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(Chest. 2006;130:947-955.)
© 2006 American College of Chest Physicians

Predictors of Mortality for Methicillin-Resistant Staphylococcus aureus Health-Care–Associated Pneumonia*

Specific Evaluation of Vancomycin Pharmacokinetic Indices

Meghan N. Jeffres, PharmD; Warren Isakow, MD; Joshua A. Doherty, BS; Peggy S. McKinnon, PharmD; David J. Ritchie, PharmD; Scott T. Micek, PharmD and Marin H. Kollef, MD, FCCP

* From the Department of Pharmacy (Drs. Jeffres, McKinnon, Ritchie, and Micek), Barnes-Jewish Hospital, St. Louis, MO; the Department of Pulmonary and Critical Care Medicine (Drs. Isakow and Kollef), Washington University School of Medicine, St. Louis, MO; and Medical Informatics (Mr. Doherty), BJC Healthcare, St. Louis, MO.

Correspondence to: Marin H. Kollef, MD, FCCP, Washington University School of Medicine, 660 South Euclid Ave, Campus Box 8052, St. Louis, MO 63110; e-mail: mkollef{at}im.wustl.edu

Abstract

Objective: The goal of this investigation was to determine whether vancomycin pharmacokinetic indexes (eg, serum trough concentrations or area under the concentration curve [AUC] values) were associated with mortality for patients with health-care–associated pneumonia (HCAP) attributed to methicillin-resistant Staphylococcus aureus (MRSA).

Design: A retrospective, single-center, observational cohort study.

Setting: Barnes-Jewish Hospital, a 1,200-bed urban teaching facility.

Patients: Adult patients requiring hospitalization who were identified as having HCAP attributed to MRSA by BAL semi-quantitative cultures.

Interventions: Retrospective data collection from automated hospital, microbiology, and pharmacy databases.

Measurements and main results: One hundred two patients with MRSA HCAP were identified over a 6.5-year period. Thirty-two patients (31.4%) died during their hospitalization. The mean (± SD) vancomycin trough concentrations (13.6 ± 5.9 vs 13.9 ± 6.7 µg/mL, respectively; p = 0.866) and AUC values (351 ± 143 vs 354 ± 109 µg/h/mL, respectively; p = 0.941) did not differ between survivors and nonsurvivors. The stratification of the vancomycin trough concentrations and AUC values yielded no relationship with hospital mortality.

Conclusions: We found no evidence that greater vancomycin trough concentrations or AUC values correlated with hospital outcome. Based on these results, aggressive dosing strategies for vancomycin (eg, trough concentrations of > 15 µg/mL) may not offer any advantage over traditional dose targets (range, 5 to 15 µg/mL).

Key Words: antibiotics • methicillin resistance • pneumonia • Staphylococcus aureus

Methicillin-resistant Staphylococcus aureus (MRSA) infections are serious and are associated with significant mortality and health-care costs.1 In most hospitals, MRSA has become the most common Gram-positive bacterial species associated with serious hospital-acquired infections.23456 The hospital mortality rate associated with MRSA sterile-site infections is reported to be > 20% in most series78910111213141516 and is highest among patients with bacteremia and pneumonia.

Until recently, the primary treatment option for MRSA pneumonia was vancomycin. Vancomycin in doses adjusted to achieve serum trough concentrations of 15 to 20 µg/mL has been recommended when empirically or definitely covering MRSA as a consequence of poor intrapulmonary distribution.6 Unfortunately, vancomycin has not undergone rigorous evaluation for this treatment indication. Several studies17181920 have suggested that vancomycin may not be adequate antibiotic treatment for health-care–associated pneumonia (HCAP) attributed to MRSA. Therefore, we performed a clinical study to determine whether pharmacokinetic (PK) indexes (eg, serum trough concentrations or area under the concentration curve [AUC] values) for vancomycin were associated with mortality for MRSA HCAP.

