Current management of Staphylococcus aureus bacteremia in a Japanese university hospital

Abstract

Objectives: Consultation with infectious disease specialists is associated with reduced patient mortality in the care of patients with Staphylococcus aureus bacteremia (SAB) through appropriate management of complications including infective endocarditis. This study aimed to determine the rates of confirmation of a negative blood culture, implementation of echocardiography, and administration of appropriate antibiotics in patients with SAB at a university hospital in Japan that provides general internal medicine and not an infectious disease consultation service.

Methods: We conducted a retrospective cohort study at Dokkyo Medical University Hospital in Japan. Patients eligible for inclusion in the study were ≥20 years of age with ≥1 positive blood culture for S. aureus identified in a clinical microbiology laboratory. The primary outcome was the proportion of patients with confirmation of a negative blood culture, implementation of echocardiography, and administration of appropriate antimicrobial agents.

Results: A total of 109 patients with SAB were included in the analysis. Follow-up blood cultures were collected in 91 patients and negative results were documented in 88 patients. Follow-up blood culture collection was performed within 4 days of the initial blood culture collection in 49 patients. Echocardiography was performed appropriately in 40 patients. Appropriate antibiotic therapy was administered in 36 patients.

Conclusions: Quality-of-care indicators were more commonly implemented in patients with SAB who received general internal medicine consultation than in those who did not.

Introduction

Staphylococcus aureus is a common pathogen in community- and hospital-acquired infections, and is associated with considerable morbidity and mortality.¹ S. aureus bacteremia (SAB) can lead to infective endocarditis and abscess formation in remote sites and is associated with a 30-day mortality rate as high as 20% even with appropriate antibiotic therapy.² Despite medical advances, the mortality rate from SAB has not greatly improved since the 1990s.² Consultation with infectious disease specialists in the care of patients with SAB is associated with reduced mortality of patients in multiple studies.^3–5 The lower mortality rate of patients with SAB who receive infectious disease consultation is attributed to the following three factors: implementation of echocardiography, confirmation of negative blood cultures, and administration of appropriate antibiotics.^4–7 These findings suggest that improving patients’ survival may be possible even if infectious disease consultation is not available, as long as these three factors are consistently implemented for patients with SAB. These three factors can be described as quality-of-care indicators.^4–7 Although studies have compared the effect of algorithm-based and standard care on patients’ outcomes, infectious disease consultation is also performed in the majority of cases.⁸ Some studies have shown that these quality-of-care bundles have reduced mortality and recurrence rates in SAB.⁶

In Japan, because of the shortage of infectious disease specialists, infectious disease consultation is not available in most hospitals, including some university hospitals.⁹ Therefore, general internal medicine (GIM) physicians in Japan often provide consultation service for patients with complex infectious diseases such as SAB, although they do not have board certification in infectious diseases. In this context, medical consultation for conditions such as fever and antimicrobial selection is provided by physicians specializing in GIM at the hospital, guided by quality-of-care indicators, clinical guidelines, and textbooks.^10,11

Currently, few studies have assessed quality-of-care indicators in the management of S. aureus bacteremia in Japanese hospitals, and studies in which infectious disease specialists did not intervene are scarce.¹² In a study involving 10 Emergency Departments, no quality-of-care indicators were used in 86% of SAB cases.¹²

This study aimed to determine the rates of confirmation of a negative blood culture, implementation of echocardiography, and administration of appropriate antibiotics in patients with SAB at a university hospital in Japan that does not have an infectious disease consultation service, but has a GIM consultation service, and to assess patients’ outcomes.

Methods

Study design

We conducted a retrospective cohort study at Dokkyo Medical University Hospital (DMUH), which operates 1195 acute care beds, in Japan. DMUH does not have an infectious disease consultation service. Participants were enrolled between 1 April 2019 and 31 March 2021.

Department of Diagnostic and Generalist Medicine at DMUH

The Department of Diagnostic and Generalist Medicine at DMUH covers GIM services, which include a medical outpatient clinic, urgent care clinic, and emergency medicine hospital medicine, and also provides medical consultation for patients with complex infection upon request.¹⁰ The Department of Diagnostic and Generalist Medicine at DMUH was founded in April 2016. At DMUH, GIM physicians do not routinely participate in the care of patients with SAB but provide a consultation service if consulted by the attending physicians of these patients.

Patients

Hospitalized patients who were ≥20 years of age and had ≥1 positive blood culture for S. aureus collected during hospitalization or collected in an outpatient clinic, which led to the hospitalization, were eligible for the study. Patients who died within 2 days of the index blood culture collection were excluded because more than 90% of SAB results in a positive blood culture within 2 days.¹³ Additionally, patients who were transferred to other hospitals within 2 days and patients treated as outpatients were excluded.

