FormalPara Key Summary Points

Why carry out this study?

Staphylococcus aureus (S. aureus) pneumonia exhibits a severe clinical course with complications and high mortality. Identifying mortality risk factors allows for early recognition and intervention, potentially improving outcomes.

Beyond its virulence, S. aureus exhibits resistance to commonly used antibiotics in pneumonia treatment protocols. Evaluating the antibiotic resistance profile of S. aureus is essential for constructing evidence-based empirical treatment strategies.

What was learned from this study?

S. aureus pneumonia exhibits a substantial 30-day mortality rate of 43.8%. Mortality risk factors identified include hemoptysis, methicillin resistance (MRSA), acidosis (pH <7.35), and fulfillment of IDSA/ATS severe pneumonia criteria.

The high MRSA prevalence (84.7%) among isolated S. aureus in this study suggests that conventional beta-lactam antibiotics may no longer be a reliable empirical therapy for clinically suspected S. aureus pneumonia.

Introduction

Pneumonia is a significant global health concern, responsible for a substantial burden of morbidity and mortality worldwide [12]. Among the diverse pathogens contributing to this disease, Staphylococcus aureus (S. aureus) stands out as a formidable pathogen because of its potential to cause severe pneumonia and its resistance against commonly used antibiotics [3]. S. aureus is a significant etiological pathogen in both community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP), accounting for approximately 2–16% of CAP cases and a notable proportion of HAP cases, ranging from 20% to 40% [11, 15, 21, 24, 32, 37, 42]. Pneumonia caused by S. aureus is associated with higher rates of morbidity and mortality compared to other bacterial etiologies, demanding urgent attention from healthcare providers and researchers. Prior investigations have revealed that S. aureus-associated mortality in nosocomial pneumonia is approximately 30–50% [2, 13, 44]. In contrast, CAP stemming from S. aureus is associated with mortality rates ranging from 20% to 50% [10, 13, 21, 39, 44], with potential escalation up to 56% in cases of necrotizing pneumonia linked to Panton-Valentine leukocidin (PVL)-producing S. aureus strains [20]. Compared to the causative pathogen Streptococcus pneumoniae, S. aureus pneumonia presents mortality rates three to four times higher [10]. This increased pathogenicity can be attributed to its high virulence factor and an array of antibiotic resistance mechanisms, resulting in formidable multidrug-resistant bacterial infections that significantly challenge treatment efforts [3].

Like many other regions, Can Tho City grapples with the challenges posed by pneumonia caused by this pathogen. A comprehensive understanding of the clinical manifestations, radiological findings, associated comorbidities, and clinical outcomes is indispensable in enhancing the diagnostic accuracy and management of S. aureus pneumonia. Furthermore, a thorough evaluation of antimicrobial susceptibility profiles in local S. aureus isolates is imperative to guide the development of evidence-based empirical antibiotic protocols. In the context of Vietnam, the impact of S. aureus pneumonia represents a pressing public health issue. Diverse factors, including geographical climate, socio-economic conditions, population density, and healthcare infrastructure, may influence this infection’s clinical presentation and outcomes in the region. Our investigation aims to delineate the clinical and laboratory features, encompassing information on antimicrobial resistance, clinical endpoints, and predictors associated with 30-day mortality in S. aureus pneumonia.

Methods

Study Design and Population

This prospective cohort study was conducted at two hospitals in Can Tho City, Can Tho Central General Hospital and Can Tho University of Medicine and Pharmacy Hospital, between May 2021 and June 2023.

We included patients aged 18 years or older diagnosed with S. aureus pneumonia on the basis of the Centers for Disease Control and Prevention (CDC) 2021 criteria for common bacterial pneumonia [6]. Exclusion criteria included active lung disease, acute hemodynamic pulmonary edema, or concurrent co-infection of S. aureus with other bacterial pathogens.