Materials and Methods

Study Location and Patients
This study was conducted at a university-affiliated, urban teaching hospital (Barnes-Jewish Hospital) with 1,200 beds. During a 6.5-year period (January 1999 to June 2005), all hospitalized patients with MRSA HCAP that had been microbiologically confirmed by BAL cultures and treated with vancomycin monotherapy were eligible for this investigation. Patients with polymicrobial infection demonstrated by BAL cultures, those treated with vancomycin for < 72 h, patients with isolation of a community-acquired phenotype for MRSA, and those with a do-not-resuscitate order in their medical records 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 hospital mortality. Additionally, we assessed the effect of vancomycin PK indexes including serum trough concentrations and AUC values on the primary outcome. The clinical characteristics evaluated are given in Tables 1 and 2 . A computerized list of patients with MRSA HCAP was generated by the Medical Informatics Department through retrospective query of the Microbiology Laboratory database at Barnes-Jewish Hospital (performed by J.A.D.), which allowed the identification of potential study patients. Patients could not be entered into the study more than once.


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  		Table 1.. Baseline Patient Characteristics at Hospital Admission*

 

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  		Table 2.. Process of Care Variable and Vancomycin Characteristics*

 
Definitions
All definitions were selected prospectively as part of the original study design. APACHE (acute physiology and chronic health evaluation) II scores were calculated based on the clinical data available on the day that the BAL was performed.21 A clinical diagnosis of MRSA HCAP was based on criteria modified from those established by the American College of Chest Physicians.22 These criteria require the occurrence of new and persistent radiographic infiltrates in conjunction with two of the following conditions: fever; leukocytosis; and purulent tracheal aspirate or sputum. For the purposes of this study, HCAP included all patients who had been hospitalized for > 2 days prior to obtaining a positive BAL culture finding and patients with a first positive BAL culture finding within 2 days of hospital admission and any of the following conditions: hospital admission from another health-care facility, including nursing homes; receiving long-term hemodialysis; and prior hospitalization within 30 days.423

In addition to the clinical criteria for HCAP, BAL cultures with appropriate semi-quantitative thresholds were obtained bronchoscopically to support the diagnosis of MRSA HCAP.22 Semi-quantitative thresholds of ≥ 104 cfu/mL for MRSA were considered to be positive for the diagnosis of MRSA HCAP. Hospital mortality was defined as those patient deaths occurring during the initial hospital admission during which they were studied. Delayed antimicrobial therapy was defined as the administration of vancomycin > 12 h after the diagnostic criteria for MRSA HCAP were met. Immunosuppression was defined as patients receiving corticosteroids, having a positive HIV antibody test result, having received chemotherapy within the past 45 days, having neutropenia (ie, absolute neutrophil count of < 1.0 x 109 cells/L) resulting from the administration of chemotherapy, or recipients of an organ transplant (renal, liver, heart, or bone marrow) requiring immunosuppressive agents.

Microbiological Data
The microbiology laboratory performed antimicrobial susceptibility tests of clinical isolates using the Kirby-Bauer disk diffusion method according to guidelines and breakpoints 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. The mean disk diffusion diameter of MRSA to vancomycin was similar for all study years evaluated (data not shown).

PK Data
All patients were initially treated with weight-based vancomycin, receiving 30 mg/kg in two divided doses during a 24-h period. Vancomycin trough values were obtained from serum concentrations collected ≤ 30 min before administration of a dose at the onset of steady-state conditions. Steady-state conditions were considered to be achieved after three doses of vancomycin in patients not receiving hemodialysis (n = 96). For patients requiring hemodialysis, the steady-state concentration was assumed to be achieved after a minimum of five estimated serum vancomycin half-lives (n = 6). Vancomycin serum concentrations collected outside of the 30-min window described above were mathematically extrapolated to represent a true trough concentration using equations 1 to 4 (see "Appendix") [n = 28]. Predicted trough concentrations were calculated using equations 4 to 6 (see "Appendix") in patients who did not have a vancomycin serum concentration documented in the medical record (n = 14).24 The predicted 24-h AUC values for vancomycin were calculated using equation 7 (see "Appendix").25 Patients with renal disease requiring hemodialysis did not have an AUC that had been calculated as a reliable estimate of the patient’s creatinine clearance, as is required for the computation of this parameter (n = 6).

Statistical Analysis
All comparisons were unpaired, and all tests of significance were two-tailed. Continuous variables were compared using the Student t test for normally distributed variables and the Mann-Whitney U test for nonnormally distributed variables. The {chi}2 test or Fisher exact test was used to compare categoric variables. The primary data analysis compared hospital nonsurvivors with survivors. We performed multiple logistic regression analysis using a statistical software program (SPSS, version 11.0 for Windows; SPSS, Inc; Chicago, IL). Multivariate analysis was performed using models that were judged a priori to be clinically sound.26 This was prospectively determined to be necessary to avoid producing spuriously significant results with multiple comparisons. All potential risk factors significant at the 0.2 level in univariate analyses were entered into the model.

