a b s t r a c t

Background: Methicillin-resistant Staphylococcus aureus (MRSA) nasal swab Polymerase chain reaction assay has a 96.1-99.2% negative predictive value (NPV) in pneumonia and may be used for early de-escalation of MRSA-active antibiotic agents. Xu (2018), File (2010) [1,2].

Objective: The objective of our study was to determine if a negative MRSA PCR nasal swab collected in the emer- gency department (ED) improves early MRSA-active antibiotic de-escalation.

Methods: A single center observational cohort study used ICD-10 codes to identify records for adults admitted to the ED with a hospital discharge diagnosis of pneumonia. The primary outcome was proportion of patients with early de-escalation on an MRSA-active agent (<= 1 dose). Secondary outcomes included rate of Acute kidney injury , positive MRSA cultures (blood culture, respiratory sputum, tracheal aspirate), hospital length of stay , in-hospital mortality, and 30-day Readmission rates.

Results: A total of 341 patients were included in the study. Of the patients with an MRSA PCR swab, 35.2% of pa- tients with a negative swab received >1 dose of MRSA-active agent compared to 52% of patients without an MRSA nasal swab (p < 0.01). There were no significant differences in secondary outcomes except readmission rate of 1.6% of patients that did not have an MRSA swab in the ED vs 6.6% of patients that received an MRSA swab in the ED.

Conclusion and relevance: MRSA PCR nasal swabs in the ED may serve as a useful tool for early MRSA-active an- tibiotic de-escalation when treating pneumonia.

(C) 2022

1. Introduction

Pneumonia is the leading infectious cause of hospitalization and mortality in the United States (U.S.) accounting for more than 80,000 deaths annually with costs exceeding $17 billion dollars [1-3]. With over 1 million visits annually, pneumonia is the most common infec- tious disease treated in the emergency department (ED) [4]. To opti- mize pneumonia-associated outcomes, early appropriate Empiric treatment must be administered in the ED. [5] Empiric Antimicrobial treatment that does not cover the causative pathogen is associated with increased mortality [6-8]. Due to this, broad-spectrum treatment, including antibiotics that cover methicillin-resistant Staphylococcus

* Corresponding author at: University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242, United States of America.

E-mail addresses: morganne-sindelar@uiowa.edu (M.A. Sindelar),

anne-zepeski@uiowa.edu (A.E. Zepeski), brooke-lawler@uiowa.edu (B.J. Lawler), stephanie-johnston@uiowa.edu (S.D. Johnston), brett-faine@uiowa.edu (B.A. Faine).

aureus (MRSA) are often empirically administered to patients with pneumonia in the ED. While appropriate empiric treatment is vital for improved patient outcomes, inappropriate and excessive use of broad- spectrum antimicrobial treatment remains a Public health concern in the U.S. due to increasing rate of Antimicrobial resistance [9].

According to the Centers for Disease Control (CDC), approximately 5% of patients in U.S. hospitals are colonized with MRSA [10,11]. MRSA is the causative pathogen in up to 40% of nosocomial pneumonias and is associated with significant morbidity and mortality [12]. However, the prevalence of MRSA in patients presenting to the ED with pneumo- nia remains low at approximately 3-5% [12-15]. Regardless of low prev- alence, MRSA-active treatment is initiated in approximately 40% of patients [16]. Unnecessary MRSA-active treatment is associated with se- rious adverse events (SAEs), including Acute Kidney Injury , Clostridioides difficile infections, increased Hospital length of stay , and death [16].

