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Open Access

Peer-reviewed

Research Article

Epidemiology and Outcome of Pneumonia Caused by Methicillin-Resistant Staphylococcus aureus (MRSA) in Canadian Hospitals

Abstract

Background

MRSA remains a leading cause of hospital-acquired (HAP) and healthcare-associated pneumonia (HCAP). We describe the epidemiology and outcome of MRSA pneumonia in Canadian hospitals, and identify factors contributing to mortality.

Methods

Prospective surveillance for MRSA pneumonia in adults was done for one year (2011) in 11 Canadian hospitals. Standard criteria for MRSA HAP, HCAP, ventilator-associated pneumonia (VAP), and community-acquired pneumonia (CAP) were used to identify cases. MRSA isolates underwent antimicrobial susceptibility testing, and were characterized by pulsed-field gel electrophoresis (PFGE) and Panton-Valentine leukocidin (PVL) gene detection. The primary outcome was all-cause mortality at 30 days. A multivariable analysis was done to examine the association between various host and microbial factors and mortality.

Results

A total of 161 patients with MRSA pneumonia were identified: 90 (56%) with HAP, 26 (16%) HCAP, and 45 (28%) CAP; 23 (14%) patients had VAP. The mean (± SD) incidence of MRSA HAP was 0.32 (± 0.26) per 10,000 patient-days, and of MRSA VAP was 0.30 (± 0.5) per 1,000 ventilator-days. The 30-day all-cause mortality was 28.0%. In multivariable analysis, variables associated with mortality were the presence of multiorgan failure (OR 8.1; 95% CI 2.5-26.0), and infection with an isolate with reduced susceptibility to vancomycin (OR 2.5, 95% CI 1.0-6.3).

Conclusions

MRSA pneumonia is associated with significant mortality. Severity of disease at presentation, and infection caused by an isolate with elevated MIC to vancomcyin are associated with increased mortality. Additional studies are required to better understand the impact of host and microbial variables on outcome.

Citation: Tadros M, Williams V, Coleman BL, McGeer AJ, Haider S, Lee C, et al. (2013) Epidemiology and Outcome of Pneumonia Caused by Methicillin-Resistant Staphylococcus aureus (MRSA) in Canadian Hospitals. PLoS ONE 8(9): e75171. https://doi.org/10.1371/journal.pone.0075171

Editor: Jan Kluytmans, Amphia Ziekenhuis, Netherlands

Received: March 11, 2013; Accepted: August 12, 2013; Published: September 17, 2013

Copyright: © 2013 Tadros et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This work was supported by an investigator-initiated grant from Pfizer Canada, Inc. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: Dr. A. Simor received research funding to conduct this investigator-initiated study from Pfizer Canada, Inc., and he has received honoraria from Pfizer Canada, Inc. and from Sunovion Pharmaceuticals Canada Inc. for lectures, and for serving on advisory boards. Dr. C. Lee has received honoraria for speaking on behalf of Sunovion Pharmaceuticals Canada Inc. Dr. A. McGeer has received investigator-initiated research funding from Pfizer Canada, Inc., and has received honoraria for serving on a Pfizer Canada, Inc. advisory board. Dr. E. Rubinstein has received honoraria as a speaker and advisor from Pfizer Canada, Inc., Astellas Canada, and Cubist. All other authors report no potential conflicts of interest. This does not alter the authors' adherence to all PLOS ONE policies on sharing data and materials.

Introduction

Methicillin-resistant Staphylococcus aureus (MRSA) is among the most frequently identified pathogens causing healthcare-associated pneumonia (HCAP), hospital-acquired pneumonia (HAP), and ventilator-associated pneumonia (VAP) worldwide [1,2]. Although it appears to be a relatively uncommon cause of community-acquired pneumonia (CAP) [3], MRSA may be an important emerging respiratory pathogen in the community, associated with severe necrotizing infection especially following recent influenza [4-6]. Regardless of the setting, MRSA pneumonia is associated with significant morbidity and mortality [7,8]. However, the epidemiology of MRSA pneumonia is not well understood, and in particular, the relative importance of host and microbial factors in affecting its outcome is uncertain. Host factors such as underlying comorbidities or measures of severity of illness have been associated with poor outcome [9,10]. Other studies examining the role of putative microbial virulence factors such as the presence of the Panton-Valentine leukocidin (PVL) gene or of reduced susceptibility to glycopeptide antimicrobial agents, have yielded conflicting results [9,11-15]. The objectives of this study were to describe the epidemiology and outcomes associated with MRSA pneumonia in adults in Canadian hospitals, and to identify host and microbial variables associated with mortality.

Materials and Methods

Ethics statement

The study was approved by the Research Ethics Board, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre (Study No. 356-2009). All data submitted to the study investigators were anonymized, and no personal identifying information was available to the investigators. The study was observational laboratory-based surveillance with review of medical records. Study investigators and research associates had no direct patient contact and the study protocol did not involve any change in patient care or management; all decisions regarding patient investigation and treatment were at the discretion of the attending physician. The Research Ethics Board approved this study without any requirement for patient consent (neither verbal nor written).

Study design

Prospective surveillance for MRSA pneumonia in adults (≥ 18 years of age) was conducted in 11 Canadian hospitals from January 1 to December 31, 2011. Participating hospitals were in four Canadian provinces, and had a mean of 610 beds (range: 404-1,500 beds); nine were tertiary-care teaching hospitals. Surveillance was laboratory-based. Whenever MRSA was recovered in culture from a respiratory specimen (sputum, endotracheal aspirate, bronchoscopy specimen, lung biopsy, or pleural fluid), or a blood culture the patient’s medical records were reviewed by experienced infection prevention and control personnel to determine whether criteria for MRSA pneumonia were present. Patients could not be included in this study more than once.