Results

Patients
A total of 247 consecutive patients having a BAL culture that was positive for MRSA were initially evaluated. From this group, patients were excluded for the following reasons: 26 patients (10.5%) underwent only a bronchial wash culture and not a BAL; 55 patients (22.3%) had poylmicrobial infection determined by BAL (50 other bacterial species, 4 fungal species, and 1 viral species); 34 patients (13.8%) were either treated with linezolid monotherapy or received < 72 h of treatment with vancomycin followed by alternative MRSA therapy; and 30 patients (12.1%) did not have clinical data supporting the diagnosis of HCAP. The hospital mortality rate of patients who had been excluded from evaluation was 26.9%. The remaining 102 patients constituted the study cohort, of whom 32 (31.4%) died during their hospitalization. Twenty-seven of the 32 nonsurvivors (84.4%) were determined to have MRSA HCAP at death. The mean (± SD) age of the study patients was 59.4 ± 15.3 years (range, 22 to 90 years), and the mean APACHE II score was 20.8 ± 8.2 (range, 3 to 37). There were 63 men (61.8%) and 39 women (38.2%); 78 patients (76.5%) were white, and 24 patients (23.5%) were African American, Hispanic, or Asian American. Sixty-five patients (63.7%) were receiving vancomycin therapy at the time BAL was performed. Among these patients, 58 (89.2%) had received vancomycin for < 24 h prior to the obtaining of the BAL specimens.

Patient Characteristics and Medical Care Processes According to Hospital Mortality
Hospital nonsurvivors were statistically more likely to have end-stage renal disease requiring hemodialysis and to have higher APACHE II scores compared to hospital survivors (Table 1). Hospital nonsurvivors also required mechanical ventilation and vasopressor support statistically more often compared to survivors (Table 2). The rate of MRSA bacteremia was not significantly different between nonsurvivors and survivors (18.8% vs 7.1%, respectively; p = 0.079).

Vancomycin PK Parameters According to Hospital Mortality
Vancomycin trough concentrations and AUC values were significantly correlated, as is shown in the scatterplot in Figure 1 . The mean vancomycin trough concentration was 13.7 ± 6.1 µg/mL (range, 4.2 to 29.8 µg/mL), and the mean AUC value was 352 ± 134 µg/h/mL (range, 119 to 897 µg/h/mL). There was no difference in the number of patients receiving vancomycin at the time the BAL cultures were obtained, the time to vancomycin administration after BAL sampling, the vancomycin disk zone diameters, the vancomycin trough concentrations, the AUC values, and the duration of vancomycin administration between nonsurvivors and survivors (Table 2, Fig 2 ). The stratification of vancomycin trough concentrations and AUC values revealed no statistically significant relationship between these parameters and hospital mortality at any of the breakpoints evaluated (Fig 3 ).


Figure 1
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  		Figure 1.. Scatterplot of vancomycin trough concentrations (x-axis) and vancomycin AUC values (y-axis). The Spearman {rho} correlation coefficient = 0.437 (significant at the 0.01 level, two-tailed). • = predicted values; {blacksquare} = actual measured values.

 

Figure 2
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  		Figure 2.. Box plot distributions for vancomycin trough concentrations (top) and AUC values (bottom). The boxes represent the 25th to 75th percentiles, with the 50th percentile shown as a solid line within the boxes. The 10th and 90th percentiles are shown as capped bars.

 

Figure 3
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  		Figure 3.. Hospital mortality according to stratification of vancomycin trough concentrations (top) and AUC values (bottom). Numbers in the white boxes within the bars represent the sample sizes. All comparisons are nonsignificant at p > 0.1.

