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 2,076 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.
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 three 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 one 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 one 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 one 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.
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 chi-square 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 (EuroSCORE, 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.