Clinical and prognostic differences between methicillin-resistant and methicillin-susceptible Staphylococcus aureus infective endocarditis

Background S. aureus (SA) infective endocarditis (IE) has a very high mortality, attributed to the age and comorbidities of patients, inadequate or delayed antibiotic treatment, and methicillin resistance, among other causes. The main study objective was to analyze epidemiological and clinical differences between IE by methicillin-resistant versus methicillin-susceptible SA (MRSA vs. MSSA) and to examine prognostic factors for SA endocarditis, including methicillin resistance and vancomycin minimum inhibitory concentration (MIC) values > 1 μg/mL to MRSA. Methods Patients with SA endocarditis were consecutively and prospectively recruited from the Andalusia endocarditis cohort between 1984 and January 2017. Results We studied 437 patients with SA endocarditis, which was MRSA in 13.5% of cases. A greater likelihood of history of COPD (OR 3.19; 95% CI 1.41–7.23), invasive procedures, or recognized infection focus in the 3 months before IE onset (OR 2.9; 95% CI 1.14–7.65) and of diagnostic delay (OR 3.94; 95% CI 1.64–9.5) was observed in patients with MRSA versus MSSA endocarditis. The one-year mortality rate due to SA endocarditis was 44.3% and associated with decade of endocarditis onset (1985–1999) (OR 8.391; 95% CI (2.82–24.9); 2000–2009 (OR 6.4; 95% CI 2.92–14.06); active neoplasm (OR 6.63; 95% CI 1.7–25.5) and sepsis (OR 2.28; 95% CI 1.053–4.9). Methicillin resistance was not associated with higher IE-related mortality (49.7 vs. 43.1%; p = 0.32). Conclusion MRSA IE is associated with COPD, previous invasive procedure or recognized infection focus, and nosocomial or healthcare-related origin. Methicillin resistance does not appear to be a decisive prognostic factor for SA IE.


Background
The incidence of infective endocarditis (IE) is low in industrialized countries (3-9 cases per 100,000 people-years) but has recently increased. This rise has been attributed to improvements in diagnostic methods, an increase in life expectancy, and a higher rate of instrumentalization (e.g., pacemaker and central venous catheter implantation, hemodialysis, etc.) in an increasingly aged and fragile population [1]. The most common type of IE is native valve endocarditis (largely mitral or aortic) [2]. Staphylococcus aureus (SA) is one of the most frequently involved bacteria [3,4] and is associated with high morbidity and mortality rates due to its strong avidity for endothelial tissue, its capacity to produce endovascular infection, and its aggressive character [5,6]. A European study of hospitalized patients with bacteremia by SA reported a higher risk of 30-day mortality in those infected with methicillin-resistant S. aureus (MRSA) versus methicillin-susceptible S. aureus (MSSA) [OR of 1.8(95%CI, 1.04 to 3.2)] [7]. Besides methicillin resistance, poor prognostic factors for bacteremia by SA include the presence of IE, comorbidities [8], inadequate antibiotic treatment [9], and a vancomycin minimum inhibitory concentration (MIC) > 1 μg/mL [10].
The objective of this study was to determine differences in epidemiological, clinical, and prognostic variables between MRSA versus MSSA IE and to analyze the prognostic value of vancomycin MIC > 1 μg/mL for MRSA.

Methods
We conducted a prospective, multicenter, longitudinal study of consecutive patients with IE hospitalized in eight hospitals of the Health Service of Andalusia (Spain) between 1984 and 2017. During this period, these hospitals prospectively enrolled a total of 2076 patients with IE from whom informed verbal consent to study participation was obtained. Ethics committee approved this procedure.
Among these patients, we prospectively enrolled in the present cohort the 437 patients with S. aureus endocarditis who met eligibility criteria. Information was prospectively gathered by attending physicians on epidemiological, clinical, analytical, and prognostic (mortality, relapse) data and on medical and surgical treatments. Heart surgery was available at five of the eight hospitals, to which candidates for surgery from the other three hospitals were transferred. Patients were followed up for 12 months after IE, monitoring clinical, analytical, and microbiological results. The EuroSCORE, logistic EUROSCORE, and modified Duke Criteria were calculated for all patients and included as study variables when they became incorporated into clinical practice, with the agreement of the endocarditis study group, as well as data on new antibiotics. There were no changes during the study period in the other study parameters, i.e., clinical, epidemiological, microbiological, analytical findings, duration of antibiotic therapy, performance of surgery, adequate antibiotic treatment (according to contemporary recommendations), or mortality data.
All information was treated in accordance with national legislation on personal data protection (Organic Law 15/1999, 13 December, of Personal Data Protection), and the study was approved by the ethics committee of the coordinating center (Hospital Universitario Virgen del Rocio, Seville).

