Methicillin-Resistant Staphylococcus aureus Pneumonia in Critically Ill Trauma and Burn Patients: A Retrospective Cohort Study

Abstract

Background:

The timing and risk factors for methicillin-resistant Staphylococcus aureus (MRSA) pneumonia in trauma patients are not well characterized. This information is critical for the selection of appropriate empiric antibiotics. The objective of this study was to determine the incidence of MRSA pneumonia in early-onset and late-onset pneumonia and to identify risk factors for MRSA in the trauma-burn intensive care unit (ICU).

Patients and Methods:

We conducted a retrospective cohort study from January 2012 to March 2015 of patients in the trauma and burn ICU with clinical and microbiologic evidence of pneumonia. Demographics, injury type and severity, co-morbidities, antimicrobial agents, and MRSA nasal colonization at ICU admission were extracted from the medical record. A multi-variable exact logistic regression was performed to assess predictors of MRSA pneumonia.

Results:

Eighty patients with 88 episodes of pneumonia were included in the cohort. Ten patients had MRSA pneumonia, an overall incidence of 11.4% of pneumonia episodes with a median onset of seven days. The proportion of MRSA pneumonia episodes was not significantly different in early-onset (<5 days) or late-onset pneumonia, and there were no statistically significant risk factors for developing MRSA pneumonia. The majority of patients with MRSA had at least one known risk factor including homelessness, substance abuse, and receipt of broad-spectrum antibiotic agents.

Conclusions:

The 11.4% overall incidence of MRSA pneumonia in this trauma-burn cohort was similar to what has been reported in other trauma populations, although MRSA was equally likely to be identified in early- and late-onset pneumonia. Our results suggest that risk factors other than duration of hospitalization may be important considerations in the decision to initiate MRSA-active empiric therapy for pneumonia in the trauma-burn ICU.

Pneumonia is a common complication after trauma and emergency surgical procedures [1,2]. Clinical practice guidelines for the empiric treatment of patients with suspected hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) and the results of a multi-center cohort study suggest that antimicrobial agents active against methicillin-resistant Staphylococcus aureus (MRSA) should be prescribed only when risk factors for MRSA are present or when there is a high incidence of MRSA in the intensive care unit (ICU) [3 –5]. Although risk factors for MRSA pneumonia have been identified in medical and surgical ICU populations, there have been few assessments of predictors specific to traumatically injured adults [6 –8].

Trauma patients represent a unique population of critically ill patients who may not be adequately described by risk factors for multi-drug–resistant organisms and recommendations for empiric antimicrobial agents in other critically ill populations [9,10]. The reported incidence of MRSA HAP and VAP in several epidemiologic studies has ranged from 12%–25% of pneumonia cases, but in trauma centers, the incidence is as low as 2%–3% in early VAP and approximately 10% in the entire cohort of trauma patients [9,11 –16]. In addition, there is variability in the literature regarding the definitions and clinical relevance of the “early-onset” and “late-onset” definitions in defining the risk for MRSA in patients with trauma [17,18]. The objectives of this study were to determine the incidence and time course of MRSA pneumonia among patients who were diagnosed with pneumonia in the trauma burn ICU and to identify risk factors for MRSA pneumonia.

Patients and Methods

We conducted a retrospective cohort study of adults diagnosed with pneumonia in the 11-bed trauma and burn ICU at Rhode Island Hospital, a level I Trauma Center serving Southeastern New England. The protocol was approved by the Rhode Island Hospital Institutional Review Board. Patients were identified as those having a complication of pneumonia in the Trauma Registry from January 1, 2012 to March 1, 2015.

The standard approach to diagnosis of pneumonia in the unit is to perform bronchoscopy with quantitative bronchoalveolar lavage cultures in patients with clinical evidence of pneumonia, including fever, low PaO₂ to FiO₂ ratio indicating poor oxygenation, leukocytosis, pulmonary secretions, and pulmonary radiograph findings. Included patients were at least 18 years old and had microbiologically confirmed pneumonia, defined as pathogenic bacteria isolated in a concentration of ≥10⁴ colony-forming units per mL in the lower respiratory tract specimen in conjunction with symptoms suggestive of pneumonia. Patients were excluded if they had evidence of empyema or parapneumonic effusion.

