Comparison of Staphylococcus Aureus Endocarditis Risk Factors With Bacteremia

Introduction: Infective endocarditis (IE) is endothelial damage of the endocardium, which is caused by infection. The etiologic agents' highest mortality and morbidity rates are associated with staphylococcus aureus (S. aureus). Accordingly, the knowledge of different risk factors for IE caused by the S. aureus is necessary. Material and methods: This study is an observational-analytical retrospective cohort study on 139 patients with staphylococcus aureus bacteremia (SAB), who referred to a cardiac center during 2011-2019. This study aimed to evaluate the risk factors in 48 patients with staphylococcus aureus endocarditis, who were selected from139 patients with S. aureus bacteremia. Results: The mean age (±SD) of the patients is 56.61 (±16.58), and85 (61.2%) persons are male. Forty-eight patients (34.5%) are diagnosed with staphylococcus aureus endocarditis regarding Duke criteria. In this study, the following risk factors were signicantly associated with S. aureus endocarditis: age (p=0.003), long-term bacteremia (p=0.041), prosthetic heart valve (p=0.016), pre-existing IE (p=0.048), and embolic events (p=0.039). Conclusion: According to the ndings, a signicant number of patients with staphylococcus aureus bacteremia (SAB) have IE with different risk factors. Future studies with a larger sample size are recommended to detect IE risk factors.


Introduction
Infective endocarditis (IE) is de ned as the infection-induced in ammation of the endocardial surface of the heart. The aggregation of activated platelets, brin, and pathogen causes the infective lesion in the endocardium (1,2). The pathogeneses of the endocarditis are the endothelial damage of the endocardium leading to platelets adhesion and microbial adherence to the valvar tissue, often in patients with pre-existing structural heart diseases (3). The predictive factors of IE are valvar heart diseases, history of prior endocarditis, intravenous drug abuse, and hemodialysis (4). Because of the high mortality and morbidity rates of S. aureus endocarditis, its immediate diagnosis and treatment are of great importance (5). The late diagnosis and treatment of S. aureus endocarditis is associated with complications such as severe heart failure, supraventricular arrhythmias, and intracardiac disturbances (6). Trans-thoracic Echocardiography (TTE) and trans-esophageal Echocardiography (TEE) which exhibit the origin, complications, and outside endocardium spread of infection, are necessary for the early diagnosis of IE (7). Sinus tachycardia, low QRS voltage, bundle blocks, ST-segment elevation, atrial brillation, and supraventricular tachycardia are the electrocardiography (ECG) ndings of IE (8). For the IE diagnosis, the above para-clinical ndings and the Duke criteria are clinically recommended in some recent guidelines. In 1994, Durack et al. developed the Duke criteria for the diagnosis of the de nite, possible and rejected IE. The Duke criteria include two major and ve minor criteria, and the clinical diagnosis of de nitive IE requires the presence of two major, one major and three minor, or ve minor criteria (9)(10)(11)(12). Naber et al. showed that the Duke criteria are the more sensitive instrument for the IE diagnosis compared to paraclinical judgments, including ECG (13).
The most common microorganisms causing IE are streptococcus and staphylococcus aureus. Whenever S. aureus is the etiologic agent of the acute disease, the patient requires more intensive care and treatment (14). S. aureus is from the Micrococcaceae series and gram-positive cocci, which grows in a cluster. The S. aureus endocarditis occurs more in intravenous drug users, elderly patients, hospitalized patients, and patients with prosthetic valves, and its symptoms usually are rapid onset with high fever (15,16). The S. aureus is in the environment, and as normal human ora of the skin and mucosa; however, it does not cause infection through healthy skin (17). Some healthcare workers are the carriers of S. aureus in their noses, and the microorganism does not cause damages to them; however, it may cause healthcare-associated infections in hospitals (18). The S. aureus can cause bacteremia and IE in healthy and immunologically-compromised individuals from communities and hospitals. Methicillinresistant S. aureus (MRSA) species are fatal if mistreated; therefore, the detection of the bacteria's prevalence and risk factors is of paramount importance (19). Berlin et al. (1995) declared that the high prevalence rate of IE was correlated with the increasing number of injecting drug users in the United States (20). In 1992, a group of scientists worked on the epidemiology of IE in the Netherlands, and the mitral valve prolapse with valvular endocarditis had the highest prevalence rate, followed by intravenous (IV) drug users. Moreover, the most common microorganisms inducing IE were streptococci, staphylococci, and enterococci (21). In a one-year survey in France in 2002, the annual incidence of IE was 30 cases per million, and streptococci was the highest etiologic agent of bacterial IE (22). In 2007, Letaief et al. represented a ten-year survey indicating that rheumatic valvar disease was the leading risk factor for IE among patients for whom staphylococcus was the most common microorganism etiology (23). However, in Spain, IE is currently rare in older adults with no pre-existing heart problems. Among those in close contact with the healthcare system, streptococcus and staphylococcus are the two most frequent IE species (24). Regarding the poor prognosis and high mortality and morbidity rates of S. aureus IE, this study aimed to determine the frequency of various risk factors for S. aureus IE in patients with staphylococcus aureus bacteremia.