Definitions

The patients were classified as having hospital-acquired or non-hospital-acquired SAB¹⁴. Hospital-acquired SAB was defined as SAB for which index positive blood cultures were obtained from patients who had been hospitalized for more than 48 hours or from patients who had been hospitalized in another hospital and then transferred. Patients who did not meet the definition of hospital-acquired SAB were defined as having non-hospital-acquired SAB.¹⁴ Uncomplicated SAB was defined when all of the following criteria were met: 1) negative blood cultures were collected within 4 days of the index positive blood culture, 2) absence of findings suggestive of infective endocarditis at least once on transesophageal echocardiography (TEE) for non-hospital-acquired SAB or at least once on transthoracic echocardiography (TTE) for hospital-acquired SAB, 3) absence of distant lesions on a physical examination, and 4) absence of implanted intravascular devices.^1,2 Complicated SAB was defined when any of these four criteria were not met. Appropriate antimicrobial therapy was defined when an appropriate agent was administered for a minimum of 2 weeks from the date of the first confirmed negative blood culture for uncomplicated SAB and a minimum of 4 weeks from the date of the first confirmed negative blood culture for complicated SAB. Patients who died in hospital were considered to have received appropriate antimicrobial therapy if they had received an appropriate agent up to the date of their death.

Appropriate antimicrobial agents included cefazolin, ceftriaxone, cefepime, and meropenem for methicillin-susceptible S. aureus (MSSA), and vancomycin, teicoplanin, and daptomycin for methicillin-resistant S. aureus (MRSA). Penicillin was not included among the appropriate agents because susceptibility to this agent was not routinely reported from the clinical microbiology laboratories.

Appropriate echocardiography was defined when TEE was performed in the presence of an implanted intravascular device or for any non-hospital-acquired SAB, or when TTE was performed for hospital-acquired SAB in the absence of an implanted intravascular device. GIM consultation was considered present if the patient was managed at least once by the Department of Diagnostic and Generalist Medicine after positive blood culture results became available during the course of the hospitalization.

The primary outcome was the proportion of patients with confirmation of a negative blood culture, implementation of echocardiography, and administration of appropriate antimicrobial agents based on the presence or absence of GIM consultation. The secondary outcome was in-hospital mortality based on the presence or absence of GIM consultation.

Data collection

Data on the patients’ age, sex, and microbiology were initially extracted. Three investigators (SH, YH, and MY) then independently reviewed the patients’ electronic medical records and collected the following data: body mass index, onset location, date of blood culture collection, echocardiographic results, presence or absence of GIM consultation, survival in hospital, recurrence within 90 days, days of antimicrobial therapy, and the antimicrobials administered. Finally, the patients were classified into having complicated or uncomplicated SAB according to the above-mentioned definition, and any ambiguity was resolved by consensus among the investigators (SH, YH, and MY).

Statistical analysis

Continuous variables are shown as the mean±standard deviation, and binary and categorical data are shown as the percentage. Continuous variables were compared using the Mann–Whitney U test, and binary and categorical variables were compared using Fisher’s test between groups with and without GIM consultation. Univariable logistic regression models were used to calculate the odds ratio of variables for outcomes. The statistical analysis was performed using EZR (version 1.61; Saitama Medical Center, Jichi Medical University, Saitama, Japan; based on R ver. 4.2.2).¹⁵

Ethical considerations

Approval of the study was obtained from the institutional review board of DMUH (record number: R3-247). We followed the Declaration of Helsinki and the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.¹⁶ Written informed consent was waived by the board under the condition that the opt-out method was used.

Results

A total of 122 patients with SAB were enrolled during the study period. Of these, 11 patients died within 2 days of blood culture collection, one was transferred within 2 days, and one was treated as an outpatient. After excluding these 13 patients, 109 patients were included in the analysis. The mean age was 65.2 years (standard deviation 16.9 years), men accounted for 77/109 (65.1%) patients, and the mean body mass index was 22.1 kg/m². In this cohort, 46 (42.2%) patients had non-hospital-acquired SAB and 63 (57.8%) had hospital-acquired SAB. MSSA was the culprit organism in 80 (73.4%) patients and MRSA in 29 (26.6%) patients. There were 96 (88.1%) patients with complicated SAB and 13 (11.9%) patients with uncomplicated SAB (Table 1).

Table1

Baseline characteristics of the patients with SAB

	All patients (n=109)
Age, years	65.2±16.9
Male sex	71 (65.1)
BMI, kg/m2	22.1±4.9
Non-hospital-acquired SAB	46 (42.2)
MSSA	80 (73.4)
Complicated SAB	96 (88.1)

Data are the mean±standard deviation or n (%).

SAB, Staphylococcus aureus bacteremia; BMI, body mass index; MSSA, methicillin-susceptible Staphylococcus aureus.

