68 yo with pneumonia

Respiratory Medicine (2013) 107, 1266e1270

Available online at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/rmed

Risk factors for methicillin-resistant Staphylococcus aureus in patients with community-onset and hospital-onset pneumonia

D.A. Wooten a,*, L.G. Winston a,b,**

a University of California, San Francisco, Department of Internal Medicine, USA b University of California, San Francisco, Department of Internal Medicine, Division of Infectious Diseases, USA

Received 19 December 2012; accepted 3 May 2013 Available online 4 June 2013

KEYWORDS Community-acquired pneumonia; Healthcare- associated pneumonia; Methicillin-resistant Staphylococcus aureus; Nosocomial pneumonia

* Corresponding author. 1000 West C ** Corresponding author. 1001 Potrer

E-mail addresses: darcy.wooten@u

0954-6111/$ - see front matter ª 201 http://dx.doi.org/10.1016/j.rmed.20

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 infec- tion 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 respira- tory 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 to- bacco use (OR 2.31, CI 1.23e4.31), chronic obstructive pulmonary disease (OR 3.76, CI 1.74 e8.08), and recent antibiotic exposure (OR 4.87, CI 2.35e10.1) in multivariate analysis while patients with hospital-onset disease had an increased MRSA risk with tobacco use (OR 2.66, CI 1.38e5.14), illicit drug use (OR 3.52, CI 2.21e5.59), and recent antibiotic exposure (OR 2.04, CI 3.54e13.01). Hospitalization within the prior three months was associated with decreased risk (OR 0.64, CI 0.46e0.89) in multivariate analysis. Conclusions: This study suggests there are common and distinct risk factors for MRSA pneu- monia based on location of onset. The decreased risk for MRSA pneumonia associated with recent hospitalization is unexpected and warrants further investigation.

arson St., Box 449, Torrance, CA 90502, USA. Tel.: þ1 415 730 7276; fax: þ1 415 353 2649. o Avenue Room 5H22, San Francisco, CA 94110, USA. Tel.: þ1 415 206 8703. csf.edu, [email protected] (D.A. Wooten), [email protected] (L.G. Winston).

3 Elsevier Ltd. All rights reserved. 13.05.006

Risk factors for MRSA pneumonia 1267

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. ª 2013 Elsevier Ltd. All rights reserved.

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.1e3 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 in- fections 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 distin- guish these infections and their risk factors has become increasingly difficult.7e9

Predicting which patients with pneumonia are at risk for MRSA infection is important since delay in appropriate anti- biotics 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.10e12 The risk factors for MRSA pneu- monia, 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 be- tween 2005 and 2010 who had either an MRSA or MSSA respiratory culture (obtained from sputum, tracheal aspi- rate, 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 de- mographic features (age, sex, race), homelessness, health- related behaviors (any history of tobacco use, alcohol use, or illicit drug use), healthcare-associated features (hospi- talization at our facility in the past three months and receipt of antibiotics or steroids as an inpatient at our fa- cility 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 pa- tients had community-onset pneumonia (defined as having a positive respiratory culture sent within 48 h from hospi- talization) 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 pa- tients met criteria for a diagnosis of S. aureus pneumonia based on the criteria described above. The majority of

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

Variable OR (95% CI)

Tobacco use 2.33 (1.45e3.75)* Illicit drug use 2.72 (1.85e3.99)* Recent hospitalization 0.15 (0.08e0.26)* Recent antibiotics 5.13 (3.01e8.76)* COPD 2.56 (1.40e4.65)* Liver disease 2.56 (1.40e4.65)* HIV infection 1.65 (1.05e2.60)*

*P < 0.05.

1268 D.A. Wooten, L.G. Winston

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.

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 an- tibiotics 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 to- bacco use, COPD, and prior antibiotic exposure in multi- variate analysis (Table 3). The majority of all patients with S. aureus pneumonia had hospital onset disease (63%). To- bacco use, illicit drug use, recent exposure to inpatient antibiotics, and liver disease significantly increased the risk for MRSA pneumonia in these patients (Table 4). Interest- ingly, for patients with community-onset and hospital-onset

Table 1 General characteristics of patients and unadjusted od

Sex Female Male

Age Mean age Race White

Non-White Black Hispanic Asian Other

Health-related behaviors Tobacco use Alcohol use Illicit drug use

Housing status Homeless Setting of infection Community-onset

Hospital-onset Healthcare associated features Recent hospitalization

Recent antibiotics Recent steroids

Co-morbidities COPD Hypertension Ischemic heart disease Diabetes Renal disease Liver disease HIV infection

Outcomes ICU admission Death at 30 days

*P < 0.05.

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.

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

ds ratios for MRSA and MSSA (control) pneumonia (N Z 619).

MRSA (273) Control (346) Unadjusted OR (95% CI)

57 85 0.81 (0.55e1.18) 216 261

54 yr 51 yr 1.01 (0.99e1.01) 107 102 1.28 (0.92e1.79) 183 224 70 65 29 58 26 52 58 49 93 62 2.37 (1.63e3.43)* 60 50 1.53 (0.40e5.10)

115 80 2.42 (1.71e3.42)* 36 34 1.39 (0.84e2.39) 87 105 1.00 (0.70e1.43)

186 241 147 223 0.64 (0.46e0.89)* 121 111 1.69 (1.21e2.34)* 47 47 1.32 (0.85e2.05) 52 27 2.78 (1.69e4.56)* 97 120 1.03 (0.74e1.45) 9 10 1.15 (0.46e2.86)

53 66 1.02 (0.68e1.52) 68 68 1.37 (0.93e1.99) 34 25 1.86 (1.06e3.14)* 74 55 1.96 (1.32e2.91)*

217 282 0.88 (0.59e1.30) 49 43 1.54 (0.98e2.40)

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

Variable OR (95% CI)

Tobacco use 2.31 (1.23e4.31)* Illicit drug use 1.59 (0.87e2.97) Recent hospitalization 0.16 (0.07e0.35)* Recent antibiotics 4.87 (2.35e10.1)* COPD 3.76 (1.74e8.08)* Liver disease 0.98 (0.39e2.49) HIV infection 1.40 (0.76e2.59)

*P < 0.05.

Risk factors for MRSA pneumonia 1269

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 pneumo- niae.17 Tobacco-associated injury to the respiratory tract facilitates bacterial adhesion, invasion, and replication, thereby increasing susceptibility to MRSA infection; how- ever, the specific mechanism by which the risk for MRSA is greater than MSSA is unknown. Similarly, patients with un- derlying 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

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

Variable OR (95% CI)

Tobacco use 2.66 (1.38e5.14)* Illicit drug use 3.52 (2.21e5.59)* Recent hospitalization 0.12 (0.06e0.24)* Recent antibiotics 7.01 (3.54e13.01)* COPD 1.40 (0.56e3.47) Liver disease 3.50 (1.51e8.11)* HIV infection 1.63 (0.86e3.11)

*P < 0.05.

studies have shown that it is associated with MRSA pneu- monia.18e20 Our study further supports this finding, sug- gesting 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 epidemi- ology 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 in- fections.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 adjust- ing 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 micro- biological sampling shows only 40% agreement with lung biopsy results.23e25 We attempted to distinguish true S. aureus pneumonia from S. aureus respiratory tract coloni- zation 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 ma- jority of the patients who met criteria for the study were in

1270 D.A. Wooten, L.G. Winston

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 re- sults 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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