Demographic information was collected for all patients in whom microbiologically confirmed pneumonia developed, including age, the type of injury, Injury Severity Score (ISS), MRSA nasal colonization on admission to the ICU, tobacco smoking status, patient's residence (long-term care facility or rehabilitation center, private home, or no permanent residence), and co-morbidities such as diabetes mellitus, ascites, malignancy, and congestive heart failure. Co-morbidities were extracted from the Trauma Registry and defined as indicated in the American College of Surgeons National Trauma Data Standard Data Dictionary. The time from admission to diagnosis of pneumonia and any courses of broad-spectrum antibiotic agents before pneumonia diagnosis, defined as at least three days of cefepime, ceftazidime, piperacillin-tazobactam, carbapenems, or fluoroquinolones, were recorded during hospitalization.

The VAP prevention strategies in place in the ICU did not change during the study period and included head-of-bed elevation greater than 30 degrees, a sedation protocol encouraging light levels of sedation assessed with a validated scale, and twice daily 0.15% chlorhexidine-based oral care. Patients with an indication for stress ulcer prophylaxis received proton-pump inhibitors. Patients were screened for MRSA nasal colonization by chromogenic medium detection (CHROMagar MRSA, Paris, France) on admission to the ICU.

Statistical analysis

Characteristics of patients in whom MRSA pneumonia developed were compared with those in whom pneumonia developed from another etiology with chi square or two-tailed Fisher exact test as appropriate for categoric variables. Normally distributed continuous variables were compared with the Student t-test and presented as mean ± standard deviation; non-normally distributed variables were compared with the Mann-Whitney U test and presented as median with interquartile range. We used a multi-variable exact logistic regression model to assess independent predictors of MRSA pneumonia and reported odds ratio (OR) with 95% confidence interval. An alpha value of 0.05 was the selected threshold for statistical significance. All analyses were performed using Stata statistical software version 13.1 (StataCorp LP, College Station, TX).

Results

The Trauma Registry query yielded 107 patients, of whom 27 were excluded because they did not have study-defined microbiologically confirmed pneumonia and whose diagnosis was made with a sputum sample or who were treated empirically for pneumonia. The cohort included 80 patients with 88 distinct episodes of microbiologically confirmed pneumonia. Demographic information of included patients is presented in Table 1. There were no statistically significant differences in characteristics between patients in whom MRSA pneumonia developed and those whose pneumonia was caused by other pathogens.

Table 1.

Demographics of Critically Ill Trauma and Burn Patients with Pneumonia in the Study Cohort, 2012–2015

	All patients (n = 80)
Age (years)	49 ± 18.4
Gender (n, %)
Female	15 (18.7)
Male	65 (81.3)
Injury Severity Score	32.7 ± 15.5
Injury Type
Blunt	66 (82.5)
Burn	9 (11.3)
Penetrating	3 (3.7)
Other	2 (2.5)
Co-morbidities
Alcoholism	16 (20)
Cancer	1 (1.3)
Cirrhosis of liver	5 (6.3)
Congestive heart failure	1 (1.3)
Diabetes mellitus	6 (7.5)
End-stage renal disease	0
Steroid use	0
Residence
Home	74 (92.5)
Skilled nursing facility, rehabilitation center	2 (2.5)
Homeless^a	4 (5)
Broad-spectrum antibiotic agents during admission (patients with at least one course	8 (10)
MRSA nasal colonization
Yes	6 (7.5)
No	71 (88.8)
Unknown	3 (3.7)
Smoker (n, %)	21 (26)

Values represent mean ± standard deviation or n (%).

No permanent residence includes shelter stays and transient stays in private homes.

MRSA = methicillin-resistant Staphylococcus aureus.

Ten patients in the cohort had MRSA pneumonia, an incidence of 11.4%. The range of days to onset of MRSA pneumonia was 2–33 days after admission, with a median onset of seven days. The majority of MRSA episodes occurred on or before eight days of hospitalization. Among all S. aureus infections, methicillin-susceptible S. aureus (MSSA) was the predominant pathogen, comprising 75.6% of S. aureus isolates.