Material And Method
This study was an observational-analytical retrospective cohort study on 200 patients referred to the Shahid Rajaee Cardiovascular, Medical & Research Center in Tehran, Iran, during 2011-2019. The participants' demographic and clinical information, including age, gender, pre-existing IE, electronic heart device usage, existence of cardiac prosthetic valves, IV drug usage, catheter-related, and dialysis, were collected from all patients' records. Duke criteria were used for the clinical diagnosis of IE and the TTEbased paraclinical diagnosis. Regarding the Duke criteria, the clinical diagnosis of de nitive IE requires the presence of two major, one major and three minor, or ve minor criteria. Three blood cultures with the minimum and maximum of one-hour and 24-hour intervals according to Duke criteria, if the results of the primitive cultures were negative after 24-48 hours, 2 or 3 more cultures including lysis-centrifuge culture were prepared and send to the laboratory for detecting speci c cultural microorganisms. Finally, the logistic regression model was used to detect the risk factors of IE in this study. The exclusion criteria were being discharged during the last 72 hours, aged below 18 years, death outcome, no TTE performed for the IE diagnosis, being transferred to other centers, and undergoing palliative care, according to which 61 patients were excluded from this study, and 139 patients were included. All the patients referred to staphylococcus aureus bacteremia (SAB) and SAB+IE were studied for the risk factors.
The collected data was imported to Statistical Package for the Social Sciences (SPSS) software version 25 to be analyzed using descriptive and inferential statistics. Regarding the descriptive statistics, mean and standard deviation (SD) were de ned for quantitative variables, and absolute and relative abundance were performed for qualitative variables. In the inferential section, Kolmogorov-Smirnov and Shapiro-Wilk tests were used. The logistic regression model was also used to detect the risk factors of staphylococcus aureus endocarditis. In this study, p< 0.05 was set as the signi cance level. This study was approved by the ethics Committee of the Islamic Azad University of Medical Sciences (Code: IR.IAU.TMU.REC1398.132), and we con rm that all experiments were performed in accordance with relevant guidelines and regulations.
In this study, S. aureus endocarditis was more frequent in patients aged below 50 years compared to those aged 50 years or above (p=0.003). Men were more susceptible to SAB+IE (p=0.480). The frequencies of different risk factors for Staphylococcus aureus endocarditis were as follows: 18 patients with long term bacteremia (p=0.041), nine patients with electronic heart devices (p=0.454), 34 patients with prosthetic cardiac valves (P=0.016), seven patients with pre-exists endocarditis (p=0.048), two IV drug abusers (p=0.118), one patient with previous embolization history (p=0.039), three patients with a history of osteomyelitis (p=0.434), two patients with dialysis (p=0.542), one patient with a history of cancer (p=0.573), and eight patients using catheter (p=0.139) ( Table 1). endocarditis can be associated with the following risk factors. In our study, the relationship among some risk factors (namely sexuality, electronic heart device, IV drug abuse, osteomyelitis, dialysis, cancer, and catheter-related) was not signi cant for S. aureus (SA)+IE; however, age, long-term bacteremia, prosthetic heart valve, pre-exists IE, and embolic events were signi cantly associated with SAB+IE.
According to Mylonakis et al., men were more likely for SAB+IE than women. In their study, the risk factors were native-valves endocarditis SAB, and IV drug abuse -the most common risk factor for SAB+IE in younger adults. Other risk factors were poor dental hygiene, long-term hemodialysis, and diabetes mellitus. In the present study, sexuality, however, does not play a signi cant role in SAB+IE, and the prevalence of the mentioned risk factors was lower and non-signi cant. The inconsistency of the ndings might have been caused by the small sample size and the patients' mean age. In general, Mylonakis et al. mentioned that the prosthetic valves and nosocomial acquired endocarditis were the possible causes of SAB+IE. The prevalence of the prosthetic valve in their study was compared to that of our study (1). In two different studies by Palraj  In another study in Taiwan, hemodialysis was introduced as an essential attribute of IE. In their study, Mccarthy et al. observed that, consistent with our ndings, IE was infrequent in 20 hemodialysis patients, and that the most common etiologic agent of their research was S. aureus (27)(28)(29). We also observed no signi cant relationship between IV drug-abusing and IE; however, in a survey in New York on 54 patients aged above 18 years, the increase in IV drug-abusing was found to be associated with the recent rise in IE (30). Regardless of our survey, Speechly-Dick and Swanton highly recommended that all IE patients were studied for osteomyelitis. In Tamura (33,39). As Warren and Butany explained, implanting prosthetic heart valve as a foreign object causes in ammatory cell exudation, thereby inducing endocarditis. Further, the infection from normal ora of the skin leads to IE (40). In line with the ndings of our survey, Hogevik et al. declined the embolic events before or after IE; however, the signi cant amount in Hogevik's work was different from ours. In this regard, the presence of vegetation on TEE is a predictive factor of embolic events in patients with IE (41,42). This study showed that patients with pre-existing IE would go through new IE. Generally, previous IE was associated with the future possibility of IE, as stated by Netzer et al., who followed up 212 pre-existing IE patients (43). In this regard, age was a variable with the strongest relationship with IE. We observed that IE was more common in patients aged below 50 years.

Conclusion
The present study revealed that many patients with SAB have IE and risk factors for SA+IE; hence, they should perform Echocardiography in all patients with SAB to diagnose IE. In this study, signi cant risk factors were aged below 50 years, pre-existing IE, prosthetic heart valve, embolic events, and long-term bacteremia. Further studies with a large sample size are recommended to rule out IE in patients referred with S. aureus bacteremia and its risk factors.
Limitations Of The Study

Declaration of interests:
We declare no con icts of interest.

Funding:
Any agency or organization did not fund this project.