https://doi.org/10.1016/j.ajem.2022.03.009

0735-6757/(C) 2022

The ED is highly influential on antimicrobial treatment prescribing making it an ideal environment to implement antimicrobial steward- ship interventions focused on early de-escalation to decrease the rate of inappropriate antimicrobial prescribing. Microbiological culture re- sults remain the gold standard to guide antimicrobial therapy [14]. Un- fortunately, the turnaround time for culture results is usually 48-72 h, so they do not represent a logical method for early de-escalation of an- timicrobial treatment in the ED. polymerase chain reaction as- says, specifically targeted to identify MRSA which have been shown to have strong negative predictive value (NPV), provide rapid and accurate pathogen identification, and represent an efficient tool to determine the necessity of MRSA-active treatment [17,18]. While MRSA nasal PCR screening can be obtained in the ED with rapid turnaround time, evi- dence suggests that most screening takes place after the patient is ad- mitted to the hospital prolonging the exposure to unnecessary treatment [19-22]. To date, there have not been any studies evaluating MRSA nasal PCR screening in the ED and the impact on MRSA-active treatment de-escalation. The objective of our study was to determine if obtaining an MRSA PCR nasal swab in the ED is a safe and effective tool for rapid de-escalation of MRSA-active antibiotics in ED patients with pneumonia.

1. Methods
   1. Design and setting

We conducted a retrospective observation cohort study at a 60,000- visit per year ED at an academic tertiary referral hospital. Patients >=18 years of age admitted through the ED with a hospital discharge diagno- sis of pneumonia between August 1, 2018 and March 31, 2021 were in- cluded. Each hospital admission was counted as a separate encounter. Electronic medical records (EMR) were reviewed for International Sta- tistical Classification of Diseases and Related Health Problems (ICD) 10 codes (appendix) for pneumonia. All patients who received a guideline recommended MRSA-active agent (vancomycin or linezolid) for pneu- monia were included in the study [14]. We elected not to include pa- tients who received ceftaroline because it is not endorsed by the IDSA guidelines as a recommended treatment option for MRSA pneumonia and at our institution prescribing is restricted to infectious diseases phy- sicians [14]. Patients who received an MRSA-active agent for an infec- tion other than pneumonia, had a positive MRSA nasal swab, were pregnant, incarcerated, or transferred from an outside hospital were ex- cluded from the study. Patients were divided into two groups: those with a negative MRSA nasal PCR collected in the ED or those with no MRSA nasal PCR in the ED. Data was abstracted by a trained research as- sistant who was blinded to the study outcomes. Approximately 30% of charts were reviewed by study personnel for quality assurance pur- poses. The institutional review board (IRB) approved the study protocol, and the design and results reporting were completed in accordance with the Strengthening the Reporting of Observational Studies in Epide- miology (STROBE) statement [23].

• 1. Data collection

We identified all patient characteristics a priori and intentionally chose variables that were readily available in the EMR. Collected data in- cluded baseline characteristics (e.g., age, sex, laboratory results, etc.), presence of comorbidities (e.g., myocardial infarction, congestive heart failure, cerebrovascular accident, etc), and MRSA PCR nasal swab collec- tion location (Cepheid Xpert SA test, Copan Dual Swab #26200) [24]. Turnaround time for MRSA PCRs at our institution is approximately 2 h from receipt of specimen in the laboratory (tests are run 24 h per day, 7 days per week). In addition to baseline characteristics, we col- lected days of MRSA-active antibiotic, doses of MRSA-active antibiotic, peak serum creatinine, positive MRSA culture results (respiratory,

trachea, and blood cultures), in-hospital mortality, hospital LOS, dis- charge status, and readmission within 30 days.

• 1. Outcome measures

The primary outcome was the proportion of patients that had early de-escalation of MRSA-active therapy based on MRSA PCR results. Early de-escalation of antibiotics was defined as receiving only 1 dose of MRSA-active agent. Secondary outcomes included rate of AKI, hospi- tal LOS, rate of positive MRSA cultures, in-hospital mortality, and read- mission rates due to any cause within 30 days of being discharged. All length of stays were measured as calendar days. The definition of AKI was based on the Kidney Disease: Improving Global Outcomes (KDIGO) classification: an absolute increase in serum creatinine >=0.3 mg/dL within 48 h or >= 50% increase within 7 days or urine output of

<0.5 mL/kg/h for >6 h [25].

