenotype of MRSA and those with health-care associated MRSA pneumonia, respectively. For all analyses, a two-tailed p value 0.05 was considered statistically significant. Results Patient Characteristics A total of 218 patients with microbiologically confirmed MRSA pneumonia were evaluated at Barnes-Jewish Hospital during the study period. Mean age of the population was years ( SD) [range, 19 to 92 years]; there were 141 male (64.7%) and 77 female (35.3%) patients. Patient characteristics and outcomes are provided in Table 2. Mean score was (range, 3 to 37). Mean CURB65 and CRB65 scores were (range, 0 to 5) and (range, 0 to 4), respectively. Among the 178 patients treated with vancomycin and having trough levels measured, mean trough value for vancomycin collected after the third dose was g/ml. Thirty-Day Mortality Forty-four patients (20.2%) died within 30 days of the development of MRSA pneumonia. Two hundred five patients (94.0%) required ICUs admission, and 167 patients (76.6%) received tracheal intubation and mechanical ventilation. Nonsurvivors were Table 2 Baseline Patient Characteristics and Outcomes* Variables 30-Day Survivors (n 174) 30-Day Nonsurvivors (n 44) p Value Age, yr Gender Male 114 (65.5) 27 (61.4) 0.61 Female 60 (34.5) 17 (38.6) Race Caucasian 122 (70.1) 35 (79.5) 0.21 African American 52 (29.9) 9 (20.5) Pao 2 /Fio Comorbidities COPD 58 (33.3) 17 (38.6) 0.51 Coronary artery disease 29 (16.7) 14 (31.8) 0.02 Underlying malignancy 38 (21.8) 10 (22.7) 0.90 Diabetes 43 (24.7) 11 (25.0) 0.97 End-stage renal disease 4 (2.3) 6 (13.6) 0.01 Immunosuppression 27 (15.5) 3 (6.8) 0.22 Processes of care Antibiotic with 12 h 129 (74.1) 33 (75.0) 0.91 Antibiotic within 24 h 144 (82.8) 38 (86.4) 0.57 Mechanical ventilation 124 (71.3) 43 (97.7) 0.01 Vasopressors 17 (9.8) 17 (38.6) 0.01 Antibiotic Vancomycin 157 (90.2) 40 (90.9) 0.99 Linezolid 17 (9.8) 4 (9.1) MRSA phenotype Community acquired 33 (19.0) 8 (18.8) 0.91 Health-care associated 141 (81.0) 36 (81.2) *Data are presented as mean SD or No. (%). CHEST / 133 / 2/ FEBRUARY,

4 Table 3 Sensitivity, Specificity, and Positive and Negative Predictive Values of 30-Day Mortality of the Different Prediction Rules* Cut-off Points Mortality Sensitivity Specificity Positive Predictive Value Negative Predictive Value CURB /13 (0.0) n/a 1 18/108 (16.7) /78 (21.8) /15 (33.3) /3 (100) /1 (100) CRB /118 (13.6) n/a 1 18/80 (22.5) /16 (37.5) /3 (100) /1 (100) /4 (0.0) n/a /13 (0.0) /61 (1.6) /50 (12.0) /45 (37.8) /31 (45.2) /14 (42.9) *Data are presented as No. total (%). n/a not applicable. Cut-off points accepted as threshold to define a low-risk group according to original study design. 16,17 statistically more likely to require mechanical ventilation compared to survivors (Table 2). Prediction of 30-Day Mortality Patients dying within 30 days of onset of MRSA pneumonia had statistically greater scores ( vs ; p 0.01), CURB65 scores ( vs ; p 0.01), and CRB65 scores ( vs ; p 0.01) compared to patients surviving 30 days. Table 3 shows the sensitivity, specificity, and positive and negative predictive values for 30-day mortality at different cut-off points for each scoring system. had higher sensitivities than CURB65 and CRB65 at all risk levels. All three prediction rules had high negative predictive values but relatively low positive predictive values at most of the cut-off points examined. ROC curves for 30-day mortality for each prediction scoring method are shown in Figure 1. The area under the ROC curve for was statistically greater than the areas under the ROC curves for CURB65 and CRB65: (95% confidence interval [CI], to 0.866) vs (95% CI, to 0.727) and (95% CI, to 0.739), respectively (p 0.05 for both comparisons). Similar results were obtained when the ROC curves were compared for the patients with the communityacquired phenotype (n 41) of MRSA and the health-care associated phenotype (n 177) [Fig 2, 3]. Of note, the area under the ROC curve for was greatest for the communityacquired phenotype compared to the overall population and the health-care associated phenotype. Two separate logistic regression analyses were performed due to concern over colinearity between CRB65 and. Logistic regression analysis identified increasing scores, increasing CRB65, decreasing Pao 2 /fraction of inspired oxygen (Fio 2 ), and vasopressor use as independent predic- Sensitivity 1 - Specificity Source of the Curve Reference Line CUR65 CURB65 Figure 1. ROC curve for each prognostic tool (n 218). The area under the ROC curves are as follows:, (95% CI, to 0.866); CURB65, (95% CI, to 0.727); CRB65, (95% CI, to 0.739). 366 Original Research