 
A secondary analysis of patients with vancomycin steady-state concentrations of < 15 µg/mL (n = 68) and ≥ 15 µg/mL (n = 34) was performed comparing baseline characteristics, process-of-care variables, and hospital outcomes. The mean trough concentrations for the patients were 9.4 ± 3.2 vs 20.4 ± 3.2 µg/mL, respectively (p < 0.001), and the mean AUC values were 318 ± 111 vs 418 ± 152, respectively (p < 0.001). The differences in baseline characteristics between patients with trough concentrations of < 15 µg/mL and those with trough concentrations of ≥ 15 µg/mL were not statistically different for all variables evaluated, including APACHE II score (19.9 ± 8.4 vs 22.8 ± 7.5, respectively; p = 0.088), PaO2/fraction of inspired oxygen (FIO2) ratio (181 ± 87 vs 193 ± 64, respectively), concomitant bacteremia (11.8% vs 8.8%, respectively; p = 0.652), and the need for mechanical ventilation (70.5% vs 85.3%, respectively; p = 0.143). The hospital mortality rate was not statistically different between the groups with low and high trough concentrations (29.4% vs 35.3%, respectively; p = 0.546). Patients with trough concentrations ≥ 15 µg/mL were statistically more likely to require therapy with vasopressors for hemodynamic support (41.2% vs 22.1%, respectively; p = 0.044). The actual vancomycin trough values for survivors (n = 21) and nonsurvivors (n = 13) with trough concentrations ≥ 15 µg/mL were similar (20.8 ± 3.4 vs 20.4 ± 5.2 µg/mL, respectively; p = 0.811).

The resolution of fever after 48 h of vancomycin treatment was similar for patients with vancomycin trough concentrations of < 15 µg/mL and those with trough concentration of ≥ 15 µg/mL (62.1% vs 63.6%, respectively; p = 0.883). A trend toward greater resolution of fever after 72 h of vancomycin treatment was observed among patients with vancomycin trough concentrations of ≥ 15 µg/mg (69.7% vs 87.5%, respectively; p = 0.055), but this difference was not statistically significant.

Analysis of the 77 patient subgroup with ventilator-associated pneumonia yielded similar results in all respects. The difference in vancomycin trough concentrations between survivors and nonsurvivors (13.4 ± 6.1 vs 14.0 ± 6.8 µg/mL, respectively; p = 0.693) and the AUC values for survivors and nonsurvivors (357 ± 160 vs 351 ± 110 µg/h/mL, respectively; p = 0.868) were not statistically different. Eleven patients (10.8%) had a repeat BAL culture that was positive for MRSA, suggesting a possible lack of response to treatment. The mean initial vancomycin trough concentrations (16.2 ± 7.0 vs 12.6 ± 6.3 µg/mL, respectively; p = 0.080) and AUC values (375 ± 114 vs 349 ± 137 µg/h/mL, respectively; p = 0.544) for patients with positive repeat BAL culture findings were not statistically different from the values for the patients with a single positive BAL specimen.

Multivariate Analysis
Multiple logistic regression analysis identified vasopressor administration and the presence of COPD as independent determinants of hospital mortality (Table 3 ). All possible combinations of variables entered into the logistic regression analysis yielded a final model with vasopressor administration as an independent determinant of hospital mortality. The same variables were found to be independent determinants of hospital mortality when the analysis was repeated, forcing vancomycin PK indexes into the model.


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  		Table 3.. Multivariate Analysis of Independent Risk Factors for Hospital Mortality*

 
Lengths of Stay
Hospital nonsurvivors had significantly longer mean durations of mechanical ventilation (26.0 ± 27.6 vs 16.2 ± 22.3 days, respectively; p = 0.014) and length of stay in the ICU (22.3 ± 15.7 vs 16.7 ± 16.9 days, respectively; p = 0.048) compared to survivors. There was no significant difference in mean hospital length of stay between nonsurvivors and survivors (44.5 ± 36.4 vs 34.1 ± 23.7 days, respectively; p = 0.244).

Discussion

Our study results found no evidence that the optimization of vancomycin PK indexes (eg, trough concentrations of ≥ 15 µg/mL or AUC of ≥ 400 µg/h/mL) correlated with hospital mortality. We also found that additional stratification of the vancomycin trough concentrations and AUC values yielded no identifiable relationship with hospital mortality.

Previous investigations2527 have identified a potential association between vancomycin PK indexes and clinical response to treatment in patients with presumed S aureus pneumonia. An important limitation of these studies is that they did not employ BAL confirmation for the diagnosis, given that S aureus is a frequent colonizer of the upper respiratory tract in hospitalized patients.5 Additionally, the methodology in these studies relied on summation values for AUC calculations, including the AUC values for other antibacterial agents employed with or without the coadministration of vancomycin, and included methicillin-susceptible isolates of S aureus. To our knowledge, this investigation is the first study evaluating a cohort of patients with BAL-positive MRSA HCAP to assess the relationship of outcome to vancomycin PK indexes.

