• Risk factors for methicillin-resistant Staphylococcus aureus in patient

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    Respiratory Medicine
    Volume 107, Issue 8, August 2013, Pages 1266-1270
    Risk factors for methicillin-resistant Staphylococcus aureus in patients with community-onset and hospital-onset pneumonia
    Author links open overlay panelD.A.WootenaL.G.Winstonab
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    https://doi.org/10.1016/j.rmed.2013.05.006
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    Summary
    Objectives
    The risk factors for methicillin-resistant Staphylococcus aureus (MRSA) pneumonia have not been fully characterized and are likely to be different depending on whether infection is acquired in the community or the hospital.

    Methods
    We conducted a case-control study of 619 adults hospitalized between 2005 and 2010 with either MRSA or methicillin-sensitive S. aureus (MSSA) pneumonia. Patients with a respiratory culture within 48 h of hospitalization had community-onset pneumonia
    whereas patients with a culture collected after this time point had hospital-onset pneumonia.

    Results
    Among patients with community-onset disease, the risk for MRSA was increased by tobacco use (OR 2.31, CI 1.23–4.31), chronic obstructive pulmonary disease (OR 3.76, CI 1.74–8.08), and recent antibiotic exposure (OR 4.87, CI 2.35–10.1) in
    multivariate analysis while patients with hospital-onset disease had an increased MRSA risk with tobacco use (OR 2.66, CI 1.38–5.14), illicit drug use (OR 3.52, CI 2.21–5.59), and recent antibiotic exposure (OR 2.04, CI 3.54–13.01). Hospitalization
    within the prior three months was associated with decreased risk (OR 0.64, CI 0.46–0.89) in multivariate analysis.

    Conclusions
    This study suggests there are common and distinct risk factors for MRSA pneumonia based on location of onset. The decreased risk for MRSA pneumonia associated with recent hospitalization is unexpected and warrants further investigation.

    Summary
    This case-control study showed that there are common and distinct risk factors associated with MRSA pneumonia depending on whether the infection onset is in the hospital or in the community. Recent hospitalization was unexpectedly shown to be associated
    with decreased risk for MRSA pneumonia and warrants further investigation.

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    Keywords
    Community-acquired pneumoniaHealthcare-associated pneumoniaMethicillin-resistant Staphylococcus aureusNosocomial pneumonia
    Introduction
    Methicillin-resistant Staphylococcus aureus (MRSA) is an important cause of both hospital-onset and community-onset pneumonia, associated with increased morbidity and use of healthcare resources compared to infections caused by nonresistant strains.1, 2,
    3 Historically, this infection was confined largely to the healthcare setting and was associated with specific risk factors including recent hospitalization, recent intravenous antibiotics, residence in a long-term care facility, dialysis, and indwelling
    percutaneous catheters.4, 5 However, over the past decade, community-onset MRSA infections in patients without traditional risk factors have emerged.6 Although initially microbiologically and clinically distinct, the boundaries between hospital-onset and
    community-onset MRSA infections have become blurred, with increasing evidence that community MRSA has spread into the hospital setting.7, 8 Moreover, the ability to distinguish these infections and their risk factors has become increasingly difficult.7,
    8, 9

    Predicting which patients with pneumonia are at risk for MRSA infection is important since delay in appropriate antibiotics may result in increased mortality and morbidity while overuse of empirical broad-spectrum antibiotics can create multidrug-
    resistant organisms and contribute to antibiotic-related complications.10, 11, 12 The risk factors for MRSA pneumonia, however, have not been fully described and are likely to be different depending on whether infection onset is in the community or in
    the hospital.8, 13, 14 We conducted a case-control study to determine which risk factors increase the likelihood of MRSA pneumonia amongst patients with S. aureus pneumonia. Additionally, we carried out an a priori subgroup analysis to determine which
    risk factors were associated with MRSA pneumonia in patients with community-onset and hospital-onset S. aureus pneumonia.

    Methods
    Study subjects
    We studied adult patients 18 years of age and older who were hospitalized at San Francisco General Hospital between 2005 and 2010 who had either an MRSA or MSSA respiratory culture (obtained from sputum, tracheal aspirate, bronchoalveolar lavage, or
    pleural fluid sampling). Patients were admitted to a variety of services (Internal Medicine, Surgery, Family Medicine) and to all levels of care within the hospital (ICU, step-down, floor).

