지속성 황색포도알균 균혈증의 미생물학적, 유전학적, 임상적 특성 연구

Abstract

Background: Staphylococcus aureus bacteremia (SAB) may persist despite proper antibiotic treatment. Persistent SAB is associated with poor clinical outcomes and high mortality. Several studies have analyzed the risk factor, clinical outcome, and microbiological characteristics of persistent SAB, but are limited. Therefore, this study aims to extensively analyze the clinical, microbiological and genotypic characteristics of persistent SAB and the factors affecting the poor clinical outcome. Methods: This prospective cohort study was conducted from August 2008 to February 2021 at the Asan Medical Center, a 2,700-bed tertiary referral center in South Korea. Among enrolled patients, The clinical characteristics, management, outcomes, microbiological, and genetic characteristics of patients with persistent SAB, including those with persistent methicillin-resistant S. aureus (MRSA) or methicillin-susceptible S. aureus (MSSA) bacteremia, were compared and analyzed. Persistent bacteremia was defined as a period of 3 days or more from the time appropriate antibiotics were administered until a negative follow-up blood culture was confirmed, or even if the period was less than 3 days, if a follow-up blood culture conducted within those 3 days was positive again. The comparator was defined as resolving bacteremia. Microbiologic data, including genotyping, sequence type (ST), Staphylococcus protein A (spa), staphylococcal cassette chromosome mec (SCCmec), and virulence genes, were analyzed. The clinical and microbiological characteristics and outcomes of major ST versus other STs in persistent SAB as well as persistent MRSA or MSSA bacteremia were also analyzed. Results: Among 1877 patients with SAB, 826 had resolving SAB and 1,051 had persistent SAB. Among these, 953 had MRSA bacteremia (resolving MRSA bacteremia, n = 318; persistent MRSA bacteremia, n = 635), and 924 had MSSA bacteremia (resolving MSSA bacteremia, n = 508; persistent MSSA bacteremia, n = 416). The multivariate analysis revealed that vascular grafts (adjust OR, 1.493; 95% CI, 1.036-2.153; P = 0.032), metastatic infection (adjusted OR, 3.447; 95% CI, 2.604-4.562; P < 0.001) and methicillin resistance (adjusted OR, 2.582; 95% CI, 2.219-3.130; P < 0.001) were significant independent risk factors for persistent SAB. For persistent MRSA bacteremia, solid organ transplantation (adjusted OR, 1.975; 95% CI, 1.088-3.583; P = 0.025), metastatic infection (adjusted OR, 3.479; 95% CI, 2.227-5.435; P < 0.001), and ST5 (adjusted OR, 1.457; 95% CI 1.103-1.925; P = 0.008) were significant independent risk factors. For persistent MSSA bacteremia, community- acquired acquisition (adjusted OR, 1.637; 95% CI 1.189-2.255; P = 0.003), vascular grafts (adjusted OR, 1.990; 95% CI, 1.190-3.328; P = 0.009), metastatic infection (adjusted OR, 3.301; 95% CI, 2.286-4.767; P < 0.001), and ST72 (adjusted OR, 1.587; 95% CI, 1.127-2.236; P = 0.008) were identified as significant risk factors. The most predominant clone in persistent MRSA bacteremia was ST5-SCCmec II-t2460 (211/635, 33.2%), and in persistent MSSA it was ST72-t126 (63/416, 15.1%). In persistent MRSA bacteremia, agr dysfunction (P = 0.025) and agr type II (P = 0.008) were significantly more prevalent. In virulence gene analysis, sec was frequent in persistent MRSA bacteremia (P = 0.033). When using bacteremia day 1 as the reference point, analysis of whether there is a significant increase in mortality with each additional day of bacteremia duration revealed significant mortality on day 3 for of SAB-related mortality (relative risk, 1.589; 95% CI, 1.060-2.355; P = 0.024) in overall SAB. The analysis revealed that ST5-spa-t9353 and ST72-spa-t126 in persistent SAB, as well as ST72-spa-t126 in persistent MSSA bacteremia, had statistically significantly higher 90-day and SAB-related mortality rates compared to resolving bacteremia. Conclusions: As a result of this study based on a large cohort, it can be helpful to treat patients with persistent SAB and achieve better outcomes by understanding the clinical, microbiological and genetic characteristics of persistent SAB as well as the characteristics of dominant ST. Keywords: Staphylococcus aureus, persistent bacteremia, sequence type, virulence genes