Adult Empyema Caused by Refractory Methicillin-Resistant Staphylococcus aureus Treated Using Linezolid as Salvage Therapeutic Option: A Report of Two Cases

Introduction

Empyema is a severe pulmonary complication of bacterial infection and usually develops from pneumonia.^1,2 Antibiotics are the main treatment, but drainage might be needed in addition to antibiotics to efficiently eliminate the causal pathogens.^1,2

Representative pathogens are aerobic bacteria related to the common causes of pneumonia, such as Streptococcus pneumoniae, Haemophilus influenzae, and gram-negative enterobacteria, such as Escherichia coli and Klebsiella pneumoniae.¹ Anaerobes are also known to cause empyema.¹

Among bacteria, methicillin-resistant Staphylococcus aureus (MRSA) might also be a representative pathogen related to empyema, although MRSA has generally been considered to be a colonizer with pulmonary epithelial cells, rather than an infective agent.^3–7 However, some cases might be considered to be MRSA empyema, and they must be treated, excluding other pathogens, with anti-MRSA glycopeptide agents, including vancomycin (VCM) and teicoplanin (TEIC).^1,3

In this report, two adult cases of MRSA empyema are presented. While VCM and TEIC were used to treat empyema initially, the patients’ conditions did not improve. Therefore, linezolid (LZD), an anti-MRSA agent known to have good tissue penetration and strong bactericidal effects, was used although larger studies are required to confirm its benefits.⁸

This report and related analyses were approved by the Institutional Review Board of Saitama Medical University International Medical Center on July 6, 2022 (#2022-030) and registered as UMIN000047690. The patients whose specimens were analyzed provided written, informed consent to have any accompanying images and their case details published. This study was conducted in accordance with the principles of the Declaration of Helsinki.

Case Series

Case 1

A 50-year-old man with non-small cell lung carcinoma received chemotherapy with four courses of anticancer drugs, and nearly complete remission was achieved. One month later, he was admitted to our hospital with high fever and chest pain. Empyema was diagnosed because his chest X-ray and computed tomography (CT) showed abnormal shadows and pleural effusions in the right lung on admission (day 0) (Figure 1A and B). Laboratory data were as follows: white blood cell (WBC) count 6.00 ×10³/μL; C-reactive protein (CRP) 22.2 mg/dL; and hemoglobin A1c (HbA1c) 6.3%, suggesting diabetes mellitus (DM).

Figure 1 Radiological findings of the Case 1 patient on admission (A and B) and at day 27 (C and D). On admission, there are abnormal shadows and pleural effusions in the right lung in chest X-ray (A) and computed tomography (B), but these shadows and effusions in chest X-ray (C) and computed tomography (D) improve after drainage and antibiotic therapy using linezolid. Arrows indicate the abnormal shadows and pleural effusions.

Drainage of the right thorax by video-assisted thoracoscopy (VATS) was performed, and MRSA alone was detected on day 3. MRSA was also isolated from his nose, but considered just colonized because it was asymptomatic. The susceptibility of the MRSA isolated from this patient is shown on the left in Table 1. The minimum inhibitor concentrations (MICs) of isolated bacteria were determined by a Phenix M-50 system (Becton Dickinson, Franklin Lakes, NJ, USA) and Lysys@S4 (Shimazu Diagnostics, Tokyo, Japan) based on the broth microdilution method. MRSA was confirmed by MRSA-CI selection agar (Kyokuto, Tokyo, Japan).

Table 1 Drug Susceptibilities of the MRSA Isolated from the Patients

An ampicillin/sulbactam (ABPC/SBT) 3-g drip infusion (div) three times per day was started on admission but was switched to VCM 1 g div twice per day on day 3. However, inflammatory markers remained elevated, with a WBC count of 8.47 ×10³/μL and CRP of 7.02 mg/dL although the trough and peak of VCM; 11.3μg/mL and 30.5μg/mL, respectively, were well controlled by the therapeutic dose monitoring (TDM) to maintain the area under curve (AUC) _24h 400–600 mg he/L. The effusion in the chest radiography and isolation of MRSA from the chest effusions had been also remained. Therefore, VCM was switched to linezolid (LZD) div 0.6 g twice per day on day 13. After 14 days on LZD (day 27), the laboratory results improved, with a WBC count of 6.54 ×10³/μL and CRP of 1.70 mg/dL. His chest X-rays and CT also showed significant improvement (Figure 1C and D). MRSA disappeared from his chest effusions.

Case 2

A 77-year-old man with hypopharyngeal cancer underwent surgery and achieved nearly complete remission. Two months later, he was admitted to our hospital with high fever and chest pain. Empyema was diagnosed because his chest X-ray and CT showed abnormal shadows and pleural effusions in the left lung on admission (day 0) (Figure 2A and B). His WBC count was 11.11 ×10³/μL, and CRP was 24.7 mg/dL.

Figure 2 Radiological findings of the Case 2 patient on admission (A and B) and at day 24 (C and D). On admission, there are abnormal shadows and pleural effusions in the left lung in chest X-ray (A) and computed tomography (B), but these shadows and effusions in chest X-ray (C) and computed tomography (D) improve after drainage and antibiotic therapy using linezolid. Arrows indicate the abnormal shadows and pleural effusions.