After informed consent was obtained, baseline data were collected and participants were followed up until 30 days or death, whichever happened first. Antibiotic treatment was administered in accordance with the established hospital protocols. This study was ethically approved by the Institutional Review Board of Can Tho University of Medicine and Pharmacy (approval number 1388/QD-DHYDCT in June 2021).

Definition of Staphylococcus aureus Pneumonia

According to the 2021 CDC criteria for common bacterial pneumonia, S. aureus pneumonia is diagnosed if the patient meets the following criteria: (1) presence of infiltrative lesions and/or progressive changes evident on chest X-ray, (2) fulfillment of at least one criterion from the following: fever above 38 °C, leukopenia (leukocyte count < 4000/mm3), leukocytosis (leukocyte count > 12,000/mm3), or altered mental status in adults aged 70 years or older with no other identifiable cause, coupled with at least one criterion from the following: new onset or worsening cough, dyspnea, tachypnea, rales or bronchial breath sounds, or deteriorating gas exchange, and (3) identification of S. aureus isolates from blood, pleural fluid, and/or lower respiratory tract specimen [6]. For lower respiratory tract secretions, to ensure that the samples were collected at the lower respiratory tract, prior to processing, they underwent a rigorous quality check by Gram-staining and quantifying the squamous epithelial cells and polymorphonuclear cells observed in the smear. A sputum specimen was deemed high quality if it exhibited fewer than 10 squamous epithelial cells and more than 25 polymorphonuclear cells per low-power field (magnification ×100). S. aureus is identified as the causative pathogen when the bacterial count in the culture exceeds the microbiological diagnostic thresholds: 103 CFU/mL for protected bronchial brush samples, 104 CFU/mL for bronchoalveolar lavage specimens, and 105 CFU/mL for both sputum and tracheobronchial aspirates.

Definition of Variables

Pneumonia was classified into (1) community-acquired pneumonia (CAP), which denotes pneumonia developing outside of hospital or healthcare facilities; (2) hospital-acquired pneumonia (HAP), characterized by pneumonia that arises after 48 h of hospital admission; and (3) ventilator-associated pneumonia (VAP), referring to pneumonia occurring 48–72 h after endotracheal intubation [6, 26, 34]. The definition of appropriate empirical therapy consisted of the administration of at least one antibiotic agent demonstrating in vitro susceptibility against the identified pathogen within 24 h of pneumonia diagnosis, preceding the availability of antimicrobial susceptibility testing results. Failure of empiric antibiotic therapy was defined as mortality during the initial treatment phase or the need to switch from the initial agents to alternative antibiotics within 48–72 h owing to clinical instability. The Charlson Comorbidity Index (CCI) is a scoring system assessing the impact of concurrent comorbidities on long-term survival rates, with CCI > 3 considered to be associated with an increased risk of mortality and treatment failure [5, 8]. Acute respiratory distress syndrome (ARDS) is diagnosed according to the Berlin 2012 criteria for definition of ARDS [17]. The diagnosis of septic shock was made in accordance with The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) [41].

Outcomes

The primary outcome was mortality during the follow-up period. Secondary outcomes were appropriate empiric antibiotic regimens, failure of empiric antibiotic regimens, ARDS, septic shock, intensive care unit admission and associated mortality, the need for mechanical ventilation, ICU stay duration, and hospital stay.

Data Collection

We collected demographic information, comorbidities, and physiologic parameters on admission. The assessed comorbidities included cancer, central nervous system (CNS) disease, chronic obstructive pulmonary disease (COPD), heart failure, coronary artery disease, kidney failure, diabetes, liver disease, kidney failure, blood disorders, and heart arrhythmia, according to the CCI. During hospitalization, we daily documented clinical manifestations, including cough, dyspnea, hemoptysis, and purulent sputum. Additionally, we collected the antibiotic resistance profiles of S. aureus through an antibiogram. The Vitek2® system (BioMerieux Inc. Marcy l’Etoile, Lyon, France) was used to measure minimum inhibitory concentrations (MICs) of antimicrobials. For patients who were discharged alive, we asked them to return for follow-up or called them via telephone on day 30, after the diagnosis of S. aureus pneumonia was established to assess the primary outcome.

