Influence of Staphylococcus aureus on Outcomes after Valvular Surgery for Infective Endocarditis

Infective endocarditis (IE) remains a condition associated with high morbidity and mortality rates despite advances in surgical techniques and medical therapy [1]. Staphylococcus aureus (SA) is one of the leading causative organisms of IE, and has shown an increasing prevalence in recent years [2]. Among the many pathogens cultured from patients with IE, SA is particularly concerning as it may be associated with higher mortality rates, ranging from 23 to 45% in published reports [3]. In addition to increased mortality, several studies have reported that SA IE is associated with a more severe clinical presentation, including embolic phenomenon and neurologic involvement, and higher rates of persistent infection than IE caused by non-Staphylococcus aureus (NSA) pathogens [4].

Few studies have been specifically devoted to characterizing the virulence of SA in comparison to patients with NSA IE, and those reports that do exist are limited by a small sample size. Additionally, no study has directly investigated the distinct presenting features or postoperative outcomes associated with SA IE compared to NSA in a surgical population requiring valvular replacement. Therefore, the aim of the current study is to evaluate the clinical presentation of patients with culture-positive SA IE, and compare postoperative morbidity and mortality to patients requiring surgery for NSA IE. Characterizing these differences may help identify high-risk patients in whom early surgery may be the optimal treatment strategy.

Staphylococcus aureus has emerged as one of the major causative organisms of IE. Studies have demonstrated that SA IE leads to an unfavorable clinical course and prognosis compared to IE caused by other bacterial organisms [4]. Our study of 323 patients with definite IE according to the modified Duke criteria demonstrate for the first time that patients with SA IE present with more severe clinical infection, as evidenced by higher rates of arrhythmia, fever, vascular complications, persistent bacteremia, annular abscess presence, septic shock, stroke, and embolic events. Mortality and morbidity rates after valve surgery were similar in patients with SA IE versus NSA IE despite the clearly increased preoperative risk, suggesting that surgery may significantly benefit SA IE patients. These novel findings may be useful to surgeons and clinicians to 1) decide if a patient represents an appropriate surgical risk, 2) predict the morbidity and mortality of a surgical intervention, and 3) potentially justify earlier operation in patients with severe SA IE.

The frequency of IE caused by SA has been reported to be increasing over recent decades [3]. SA was responsible for 26.3% of all cases of IE in the current study. Debilitating clinical scenarios such as intravenous drug use (IVDU) may be partially responsible for this trend [4]. The association between IVDU and SA IE was confirmed in our study as 10.6% of patients with IE caused by SA were active IV drug users, significantly more frequent than NSA IE patients.

Generally, SA is more aggressive than other causative organisms for IE resulting in patients presenting with more comorbidities and complications at the time of surgery. Particularly, embolic episodes and neurological complications have been well described in SA IE [5]. This virulence has been ascribed to a variety of complex factors, including its capsule and cell wall, capability to endure phagocyte’s intracellular environment, ability to attack the tissue via extracellular enzymes, and potential to acquire resistance to antibiotics [6]. Accordingly, we overall found that pre-operative development of an embolic event was significantly more frequent in SA IE patients as 33.3% of them developed embolic events compared to 20.7% of patients with IE caused by other bacterial microorganisms. Likewise, patients with SA IE were more likely to develop embolic events postoperatively (p = 0.020). Embolic events have a significant impact on prognosis and therefore, identifying subgroups of patients with IE who are at higher risk for embolism may be crucial for improving survival rates.

In parallel with this trend in embolic events, IE due to SA is associated with higher rates of neurological complications [5] and is the most important risk factor for all neurological complications, with an impact 2 to 3 times higher than that of other IE-causing pathogens [7]. Our study agrees with such findings, as a high frequency of pre-operative stroke (27.1% vs. 13.5%, p = 0.004) in overall SA versus NSA IE patients was observed. The types of stroke in our study included both ischemic and hemorrhagic stroke. It is generally suggested to delay the surgical intervention for patients with preoperative hemorrhagic stroke. In cases with hemorrhagic stroke, prognosis is worse and valve surgery is generally suggested to be postponed for at least 2–4 weeks. Conversely, if surgery is indicated after an ischemic stroke, it should not be delayed [8]. Further studies are needed to characterize the origin of stroke in SA IE patients and to evaluate whether earlier surgery for selected patients will improve the outcome of SA IE.