    Inclusion criteria
    Using modified definitions from the CDC criteria for healthcare-associated infections, patients with a S. aureus respiratory culture who had at least three out of four clinical features of pneumonia (fever, leukocytosis, cough, and/or opacity on chest X-
    ray) and/or had a diagnosis of pneumonia documented in their discharge summary were included. Cases were defined as patients with the features listed above and a respiratory culture positive for MRSA; controls were defined as patients with the features
    above and a respiratory culture positive for MSSA.

    Exclusion criteria
    Patients with a positive S. aureus respiratory culture but who did not meet the criteria for a diagnosis of pneumonia were excluded.

    Study design
    We conducted a case-control study comparing patients with MRSA pneumonia to those with MSSA pneumonia through a retrospective chart review. We collected data on demographic features (age, sex, race), homelessness, health-related behaviors (any history of
    tobacco use, alcohol use, or illicit drug use), healthcare-associated features (hospitalization at our facility in the past three months and receipt of antibiotics or steroids as an inpatient at our facility in the past three months), major medical co-
    morbidities as determined by ICD-9 coding, admission to the ICU, and death at 30 days from diagnosis. We were unable to obtain data regarding whether patients had been hospitalized at another facility other than our hospital within the past 90 days. We
    also determined whether patients had community-onset pneumonia (defined as having a positive respiratory culture sent within 48 h from hospitalization) or hospital-onset pneumonia (defined as having a positive respiratory culture sent after 48 h from
    admission). Data on pathogen strain typing and susceptibility patterns were not available.

    Data analysis
    We performed bivariate (Fisher's exact and Chi-square) and stratified multivariate analyses. All variables that were statistically significant in bivariate analysis or potentially important with respect to risk for MRSA were included in logistic
    regression analyses. All data were analyzed with STATA version 9.2.

    Results
    There were 1143 patients with respiratory cultures positive for S. aureus between 2005 and 2010. Of these, 619 patients met criteria for a diagnosis of S. aureus pneumonia based on the criteria described above. The majority of patients were middle-age
    men with high rates of substance use (Table 1). Most had traditional risk factors for hospital-onset pneumonia; 370 (60%) had been hospitalized in the past three months, and 232 (37%) had received inpatient antibiotics during this time period. The
    majority (81%) of patients were in the ICU at the time of diagnosis. Of the 619 patients with S. aureus pneumonia, 273 (44%) were infected with MRSA.

    Table 1. General characteristics of patients and unadjusted odds ratios for MRSA and MSSA (control) pneumonia (N = 619).

    MRSA (273) Control (346) Unadjusted OR (95% CI)
    Sex Female 57 85 0.81 (0.55–1.18)
    Male 216 261
    Age Mean age 54 yr 51 yr 1.01 (0.99–1.01)
    Race White 107 102 1.28 (0.92–1.79)
    Non-White 183 224
    Black 70 65
    Hispanic 29 58
    Asian 26 52
    Other 58 49
    Health-related behaviors Tobacco use 93 62 2.37 (1.63–3.43)*
    Alcohol use 60 50 1.53 (0.40–5.10)
    Illicit drug use 115 80 2.42 (1.71–3.42)*
    Housing status Homeless 36 34 1.39 (0.84–2.39)
    Setting of infection Community-onset 87 105 1.00 (0.70–1.43) Hospital-onset 186 241
    Healthcare associated features Recent hospitalization 147 223 0.64 (0.46–0.89)*
    Recent antibiotics 121 111 1.69 (1.21–2.34)*
    Recent steroids 47 47 1.32 (0.85–2.05)
    Co-morbidities COPD 52 27 2.78 (1.69–4.56)*
    Hypertension 97 120 1.03 (0.74–1.45)
    Ischemic heart disease 9 10 1.15 (0.46–2.86)
    Diabetes 53 66 1.02 (0.68–1.52)
    Renal disease 68 68 1.37 (0.93–1.99)
    Liver disease 34 25 1.86 (1.06–3.14)*
    HIV infection 74 55 1.96 (1.32–2.91)*
    Outcomes ICU admission 217 282 0.88 (0.59–1.30)
    Death at 30 days 49 43 1.54 (0.98–2.40)
    *P < 0.05.