Statistical Analysis

Continuous variables with non-normal distributions were summarized as medians with corresponding interquartile ranges (IQRs). Group comparisons of categorical variables were performed using the chi-square test or Fisher’s exact test, as determined by the appropriateness of each test. Continuous variables were compared using Student’s t test or the Mann–Whitney U test, depending on the normality of their distribution. The least absolute shrinkage and selection operator (LASSO) method was combined with Cox proportional hazards regression to identify independent factors associated with 30-day mortality. Hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) and P values were derived from multivariate models. An odds ratio (OR) > 1 denotes an increased risk of the outcome. All statistical tests were two-sided, and a P value less than 0.05 was deemed statistically significant. Data analysis was performed using R version 3.6.2 (The R Foundation).

Results

Baseline Characteristic of Study Patients

Between May 2021 and June 2023, a total of 118 eligible patients were recruited to the study (Fig. 1), among which 76 (64.4%) had CAP, 31 (26.3%) HAP, and 11 (9.3%) VAP.

Fig. 1
figure 1

Flow diagram of the study population

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More than 60% of patients were ≥ 60 years of age. The most common comorbidities included diabetes mellitus (30.5%), CNS disease (28.8%), and coronary artery disease and heart failure (18.6%).

Fifty-seven (48.3%) patients died on day 30. Comparing survivors and non-survivors at day 30, no statistically significant differences were observed in terms of age, gender, pneumonia classifications, underlying medical conditions, and lung imaging abnormalities (Table 1). However, non-survivors had a significantly higher percentage of severe dyspnea (84.2% vs. 63.9%, p = 0.012), hemoptysis (17.5% vs. 3.3%, p = 0.01), respiratory distress (PaO2 < 60 mmHg or SpO2 < 90% or oxygen therapy requirement) (96.5% vs. 68.9%, p < 0.001), PaO2/FiO2 ≤ 250 (73.7% vs. 32.8%, p < 0.001), pH < 7.35 (26.3% vs. 3.3%), and platelet count < 100,000/mm3 (14% vs. 1.6%, p = 0.011). Non-survivors also had more severe pneumonia manifestations according to the Infectious Diseases Society of America/American Thoracic Society (IDSA/ATS) criteria (75.4% vs. 23%, p < 0.001).

Table 1 Baseline characteristics of the 118 subjects enrolled in the study stratified by survival outcome
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Microbiological Findings and Antibiotic Resistance

Among the isolated strains of S. aureus, 84.7% were methicillin-resistant Staphylococcus aureus (MRSA). The proportion of MRSA increased from CAP and HAP to VAP (83.1%, 86.7%, and 90.9%, respectively, p = 0.753). Non-survivors had a statistically significant higher percentage of resistance to oxacillin, levofloxacin, and gentamicin (Table 2).

Table 2 Antibiotic resistance profiles of Staphylococcus aureus isolated from 118 study subjects according to survival outcome
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Clinical Outcomes and Complications

Non-survivors had higher incidence of severe complications including ARDS (42.1% vs. 3.3%, p < 0.001), septic shock (47.4% vs. 6.6%, p < 0.001), and AKI (21.1% vs. 8.2%, p = 0.047) and a shorter median length of hospital stay (8 vs. 15 days, p < 0.001). Patients who responded to empiric antibiotic therapy also had longer hospital stay compared to those who did not respond (median (Q1–Q3) 13 (8–20.5) vs. 10 (5–18) days, p < 0.028).

Among patients with MRSA pneumonia treated with vancomycin (n = 40), patients with a vancomycin MIC ≤ 1 had a significantly higher cumulative survival at day 30 compared to patients with MIC ≥ 2 (log-rank test p = 0.04) Fig. 2.