Polymicrobial pneumonia represented 27 (30.6%) of the pneumonia episodes in our population, the majority of which were S. aureus and one additional gram-negative organism. Enterobacteriaceae, Hemophilus influenzae, and S. aureus species were the most commonly identified microorganisms, as described in Table 2. There was not a statistically significant difference in the proportion of MRSA pathogens in the first four days of hospitalization compared with after five days. There were no statistically significant risk factors for MRSA pneumonia compared with other pathogens identified in our cohort of patients (Table 3). Table 4 describes the potential risk factors for MRSA infection by individual case.

Table 2.

Microbiology of Pneumonia in Critically Ill Trauma and Burn Patients, 2012–2015 ^*

Organism	Pneumonia onset <5 d (n = 21)	Pneumonia onset ≥5 d (n = 92)	Total (n = 113)
Gram positive
MSSA	6 (28.6)	25 (27.2)	31 (27.4)
MRSA	2 (9.5)	8 (8.7)	10 (8.8)
Streptococcus spp.	2 (9.5)	3 (3.3)	5 (4.4)
Gram negative
Haemophilus influenzae	5 (23.8)	8 (8.7)	13 (11.5)
Enterobacter cloacae	2 (9.5)	16 (17.4)	18 (15.9)
Serratia spp.	2 (9.5)	9 (9.8)	11 (9.7)
Klebsiella pneumoniae	-	7 (7.6)	7 (6.2)
Escherichia coli	1 (4.8)	2 (2.2)	3 (2.7)
Citrobacter koseri	-	2 (2.2)	2 (1.8)
Proteus mirabilis	-	1 (1.1)	1 (0.9)
Nonfermenting gram negative bacilli
Pseudomonas aeruginosa	1 (4.8)	3 (3.3)	4 (3.5)
Acinetobacter baumanii	1 (4.8)	2 (2.2)	3 (2.6)
Moraxella catarrhalis	-	3 (3.3)	3 (2.7)
Stenotrophomonas maltophilia	-	3 (3.3)	3 (2.7)
Burkholderia spp.	-	1 (1.1)	1 (0.9)

Polymicrobial infections account for the number of organisms exceeding the number of identified pneumonia espisodes.

Data presented as number of cases in which pathogen was isolated (% of total pathogens).

MSSA = methicillin-susceptible S. aureus; MRSA = methicillin-resistant S. aureus.

Table 3.

Potential Risk Factors for Methicillin-Resistant Staphylococcus aureus Pneumonia among Trauma and Burn Patients with Pneumonia in the Study Cohort, 2012–2015

	MRSA pneumonia (n = 10)	Non-MRSA pneumonia (n = 70)	OR (95% CI)	p
Age (years)	56.8 ± 16.4	48 ± 18.5	1.03 (0.99–1.07)	0.15
Gender
Female	4 (40)	11 (15.7)	0.26 (0.05–1.46)^a	0.09
Male	6 (60)	59 (84.3)
Injury Severity Score	26.1 ± 9	33.6 ± 16	0.97 (0.92–1.01)	0.15
Injury type
Blunt	7 (70)	59 (84)		0.15
Burn	1 (10)	8 (11.4)
Penetrating	1 (10)	2 (2.8)
Other	1 (10)	1 (1.4)
Co-morbidities
Alcoholism	3 (30)	13 (18.6)		0.41
Cancer	1 (10)	0		0.13
Cirrhosis of liver	0	5 (7.1)		1.00
Congestive heart failure	0	1 (1.4)		1.00
Diabetes mellitus	1 (10)	5 (7.1)		0.56
Residence
Home	9 (90)	65 (92.9)		0.56
Skilled nursing facility	0	2 (2.8)		1.00
Homeless	1 (10)	3 (4.3)		0.42
Hospitalized in previous 60 days	1 (10)	0		0.13
MRSA nasal colonization	2 (20)	4 (5.7)	4.13 (0.32–34.7)	0.19
Smoker	4 (40)	17 (24.3)	1.37 (0.21–6.84)	0.71
Pneumonia onset (days, median with IQR)	7.5 (4.75–12.75)	7 (4–12)		0.51
Antibiotic use^b	1 (10)	7 (10)	0.91 (0.11–3.27)	1.00

Male gender vs. female gender.