Study definitions

The diagnosis of pneumonia required clinical features (fever or hypothermia, new or increasing cough or dyspnea, production of purulent sputum, or leukocytosis) in association with new or progressive pulmonary infiltrates suggestive of infection on chest x-ray [16]. MRSA was considered to be the etiologic agent if it was cultured from pleural fluid or a protected bronchoscopy specimen, or from another respiratory specimen in association with a Gram stain that revealed ≥ 25 white blood cells per high power field and concordant bacterial morphology. If the organism was recovered only from a blood culture, a diagnosis of MRSA pneumonia was accepted if criteria for pneumonia were met, and the bacteremia was not associated with another site of infection. Patients with infective endocarditis were excluded.

HCAP, HAP, and VAP were defined using previously published criteria [1,17]. CAP was defined as lower respiratory infection with onset less than 48 hours after hospital admission and no other hospitalization in the previous 90 days or other significant healthcare exposure in the prior 30 days. Place of MRSA acquisition (healthcare facility or community) was ascertained based on available epidemiologic data and using previously published criteria [18].

Necrotizing pneumonia was determined to be present based on typical radiographic features detected on a contrast-enhanced chest CT scan [19]. Multiorgan failure was defined as hypotension in association with at least two of acute renal injury, acute hepatic injury, or coagulopathy. Empiric antimicrobial therapy was defined as treatment prescribed within the first 48 hours after a diagnosis of pneumonia was made, but before MRSA had been identified in culture. Appropriate antimicrobial therapy included treatment with vancomycin or linezolid; treatment with clindamycin was also considered to be appropriate if the isolate was susceptible in vitro [20].

Data collection

The medical records of all eligible patients were reviewed for demographic, clinical and epidemiologic data. If treatment included vancomycin, the initial trough vancomycin levels were noted. Outcome (all-cause mortality) and complications related to the pneumonia were determined at 30 days of follow-up from the diagnosis of infection.

Laboratory methods

The initial MRSA isolate from each patient was characterized in a central microbiology laboratory. MRSA was confirmed by detection of the nuc and mecA genes by polymerase chain reaction (PCR) [21]. Antimicrobial susceptibility testing was done by broth microdilution in accordance with Clinical and Laboratory Standards Institute guidelines [22]. Inducible clindamycin resistance was detected using the D-test disk diffusion method [22]. Vancomycin minimum inhibitory concentrations (MICs) were determined using the Etest (AB bioMérieux, Solna, Sweden).

Molecular typing of isolates was done by pulsed-field gel electrophoresis (PFGE) following DNA extraction and digestion with SmaI. PFGE-generated profiles were digitized and analyzed using BioNumerics software, version 5.10 (Applied Maths) [18,23]. Strains designated as PFGE CMRSA-10 resemble the community-associated (CA-MRSA) genotype USA300 (multilocus sequence type 8 [ST8]; clonal complex 8 [CC8]); CMRSA-2 resembles USA100/800 (ST5; CC5). The presence of the PVL gene was determined by PCR [24].

Statistical methods

The incidence of MRSA pneumonia was calculated as the number of cases per 1,000 admissions and per 10,000 patient-days. VAP incidence was calculated as the number of cases per 1,000 ventilator-days. To assess differences between patient populations, categorical variables were expressed as proportions and were compared using the chi-square test or the Fisher exact test as appropriate. Continuous variables were compared using Student’s t test. All tests were 2-tailed, and a P value < 0.05 was considered to be statistically significant. Logistic regression was done to evaluate the association between outcome (30-day all-cause mortality) and certain host- or microbial-related variables. Variables considered in the model were selected a priori based on previously published data [9,13,25], and included age (as a continuous variable), presence of underlying comorbidities (chronic pulmonary, cardiac, or renal disease), pneumonia acquisition (CAP or HCAP/HAP), presence of MRSA bacteremia or multiorgan failure, use of appropriate empiric antimicrobial therapy (prior to identification of MRSA), infecting strain of MRSA with the PVL gene, or with reduced susceptibility to vancomcyin. The goodness of fit of the final model was tested using the goodness-of-fit chi-squared test. All analyses were done using SPSS, Version 16.0 (SPSS Inc., Chicago IL).

Results

A total of 161 patients with MRSA pneumonia were identified: 90 (55.9%) had HAP, 26 (16.1%) had HCAP, and 45 (28.0%) had CAP. Thirty-eight (42.2%) of the nosocomial pneumonias were acquired in an intensive care unit (ICU), and 23 patients (14.3%) had VAP. The mean (± SD) incidence of MRSA pneumonia was 0.34 (± 0.17) per 1,000 admissions (range: 0.14-0.65/1,000 admissions). The mean incidence of MRSA HAP was 0.32 (± 0.26) cases per 10,000 patient-days (range: 0.11-0.78/10,000 patient-days), and of MRSA VAP was 0.30 (± 0.5) per 1,000 ventilator-days (range: 0-1.76/1,000 ventilator-days).

Most (67.1%) patients with MRSA pneumonia were male, and the mean age was 64.2 (± 17.8) years (median age, 68 yrs). Almost all patients (95.0%) had at least one underlying comorbidity, most commonly cardiac disease (31.7%), chronic pulmonary disease (29.2%), or diabetes mellitus (28.0%) (Table 1). Only two (1.2%) patients had prior laboratory-confirmed influenza virus infection. Approximately half (50.9%) of the patients were previously known to have been colonized with MRSA. The initial respiratory specimen that yielded MRSA in patients with pneumonia was sputum in 38%, endotracheal aspirate (28%), and bronchoalveolar lavage (14%); protected bronchoalveolar lavage or brushings were infrequently available. Blood cultures from 31 (19%) patients yielded MRSA, and two (1.2%) patients had MRSA recovered from pleural fluid specimens. MRSA was the only respiratory pathogen identified in most (77%) patients.