Fig. 2
figure 2

Kaplan–Meier curve of 30-day survival stratified by vancomycin MIC

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Risk Factors for 30-Day Mortality

Shortness of breath, PaO2 < 60 mmHg or SpO2 < 90% or oxygen therapy requirement, PaO2/ FiO2 ≤ 250, hemoptysis, acidosis (pH < 7.35), WBC < 4000/mm3, platelet count < 100,000/mm3, methicillin resistance, and meeting IDSA/ATS criteria for severe pneumonia were included in the final multivariable Cox proportional hazards model after selection using LASSO. The multivariate Cox regression model based on the adaptive LASSO demonstrated that hemoptysis, methicillin resistance, acidosis (pH < 7.35), and meeting IDSA/ATS criteria for severe pneumonia were significantly associated with mortality in patients with S. aureus pneumonia (Table 3).

Table 3 Risk factors correlated with mortality in Cox proportional hazards regression analysis among 118 patients with Staphylococcus aureus pneumonia
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Discussion

In this study, we investigated the mortality and associated factors in patients with S. aureus pneumonia. We found that these patients had a high mortality rate and severe complications such as ARDS, septic shock, and AKI. We also identified several important risk factors for mortality, including hemoptysis, methicillin resistance, acidosis (pH < 7.35), and meeting the IDSA/ATS criteria for severe pneumonia. Additionally, this study demonstrated a dramatic increase in the prevalence of MRSA in Can Tho City, Vietnam.

The 30-day mortality in our patients was nearly 50% and was not associated with pneumonia classification (CAP, HAP, and VAP). Our findings were consistent with previous reports [13, 44]. HAP and VAP caused by S. aureus are often associated with high mortality rates, ranging from 30% to 50% [2, 13, 44]. This is because these infections typically occur in elderly patients with multiple comorbidities, as well as the increasing prevalence of multidrug-resistant S. aureus strains in healthcare settings [51]. CAP caused by S. aureus is often a secondary infection following influenza in young, healthy patients. Despite this, the mortality rate of CAP caused by S. aureus is still high, ranging from 20% to 50% [10, 13, 21, 39, 44]. This is because these infections are often associated with high-virulence strains of S. aureus that produce the PVL toxin [23, 43, 50, 51]. We also found that patients who died had a significantly higher incidence of ARDS, septic shock, and AKI. In a study by Gillet et al., refractory shock and respiratory failure requiring mechanical ventilation were the sole causes of mortality in patients with S. aureus pneumonia [20]. These severe complications are associated with several toxins produced by S. aureus, with PVL and toxic shock syndrome toxin-1 (TSST-1) playing a major role in the pathogenesis of these complications [1, 20, 23, 50]. Toxin suppression therapies, such as neutralizing antibodies or protein synthesis inhibitors such as linezolid, clindamycin, and rifampicin, have been shown to improve outcomes in patients with S. aureus pneumonia caused by PVL- and TSST-1-producing strains [1, 23, 35, 40, 49].

The prevalence of MRSA in this study (84.7%) was markedly higher than the regional and global averages (14–60%) [10, 39, 45, 46, 52]. A recent study conducted in Vietnam by Tran et al. on children with CAP caused by S. aureus found that 74% of the isolates were MRSA [47]. The higher prevalence of MRSA in our study may be due to the older age of our study participants, the presence of comorbidities, a higher risk of prior antibiotic exposure, and the fact that our study did not exclude HAP cases. These findings indicate a concerningly rapid increase in MRSA prevalence in Vietnam compared to the global average. Remarkably, we found no significant differences in MRSA prevalence across pneumonia categories based on infection source, contrary to earlier seminal studies that asserted higher MRSA rates in HAP compared to community-acquired cases [25, 44]. These findings underscore the concerning reality of the increasing prevalence of MRSA in the community in Vietnam. The higher MRSA prevalence also suggests that conventional beta-lactam antibiotics may no longer be a reliable empirical therapy for clinically suspected S. aureus pneumonia.