Follow-up blood cultures were collected in 91 (83.5%) patients and negative results were documented in 88 (80.7%) patients. Follow-up blood culture collection was performed within 4 days of the initial blood culture collection in 49 (45%) patients, and these follow-up cultures were negative in 34 (31.2%) patients. TTE was performed at least once in 77 (70.6%) patients and TEE was performed at least once in 16 (14.7%) patients. TTE was not performed in 7 (15.2%) patients with non-hospital-acquired SAB and in 25 (39.7%) patients with hospital-acquired SAB. TEE was not performed in 33 (71.7%) patients with non-hospital-acquired SAB. Appropriate echocardiography was performed in 40 (36.7%) patients. Appropriate antimicrobial therapy was administered to 36 (33.0%) patients. There were 13 in-hospital deaths and 15 deaths within 90 days (Table 2).

Table2

Outcomes of the patients with SAB

	All patients (n=109) unless otherwise specified
Negative blood culture documented	88 (80.7)
Follow-up blood culture collected within 4 days	49 (45.0)
TTE implemented	77 (70.6)
Echocardiography performed appropriately	40 (36.7)
TEE for patients with non-hospital-acquired SAB	12/46 (26.1)
Appropriate antimicrobial therapy provided	36 (33.0)
Death in hospital	13 (11.9)
Recurrence 90 days after completion of antimicrobial therapy	6/98 (6.1)
Death within 90 days of the first positive blood culture	15/99 (15.2)

Data are n (%).

SAB, Staphylococcus aureus bacteremia; TTE, transthoracic echocardiography; TEE, transesophageal echocardiography.

When we compared patients for whom GIM was consulted (n=25) with those for whom GIM was not consulted (n=84), the baseline characteristics were not different between the two groups, except for the proportion of patients with non-hospital-acquired SAB. The proportion of patients with non-hospital-acquired SAB was higher in those seen by the GIM service than in those who did not use the GIM service (19/25, 76% vs. 27/84, 32%, P<.001) (Table 3). The proportions of patients with confirmation of a negative blood culture (25/25 patients, 100% vs. 63/84 patients, 75.0%, P=.006), implementation of TTE (23/25 patients, 92.0% vs. 54/84 patients, 64.3%, P=.006), and appropriate antimicrobial therapy (18/25 patients, 72.0% vs. 18/84 patients, 21.4%, P<.001) were significantly higher in patients who received GIM consultation than in those who did not receive GIM consultation. In-hospital death occurred in 3 (12.0%) patients with GIM consultation and in 10 (11.9%) patients without GIM consultation, with no significant difference between the two groups of patients. Recurrence within 90 days was also not different between the two groups (Table 4).

Table3

Baseline characteristics of patients with SAB with or without GIM consultation

	With GIM consultation (n=25)	Without GIM consultation (n=84)	P value
Age, years	69.3±14.6	64.0±17.4	.19
Male sex	14 (56.0)	57 (67.9)	.34
BMI, kg/m2	22.0±4.5	22.2±5.0	.99
Non-hospital-acquired SAB	19 (76.0)	27 (32.1)	<.001
MSSA	17 (68.0)	63 (75.0)	.61
Complicated SAB	22 (88.0)	74 (88.1)	>.99

Data are the mean±standard deviation or n (%).

SAB, Staphylococcus aureus bacteremia; GIM, general internal medicine; BMI, body mass index; MSSA, methicillin-susceptible Staphylococcus aureus.

Table4

Outcomes of patients with SAB with or without GIM consultation

	With GIM consultation (n=25)	Without GIM consultation (n=84)	Odds ratio (95% CI)	P value
Negative blood culture documented	25 (100)	63 (75.0)	1.33 (1.18–1.51)	.006
Follow-up blood culture collected within 4 days	21 (84.0)	28 (33.3)	2.52 (1.78–3.57)	<.001
TTE implemented	23 (92.0)	54 (64.3)	1.43 (1.18–1.74)	.006
Echocardiography implemented appropriately	11 (44.0)	29 (34.5)	1.27 (0.75–2.17)	.48
TEE for patients with non-hospital-acquired SAB	9/20 (45)	3/26 (11.5)	3.90 (1.21–12.56)	.010
Appropriate antimicrobial therapy provided	18 (72.0)	18 (21.4)	3.36 (2.09–5.41)	<.001
Death in hospital	3 (12.0)	10 (11.9)	1.01 (0.30–3.38)	>.99
Recurrence 90 days after completion of antimicrobial therapy	1/23 (4.3)	5/75 (6.7)	0.65 (0.08–5.30)	.69
Death within 90 days of the first positive blood culture	3/22 (13.6)	12/77 (15.6)	0.88 (0.27–28.3)	>.99

Data are n (%).