No. (%) with the characteristic
VariableAll (n=161)HCAP/HAP (n=116)CAP (n=45)P value
Mean age (± SD), yrs64.2 ± 17.868.4 ± 14.753.5 ± 20.5< 0.001
No. (%) male108 (67.1)76 (65.5)32 (67.1)0.577
Underlying comorbidities
None8 (5.0)3 (2.6)5 (11.1)0.039
Cardiac disease51 (31.7)43 (37.1)8 (17.8)0.023
Chronic pulmonary disease47 (29.2)34 (29.3)13 (28.9)0.992
Diabetes mellitus45 (28.0)36 (31.0)9 (20.0)0.177
Renal disease19 (11.8)18 (15.5)1 (2.2)0.026
Cirrhosis or chronic hepatitis7 (4.3)7 (6.0)00.192
Chemotherapy/radiotherapy7 (4.3)6 (5.1)1 (2.2)0.671
Neutropenia4 (2.5)2 (1.7)2 (4.4)0.311
HIV infection3 (1.9)03 (6.7)0.021
Prior laboratory-confirmed influenza2 (1.2)2 (1.7)00.991
Prior known MRSA colonization82 (50.9)62 (53.4)20 (44.4)0.383
MRSA acquisition
Nosocomial/healthcare-associated139 (86.3)111 (95.7)28 (62.2)< 0.001
Community22 (13.7)5 (4.3)17 (37.8)
Complications
MRSA bacteremia38 (23.6)24 (20.7)14 (31.1)0.153
Admitted to ICU (% of those not already in ICU)39 (31.7)21 (26.9)18 (40.0)0.538
Necrotizing pneumonia/empyema/lung abscess13 (8.1)6 (5.2)7 (15.6)0.049
Multiorgan failure21 (13.0)17 (14.7)4 (8.9)0.438
All-cause 30-day mortality45 (28.0)36 (31.0)9 (20.0)0.177
Death within 48 hrs of onset of pneumonia10 (6.2)8 (6.9)2 (4.4)0.727
Management
Infectious diseases consultation66 (41.0)45 (38.8)21 (46.7)0.350
Appropriate empiric antimicrobial therapya52 (32.2)36 (31.0)16 (35.6)0.579
Mean (± SD) days of antimicrobial therapy14.0 (± 13.0)14.3 (± 14.0)13.2 (± 10.2)0.651
Mean (± SD) vancomycin trough level (µg/mL)b14.4 (± 9.4)15.3 (± 10.4)12.1 (± 6.4)0.125
MRSA PFGE typec
CMRSA-2 (USA100/800)83 (57.2)73 (70.9)10 (23.8)< 0.001
CMRSA-10 (USA300)40 (27.6)20 (19.4)20 (47.6)
Other types 22 (15.2)10 (9.7)12 (28.6)
PVL gene present41 (28.3)19 (18.4)22 (52.4)< 0.001
Vancomycin MIC (µg/mL)d
≤ 0.57 (4.8)5 (4.8)2 (4.9)
1.0 58 (40.0)39 (37.9)19 (45.2)
1.5 73 (50.3)52 (50.5)21 (50.0)
2.0 7 (4.8)7 (6.8)00.102

Table 1. Characteristics of patients with healthcare-associated (HCAP), hospital-acquired (HAP), and community-acquired (CAP) methicillin-resistant Staphylococcus aureus (MRSA) pneumonia.

aAppropriate empiric antimicrobial therapy, treatment with vancomycin, linezolid, or clindamycin if the MRSA isolate was susceptible, in the 24-48 hrs prior to the availability of culture results.
bVancomycin trough levels, among those treated with vancomycin and for whom vancomycin levels were available.
cPFGE, pulsed-field gel electrophoresis (145 isolates available for molecular typing).
dVancomycin MIC, minimal inhibitory concentration (µg/mL) as determined by Etest (145 isolates available for susceptibility testing).
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As compared to patients with MRSA HCAP or HAP, patients with MRSA CAP were younger (mean age 53.5 ± 20.5 yrs vs 68.4 yrs ± 14.7 yrs respectively; P < 0.001), and more likely to be without underlying comorbidities (11.1% vs 2.6% respectively; Odds Ratio [OR] 4.72, 95% Confidence Interval [CI] 1.08-20.41; P = 0.039) (Table 1). MRSA CAP was more likely to have been associated with the development of necrotizing pneumonia, empyema, or lung abscess, although only 10 (6.2%) patients had these complications.

Only 52 (32.2%) patients received empiric antimicrobial therapy with an agent to which MRSA was susceptible in vitro (50 patients treated with vancomycin, one patient with linezolid, and one with clindamycin). Eventually, 133 (82.6%) patients were treated with vancomycin, and 15 (9.3%) received linezolid. The mean (±SD) duration of antimicrobial therapy was 13.3 (± 10.6) days. Of those treated with vancomycin, trough levels were measured at least once and the results were available for 97 (72.9%) patients; the mean (±SD) initial trough vancomycin level was 14.3 (± 9.4) mg/L.

There were 145 (90.0%) MRSA isolates available for laboratory characterization. Of these, 57.2% were healthcare-associated strains (CMRSA-2/USA100/800) based on PFGE typing, and 27.6% were a CA-MRSA clone (CMRSA-10/USA300). Isolates associated with CAP were more likely to be CMRSA-10/USA300 (47.6% vs 19.4% respectively; OR 7.30, 95% CI 2.95-18.06; P<0.001) and to possess the PVL gene (52.4% vs 18.4% respectively; OR 4.86, 95% CI 2.22-10.65; P<0.001) (Table 1). There were 41 (28.3%) isolates that had the PVL gene, and these strains were more likely to be recovered from younger patients, from those without underlying comorbidities, and from those with CAP (Table 2). Infection with a PVL-positive isolate was also more likely to be complicated by necrotizing pneumonia, empyema, or lung abscess (17.1% vs 4.8% respectively; OR 4.08, 95% CI 1.21-13.70 P = 0.038), but there was no difference in the 30-day mortality in those patients who were infected by strains with or without the PVL gene (26.8% vs 28.8% respectively; P = 0.96). The distribution of vancomycin MICs as determined by Etest is summarized in Table 1. Resistance to vancomycin was not detected, and only 7 (4.8%) had a vancomycin MIC of 2.0 µg/mL. Most isolates were resistant to clindamycin and erythromycin (68.3% and 91.0%, respectively), but the majority were susceptible to cotrimoxazole (95.5%), tetracycline (92.5%), and tigecycline (97.9%). All isolates were susceptible to linezolid.