• 1. Statistical analysis

The objective of our study was to evaluate early de-escalation of MRSA-active antibiotic treatment for those who had a negative MRSA Nasal Swab PCR, therefore patients who had a positive swab were re- moved from the data set. Because de-escalation of MRSA-active therapy after a negative MRSA nasal swab PCR typically occurs after the patient is admitted to the hospital, we estimated that approximately 60% of the patients who did not have an MRSA nasal swab PCR obtained in the ED would receive multiple doses of MRSA-active treatment. Assuming ? =

0.05 and power = 0.80 (two-tailed), 340 patients were required to

identify a 15% reduction in patients receiving multiple doses of MRSA- active treatment after hospital admission.

Categorical variables, such as demographic factors and clinical char- acteristics, were summarized with frequencies and percentages. Be- cause of relatively small frequencies for categories (e.g., mortality, incidence of AKI), Fisher’s exact test was used for most of the calcula- tions. A Chi-Squared test was used when comparing the number of patients who received more than one dose of treatment, the only data that met the assumptions for the test. Quantitative variables were sum- marized by median and interquartile range (IQR) and were analyzed using a Mann Whitney U test. Statistical significance was defined at p < 0.05. R statistical software was used for all statistical analyses in the trial.

1. Results
   1. Patient demographics

From August 1, 2018 – March 31, 2021, we identified 606 patients who were diagnosed with pneumonia and received MRSA-active ther- apy (Fig. 1). Of the excluded patients only 7 patients had a positive MRSA PCR. A negative MRSA PCR was collected in 91/341 (26.6%) of pa- tients included in the study. Baseline characteristics were similar among the two groups. The median age was 64 (IQR: 15) in the negative MRSA swab group and 63 (IQR:19) in the no MRSA swab group. The majority of patients were male, 64.8% of patients in the no MRSA swab group vs 70.3% of patients who had a negative MRSA swab in the ED. The most common chronic medical conditions were chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF), diabetes mellitus, and malignant solid tumors. Addi- tional baseline demographics are summarized in Table 1.

• 1. Primary outcome

The primary outcome of receiving greater than one dose of MRSA- active antibiotic occurred in 32 (35.2%) patients with a negative MRSA nasal swab in the ED compared to 130 (52%) patients in the no MRSA swab group (p < 0.01). Patients with a negative MRSA swab in the ED

Fig. 1. Flow diagram for study inclusion.

who received more than one dose of an MRSA-active agent had a me- dian 24 h (IQR: 24) of MRSA-active therapy. Patients with no MRSA swab in the ED who received more than one dose of MRSA-active agent had a median 48 h (IQR: 48) of MRSA-active therapy (p < 0.01).

• 1. Secondary outcomes

Rates of AKI, hospital LOS and in-hospital mortality were similar be- tween the two treatment groups. Readmission rates were higher in the treatment group that had a negative MRSA nasal swab collected in the

Table 1

Demographics and baseline characteristics

Demographics	No MRSA Swab (n = 250)	(-) MRSA Swab (n = 91)
Age, median (IQR), years	62.5 (19)	64 (15)
Gender, n (%), male	162 (64.8)	64 (70.3)
Charlson Comorbidity Index, median (IQR)	4 (3)	4 (4)

Myocardial infarction 3 1

Congestive heart failure 35 12

Peripheral vascular disease 14 4

CVA/TIA 21 6

Dementia 11 3

COPD 49 17

Peptic ulcer disease 4 1

Liver Disease 8 3

Diabetes Mellitus 63 26

Moderate/Severe CKD (SCr > 2) 51 11

Solid Tumor 56 24

Leukemia 2 2

Lymphoma 10 9

Baseline Characteristics

Baseline Serum Creatinine, median (range) 1.1 (0.3-13) 1 (0.1-11.3)

Hemodialysis dependence (%) 12 (4.8) 4 (4.4) Antibiotics Received during hospitalization (%)

ED; however, only one of the readmissions in this group was due to pneumonia (Table 2).

1. Discussion

In this retrospective analysis the proportion of patients who had early de-escalation of MRSA-active agent was significantly higher in pa- tients who had a negative MRSA PCR nasal swab collected in the ED compared to patients without an MRSA PCR nasal swab collected in the ED.