Patients with at least one course of broad-spectrum antibiotics.

Values represent mean ± standard deviation or n (%) unless otherwise noted.

OR = odds ratio; CI = confidence interval; MRSA = methicillin-resistant Staphylococcus aureus; IQR = interquartile range.

Table 4.

Qualitative Description of Potential Risk Factors for MRSA Pneumonia among Critically Ill Trauma and Burn Patients with Methicillin-Resistant Staphylococcus aureus Pneumonia, 2012–2015

Patient	Days to pneumonia onset	Risk factors for MRSA ^a
1	2	Intravenous drug use, tobacco
2	4	Alcoholism
3	5	Positive nasal swab
4	6	None
5	7	Hospitalized within 60 days, metastatic colon cancer
6	8	Homeless, tobacco, alcoholism
7	12	Polysubstance abuse, incarcerations within 6 months, tobacco
8	12	Positive nasal swab (had been decolonized with subsequent negative swab before diagnosis)
9	15	Alcoholism, tobacco
10	33	Previous carbapenem receipt

Excludes timing of pneumonia diagnosis, includes homelessness, illicit drug use, MRSA nasal colonization, immunosuppression, hospitalizations within 60 days, previous broad-spectrum antimicrobials, comorbidities as defined in the text.

MRSA = methicillin-resistant Staphylococcus aureus.

There was not a statistically significant difference in the proportion of patients with MRSA pneumonia with a positive MRSA nasal swab on admission. The nasal screening demonstrated a susceptibility of 20%, specificity of 95.2%, positive predictive value of 33.3%, and negative predictive value of 90.9% for MRSA pneumonia when limited to diagnoses within the first seven days of hospitalization.

Discussion

The incidence of MRSA among pneumonia episodes in this cohort of primarily male patients with blunt trauma was similar to that reported in other geographic regions, and there was not a significant difference in terms of MRSA incidence in early- or late-onset pneumonia defined as five or more hospital days. Although approximately half of S. aureus isolates in medical and surgical ICU VAP surveillance studies are methicillin resistant, our study's reported 25% rate of methicillin resistance is consistent with other trauma populations' rates of 20%–30% [9,14,16,19].

Statistically significant risk factors for the development of MRSA pneumonia were not identified, likely secondary to the limited statistical power. The descriptive review of MRSA infection, however, suggests that the majority of the patients had established risk factors for MRSA such as receipt of broad-spectrum antibiotic agents, illicit drug use, tobacco use, homelessness, or MRSA colonization [6 –8]. Alcoholism was a co-morbidity in several of the MRSA patients; a history of alcohol abuse has been associated with acquisition of MRSA in the inpatient setting [20].

Guidelines for the management of HAP and VAP released by the Infectious Diseases Society of America and American Thoracic Society in 2016 recommend that empiric regimens are selected on the basis of local susceptibility patterns. An agent active against MRSA is recommended for patients who have received intravenous antibiotic agents within 90 days or in units where more than 10%–20% of S. aureus isolates are methicillin resistant, with the expectation that this would constitute 2.5%–5% of all VAPs [5]. The authors of the guidelines note that there are no established thresholds for which treatment is indicated, and that individual units can select thresholds in accordance with local values and preferences. Omission of anti-MRSA empiric therapy has not definitively been associated with increased death in the absence of bacteremia in several pneumonia populations, so a higher resistance threshold could be reasonable in this context [17,21 –23].

The trauma literature is heterogeneous with regard to reported incidence of early and late MRSA pneumonia and conclusions about empiric therapy. Hill et al [17] reported an incidence of MRSA pneumonia in patients with trauma in early VAP (first seven days of hospitalization) of 15% in 2009, an increase from 8%–10% in 2004 and 2005. The authors concluded that empiric MRSA therapy in the first seven days of hospitalization was unnecessary because there was no significant difference in outcomes in early MRSA patients who did not receive therapy compared with early MSSA patients.