VariableNo. (%)Odds Ratio (95% CI)P value
PVL gene present (n=41)PVL gene absent (n=104)
Mean age (± SD), yrs 55.2 ± 16.867.9 ± 16.0< 0.001
No. (%) male28 (68.3)68 (65.4)1.14 (0.53-2.47)0.577
Underlying comorbidities
None4 (9.8)2 (1.9)1.82 (0.83-1.93)0.054
Cardiac disease7 (17.1)39 (37.5)0.34 (0.14-0.85)0.018
Chronic pulmonary disease14 (34.1)30 (28.8)1.28 (0.59-2.77)0.552
Diabetes mellitus 5 (12.2)31 (29.8)0.33 (0.12-0.91)0.033
Renal disease1 (2.4)15 (14.4)0.15 (0.02-1.02)0.041
Cirrhosis or chronic hepatitis0 6 (5.8)Undefined 0.184
Neutropenia3 (7.3)0Undefined0.021
HIV infection 2 (4.9)1 (1.0)5.28 (0.47-59.91)0.193
Prior laboratory-confirmed influenza1 (2.4)1 (1.0)2.58 (0.16-42.17)0.487
Prior known MRSA colonization17 (41.5)56 (53.8)0.61 (0.29-1.26)0.200
MRSA acquisition
Nosocomial/healthcare-associated 29 (70.7)95 (91.3)
Community12 (29.3)9 (8.7)4.37 (1.67-11.40)0.003
MRSA pneumonia
HCAP/HAPa19 (46.3)84 (80.8)
CAPa22 (53.7)24 (19.2)4.86 (2.22-10.65)< 0.001
Complications
MRSA bacteremia14 (34.1)20 (19.6)2.13 (0.95-4.78)0.082
Admitted to ICU (% of those not already in ICU)15 (48.4)22 (36.7)1.62 (0.67-3.90)0.368
Necrotizing pneumonia/empyema/lung abscess7 (17.1)5 (4.8)4.08 (1.21-13.70)0.038
Multiorgan failure5 (12.2)13 (12.5)0.97 (0.32-2.92)0.998
All-cause 30-day mortality11 (26.8)30 (28.8)0.90 (0.40-2.04)0.987
Death within 48 hrs of onset of pneumonia3 (7.3)7 (6.7)1.09 (0.27-4.45)0.900
Management
Infectious diseases consultation21 (51.2)38 (37.6)1.74 (0.84-3.62)0.188
Appropriate empiric antimicrobial therapyb17 (41.5)28 (26.9)1.92 (0.81-4.12)0.111
Mean (± SD) days of antimicrobial therapy11.9 (± 10.0)15.1 (± 14.5)0.209
Mean (± SD) vancomycin trough level (µg/mL)c9.7 (± 6.6)15.7 (± 9.9)0.008
Vancomycin trough level (µg/mL)c
< 15.017 (73.9)36 (53.7)
≥ 15.06 (26.1)31 (46.3)0.41 (0.14-1.17)0.14
MRSA PFGE typed
CMRSA-2 (USA100/800)0 83 (79.8)
CMRSA-10 (USA300)36 (87.8)4 (3.8)18.9 (7.99-44.74)< 0.001
Other types 5 (12.2)17 (16.4)
Vancomycin MIC (µg/mL)e
≤ 1.028 (68.3)37 (35.6)
≥ 1.513 (31.7)67 (64.4)0.26 (0.12-0.55)< 0.001

Table 2. Characteristics of patients with methicillin-resistant Staphylococcus aureus (MRSA) pneumonia associated with the presence or absence of the Panton-Valentine Leukocidin (PVL) gene.

aHCAP, healthcare-associated pneumonia; HAP, hospital-acquired pneumonia; CAP, community-acquired pneumonia
bAppropriate empiric therapy, treatment with vancomycin, linezolid, or clindamycin if the MRSA isolate was susceptible, in the 24-48 hrs prior to the availability of culture results.
cVancomycin trough levels, among those treated with vancomycin and for whom vancomycin levels were available.
dPFGE, pulsed-field gel electrophoresis (145 isolates available for molecular typing).
eVancomycin MIC, minimal inhibitory concentration (µg/mL) as determined by Etest (145 isolates available for susceptibility testing).
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MRSA bacteremia was detected in 38 (23.6%) patients, and 21 (13.0%) had evidence of multiorgan failure within 24 hours of the onset of the pneumonia. Of those who were not already in an ICU at the time MRSA pneumonia was identified, 39 (31.7%) were subsequently admitted or transferred to an ICU. A total of 45 patients died (all-cause 30-day mortality, 28.0%); 10 (6.2%) patients died within 48 hours of the onset of the infection. The results of a univariate analysis of variables associated with 30-day mortality are summarized in Table 3. Mortality was higher in patients with underlying cirrhosis or chronic hepatitis, MRSA bacteremia, or multiorgan failure. Infection caused by isolates with vancomycin MIC ≥ 1.5 µg/mL was also associated with increased risk of dying, but vancomycin trough levels ≥ 15 µg/mL were not associated with improved outcome.

