Native Valve Endocarditis Due to Coagulase-Negative Staphylococci: Report of 99 Episodes from the International Collaboration on Endocarditis Merged Database

Abstract

Using a large cohort of patients from the International Collaboration on Endocarditis Merged Database, we compared coagulase-negative staphylococcal (CoNS) native-valve endocarditis (NVE) to NVE caused by more common pathogens. Rates of heart failure and mortality were similar between patients with CoNS NVE and patients with Staphylococcus aureus NVE, but rates for both groups were significantly higher than rates for patients with NVE due to viridans streptococci. These results emphasize the importance of CoNS as a cause of NVE and the potential for serious complications with this infection.

Coagulase-negative staphylococci (CoNS) accounts for ∼5% of all episodes of native-valve endocarditis (NVE) [1–3]. Rates of CoNS bacteremia [4, 5] and CoNS endocarditis [6] have increased, underscoring the need to improve our knowledge of this pathogen. Although prior case reports and retrospective series [6–9] have suggested high rates of complications among patients with NVE due to CoNS, our understanding of this infection has been limited by its relative infrequency at any single center.

In the current investigation, we sought to define the characteristics of and outcomes for patients with CoNS NVE using the International Collaboration on Endocarditis Merged Database (ICE-MD), which is a large, well characterized cohort of 2212 prospectively identified patients with infective endocarditis from 7 individual centers in 5 countries. We compared the demographic characteristics, comorbidities, predisposing factors, and outcomes for patients with NVE caused by CoNS to those for patients with NVE due to S. aureus and viridans group streptococci.

Methods. ICE-MD is a multicenter international database of infective endocarditis cases. The objective of ICE-MD was to create a large, well-characterized international cohort of patients with infective endocarditis that would allow detailed analyses of etiologic subgroups and regional differences in the presentation, management, and outcome of infective endocarditis. To accomplish this objective, existing databases of prospective data collected between 1979 and 1999 at 7 individual sites in 5 countries (2 sites in France, the United Kingdom, Spain, Sweden, and 2 sites in the United States) were merged. The merging of each database to create ICE-MD has been described in detail elsewhere [10]. Briefly, data for individual variables from each of the eligible sites were characterized and defined at the coordinating center (Duke Clinical Research Institute, Durham, North Carolina). From these variables, a set of core variables that was common to each database was used to form ICE-MD. Because ICE-MD was created by the assimilation of preexisting databases, 6 cases of CoNS NVE included in this study have been previously reported [11].

Adult patients (i.e., ages ⩾18 years) were included in this analysis. Patients with a history of injection drug use were excluded. Infective endocarditis was diagnosed according to the Duke Criteria [12]. Patients were classified as having health care-associated endocarditis if the infection was hospital acquired or if the patient received home health care, received home or clinic-based parenteral therapy or dialysis, resided in a nursing home, or had been hospitalized during the previous 90 days [13]. Total systemic embolization refers to all emboli that were clinically detectable, including peripheral, brain, pulmonary, abdominal organ, and retinal emboli. In-hospital surgical and mortality rates were also reported.

Isolates of CoNS were characterized according to the standard procedure of the clinical microbiology laboratory at each participating site. Thus, not all CoNS isolates were speciated in this investigation.

Descriptive statistics for age are expressed as medians along with 25th and 75th percentiles. Data for categorical variables are presented as the percentage of patients for whom data on a particular variable was available from the electronic databases. Wilcoxon rank sum testing was used to evaluate group differences for continuous variables, and χ² testing was used to evaluate group differences for categorical variables. Analyses were performed using SAS software versions 6.12 and 8.2 (SAS Institute).