The 2019 American Thoracic Society and Infectious Diseases Society of America (IDSA) community acquired pneumonia treatment guide- lines recommend initiation of MRSA-active agents in adults with vali- dated risk factors for MRSA which include prior isolation of MRSA or history of hospitalization with parenteral antibiotic exposure in the last 90 days [14]. To aid as a de-escalation tool, guidelines recommend collecting an MRSA nasal PCR for severe inpatient pneumonia where MRSA-active agents are warranted but lack specific guidance on when to obtain an MRSA nasal PCR [14]. The goal of this study was to demon- strate the utility of a MRSA nasal swab PCR to optimize antibiotic ther- apy in patients presenting with pneumonia. While there is concern

Table 2

Primary and secondary outcomes.

No MRSA		(-) MRSA	P-Value
Swab (n = 250)		Swab (n = 91)
Primary Outcome Days of therapy, median (IQR)	2 (2)	1 (1)	0.001
Doses of therapy, median (IQR)	2 (3)	1 (1)	0.001
Received >1 dose MRSA-active agent, n (%)	130 (52)	32 (35.2)	0.008

Vancomycin	241 (96)	73 (80)	Secondary Outcomes
Linezolid	5 (2)	13 (14)	Hospital length of stay, median (IQR), days	6 (8)	5 (5.5)	0.45
Both vancomycin & linezolid	4 (2)	5 (6)	In hospital mortality, n (%)	20 (8.8)	5 (5.5)	0.49
Positive MRSA culture results			Development of AKI, n (%)	10 (4)	4 (4.4)	1
Blood, respiratory, trachea	9	0	Readmission within 30 days, n (%)	4 (1.6)	6 (6.6)	0.03

that early de-escalation could lead to harm, the early de-escalation group did not have higher rates of inadequately treated pneumonia or positive MRSA culture results. Additionally, our results showed early de-escalation of MRSA-active agents in pneumonia did not increase risk for SAEs, however, this could be because rates of SAEs remain rare and are unlikely to be discovered with a small sample size. Additionally, while we showed a significant reduction in unnecessary exposure to MRSA-active treatment, rates of important clinical outcomes such as AKI, hospital LOS, and mortality were not significantly different. Read- mission rates were higher in the treatment group that had a negative MRSA nasal swab collected in the ED; however, only one of the readmis- sions in this group was due to pneumonia. Interestingly, all patients started on linezolid (n = 9) in the ED had their treatment transitioned to vancomycin once they were transferred to an Inpatient unit. Results of this study suggest collection of MRSA nasal swab PCR in the ED can serve as a tool for early de-escalation of MRSA-active antibiotics.

IDSA guidelines recommend de-escalation of empiric treatment to a narrower spectrum at 48 h if the patient is clinically improving and mi- crobiological cultures do not reveal a multi-drug resistant pathogen [14]. However, several large observational studies demonstrated that only a small percentage of patient have de-escalation of antibiotics by hospital day 4. In our study, the median duration of treatment was 48 h (IQR: 48) for patients who did not have early de-escalation. This highlights that de-escalation occurred early during hospitalization, was much shorter than previous studies evaluating de-escalation, and underscores the importance of early diagnostic tools to impact antibi- otic Treatment decisions after hospital admission [26,27]. Unfortunately, due to the retrospective nature of our study it is unclear if the result of the MRSA PCR swab was the primary reason behind the decision to de-escalate.

To date, there has only been one study evaluating early de- escalation of MRSA-active agents in the ED. [28] Renzoni et al. evalu- ated the use of MRSA nare cultures to de-escalate MRSA-active anti- biotics in patients with pneumonia to determine the impact on treatment duration at a single center. The median duration of MRSA-active treatment was similar for both groups (no MRSA screen,

30.5 h [IQR 20.5-52.5] vs. MRSA screen, 24.5 h [IQR 20.6-40.3], p =

0.28). A significant limitation of this study was the use of MRSA nare cultures as the tool for MRSA screening. The median time from collection to result was 31.3 h [IQR27-37.3] [28]. While our results are contradictory to this study’s findings, using a PCR test with a turn- around time of 2 h at our institution may represent a more feasible and effective approach for early de-escalation of MRSA-active antibi- otics in the ED.