VariableNo. (%)Odds Ratio (95% CI)P value
Alive at 30 days (n=116)Dead at 30 days (n=45)
Mean age (± SD), yrs 63.0 (18.5)67.4 (15.5)0.152
No. (%) male78 (67.2)30 (66.7)0.97 (0.47-2.02)0.998
Underlying comorbidities
None7 (6.0)1 (2.22)0.48 (0.34-23.64)0.444
Cardiac disease36 (26.7)15 (33.3)1.11 (0.53-2.32)0.851
Chronic pulmonary disease30 (25.9)17 (37.8)1.74 (0.84-3.62)0.176
Diabetes mellitus31 (26.7)14 (31.1)1.24 (0.58-2.63)0.565
Renal disease11 (9.5)8 (17.8)2.06 (0.77-5.26)0.174
Cirrhosis or chronic hepatitis2 (1.7)5 (11.1)7.13 (1.33-38.19)0.019
Neutropenia1 (0.9)3 (6.7)8.21 (0.83-81.16)0.067
HIV infection2 (1.7)1 (2.2)1.30 (0.12-14.65)1.00
Prior laboratory-confirmed influenza2 (1.7)00.98 (0.96-1.01)1.00
Prior known MRSA colonization56 (48.3)26 (57.8)1.47 (0.73-2.94)0.30
MRSA acquisition
Nosocomial/healthcare-associated99 (85.3)40 (88.9)
Community17 (14.7)5 (11.1)0.73 (0.25-2.11)0.621
Pneumonia acquisition
HCAP/HAPa 80 (69.0)36 (80.0)
CAPa 36 (31.0)9 (20.0)0.56 (0.24-1.27)0.177
Complications
MRSA bacteremia20 (17.2)18 (41.9)3.46 (1.59-7.49)0.003
Multiorgan failure5 (4.3)16 (35.6)12.25 (4.14-36.22)<0.001
Necrotizing pneumonia, empyema, or lung abscess10 (8.6)3 (6.7)0.76 (0.20-2.89)0.997
Management
Infectious diseases consultation49 (42.2)17 (39.5)0.87 (0.42-1.77)0.721
Appropriate empiric antimicrobial therapyb36 (31.0)16 (35.6)1.23 (0.59-2.53)0.579
Vancomycin trough levelc
< 15 µg/mL45 (59.2)11 (52.4)
≥ 15 µg/mL31 (40.8)10 (47.6)1.32 (0.50-3.48)0.623
Mean (± SD) vancomycin level (µg/ml)c14.3 (10.1)14.5 (6.7)0.945
MRSA PFGE typed
CMRSA-2 (USA100/800)57 (54.8)26 (63.4)0.83 (0.36-1.92)0.665
CMRSA-10 (USA300)29 (27.9)11 (26.8)
Other types18 (17.3)4 (9.8)
PVL gene present30 (28.8)11 (26.8)0.90 (0.40-2.04)0.998
Vancomycin MIC (µg/mL)e
≤ 1.052 (50.0)13 (31.7)
≥ 1.552 (50.0)28 (68.4)2.15 (1.01-4.61)0.053

Table 3. Variables associated with 30-day all-cause mortality in univariate analysis in patients with methicillin-resistant Staphylococcus aureus (MRSA) pneumonia.

aHCAP, healthcare-associated pneumonia; HAP, hospital-acquired pneumonia; CAP, community-acquired pneumonia
bAppropriate empiric antimicrobial therapy, treatment with vancomycin, linezolid, or clindamycin if the MRSA isolate was susceptible, in the 24-48 hrs prior to the availability of culture results.
cVancomycin trough levels, among those treated with vancomycin and for whom vancomycin levels were available.
dPFGE, pulsed-field gel electrophoresis (145 isolates available for molecular typing)
eVancomycin MIC, minimal inhibitory concentration (µg/mL) as determined by Etest (145 isolates available for susceptibility testing)
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In the multivariable analysis the only variables that were associated with mortality were the presence of multiorgan failure (OR 8.1, 95% CI 2.5-26.0; P<0.001), and infection caused by MRSA isolates with reduced susceptibility to vancomcyin (MIC 1.5-2.0 µg/mL) (OR 2.5, 95% CI 1.0-6.3; P=0.05) (Table 4).

VariablesAdjusted Odds Ratio (95% Confidence Interval)P value
Age (yrs)1.03 (1.00-1.06)0.071
Underlying cardiac or chronic pulmonary disease0.94 (0.39-2.26)0.886
Underlying chronic renal disease1.61 (0.47-5.46)0.449
CAP (community-acquired pneumonia)0.68 (0.22-2.11)0.506
MRSA bacteremia2.25 (0.87-5.80)0.094
Presence of multiorgan failure8.09 (2.51-26.04)< 0.001
Appropriate empiric antimicrobial therapya1.52 (0.61-3.78)0.373
MRSA isolate with PVL gene1.82 (0.57-5.80)0.312
MRSA with vancomycin MIC ≥ 1.5 µg/mLb2.50 (1.00-6.28)0.051

Table 4. Multivariate analysis of variables associated with 30-day all-cause mortality in patient with methicillin-resistant Staphylococcus aureus (MRSA) pneumonia.

aAppropriate empiric antimicrobial therapy, treatment with vancomycin, linezolid, or clindamycin if the MRSA isolate was susceptible, in the 24-48 hrs prior to the availability of culture results.
bVancomycin MIC, minimal inhibitory concentration (µg/mL) as determined by Etest
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Discussion

In the past decade a decrease in the incidence of invasive healthcare-associated MRSA infections attributed to the implementation of effective infection prevention and control measures has been observed in many countries [26,27]. However, the burden of respiratory infections due to MRSA remains substantial. Approximately 36,540 pneumonias attributed to MRSA were estimated to have occurred in US hospitals in 2005 [28], and MRSA remains among the most frequently identified pathogens associated with nosocomial respiratory tract infections. However, there is considerable geographic variability in reported MRSA infection rates and assessment of the burden of disease associated with MRSA pneumonia has been difficult. Most investigations have been single center studies, and incidence has infrequently been determined. The results of this study indicate that MRSA HAP and VAP rates in Canadian hospitals are lower than those reported from a number of other countries. The incidence of MRSA HAP in French ICUs ranged from 0.50-0.90 per 1,000 patient-days [29], and mean VAP rates in US medical/surgical ICUs participating in surveillance conducted by the National Healthcare Safety Network were 0.47-0.59 per 1,000 ventilator-days [30]. A little more than one-quarter (28%) of all the pneumonias identified in our study were thought to have been community-acquired. However, MRSA appears to be an uncommon cause of CAP overall, accounting for just a small percentage of cases requiring hospital admission [3,31]. Our study was not population-based, so we were unable to determine the incidence of MRSA CAP, but estimated rates have ranged from 0.51-0.64 per 100,000 population [32].

CMRSA-10/USA300 strains represented the second most common clone identified in our study, occurring in 27.6% of cases. Most of the infections associated with CA-MRSA strains were CAP (infrequently post-influenza), but these strains were also identified in nearly 20% of patients with HAP and HCAP. These results are similar to those recently reported in a study of isolates obtained in a large international clinical trial involving patients with MRSA pneumonia [33]. Most (56.0%) of the isolates obtained globally were representative of traditional healthcare-associated strains, but the second most common (23.3%) clone was CC8, corresponding to CA-MRSA strains with SCCmec type IV; in the US most of these isolates were USA300 strains, PVL-positive.