Results. There were 1504 cases of definite NVE in the ICE-MD that were not associated with injection drug use. Of the 1504 cases, 99 (6.6%) were caused by CoNS. The proportions of NVE cases due to CoNS were similar in Europe (7%) and the United States (6%). Of the CoNS NVE cases with an etiologic agent specified, 55 (85%) of 65 were attributed to Staphylococcus epidermidis; while the remainder of cases were due to Staphylococcus hominis (4), Staphylococcus lugdenesis (3), Staphylococcus capitis (1), Staphylococcus capris (1), and Staphylococcus simulans (1). The infecting species was not specified for 34 cases. The median age of 99 patients with CoNS NVE was 68 years; 76 (77%) were male. Twelve (20%) of 60 patients had a long-term intravascular catheter and 27 (40%) of 67 patients had health care-associated infective endocarditis. Heart failure was reported in 49 (49%) of 99 patients, and intracardiac abscess was reported in 15 (15%) of 99 patients. More than half of the patients (53 of 99 [54%]) underwent surgery during the index hospitalization. The in-hospital mortality rate was 19% (19 of 99 patients).

Patients with CoNS NVE and patients with S. aureus NVE were similar with respect to median age (68 years vs. 63 years; P = .26), presence of comorbidities (33% vs. 36% of patients; P = .71), presence of a long-term intravascular catheter (20% vs. 21%; P = .86), and presence of health care—associated infection (40% vs. 33%; P = .36). Although rates of heart failure (49% vs. 42% of patients; P = .18) and in-hospital mortality (19% vs. 25%; P = .21) did not differ significantly between groups, patients with CoNS NVE experienced lower rates of brain embolization (5.5% vs. 24%; P < .001) and higher rates of intracardiac abscess formation (15% vs. 8.2%; P = .04) and underwent surgery more frequently (54% vs. 35%; P < .001) than did patients with S. aureus NVE.

Patients with CoNS NVE, compared with patients with NVE due to viridans group streptococci, were more likely to be older (median age, 68 vs. 59 years; P < .01) and have a long-term intravascular catheter (20% vs. 1.0% of patients; P < .001), or health care-associated infective endocarditis (40% vs. 1.34%; P < .001). Patients with CoNS NVE had higher rates of heart failure (49% vs. 31%; P < .001), intracardiac abscess (15% vs. 8.0%; P = .03), pulmonary embolism (5.1% vs. 0.49%; P < .001), surgery (54% vs. 35%; P < .001), and in-hospital mortality (19% vs. 6.6%; P < .001) than did patients with viridans streptococcal NVE (table 1).

Table 1

Demographic and clinical characteristics of patients with native-valve endocarditis due to coagulase-negative staphylococci, S taphylococcus aureus, and viridans group streptococci (VGS).

Because CoNS is a common blood-culture contaminant, we repeated the analysis using only the subset of CoNS NVE patients with echocardiographically confirmed endocarditis (n = 62). The findings for this subset analysis were qualitatively similar to those of the overall cohort (data not shown).

Discussion. To our knowledge, the current investigation represents the largest study of patients with CoNS NVE to date. This multicenter, multinational approach has made it possible to further define important details regarding the demographic characteristics, comorbidities, predisposing factors, and outcomes for patients with CoNS NVE.

CoNS are an important cause of NVE. Approximately 1 in 20 cases of NVE in this investigation were due to CoNS, an observation that may reflect a growing number of patients with health care-associated staphylococcal bacteremia [2, 5, 13–17]. In the current investigation, patients with NVE due to staphylococci (CoNS or S. aureus) were significantly more likely to have health care-associated endocarditis than patients with viridans streptococcal NVE, an observation that agrees with a recent report [18]. Given the increasingly invasive nature of health care in the modern era, these observations suggest that the importance of CoNS as a cause of NVE will likely increase in the future.