Inclusion criteria
Inclusion criteria were: age ≥ 18 years with "definite" or "possible" S. aureus IE according to modified Duke Criteria [11], which were retrospectively applied to patients enrolled before their publication.

Definitions
Previous valve disease included any rheumatic, congenital, degenerative/myxoid, or degenerative/calcified valve disease in the patient's clinical records.
History of invasive procedure or previous infection focus included previous dental manipulation (extraction or other invasive dental or maxillofacial technique) or invasive urinary or vascular procedure (e.g., central/peripheral catheterization) and/or the presence of a focus of infection (urinary, cutaneous, vascular, etc.) in the 3 months before the IE episode.
Central nervous system (CNS) symptoms included encephalopathy, meningitis, brain abscess, hemorrhagic or ischemic embolism, and transient stroke.
Acute kidney failure during hospitalization was defined by creatinine > 1.5 mL or 25% increase versus baseline.
The age-adjusted Charlson comorbidity index was used to estimate the 10-year life expectancy of our patients as a function of age and comorbidities [12], determined at admission to hospital for the endocarditis episode.
Surgical risk was estimated at admission in all patients using EuroSCORE I or II (European System for Cardiac Operative Risk Evaluation), which predicts early mortality after cardiac valve surgery [13,14]. We used both scores in order compare their capacity to predict the prognosis. In cases of IE between 1998 and 2017, this scale was calculated prospectively by the attending physician. In cases of IE before 1998, the EuroSCORE was calculated retrospectively from data in the clinical records.
IE relapse was defined by an episode of S. aureus endocarditis within 12 months of a first episode that had met cure criteria. IE reinfection was defined by a second IE due to a microorganism other than SA during the follow-up year.
Mortality rates considered deaths for any cause during hospitalization or the first 30 days post-discharge (hospital mortality) as well as the IE-related mortality [e.g., heart failure due to valve dysfunction] and the non-IE-related mortality [e.g., cancer] at 1 year post-discharge.
Severe sepsis was defined by ≥2 criteria of systemic inflammatory response syndrome with organ dysfunction; and Septic shock by sepsis with refractory hypotension and end-organ perfusion dysfunction despite adequate fluid resuscitation [15].
Early prosthetic IE was defined by onset during the first year post-surgery and Late prosthetic IE by onset after more than 1 year post-surgery [16].
Nosocomial IE was defined by symptom onset more than 48 h after hospital admission [17].
Healthcare-related IE was defined by symptom onset more after medical manipulation in the 3 months preceding the diagnosis (intravenous treatments, wound healing, hemodialysis, and stays at care home or assisted centers) [17].
The indication for surgery was initially assessed by the attending physician, based on universally accepted criteria at the time [18][19][20], and was confirmed by consensus of a multidisciplinary team that included attending physicians and heart surgeons, who also considered the quality of life, comorbidities, surgical prognosis, and life expectancy of patients.
Indications for surgery were divided into five groups: a) Surgery not indicated; b) Surgery indicated and performed without delay; c) Surgery indicated and performed with delay > 72 h in grade IV left ventricular failure (LVF) or delay > 1 week in progressive LVF; d) Surgery indicated but not performed for any cause (e.g., technical impossibility, neurological complication, death before surgery, patient refusal, etc.); and e) Surgery indicated but not proposed by the attending physician due to the condition of patients (e.g., comorbidity with low life expectancy, critical status, etc.).
Postponed surgery was defined by its performance after 1 month of hospitalization.
Methicillin resistance was defined by an inhibition halo for oxacillin of ≤10 mm or oxacillin MIC ≥4 mg/L. The E-test with oxacillin strip was used in some centers [21] and automated microdilution systems in others [22].
Adequacy of antibiotic treatment was defined by its accordance with antibiogram results and its recommendation for IE in clinical practice guidelines.
Diagnostic delay was defined by an interval of ≥7 days between symptom onset and first hospital consultation.