The 30-day all-cause mortality of 28.0% in this study is within the range (16% to 37%) of mortality rates reported in other investigations [8,9,11,34]. The role of microbial, host, and treatment variables on patient outcomes remains uncertain. In a number of studies the only independent risk factors for mortality in patients with MRSA pneumonia included host factors such as older age, and the presence of underlying chronic pulmonary disease [9,10,25]. Markers of disease severity, such as the Acute Physiology and Chronic Health Evaluation II (APACHE II) score, or requirement for vasopressor administration have also been associated with higher mortality rates [9,25]. In our study, we were unable to document APACHE II scores, but the presence of multiorgan failure, a marker for severity of disease, was the variable most strongly associated with increased risk of dying. Although we found a trend for increased mortality with increasing age, the association was not statistically significant.

The PVL gene is commonly found in CA-MRSA strains, and it has been associated with severe necrotizing S. aureus pneumonia with increased mortality [35,36]. However, our results are similar to those of other recent studies of MRSA HAP that did not find an association between the presence of PVL genes and increased mortality or higher risk of treatment failure [9,13,14]. A recent systematic review also found no evidence of an association between strains with PVL genes and severity of staphylococcal pneumonia [37].

Infection caused by isolates with reduced susceptibility to vancomycin has been associated with increased mortality in patients with HCAP, HAP or VAP caused by MRSA [9,11,12,38]. In our study, pneumonia caused by an isolate with a vancomycin MIC ≥ 1.5 µg/mL (as determined by Etest) was associated with increased mortality. We were not able to determine whether there were any heteroresistant vancomycin-intermediate (hVISA) isolates, but this phenotype was not associated with increased mortality in two previous studies [11,15].

Almost all patients with MRSA pneumonia in this study were treated with vancomycin, so it was not possible to assess the effect of specific antimicrobial agents on outcome. Only about one-third of patients received either vancomycin or linezolid as empiric therapy, presumably because MRSA is perceived to be a relatively uncommon cause of pneumonia in hospitalized patients in Canada. The delay in starting appropriate therapy was not associated with increased mortality, similar to findings in a study of patients with nosocomial bacteremic staphylococcal pneumonia [39], although these studies have limited power to detect a clinically significant effect. Treatment guidelines have recommended aiming for higher vancomycin trough levels (15-20 µg/mL) when this drug is being used to treat serious MRSA infections such as pneumonia [20]. However the benefit of higher vancomycin dosing has not been documented. In this study, we did not find an association between higher vancomycin trough levels and improved outcome, similar to results reported in two other investigations [25,34].

This study is the first to describe the incidence and epidemiology of MRSA pneumonia in Canadian hospitals, and was also able to identify certain host and microbial characteristics associated with outcome. However, a number of study limitations should be noted. Although we used standardized case definitions, the diagnosis of pneumonia was based on clinical criteria, and was not based on quantitative bronchoalveolar lavage cultures. As a result, cases of pneumonia may have been overdiagnosed, and patients colonized but not infected with MRSA may have been included. There may have been a survivor bias for patients with CAP, as it is possible that some patients with MRSA CAP may have died prior to hospital admission. We believe this is unlikely to have had a major impact on our results because death prior to hospitalization in patients with pneumonia in Canada is thought to occur rarely (unpublished data, Ontario Ministry of Health and Long Term Care). We also performed a left truncated survival analysis, and a logistic regression analysis stratified by whether the infection was healthcare-associated or not (data not shown), and the results of these analyses did not substantially affect the results. Although an effort was made to account for important confounders in the analysis of variables associated with mortality, important confounding covariates or interactions may have been missed. We were unable to measure severity of infection by determining clinical pulmonary infection scores (CPIS), but relied on the presence of mutiorgan failure as a clinical marker of severity of disease. The analysis of vancomycin trough levels included only the first levels obtained, and may not have reflected adjustments made to optimize vancomycin dosing. The study included a convenience sample of hospitals, predominantly teaching hospitals, and may not be representative of other healthcare facilities.

In conclusion, MRSA pneumonia rates in Canadian hospitals are relatively low, but the infection is associated with significant morbidity and 30-day mortality (28.0%). Variables independently associated with mortality were the presence of multiorgan failure, and infection caused by an isolate with reduced susceptibility to vancomycin. Additional studies are required to better understand the interaction of host factors, microbial virulence, and the impact of treatment variables on outcome in patients with MRSA pneumonia.

Author Contributions

Conceived and designed the experiments: MT BLC AJM ER LJ GT AES. Performed the experiments: MT VW BLC AJM SH CL HI ER MJ LJ SM KK NL KNS JP SS GT CW AES. Analyzed the data: MT VW BLC AJM AES. Contributed reagents/materials/analysis tools: MT VW BLC AJM CW AES. Wrote the manuscript: MT VW BLC AJM AES. The following provided important critical revisions of the manuscript: MT VW BLC AJM SH CL HI ER MJ LJ SM KK NL KNS JP SS GT.