Among patients treated with vancomycin for MRSA, higher vancomycin MIC (≥ 2 µg/mL) was associated with increased mortality. Studies on the association of vancomycin MIC and treatment outcomes among patients with MRSA pneumonia have not shown consistent results regarding the impact of vancomycin MIC on clinical outcomes [9, 22, 33, 36, 44, 48]. The heterogeneity in the results of these studies may be attributed to differences in the study population, pneumonia classification, vancomycin dosing, the use of therapeutic drug monitoring, and the methods used to determine and interpret vancomycin MIC. Our findings underscore the need for cautious vancomycin administration in patients with MRSA pneumonia caused by isolates with an MIC ≥ 2 µg/mL, and alternative antibiotic therapies should be considered.

We found that the risk factors for mortality in patients with S. aureus pneumonia included hemoptysis, methicillin resistance, acidosis (pH < 7.35), and meeting the IDSA/ATS criteria for severe pneumonia. Hemoptysis is one of the independent prognostic factors for mortality in S. aureus pneumonia, as documented in prior studies [4, 18, 20, 27, 30, 40]. This manifestation is associated with necrotizing pneumonia, which is observed in infections by certain strains of S. aureus capable of producing PVL toxins. This toxin constitutes a significant virulence factor that exacerbates the severity and mortality of S. aureus pneumonia, as reported in several previous studies [4, 18, 20, 29, 31, 40]. Methicillin resistance in S. aureus pneumonia confers resistance to common beta-lactam antibiotics, leading to increased therapeutic failure, prolonged hospital stay, and increased treatment costs [19, 38, 52]. However, Sicot et al. suggest that methicillin resistance does not adversely impact the outcomes of S. aureus pneumonia [40]. In their study, Sicot et al. investigated CAP caused by PVL-producing S. aureus and found that patients exhibited high mortality despite appropriate antibiotic therapy. This is attributed to the upregulation of PVL toxin production by S. aureus in response to beta-lactam antibiotics, which are commonly prescribed for methicillin-sensitive S. aureus pneumonia, thereby enhancing the virulence of S. aureus [53, 54]. Arterial pH < 7.35 is a criterion contributing to the assessment of severity and 30-day mortality in CAP according to the Pneumonia Patient Outcomes Research Team (PORT) score [16]. Arterial pH is also a criterion in the severity assessment of CAP, such as SCAP and SMART-COP [7, 14]. Once again, our research underscores the significance of this risk factor in predicting 30-day mortality, particularly in S. aureus pneumonia. The IDSA/ATS criteria for pneumonia severity are recommended for assessing the need for ICU admission and 30-day mortality in pneumonia [28, 55]. These criteria exhibit higher specificity than CURB-65 and greater sensitivity than PSI, demonstrating efficacy in predicting outcomes for Streptococcus pneumoniae pneumonia [28, 55]. Our study provides evidence of risk factors predicting mortality in patients with S. aureus pneumonia. When clinical scenarios of pneumonia strongly suggest S. aureus as the likely causative bacterium, with Gram stain results suggestive of S. aureus or confirmed by microbiological testing, clinicians should be attentive to these risks to detect cases prone to adverse outcomes early and implement appropriate therapeutic interventions.

The strengths of the study include a prospective study design with a data collection period of approximately 2 years, conducted at two major hospitals in Can Tho City, Vietnam. However, the study has several limitations, including a relatively short follow-up period, lack of assessment of recurrent pneumonia cases and subsequent outcomes, limited precision in MIC measurement, and absence of a unified scoring system to assess overall pneumonia severity.

Conclusion

S. aureus pneumonia manifests as a severe clinical condition with high mortality and morbidity rates. MRSA has a high prevalence in Can Tho City, suggesting that beta-lactam antibiotics may not be appropriate for empirical antibiotic therapy in suspected S. aureus pneumonia. Hemoptysis, methicillin resistance, acidosis (pH < 7.35), and meeting the IDSA/ATS criteria for severe pneumonia are risk factors for mortality in S. aureus pneumonia. These risk factors can help clinicians identify patients at risk for severe disease progression and then implement timely medical interventions to improve patient outcomes.