Statistical analysis
In a descriptive analysis, central tendency and dispersion measures (mean, standard deviation, median, percentiles) were calculated for quantitative variables and absolute frequencies with 95% confidence interval (CI) for qualitative variables. In bivariate analyses, prognostic, clinical, epidemiological, and therapeutic variables were compared between patients with MRSA IE versus MSSA IE, and mortality rates for SA endocarditis were compared with prognostic factors. The Student's t-test for independent samples was used for quantitative variables with a normal distribution and the Mann-Whitney U test for those with non-normal distribution. Qualitative variables were analyzed using Pearson's or Fisher's chisquare test, as appropriate. The normality of variable distribution was checked with the Kolmogorov-Smirnov test. Two multivariate logistic regression models were developed according to Freeman's formula [n = 10*(k + 1)] [23], one for differences between MRSA IE versus MSSA IE and the other for factors related to mortality in patients due to SA IE. The models included variables found to be statistically significant in bivariate analyses or considered clinically relevant. A stepwise procedure was used, considering an entry probability of 0.05 and exit probability of 0.10. Goodness of fit was evaluated with the Hosmer-Lemeshow test. The regression model for differences between MRSA versus MSSA IE included the following variables: history of myocardiopathy, congenital heart disease, hemodialysis, chronic obstructive pulmonary disease (COPD); intravenous drug addiction; Charlson index; early prosthetic IE; perivalvular involvement diagnosed by echocardiography; previous invasive procedure or focus of infection; place of IE acquisition; interval between symptom onset and hospital admission; cutaneous manifestations (Osler's nodes, Janeway lesions); Duke vascular or embolic phenomena; and adequate treatment administration. The regression model for risk factors associated with mortality due to IE included: hospital where IE was treated, decade of IE onset, previous valve disease, early prosthetic IE, IE on pacemaker or defibrillator lead, IE on mitral valve, onset of IE as severe sepsis/septic shock, CNS involvement, kidney failure, heart failure, infectious osteoarticular involvement (arthritis/osteomyelitis), surgical risk (Euro-SCORE, logistic EuroSCORE), heart surgery indicated without delay and performed during hospitalization, and surgery indicated but not performed. IBM SPSS Statistics 20.0 software was used for data analyses. The level of significance was 0.05 for all tests.
The risk factors associated with MRSA in the multivariate analysis were: history of COPD (OR 3.19; 95% CI 1.41-7.23), previous invasive procedure or recognized focus of infection in the three-month period before IE onset (OR 2.9; 95% CI 1.14-7.65), and a delay of ≥7 days between symptom onset and hospital admission (OR 3.94; 95% CI 1.64-9.5) (