Multiple meta-analyses and large Observational cohort studies report NPVs ranging from 96 to 99% for MRSA nasal swab PCRs [18,29,30]. Community-acquired pneumonia treatment guidelines highlight that data are robust to de-escalate MRSA-active treatment in the setting of a negative MRSA nasal swab, yet in practice MRSA nasal swab PCRs are rarely utilized and MRSA-active agents are continued for multiple days before de-escalation occurs [14,19-22]. Early de- escalation of MRSA-active agents aligns with Antimicrobial stewardship initiatives to prevent drug resistance and associated SAEs through use of broad-spectrum antibiotics without indication [9]. To minimize risks of SAEs and antimicrobial resistance, collection of an MRSA nasal swab upon admission in the ED represents a viable antimicrobial stewardship target to help mitigate risk.

This study is not without limitations. First, this was a single-center, retrospective chart review presenting the risk of unmeasured con- founders. Additionally, the decision to order MRSA nasal swabs was de- termined by the treating physician, which may have introduced confounding by indication. Second, we relied on characteristics docu- mented in the EMR. While there is some risk of incomplete documenta- tion, we intentionally chose variables that are commonly documented for all patients and are easy to abstract from the EMR. Third, there

could have been differences in baseline severity of illness that could have been missed based on lack of or inAccurate documentation in the EMR. To help identify any differences in severity of illness, we calculated the Charlson Comorbidity Index score upon ED admission for all in- cluded patients. Fourth, our institution has a 2-h turnaround time for MRSA PCRs which may not be achievable at some institutions. This may limit the generalizability of our findings but also highlights what turnaround time is necessary to have successful early de-escalation of anti-MRSA treatment in the ED. Finally, this study evaluated the rate of positive MRSA cultures that resulted after early de-escalation of the MRSA-active agent. These cultures included blood cultures, and various respiratory cultures including sputum, tracheal aspirate, and bronchoal- veolar lavage cultures which may produce different percentage yields of positive cultures. The timing of these blood and respiratory cultures in relation to antibiotic administration was not collected and could affect MRSA positivity results.

1. Conclusion and relevance

The results of our study suggest that performing MRSA PCR nasal swabs in the ED for patients admitted with concern for MRSA pneumonia represents a valuable tool to guide early de-escalation of MRSA-active treatment. Future studies should evaluate the impact of implementing a protocol for MRSA PCR nasal swabs in the ED and the safety of withholding MRSA-active treatment until the nasal swab has resulted.

Funding

This research did not receive any specific grant from funding agen- cies in the public, commercial, or not-for-profit sectors.

CRediT authorship contribution statement

Morganne A. Sindelar: Conceptualization, Data curation, Investiga- tion, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. Anne E. Zepeski: Visualization, Writing – original draft, Writing – review & editing. Brooke J. Lawler: Data curation, Software, Writing – original draft, Writing – review & editing. Stephanie D. Johnston: Formal analysis, Visualization, Writing – original draft, Writing – review & editing. Brett A. Faine: Conceptualization, Methodology, Resources, Visualization, Writing – original draft, Writing – review & editing.

Declaration of Competing Interest

None.

Appendix A

ICD 10 Diagnostic codes used to identify patient encounters:

• B44.9 Aspergillus pneumonia
• B49 Fungal pneumonia
• J17 Fungal pneumonia
• B59 Pneumonia due to Pneumocystis
• J18.9 Community Acquired pneumonia
• J69 Aspiration pneumonia
• J12.1 Pneumonia due to respiratory symptoms
• J15.6 Pneumonia of lower lobe
• J15.9 Bacterial pneumonia
• J18.1 Lobar pneumonia
• J18.8 unspecified pneumonia
• R78.81 klebsiella pneumonia
• J85.1 abscess of lung with pneumonia

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