The findings of this investigation also emphasize the morbidity of NVE due to CoNS. Although CoNS NVE are often considered to be low-virulence pathogens, patients with CoNS NVE had rates of heart failure and mortality similar to and rates of cardiac valvular surgery higher than patients with NVE due to S. aureus. It is unclear whether these findings are due to the aggressive nature of CoNS NVE or patient comorbidity status. Nevertheless, these findings are consistent with prior reports [6, 7, 19–22]. Patients with staphylococcal (CoNS and S. aureus) NVE also shared high rates of predisposing comorbid conditions, including advanced age, presence of long-term intravascular catheters, and health care-associated infection. By contrast, episodes of viridans streptococcal NVE tended to occur among younger subjects with fewer comorbid conditions and were associated with lower rates of surgery and better clinical outcomes. These observations suggest a common set of risk factors for infection for both S. aureus and CoNS, and they underscore the devastating and increasingly health care-associated nature of CoNS NVE.

This study has several limitations. The characteristics considered in this study were selected from several preexisting databases, limiting the availability of some demographic details. Furthermore, speciation of the CoNS was not performed at all centers. Referral bias may be present because of the tertiary care nature of the participating centers. It is possible that complicated cases of CoNS NVE were overrepresented and occult cases were underdiagnosed. Also, the time to diagnosis, an important factor that may be related to morbidity among patients with CoNS NVE, was not evaluated in the current investigation. Finally, this dataset represents a compilation of small series from different centers in which uniform definitions have been applied. Thus, the findings of this study should be viewed as hypothesis-generating until externally validated.

Despite these limitations, the findings of the current investigation provide further evidence supporting previous studies [6, 7, 19–22] that suggest CoNS NVE has the potential for serious complications and death. An increasing reliance upon intravascular catheters, indwelling devices, and other invasive procedures within the health care system will likely increase the number of patients at risk for bacteremia and endocarditis due to CoNS. A large multinational prospective cohort investigation is currently underway to confirm the observations made in the present study, to clarify risk factors for the development of CoNS endocarditis, and to identify ways to improve the diagnosis and outcomes of this disease.

Members of the International Collaboration on Endocarditis Merged Database (ICE-MD). Barcelona, Spain (Hospital Clinic-IDIBAPS): Miró J. M., del Río A., Baraldes M. A., Jiménez-Expósito M. J., de Benito N., Claramonte X., Díaz M. E., Soriano A., Moreno A., Gatell J. M., Marco F., García de la María C., Armero Y., Almela M., Jiménez de Anta M. T., Paré J. C., Azqueta M., Mestres C. A., Ninot S., Cartaña R., Pomar J. L., Pérez N., Ramírez J., and Ribalta T. Besancon/Nancy, France: Hoen B., Selton-Suty C., Doco-Lecompte T., Duchêne F., Khayat N., and Bernard Y., Chirouze C.; Durham, North Carolina, United States: Corey G. R., Sexton D. J., Fowler Jr. V. G., Woods C. W., Wang A., Peterson G. E., Jollis J. G., Anderson D. J., Singh R., Cabell C. H., Glower D., Chen A., Stafford J., Anstrom K., and Pappas P., Goteborg, Sweden: Olaison L. and the Swedish Society of Infectious Diseases Quality Assurance Study Group for Endocarditis. London, United Kingdom: Eykyn S. Marseille, France: Raoult D., Habib G., Casalta J. P., Barrau K., and Fournier P. E.; Philadelphia, Pennsylvania, United States: Abrutyn E., Strom B. L., Berlin J. A., Kinman J. L., Feldman R. S., Levison M. E., Korzeniowski O. M., and Kaye D.

Acknowledgments

Financial support. This study was supported in part by the National Institutes of Health (grants R01AI59111 [to V.G.F.] and HL70861 [to C.H.C.]), the Tenet Healthcare Foundation (to E.A.), the “Red Española de Investigación en Patología Infecciosa (V-2003-REDC14A-O)” (to J.M.M.); the Fundación Privada Máximo Soriano Jiménez (to J.M.M.); and a Research Grant from the Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona (to J.M.M.).

Potential conflicts of interest. All authors: No conflict.