Rello and coworkers20 recently evaluated 75 patients with BAL-positive MRSA pneumonia who had been treated with either vancomycin or teicoplanin, both of which are glycopeptide antibiotics. These investigators attempted to optimize the administration of the glycopeptide antimicrobial agents, including the use of continuous infusion in some patients. Overall, the hospital mortality rate was 48% despite optimized treatment with glycopeptide agents. These investigators concluded that, despite the administration of appropriate glycopeptide therapy, there was an increased attributable mortality rate for MRSA pneumonia after adjustment for disease severity and diagnostic category.

There is growing evidence that vancomycin may not be as effective against all strains of staphylococci as it was 25 years ago.28 S aureus strains with intermediate susceptibility to vancomycin have been reported and typically present as clinically resistant to vancomycin, which is manifested by lack of response to treatment and recurrent MRSA infections.2930 Additionally, the upward drift in the minimum inhibitory concentration of MRSA isolates to vancomycin (1.0 to 2.0 µg/mL), which is still within the currently accepted susceptible range, have also been associated with lack of response to treatment and recurrent infections, including bacteremia.3132 A further limitation of vancomycin is its limited ability to concentrate within tissue, especially the lung.3334 This combination of factors has recently led the Clinical and Laboratory Standards Institute35 to recommend to the US Food and Drug Administration that the susceptibility breakpoint for MRSA to vancomycin be dropped from 4 to 2 µg/mL.

Given the increasing recognition of the lack of response to treatment due to vancomycin, alternative agents have been sought for treatment of MRSA HCAP. In a retrospective analysis of data from two prospective, randomized, double-blind studies,1819 treatment outcomes with linezolid (600 mg q12 h) and vancomycin (1 g q12 h) were compared in patients with HCAP due to MRSA. The Kaplan-Meier survival rates for linezolid were 80.0% (60 of 75 patients), as opposed to 63.5% (54 of 85 patients) for vancomycin, in the MRSA subset of patients (p = 0.03). Linezolid appears to be a suitable alternative to vancomycin in patients with HCAP attributed to MRSA. Although a general agreement on the superiority of linezolid to vancomycin is lacking, a current randomized, controlled trial is being undertaken to elucidate this controversy. In addition, newer approved agents, including tigecycline,36 and others in development, such as ceftobiprole (BAL5788), which is the water-soluble prodrug of BAL9141,3738 and telavancin,3940 may be of value for the treatment of MRSA HCAP.

Our study has several important limitations. First, this was a retrospective analysis that was primarily aimed at generating hypotheses for future study. Second, we did not directly measure the minimum inhibitory concentration of the isolates but relied on the disk zone diameter for vancomycin susceptibility. While the disk diffusion size did not differ between survivors and nonsurvivors and the average disk diffusion size did not differ from year to year over the course of the study, a correlation between disk zone diameters and minimum inhibitory concentration measurements is not robust.41 Therefore, we cannot exclude the possibility of variability in the minimum inhibitory concentration measurements between survivors and nonsurvivors. Third, we did not assess the time to achieving a vancomycin steady-state trough concentration of ≥ 15 µg/mL as a predictor of outcome. This may be an important predictor of outcome. Fourth, we did not evaluate the MRSA isolates for the presence of virulence factors such as exotoxin production or accessory gene regulator (agr) II polymorphisms. Fifth, we did not attempt to determine whether higher AUC levels were associated with a greater risk of nephrotoxicity. Last, our results may not be applicable to other centers as our study was carried out in a single institution. However, our findings are consistent with the results of other recent investigations.2042

In summary, we were not able to demonstrate any relationship between vancomycin PK indexes and mortality for patients with BAL-positive MRSA HCAP. These findings question the recommendation of achieving vancomycin steady-state trough concentrations of ≥ 15 µg/mL as a predictor of successful patient outcome. However, the answer to this important question can only come from a prospective, randomized assessment of traditional vs aggressive vancomycin dosing strategies.2843

Appendix


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  		Table 4.. PK Equations*

 
Footnotes

Abbreviations: APACHE = acute physiology and chronic health evaluation; AUC = area under the concentration curve; FIO2 = fraction of inspired oxygen; HCAP = health-care–associated pneumonia; MRSA = methicillin-resistant Staphylococcus aureus; PK = pharmacokinetic

The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Received for publication March 28, 2006. Accepted for publication May 15, 2006.

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