SAB, Staphylococcus aureus bacteremia; GIM, general internal medicine; TTE, transthoracic echocardiography; TEE, transesophageal echocardiography.

Discussion

This study showed that at a university hospital without an infectious disease consultation service, the rates of confirmation of a negative blood culture, implementation of echocardiography, and administration of an appropriate antibiotic in patients with SAB were significantly higher in those who received GIM consultation than in those who did not.

The proportions of patients with confirmation of a negative blood culture and who underwent any echocardiography are comparable to those described in studies with infectious disease consultation.^4,5,13 However, the proportion of patients who received appropriate treatment in this study is 40% lower than that in studies in which infectious disease consultation was available.^4,5,13 Only 26% (12/46 patients) of patients with non-hospital-acquired SAB underwent TEE. This result is similar to that in a previous study, which mostly included patients with non-hospital-acquired SAB, and showed that TEE was performed in only 24% of SAB cases.¹⁷ Infective endocarditis is more common in non-hospital-acquired SAB than in hospital-acquired SAB.^18,19 Additionally, TEE, which has a higher sensitivity of detecting structural abnormalities related to infective endocarditis than TTE, is recommended for patients with non-hospital-acquired SAB.^20–22 Suboptimal implementation of TEE suggests that its indication may not have been adequately evaluated in these settings.^23,24

Among the quality-of-care indicators for managing SAB, some studies have suggested that consultation with infectious disease specialists is the most effective in improving patients’ outcomes.²⁵ However, there is a shortage of infectious disease specialists in Japan (0.9/100,000 people in Japan compared with 2.4/100,000 people in the USA).²⁶ In fact, as of May 2023, there were only 1770 board-certified infectious disease specialists in Japan (1.4/100,000 people).⁹ Bundled approaches to SAB,^6,27 although less effective than infectious disease consultation, have also been attempted and may improve outcomes for patients with SAB. In our study, the rates of confirmation of a negative blood culture, implementation of TTE, and appropriate antimicrobial administration were higher in patients who were seen by the GIM service than in those who were not. Our study and a previous study showed that patients with GIM consultation were almost as likely to have blood cultures drawn for confirmation of culture negativity as those with infectious diseases consultation.⁵ Additionally, in our study and this previous study, the rate of echocardiographic implementation was higher in the GIM consultation group but the percentage of appropriate antimicrobial therapy was lower in the GIM consultation group than in the infectious disease specialist consultation group.⁵ The reason why GIM physicians are able to perform well in implementing essential interventions may be because GIM physicians, who generally serve as hospitalists in Japan, tend to be familiar with practice guidelines and are likely to follow them in clinical care.^28–30 However, there appear to be opportunities for GIM physicians to further improve the appropriateness of antimicrobial therapy compared with infectious disease specialists. Indeed, follow-up blood cultures within 4 days and implementation of TTE, which are recommended by the MRSA infection guidelines by the IDSA,¹ were also significantly more common in patients with GIM consultation than in those without GIM consultation in this study. This finding suggests that GIM consultation may be a way of providing appropriate treatment for SAB in hospitals where infectious disease specialists are not available.

This study has several limitations. First, because this study focused on the treatment of SAB, the duration of treatment was defined only based on complicated and uncomplicated SAB and did not evaluate other conditions that may require longer treatment, such as prosthetic valve endocarditis. Second, the duration of antimicrobial therapy may have been underestimated because the duration of appropriate therapy did not include patients who were switched to agents that are not considered standard for SAB but still have coverage against organisms (e.g., ampicillin-sulbactam for patients who had pneumonia in addition to SAB by MSSA). Third, TTE by itself cannot be used to assess the quality of a patient’s care. However, the implementation of TTE in patients with SAB suggests that infectious endocarditis was considered and assessed. Fourth, because this was a single-center study, the findings may not be generalizable to comparable patients at other hospitals. In the present study, the mortality and recurrence rates were similar, regardless of the presence or absence of GIM consultation. This finding may have been due to unmeasured differences in patients’ care between the specialties of infectious diseases and GIM or the relatively small number of patients included in this study.

Conclusion

Quality-of-care indicators in the care of patients with SAB were more commonly implemented in patients who received GIM consultation than in those who did not. This finding suggests that quality of care may be improved in patients with SAB and GIM consultation even when infectious disease consultation is not available.

Notes

Funding Source

None

Conflict of Interest

YD reports grants from Entasis and Shionogi that were paid to his institution; consulting fees from GSK, Meiji Seika Pharma, Shionogi, Gilead, FujiFilm, and bioMérieux that were paid directly to him; and speaker payments from MSD, Shionogi, and Gilead. The other authors declare no conflicts of interest. The funding source had no role in the design, practice, or analysis of this study.

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