References

  1. 1. Kollef MH, Shorr A, Tabak YP, Gupta V, Liu LZ et al. (2005) Epidemiology and outcomes of health-care-associated pneumonia: results from a large US database of culture-positive pneumonia. Chest 128: 854-862. PubMed: 16354854.
  2. 2. Rubinstein E, Kollef MH, Nathwani D (2008) Pneumonia caused by methicillin-resistant Staphylococcus aureus. Clin Infect Dis 46(Suppl. 5): S378-S385. doi:https://doi.org/10.1086/533594. PubMed: 18462093.
  3. 3. Moran GJ, Krishnadasan A, Gorwitz RJ, Fosheim GE, Albrecht V et al. (2012) Prevalence of methicillin-resistant Staphylococcus aureus as an etiology of community-acquired pneumonia. Clin Infect Dis 54: 1126-1133. doi:https://doi.org/10.1093/cid/cis022. PubMed: 22438343.
  4. 4. Francis JS, Doherty MC, Lopatin U, Johnston CP, Sinha G et al. (2005) Severe community-onset pneumonia in healthy adults caused by methicillin-resistant Staphylococcus aureus carrying the Panton-Valentine leukocidin gene. Clin Infect Dis 40: 100-107. doi:https://doi.org/10.1086/427148. PubMed: 15614698.
  5. 5. Hageman JC, Uyeki TM, Francis JS, Jernigan DB, Wheeler JG et al. (2006) Severe community-acquired pneumonia due to Staphylococcus aureus, 2003-04 influenza season. Emerg Infect Dis 12: 894-899. doi:https://doi.org/10.3201/eid1206.051141. PubMed: 16707043.
  6. 6. Kallen AJ, Brunkard J, Moore Z, Budge P, Arnold KE et al. (2009) Staphylococcus aureus community-acquired pneumonia during the 2006 to 2007 influenza season. Ann Emerg Med 53: 358-365. doi:https://doi.org/10.1016/j.annemergmed.2008.04.027. PubMed: 18534715.
  7. 7. Shorr AF, Tabak YP, Gupta V, Johannes RS, Liu LZ et al. (2006) Morbidity and cost burden of methicillin-resistant Staphylococcus aureus in early onset ventilator-associated pneumonia. Crit Care 10: R97. doi:https://doi.org/10.1186/cc4934. PubMed: 16808853.
  8. 8. Shorr AF, Haque N, Taneja C, Zervos M, Lamerato L et al. (2010) Clinical and economic outcomes for patients with health care-associated Staphylococcus aureus pneumonia. J Clin Microbiol 48: 3258-3262. doi:https://doi.org/10.1128/JCM.02529-09. PubMed: 20631118.
  9. 9. Haque NZ, Arshad S, Peyrani P, Ford KD, Perri MB et al. (2012) Analysis of pathogen and host factors related to clinical outcomes in patients with hospital-acquired pneumonia due to methicillin-resistant Staphylococcus aureus. J Clin Microbiol 50: 1640-1644. doi:https://doi.org/10.1128/JCM.06701-11. PubMed: 22337980.
  10. 10. Bouza E, Giannella M, Bunsow E, Torres MV, Granda MJ et al. (2012) Ventilator-associated pneumonia due to meticillin-resistant Staphylococcus aureus: risk factors and outcome in a large general hospital. J Hosp Infect 80: 150-155. doi:https://doi.org/10.1016/j.jhin.2011.11.013. PubMed: 22226126.
  11. 11. Haque NZ, Zuniga LC, Peyrani P, Reyes K, Lamerato L et al. (2010) Relationship of vancomycin minimum inhibitory concentration to mortality in patients with methicillin-resistant Staphylococcus aureus hospital-acquired, ventilator-associated, or health-care-associated pneumonia. Chest 138: 1356-1362. doi:https://doi.org/10.1378/chest.09-2453. PubMed: 20558550.
  12. 12. Choi EY, Huh JW, Lim CM, Koh Y, Kim SH et al. (2011) Relationship between the MIC of vancomycin and clinical outcome in patients with MRSA nosocomial pneumonia. Intensive Care Med 37: 639-647. doi:https://doi.org/10.1007/s00134-011-2130-7. PubMed: 21253703.
  13. 13. Peyrani P, Allen M, Wiemken TL, Haque NZ, Zervos MJ et al. (2011) Severity of disease and clinical outcomes in patients with hospital-acquired pneumonia due to methicillin-resistant Staphylococcus aureus strains not influenced by the presence of the Panton-Valentine leukocidin gene. Clin Infect Dis 53: 766-771. doi:https://doi.org/10.1093/cid/cir541. PubMed: 21880581.
  14. 14. Sharma-Kuinkel BK, Ahn SH, Rude TH, Zhang Y, Tong SYC et al. (2012) Presence of genes encoding Panton-Valentine leukocidin is not the primary determinant of outcome in patients with hospital-acquired pneumonia due to Staphylococcus aureus. J Clin Microbiol 50: 848-856. doi:https://doi.org/10.1128/JCM.06219-11. PubMed: 22205797.
  15. 15. van Hal SJ, Paterson DL (2011) Systematic review and meta-analysis of the significance of heterogeneous vancomycin-intermediate Staphylococcus aureus isolates. Antimicrob Agents Chemother; 55: 405-410. doi:https://doi.org/10.1128/AAC.01133-10. PubMed: 21078939.
  16. 16. Horan TC, Andrus M, Dudeck MA (2008) CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting. Am J Infect Control 36: 309-332. doi:https://doi.org/10.1016/j.ajic.2008.03.002. PubMed: 18538699.
  17. 17. American Thoracic Society, Infectious Diseases Society of America (2005) Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 171: 388-416. doi:https://doi.org/10.1164/rccm.200405-644ST. PubMed: 15699079.
  18. 18. Simor AE, Gilbert NL, Gravel D, Mulvey MR, Bryce E et al. (2010) Methicillin-resistant Staphylococcus aureus colonization or infection in Canada: national surveillance and changing epidemiology, 1995-2007. Infect Control Hosp Epidemiol 31: 348-356. doi:https://doi.org/10.1086/651313. PubMed: 20148693.
  19. 19. Tsai Y-F, Ku Y-H (2012) Necrotizing pneumonia: a rare complication of pneumonia requiring special consideration. Curr Opin Pulm Med 18: 246-252. doi:https://doi.org/10.1097/MCP.0b013e3283521022. PubMed: 22388585.
  20. 20. Liu C, Bayer A, Cosgrove SE, Daum RS, Fridkin SK et al. (2011) Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children: Executive summary. Clin Infect Dis 52: 285-292. doi:https://doi.org/10.1093/cid/cir034. PubMed: 21217178.