In contrast, Becher et al. [18] reported that from 2008 through 2010, MRSA pneumonia accounted for 10.2% of pathogens identified in the trauma ICU from hospital day 2–4 and that vancomycin should be a component of the empiric regimen for HAP and VAP regardless of onset. A surgical ICU cohort reported an overall incidence of MRSA VAP of 4.3% from 2003 to 2008, with one episode occurring within the first four days and six episodes occurring after day five. No specific conclusions were made about the optimal timing of empiric MRSA coverage in this institution [24].

The most recently published study of MRSA VAP among patients with trauma [11] describes VAP diagnosed by lower respiratory culture between 2010 and 2013 at a Denver trauma center. Among 438 cases of VAP, MRSA was identified as a pathogen in 10.7% of cases, representing 2.8% from early VAP and 12.3% with late VAP defined as occurring five or more days after intubation. Early MRSA VAP developed in only three patients, all of whom had risk factors for MRSA including positive nasal swab, intravenous drug use, and homelessness. The authors concluded that the optimal time for addition of specific MRSA therapy would be after day seven.

Colonization with MRSA as determined by nasal swab on admission to the ICU was not an independent predictor of development of MRSA pneumonia in this study. Our results, however, are similar to those of other studies that have evaluated an association between nasal MRSA colonization and confirmed MRSA pneumonia in which sensitivity ranges 24.2%–88.0%, specificity 78.5%–90.1%, positive predictive value 17.7%–35.4%, and negative predictive value 84.4%–99.2% for infections within seven days of initial testing [25,26].

This study was limited by the retrospective nature of data collection, which may have prevented accurate collection of demographic characteristics including homelessness, intravenous drug use, and hospitalizations occurring outside our healthcare system. The study did not include an assessment of several factors that may have been potential risk factors for MRSA pneumonia, including pulmonary contusion and outpatient courses of antibiotic agents.

Although patients were intubated at the time of bronchoscopy, we did not attempt to differentiate between community-acquired pneumonia (CAP), HAP, and VAP or quantify days of intubation before pneumonia diagnosis. This decision was based on the fact that guideline-recommended antimicrobial treatment and the risk of multi-drug–resistant organisms are based typically on time from admission and not intubation. We also did not attempt to verify independently the signs and symptoms of pneumonia that prompted the treating surgeon to pursue infectious workup including bronchoscopy. A notable limitation in terms of drawing conclusions about risk factors for the development of MRSA pneumonia was the small number of patients in our cohort during the 3.5-year period, although the nature of the target population precludes inclusion of a large number of patients. Last, the results of our single-institution study may not be generalizable to trauma centers with dissimilar trauma or burn patient populations.

Strengths of this study include the standardized approach to pneumonia diagnosis, including quantitative lower respiratory cultures as a standard of care for diagnosis, and the fact that it describes the incidence of MRSA pneumonia in the only level I trauma center serving our geographic region.

Conclusion

MRSA pneumonia represented 11.4% of microbiologically confirmed pneumonia episodes in this cohort of primarily male patients with blunt trauma, the majority of whom were diagnosed between hospital day four and eight. There were no statistically significant differences between trauma or burn patients in whom MRSA pneumonia developed compared with other pathogens or independent risk factors for MRSA infection, but MRSA nasal colonization on admission had a high negative predictive value for MRSA pneumonia within seven days. Most patients with MRSA had at least one established risk factor from larger epidemiologic studies in other populations, such as homelessness, substance abuse, and receipt of broad-spectrum antibiotic agents. The small number of MRSA cases and the lack of association with time to onset suggest that empiric MRSA therapy for suspected pneumonia in patients with trauma and burns should be used selectively with consideration of risk factors in addition to duration of hospitalization before diagnosis.

Footnotes

Acknowledgments

The authors would like to acknowledge Ann George, RN, trauma program manager, and Naomi Hagan for providing data from the institutional Trauma Registry for the conduct of this study.

Dr. Zullo's work is supported in part from an Agency for Healthcare Research and Quality award (5K12HS022998-02).

Author Disclosure Statement

No competing financial interests exist.

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