    The risk for MRSA pneumonia was significantly increased for smokers, illicit drug users, patients with COPD, HIV, or liver disease, and patients who had received inpatient antibiotics within the past three months (Table 1). There was no difference in
    admission to the ICU or death at thirty days in patients infected with MRSA compared to those infected with MSSA.

    In multivariate analysis, tobacco use, drug use, recent inpatient antibiotic exposure, and COPD independently increased the risk for MRSA compared to MSSA pneumonia (Table 2). Thirty-seven percent of patients with S. aureus pneumonia had community onset
    disease. For this sub-group, the risk of MRSA pneumonia was increased by tobacco use, COPD, and prior antibiotic exposure in multivariate analysis (Table 3). The majority of all patients with S. aureus pneumonia had hospital onset disease (63%). Tobacco
    use, illicit drug use, recent exposure to inpatient antibiotics, and liver disease significantly increased the risk for MRSA pneumonia in these patients (Table 4). Interestingly, for patients with community-onset and hospital-onset disease,
    hospitalization in the preceding three months was associated with a decreased the risk for MRSA (OR 0.46 and 0.50, respectively), even after adjusting for measured covariates.

    Table 2. Adjusted odds ratios for MRSA pneumonia amongst all patients (N = 619).

    Variable OR (95% CI)
    Tobacco use 2.33 (1.45–3.75)*
    Illicit drug use 2.72 (1.85–3.99)*
    Recent hospitalization 0.15 (0.08–0.26)*
    Recent antibiotics 5.13 (3.01–8.76)*
    COPD 2.56 (1.40–4.65)*
    Liver disease 2.56 (1.40–4.65)*
    HIV infection 1.65 (1.05–2.60)*
    *P < 0.05.


    Table 3. Adjusted odds ratios for MRSA pneumonia amongst patients with community-onset disease (N = 229).

    Variable OR (95% CI)
    Tobacco use 2.31 (1.23–4.31)*
    Illicit drug use 1.59 (0.87–2.97)
    Recent hospitalization 0.16 (0.07–0.35)*
    Recent antibiotics 4.87 (2.35–10.1)*
    COPD 3.76 (1.74–8.08)*
    Liver disease 0.98 (0.39–2.49)
    HIV infection 1.40 (0.76–2.59)
    *P < 0.05.


    Table 4. Adjusted odds ratios for MRSA pneumonia amongst patients with hospital-onset pneumonia (N = 390).

    Variable OR (95% CI)
    Tobacco use 2.66 (1.38–5.14)*
    Illicit drug use 3.52 (2.21–5.59)*
    Recent hospitalization 0.12 (0.06–0.24)*
    Recent antibiotics 7.01 (3.54–13.01)*
    COPD 1.40 (0.56–3.47)
    Liver disease 3.50 (1.51–8.11)*
    HIV infection 1.63 (0.86–3.11)
    *P < 0.05.


    Discussion
    In this study, we investigated the risk factors for MRSA pneumonia amongst patients with S. aureus pneumonia, and we identified specific risk factors for patients who had community-onset vs. hospital-onset disease. Our results suggest that the risk
    factors for MRSA pneumonia may be different than those that have traditionally been associated with this infection in the past and that there may be distinct risk factors for community-onset compared to hospital-onset infections.

    The receipt of inpatient antibiotics at our facility within the three months prior to infection was the strongest risk factor for MRSA pneumonia in patients with community and hospital-onset disease. Prior antibiotic exposure is an identified risk factor
    for methicillin-resistance in patients with S. aureus pneumonia.4 Our findings validate this as a risk factor and suggest that clinicians should pay particular attention to this when assessing patients with pneumonia.

    Tobacco use independently increased the risk for MRSA pneumonia in both settings. Smoking tobacco is a well-established, dose-dependent risk factor for pneumonia, especially in patients with additional co-morbidities like HIV infection.15, 16 This risk
    has been described in animal models and in clinical studies for Streptococcus pneumoniae.17 Tobacco-associated injury to the respiratory tract facilitates bacterial adhesion, invasion, and replication, thereby increasing susceptibility to MRSA infection;
    however, the specific mechanism by which the risk for MRSA is greater than MSSA is unknown. Similarly, patients with underlying COPD have underlying damage to the respiratory tract and increased susceptibility, but the reason for a differential risk with
    respect to MRSA found in this study is unclear.