  21. 21. Louie L, Goodfellow J, Mathieu P, Glatt A, Louie M et al. (2002) Rapid detection of methicillin-resistant staphylococci from blood culture bottles by using a multiplex PCR assay. J Clin Microbiol 40: 2786-2790. doi:https://doi.org/10.1128/JCM.40.8.2786-2790.2002. PubMed: 12149330.
  22. 22. Clinical and Laboratory Standards Institute (2012) Performance standards for antimicrobial susceptibility testing; 22nd informational supplement. M100-MS22 Wayne, PA: Clinical and Laboratory Standards Institute. PubMed: 22476137.
    • 23. Christianson S, Golding GR, Campbell J, the Canadian Nosocomial Infection Surveillance Program, Mulvey MR (2007) Comparative genomics of Canadian epidemic lineages of methicillin-resistant Staphylococcus aureus. J Clin Microbiol 45: 1904-1911. doi:https://doi.org/10.1128/JCM.02500-06. PubMed: 17428941.
    • 24. Lina G, Piémont Y, Godail-Gamot F, Bes M, Peter MO et al. (1999) Involvement of Panton-Valentine leukocidin-producing Staphylococcus aureus in primary skin infections and pneumonia. Clin Infect Dis 29: 1128-1132. doi:https://doi.org/10.1086/313461. PubMed: 10524952.
    • 25. Jeffres MN, Isakow W, Doherty JA, McKinnon PS, Ritchie DJ et al. (2006) Predictors of mortality for methicillin-resistant Staphylococcus aureus health-care-associated pneumonia: specific evaluation of vancomycin pharmacokinetic indices. Chest 130: 947-955. doi:https://doi.org/10.1378/chest.130.4.947. PubMed: 17035423.
    • 26. Kallen AJ, Mu Y, Bulens S, Reingold A, Petit S et al. (2010) Health care-associated invasive MRSA infections, 2005-2008. JAMA 304: 641-648. doi:https://doi.org/10.1001/jama.2010.1115. PubMed: 20699455.
    • 27. Johnson AP, Davies J, Guy R, Abernethy J, Sheridan E et al. (2012) Mandatory surveillance of methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia in England: the first 10 years. J Antimicrob Chemother 67: 802-809. doi:https://doi.org/10.1093/jac/dkr561. PubMed: 22223229.
    • 28. Klein E, Smith DL, Laxminarayan R (2007) Hospitalizations and deaths caused by methicillin-resistant Staphylococcus aureus, United States, 1999-2005. Emerg Infect Dis 13: 1840-1846. doi:https://doi.org/10.3201/eid1312.070629. PubMed: 18258033.
    • 29. Moalla M, Baratin D, Giarrd H, Vanhems P (2008) Incidence of methicillin-resistant Staphylococcus aureus nosocomial infections in intensive care units in Lyon University Hospitals, France, 2003-2006. Infect Control Hosp Epidemiol 29: 454-456.
    • 30. Hidron AI, Edwards JR, Patel J, Horan TC, Sievert DM et al. (2008) NHSN Annual Update. Antimicrobial-resistant pathogens associated with healthcare-associated infections: annual summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2006-2007. Infect Control Hosp Epidemiol 29: 996-1011. doi:https://doi.org/10.1086/591861. PubMed: 18947320.
    • 31. Lobo LJ, Reed KD, Wunderink RG (2010) Expanded clinical presentation of community-acquired methicillin-resistant Staphylococcus aureus pneumonia. Chest 138: 130-136. PubMed: 20173050.
    • 32. Vardakas KZ, Matthaiou DK, Falagas ME (2009) Incidence, characteristics and outcomes of patients with severe community-acquired MRSA pneumonia. Eur Respir J 34: 1148-1158. doi:https://doi.org/10.1183/09031936.00041009. PubMed: 19541719.
    • 33. Mendes RE, Deshpande LM, Smyth DS, Shopsin B, Farrell DJ et al. (2012) Characterization of methicillin-resistant Staphylococcus aureus strains recovered from a phase IV clinical trial for linezolid versus vancomycin for treatment of nosocomial pneumonia. J Clin Microbiol 50: 3694-3702. doi:https://doi.org/10.1128/JCM.02024-12. PubMed: 22972817.
    • 34. Wunderink RG, Niederman MS, Kollef MH, Shorr AF, Kunkel MJ et al. (2012) Linezolid in methicillin-resistant Staphylococcus aureus nosocomial pneumonia: a randomized, controlled study. Clin Infect Dis 54: 621-629. doi:https://doi.org/10.1093/cid/cir895. PubMed: 22247123.
    • 35. Vandenesch F, Naimi T, Enright MC, Lina G, Nimmo GR et al. (2003) Community-acquired methicillin-resistant Staphylococcus aureus carrying Panton-Valentine leukocidin genes: worldwide emergence. Emerg Infect Dis 9: 978-984. doi:https://doi.org/10.3201/eid0908.030089. PubMed: 12967497.
    • 36. Gillet Y, Issartel B, Vanhems P, Fournet JC, Lina G et al. (2002) Association between Staphylococcus aureus strains carrying gene for Panton-Valentine leukocidin and highly lethal necrotising pneumonia in young immunocompetent patients. Lancet 359: 753-759. doi:https://doi.org/10.1016/S0140-6736(02)07877-7. PubMed: 11888586.
    • 37. Shallcross LJ, Fragaszy E, Johnson AM, Hayward AC (2013) The role of the Panton-Valentine leucocidin toxin in staphylococcal disease: a systematic review and meta-analysis. Lancet Infect Dis 13: 43-54. doi:https://doi.org/10.1016/S1473-3099(12)70238-4. PubMed: 23103172.
    • 38. van Hal SJ, Lodise TP, Paterson DL (2012) The clinical significance of vancomycin minimum inhibitory concentration in Staphylococcus aureus infections: a systematic review and meta-analysis. Clin Infect Dis 54: 755-771. doi:https://doi.org/10.1093/cid/cir935. PubMed: 22302374.
    • 39. DeRyke CA, Lodise TP Jr, Rybak MJ, McKinnon PS (2005) Epidemiology, treatment, and outcomes of nosocomial bacteremic Staphylococcus aureus pneumonia. Chest 128: 1414-1422. doi:https://doi.org/10.1378/chest.128.3.1414. PubMed: 16162737.