5 Table 4 Multivariate Analysis of Independent Risk Factors for 30-Day Mortality* Variables Adjusted Odds Ratio 95% CI p Value Sensitivity tors of 30-day mortality in the two models (Table 4). CRB65 provided a model that held a better fit to the data compared to CURB65 based on the Hosmer- Lemeshow goodness-of-fit statistic. Discussion We showed that the modified score outperformed the CURB65 and CRB65 pneumonia severity scores as a predictor of 30-day mortality in patients with MRSA pneumonia. Analysis of the ROC curves demonstrated that the modified score was statistically superior to both CURB65 and CRB65 as a predictor of 30-day mortality. This was true for patients with the community-acquired phenotype of Sensitivity 1 - Specificity 1 - Specificity Source of the Curve Reference Line CUR65 CURB65 Figure 3. ROC curve for each prognostic tool for patients with the community-acquired phenotype of MRSA (n 41). The area under the ROC curves are as follows:, (95% CI, to 0.994); CURB65, (95% CI, to 0.951); and CRB65, (95% CI, 01 to 0.949). Source of the Curve Reference Line CUR65 CURB65 Figure 2. ROC curve for each prognostic tool for patients with health-care associated MRSA pneumonia (n 177). The area under the ROC curves are as follows:, (95% CI, to 0.855); CURB65, (95% CI, 00 to 0.708); and CRB65, (95% CI, to 0.727). Model 1 score (1-point increments) Pao 2 /Fio (1-point decrements) Model 2 CRB (1-point increments) Pao 2 /Fio (1-point decrements) Vasopressor use *Because of colinearity between variables included in and CRB65, two separate models are displayed, with only one of these two variables entered into each model, respectively. Other covariates not presented in the table had a p value 0.05 including age, presence of coronary artery disease, end-stage renal disease, and mechanical ventilation. The Hosmer-Lemeshow goodness-of-fit findings for each model are p 0.23 and p 0.94, respectively. MRSA pneumonia as well as those with health-care associated MRSA pneumonia. However, in our multivariate models both and CRB65 were independent predictors of 30-day mortality. The odds of death by day 30 was greater for CRB65, which, in large part, was related to the smaller number of discriminating units in CRB65 compared to APACHE II. Nevertheless, the ROC curves suggest that for individual patient predictions, is more accurate than CRB65. CURB65 and CRB65 have been validated as tools to predict mortality and the need for ICU admission in patients with CAP. 16,17 These scoring systems are easy to employ, and the CRB65 requires only data immediately available at the time of clinical evaluation. More recent studies have further demonstrated the utility of CURB65 and CRB65 as outcome predictors in CAP. Man et al 23 found that CURB65 and CRB65 were accurate predictors of 30-day mortality among patients in Hong Kong with CAP. Similarly, Barlow et al 24 found that CURB65 outperformed generic sepsis scores as a predictor of mortality. Both of these studies had ROC curve areas in the range of 0.69 to 0.78, which were higher than the values observed in our study. The main differences are that these previous evaluations of CURB65 and CRB65 involved patients with CAP with a variety of infectious pathogens. Our study differed by involving only hospitalized patients with either community-acquired or health-care associated MRSA pneumonia. Other investigators have attempted to identify predictors of mortality in patients with nosocomial pneumonia. Combes et al 25 identified the Sepsis- CHEST / 133 / 2/ FEBRUARY,

6 Related Organ Failure Assessment as a predictor of 28-day mortality when measured on day 1, day 3, and day 8 following onset of ventilator-associated pneumonia. Similar studies focusing on MRSA pneumonia are not available. Rello et al 26 evaluated a cohort of patients with MRSA pneumonia optimally treated with glycopeptide antibiotics. They found that bacteremia and the absence of vancomycin administration by a continuous infusion were associated with intensive care mortality. They did not identify severity of illness using as a predictor of mortality in their study. Their study cohort differed from ours in being smaller, from four different hospitals, and selected to be included in a study of glycopeptide optimization. Kollef et al 21 evaluated 4,543 patients with CAP, hospital-acquired pneumonia, ventilator-associated pneumonia, and health-care associated pneumonia. MRSA was the most common single pathogen identified in patients with health-care associated pneumonia and the second most common pathogen in hospitalassociated pneumonia. Although a severity-of illness score was not evaluated in that study, independent predictors of hospital mortality included those variables that make up the score (age, coma, ph value, creatinine value, WBC count, temperature, and respiratory rate). Several important limitations of this investigation should be noted. First, we employed the CURB65 scoring system that has previously only been validated in CAP while not examining other pneumonia prediction tools including the Pneumonia Severity Index. This may be an important reason why the CURB65 did not perform as well in patients with MRSA pneumonia. We also performed this study at a single center, limiting the application of these results to other hospitals. More studies are warranted to determine the optimal prediction tool for patients with nosocomial pneumonia including MRSA. We limited our analysis to patients with microbiologically confirmed MRSA pneumonia. Therefore, we do not know the comparative accuracy of these prediction scores in patients with clinically diagnosed MRSA pneumonia. Moreover, the study results may be confounded due to the retrospective nature of this analysis. Another important limitation is that we only tracked patients within one hospital system. It is possible that we may have missed patient deaths occurring after hospital discharge but within 30 days in individuals not readmitted to a BJC Healthcare hospital. Finally, we used a modified calculation, relied on medical chart review to assess confusion for the CURB65 and CRB65 measurements, and limited the mortality assessment to 30 days, which may all limit the overall applicability of these data to other populations. 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