    We identified several variables associated with an increased risk for MRSA pneumonia in patients with hospital-onset disease. Illicit intravenous drug use is a risk factor for MRSA skin and soft tissue infections, and some studies have shown that it is
    associated with MRSA pneumonia.18, 19, 20 Our study further supports this finding, suggesting that the presence of illicit drug use should be considered when starting empirical antibiotics. We also found that liver disease was independently associated
    with increased risk for MRSA pneumonia in patients with hospital-onset disease. To our knowledge, this association has not been previously described.

    Unexpectedly, the risk for MRSA pneumonia was decreased in patients who had been hospitalized within the preceding three months in both the community-onset and hospital-onset groups. This finding was inconsistent with our initial hypothesis and with
    results from prior studies.4, 5 There are several possible explanations for our findings. First, recent studies have shown that the MRSA epidemiology has changed such that specific strains previously seen only in the community are spreading into the
    hospital setting. Neofytos et al. found that 20% of MRSA responsible for ventilator-associated pneumonia at their institution were Panton-Valentine-Leukocidin (PVL) positive, a feature previously seen primarily in community-acquired MRSA infections.21
    Second, patients recently hospitalized may be different in some unmeasured way that protects them from MRSA infection compared to those without this exposure. Data on whether patients had been hospitalized recently at a facility other than our own were
    unavailable and may have confound our results however this would not account for why there was such a high rate of recent hospitalization amongst those patients with MSSA pneumonia in our patient population.

    There were no differences in risk for ICU admission or death at 30 days between the MRSA and MSSA group, regardless of onset of infection. Although other earlier studies suggested that MRSA infections were associated with increased mortality, more recent
    studies demonstrate similar outcomes in patients with pneumonia after adjusting for confounders and receipt of adequate therapy upfront.22

    There are several limitations to our study, most notably the retrospective design with its potential to introduce bias and confounding. Additionally, since we defined hospital-onset disease by the timing of the culture and not the development of clinical
    symptoms, there is the potential for misclassifying hospital-onset disease as community-onset and vice versa. Another limitation is the ability to distinguish patients with true pneumonia vs. patients who were colonized with S. aureus. Chest X-ray
    abnormality has low diagnostic accuracy for VAP and endotracheal microbiological sampling shows only 40% agreement with lung biopsy results.23, 24, 25 We attempted to distinguish true S. aureus pneumonia from S. aureus respiratory tract colonization by
    requiring cases and controls to exhibit signs and symptoms of pneumonia or to have a clinical diagnosis of pneumonia; however, it is possible that some patients with colonization and not true infection were included in our study. Finally, data on S.
    aureus strain typing was not available, limiting our ability to analyze the impact of phenotypic patterns on risk factors and outcomes.

    Caution should be used in generalizing these results. This was a single-center study of patients hospitalized at an urban county hospital with S. aureus pneumonia. The majority of the patients who met criteria for the study were in the ICU, most likely
    because intubated patients are more likely to have a respiratory sample sent as part of the work-up for pneumonia compared to non-intubated patients. Also S. aureus pneumonia tends to be more severe than other infectious etiologies.24, 26 Thus, the
    results may not apply to patients in other settings or to those hospitalized on a general ward. Additionally, we measured the risk of MRSA pneumonia compared to MSSA pneumonia, not to pneumonia from any cause. While this enabled us to control for
    unmeasured differences that could have been present in patients infected with other organisms or who did not have microbiological data, it limits the ability to apply our results to patients with all causes of pneumonia.

    In conclusion, this study suggests that the traditional risk factors associated with MRSA pneumonia may be less applicable and that risk factors may vary for community-onset vs. hospital-onset disease. Tobacco use appears to be a more important risk
    factor than previously described, whereas recent hospitalization did not confer risk for MRSA pneumonia. Recent receipt of antibiotics was associated with significant risk. Using these features, along with severity of illness, to risk stratify patients
    may allow for more appropriate selection of empirical antibiotic therapy.

    Conflict of interest
    None.

    Acknowledgments
    The authors would like to thank Michael Jula and Jeff Tice, MD, for their assistance with this manuscript. This study was supported with a resident-research grant from the UCSF Clinical and Translational Science Institute.

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