Drainage of the left thorax was performed, and MRSA alone was detected on day 3. The MICs of isolated MRSA were determined as described same as Case 1, where MRSA was also isolated from her nose but considered just colonized because it was asymptomatic. The susceptibility of the MRSA isolated from this patient is shown on the right in Table 1. An ABPC/SBT 3-g drip infusion (div) three times per day was started on admission but was switched to TEIC 0.4 g div twice per day for the first two days, followed by 0.2 g div twice per day on day 3. However, inflammatory markers remained elevated, with a WBC count of 9.24 ×10³/μL and CRP of 12.02 mg/dL although the trough of TEIC; 13.2 μg/mL was well controlled by the TDM. The effusion in the chest radiography and isolation of MRSA from the chest effusions had also remained. Therefore, TEIC was switched to LZD div 0.6 g twice per day from day 10. After 14 days on LZD (day 24), the inflammatory markers were improved, with a WBC count of 5.23 ×10³/μL and CRP of 1.16 mg/dL. His chest X-rays and CT had also improved significantly (Figure 2C and D). MRSA disappeared from her chest effusions.

Discussion

Empyema is the accumulation of pus within the pleural space and can be a serious complication of pneumonia, requiring extensive treatment with antibiotics and adequate drainage.^1,2

In this report, two cases of empyema thought to be caused by MRSA infection treated initially by VCM/TEIC followed by LZD were presented. Isolation of MRSA is usually only considered to indicate colonization, not infection;^5,6 however, in a patient hospitalized with community-acquired pneumonia complicated by empyema, the Infectious Diseases Society of America (IDSA) guidelines recommend empirical treatment for MRSA while awaiting culture results.⁴ Once MRSA is confirmed, the recommended antibiotic regimen includes 7 to 21 days of VCM div 600 mg twice per day, div or oral LZD 600 mg twice per day, or div or oral clindamycin 600 mg 3 times per day.⁴ MRSA was found to be one of the major pathogens in cases of hospital-acquired pneumonia and ventilator-associated pneumonia (VAP), and treatment for MRSA might be critical in these cases because MRSA was detected significantly more frequently in non-survivors of VAP in our previous study.⁹ Furthermore, our meta-analysis strongly suggested that MRSA pneumonia and empyema should be treated as such when only MRSA is isolated from respiratory specimens, including nose, sputum and pleural effusions.¹⁰

Both patients in the two cases presented showed typical radiographic findings on chest X-ray and CT with high levels of inflammatory markers, and only MRSA was isolated from their pleural effusions. High inflammation due to non-isolated pathogens, such as anaerobes was suspected, but ABPC/ABT was not effective in both cases. Empyema cases usually show higher inflammation, compared with pneumonia cases.^1–3 They finally improved with administration of anti-MRSA agents. These findings suggest that the present patients truly had MRSA empyema and highlight the benefits of anti-MRSA agent administration.

In addition, elevation of inflammatory markers persisted in the present cases despite the administration of the glycopeptide antibiotics VCM and TEIC. Therefore, they were switched to LZD, which is the first available antibiotic agent in the oxazolidinone class, and shows a strong but bacteriostatic effect against MRSA.¹¹ LZD has been shown to have epithelial lining fluid concentrations several-fold higher than serum concentrations, and this has been perceived as a significant advantage over VCM.¹² On the basis of the better penetration of LZD into respiratory secretions than VCM, LZD has demonstrated a survival advantage in patients with documented MRSA nosocomial pneumonia. Recent guidelines indicate that LZD may be preferred over glycopeptide antibiotics for MRSA pneumonia.^4,13 Two meta-analyses also showed the clinical and microbiological advantages of LZD over VCM in the treatment of MRSA pulmonary infections, including pneumonia and empyema.^14,15 In fact, LZD showed more effectiveness than VCM or TEIC in the present cases. These findings suggest that use of LZD rather than VCM and/or TEIC might be recommended in the treatment of not only MRSA pneumonia, but also MRSA empyema.

Due to limitations, we first presented the advantage of treatment by LZD, compared with VCM/TEIC; however, the results were based on only two cases although we found the preliminary data and meta-analysis. Second, we could not show the detailed laboratory, microbiological, and radiography data, however, predefined criteria to be considered the treatment success, such as decrease in inflammation markers (WBC and CRP), disappearance of causative pathogens, and improvement of chest X-ray/CT findings, did not achieved in both cases. From the view of antimicrobial stewardship settings, we should be more clear the antibiotic uses in refractory cases according to the guideline and guidance.¹⁶ Third, microbiological characterization of the MRSA isolates was limited to phenotypic antimicrobial susceptibility testing. No molecular investigations, such as SCCmec typing, virulence gene detection, molecular typing, or whole-genome sequencing, were performed. From the phenotypic antimicrobial susceptibility testing data, the isolated MRSA from two patients might be hospital-acquired SCC mec II, and non-toxin, such as Panton-Valentine Leukocidin (PVL) producing types.^17,18 LZD is also suggested clinically effective against PVL-positive MRSA.¹⁸ Detailed microbiological investigation should be also performed simultaneously with clinical study.

In conclusion, two cases of MRSA empyema were successfully treated using an anti-MRSA agent. Only MRSA was isolated from their pleural effusions, and LZD had better effectiveness than VCM/TEIC. Further investigations with large sample sizes and detailed patient information will be needed to establish the indications for using an anti-MRSA agent such as LZD, rather than VCM or TEIC, for treating MRSA empyema.