Discussion
In this study of patients with S. aureus endocarditis, 13.5% were MRSA, all elderly men with multiple diseases, elevated Charlson index, and high surgical risk. Around half of the patients with MRSA had prior valve disease, which was rheumatic or degenerative in onethird of cases and of nosocomial origin or healthcarerelated in the remainder. The IE predominantly involved left-sided native valves (predominantly mitral valves) and less frequently cardiac devices, although such cases have become increasingly frequent. The mortality rate was very high, with around half of the patients dying from IE in hospital or within 30 days of their discharge. These data are similar to previous reports associating endocarditis with high morbidity and mortality rates and linking its acquisition to health care in up to 30% of cases [24]. These trends have been attributed to the increasing incidence of aortic valve disease in elderly populations, with a greater use of valve prostheses and intracardiac devices [25]. The main risk factors for in-hospital mortality in patients with IE were recently reported to be SA etiology, high Charlson index score, and EuroSCORE II ≥ 9 [26]. In our patients with MRSA endocarditis, surgery was considered appropriate in 41 patients but was only carried out in 15 (36.5%), being ruled out in 7 patients due to their poor clinical status. The percentage of patients who receive surgery when indicated ranged between 15 and 45% in a recent review of S. aureus and endocarditis; this review reported contradictory data on the benefits of early surgery, observing that surgery was sometimes delayed for weeks or months beyond the end of antibiotic IE treatment to correct the valve damage responsible for heart failure [27].
The main differences between MRSA and MSSA endocarditis in our study population was the greater frequency of the former in patients with COPD and its association with a longer interval between symptom onset and hospital admission (≥ 7 days in around 60% of cases). One reason may be the higher MRSA colonization rate in patients with COPD due to their repeated contact with the health care system [28]. The exacerbation of COPD, mainly during the winter, is one of the principal causes of hospitalization and is often responsible for iatrogenesis, adverse effects, and functional   [29]. This may be an important reason for the delay in hospital care. Previous invasive procedures and/or infectious foci were also more frequent in the patients with MRSA versus MSSA IE, with 70% of the former being of nosocomial origin. There were no significant differences between MRSA and MSSA IE in surgical intervention or mortality rates or in the receipt of adequate antibiotic therapy. Many authors have associated mortality due to SA with methicillin resistance. A recent meta-analysis of 62 studies of bacteremia (13 of IE alone) found a higher mortality risk for MRSA versus MSSA, with an OR of 2.65 (95% CI, 1.46-4.80) [6]. It should be noted that most published studies on the role of methicillin resistance in the prognosis of S. aureus bacteremia do not include cases of endocarditis. It should also be acknowledged that the prognosis of IE is influenced by numerous factors; therefore, the added prognostic value of data on methicillin resistance and vancomycin MIC may be limited. The association of methicillin resistance with higher treatment failure rate in our cohort did not reach statistical significance, possibly due to the low relapse rate after IE treatment with prolonged antimicrobial therapy and frequent removal of the infection focus (heart surgery).
The importance of vancomycin susceptibility in methicillin-resistant and even methicillin-susceptible strains is controversial. After initial studies described worse outcomes for methicillin-resistant strains with high vancomycin MIC values [9,30], various metaanalyses on the relevance of MIC in SA infections have associated values ≥2 μg/mL with higher mortality (OR 1.72; 95% CI: 1.34-2.21) and values ≥1.5 μg/mL with   [10]. These associations have been observed not only in MRSA but also in Staphylococcus coagulase-negative IE with vancomycin MIC ≥2 μg/mL [31] and even in IE [32] and bacteremia due to MSSA with MIC ≥1.5 μg/ mL, which was associated with a higher risk of complicated bacteremia [33,34]. In contrast, a longitudinal, prospective, multicenter study of MRSA endocarditis found no association of vancomycin MIC ≥1.5 μg/mL with higher mortality, although it was related to a greater persistence of bacteremia and a higher frequency of sepsis/septic shock, peripheral embolism, and arthritis/osteomyelitis [35]. Likewise, a study on beta-lactamtreated left-sided MSSA endocarditis found no relationship between vancomycin MIC and mortality or microorganism virulence [36]. The mortality rate of S. aureus endocarditis was very high in our cohort, despite the receipt of antibiotic treatment that accorded with antibiogram results and was recommended in available clinical practice guidelines by 90% of the patients. Active neoplasm, sepsis/shock, and decade of endocarditis onset (1985-1999 or 2000-2009 vs. 2010-2017) emerged as poor prognostic factors, but early surgery (within first 2 weeks) did not appear to influence the prognosis. A recent multicenter, longitudinal, observational study of SA IE (n = 213 cases) reported a mortality rate of   37% and identified a high Charlson index, congestive heart failure, CNS involvement, and sepsis/septic shock as risk factors [35].
With regard to the possible beneficial effect of early surgery in SA endocarditis, a meta-analysis reported a lower mortality rate when the surgery was conducted within the  [37]. Another study found no reduction in one-year mortality in patients with S. aureus IE on prosthetic valve when the surgery was performed during the first 60 days of hospitalization rather than later (risk ratio, 0.67 [95% CI: 0.39-1.15]; p = 0.15). The authors therefore recommended that surgery be considered on a case-by-case basis, regardless of whether SA is involved [38].
One study limitation is that our analysis considered data gathered over three decades rather than shorter time periods in order to obtain adequate statistical power. Strengths include the large patient sample and its prospective longitudinal multi-center design, involving specialist hospitals that formed a specific study group for this purpose. The results provide a reliable understanding of the current state of endocarditis in our region and may possibly be extrapolated to other regions of our country.

Conclusion
S. aureus endocarditis has a very high mortality rate in our setting. MRSA IE is associated with COPD, previous invasive procedure or recognized infection focus, and nosocomial or healthcare-related origin. Although methicillin resistance does not appear to have a decisive influence on the mortality risk, it may increase the therapeutic failure rate among patients receiving recommended treatments.