Previous studies have shown that SA infections are associated with septic shock of any origin [9]. Based on the study by Olmos et al. [10], SA IE patients with septic shock experienced an acute clinical onset more frequently and a more aggressive clinical course. Infection with SA leads to an increased risk for septic shock as the expression of certain virulence factors contributes to the activation of host immune system and coagulation pathways, and the pathogen replication [9, 10]. In agreement with such findings, we observed that IE caused by SA was characterized by a significantly higher incidence of preoperative septic shocks compared to NSA IE.

Prior studies have found higher mortality rates among IE patients with SA infection than among those infected with NSA. In recent large studies of endocarditis, SA has been likewise linked to a greater risk of death than other pathogens [11]. However, contrary to this general trend, our study revealed that there is no statistical significance difference in mortality in SA IE following surgery (30-day: 9.4%; 1-year: 20.3%) compared to NSA IE (30-day: 7.8%; 1-year: 14.1%, p = 0.22). The mortality in SA endocarditis is similar to the rates in previous studies which range from 12 to 45% [1, 12], but the present study showed that in IE, independent of risk factors, SA infection after surgical replacement does not lead to a prohibitive risk of overall mortality. Absence of difference in mortality between two groups treated surgically suggests that mortality could be effectively moderated by valvular surgery. Moreover, it is possible that the SA IE mortality would be higher if measured for a longer period of time postoperatively or if a larger sample size were studied. It is important to consider several confounding factors to the mortality outcome, including co-morbidities on presentation, site of infection, and possible disparities in patient populations. SA IE usually occurs in a debilitated clinical setting: chronic renal failure, hemodialysis, diabetes, alcoholism, cancer, immune-depression, and drug abuse [2, 4]. Our multivariate analysis also showed that SA is not an independent predictor of short and long term post-operative outcomes. Roughly equivalent surgical results between two groups despite more severe clinical presentation of SA IE patients suggests that surgery may allow convergence of the risk curves. Consequently, more detailed studies focused on identifying a relationship between SA and mortality, and on the association of valvular surgery with the improved clinical outcomes in SA IE patients are required. Finally, a full examination of all patients with SA infections who did not receive surgery is necessary to determine a complete representative risk profile of SA.

Major limitations of this study are the small number of cases and the inherent nature of the retrospective analysis. It is possible that the mortality among patients with SA IE would be higher, compared with that of NSA IE patients, if the sample size were greater. Furthermore, we cannot exclude the fact that our hospital is a tertiary referral hospital where patients with severe illnesses are referred. These patients might be a selected group with more severe complications/clinical presentation than the average population with IE. Thus, the difference in clinical characteristics and prognosis of our patients with SA IE may have been the result of referral bias. However, to our knowledge, this is the first and most detailed study to compare the clinical features and prognosis of SA IE with IE caused by other bacterial pathogens.

In conclusion, this study provides data indicating that SA IE is a severe infection with worse clinical features and prognosis than IE caused by other bacterial pathogens. Our findings suggest that SA IE is associated with higher morbidity during hospitalization, such as pre-operative septic shock, embolic events, stroke and annular abscess, compared to IE caused by other bacterial organisms. Furthermore, patients with SA IE should be monitored for embolic events and acute renal failure postoperatively. Surgery may partially ameliorate the pre-operative risks of SA IE patients and early mortality from SA IE but long-term survival remains worse for patient with SA infections. Future prospective, multi-center studies are required to validate our observations and to determine the appropriate timing of surgery for patients with SA IE.