Endocarditis due to Staphylococcus lugdunensis—a retrospective national registry–based study

We present characteristics of infective endocarditis (IE) caused by Staphylococcus lugdunensis and compare with IE caused by Staphylococcus aureus and other CoNS, in the National Swedish Registry of IE (2008–2018). Thirty episodes of S. lugdunensis IE were registered, of which 21 cases affected native valves, and 7 patients were subjected to surgery. The mortality rate at 30 days was significantly higher for S. lugdunensis IE (20%, n = 6), than for IE caused by other CoNS (7%) or S. aureus (9%) p = 0.016. Septic embolisation was only reported in two cases (7%). The most common treatment was isoxazolyl penicillin (n = 18).


Introduction
Staphylococcus lugdunensis belongs to the group of CoNS and was first described in 1988 [1][2][3]. Since then, S. lugdunensis has attracted increasing interest as a cause of infective endocarditis (IE). It is known to infect native valves to a larger extent than other CoNS, and to have a clinical presentation more similar to S. aureus [4]. Several case reports indicate that S. lugdunensis can cause severe IE with rapid destruction of heart valves and massive septic embolisation [5][6][7][8][9], and many studies have emphasised the importance of early surgical intervention [7,8,10]. S. lugdunensis is also often susceptible to narrow-spectrum antibiotics including penicillin, and recent reports have indicated that benzyl penicillin may be a better alternative for susceptible isolates than standard treatment with isoxazolyl penicillin or vancomycin [11][12][13].
Our aim was to describe the clinical presentation of IE caused by S. lugdunensis, and to compare it with the clinical presentation of IE caused by other CoNS and S. aureus. A secondary aim was to present the antibiotic treatment of S. lugdunensis IE.

Material and methods
We retrospectively reviewed cases of IE caused by S. lugdunensis, S. aureus and other CoNS from the Swedish Registry of Infective Endocarditis between 2008 and 2018.
Cases were classified according to Duke's criteria [14,15]. If information about comorbidities were missing, we interpreted it as a negation of that condition. For other missing data, no imputations were made. Treatment delay was defined as days from onset of symptoms until start of IE treatment. Definite antibiotic treatment was defined as the antibiotic given more than 50% of the treatment time. Antibiotic susceptibility data were received by personal contact with the local microbiological department at each site. Antibiotic susceptibility testing was performed according to EUCAST guidelines [16].
Comparisons between groups were made with chisquared test when testing categorical variables and Mann-Whitney U test for continuous data. Survival data were calculated with a Kaplan-Meier survival curve and log-rank test. Two-tailed p < 0.05 was regarded as statistically significant. Analyses were performed using the SPSS software, version 25 (SPSS, Armonk, NY, USA).
The study was approved by the Medical Ethics Committee (Institutional Review Board) of Lund University (Dnr 2017/1002).

Results and discussion
In total, we found 30 cases of IE caused by S. lugdunensis, 262 cases of IE caused by other CoNS and 1892 cases of IE caused by S. aureus. Clinical characteristics of the different groups are summarised in Table 1. Patients with S. lugdunensis IE were significantly older than patients with IE caused by S. aureus (73 vs 66 years, p = 0.01). When iv-drug users were excluded, the median age of S. aureus cases increased to 69.5 years, and the age difference between the groups was no longer significant (p = 0.44). In agreement with previous reports, 21 patients (70%) in the S. lugdunensis group had native valve IE, and the most common localisation was the aortic valve (60%) [7,17]. The proportion of native valve IE in the S. lugdunensis group was similar to that in S. aureus IE, but significantly higher than for other CoNS (70% vs 35%, p = 0.0001). There was a significantly lower occurrence of septic embolisation in patients with S. lugdunensis IE (7%, n = 2), both compared with the S. aureus group (48%, p < 0.001) and the other CoNS group (24%, p = 0.033). This is in contrast to earlier published studies, reporting a high frequency of severe septic embolisation [5,6,8,9]. This discrepancy could be a result of previous publication bias, unthorough clinical examination or failure to report correctly to the database registry. Speaking against the latter is that the embolisation frequency for S. aureus was in line with previously published data [18].
Moreover, earlier studies have reported a need of surgical intervention in a large proportion of cases [5,7,19], but only seven patients with S. lugdunensis IE (23%) underwent surgery in our cohort. This was similar to the S. aureus group (24%) but lower than for other CoNS cases (42% vs 23%, p = 0.044), which can probably be attributed to the high proportion of prosthetic valve IE in the other CoNS group.
In-hospital mortality was comparable between the groups. However, death occurred after a median time of 9 days in the S. lugdunensis group, which was significantly earlier than both the groups of S. aureus (median 25 days, p = 0.016) and other CoNS (median 36 days, p = 0.007) as visualised in Fig. 1 and Table 1. This makes all-cause mortality at 30 days significantly higher in the S. lugdunensis group (20%, n = 6) compared with other CoNS (7%, n = 17) and S. aureus (9%, n = 166), p = 0.016. This indicates, as pre-viously reported, that S. lugdunensis on some occasions can cause an aggressive form of IE, which supports the importance of early identification and early surgical intervention for this pathogen [7,8,10].
The most common antibiotic treatment of S. lugdunensis IE, given to 18 cases (60%), was an isoxazolyl penicillin. All isolates were reported susceptible to isoxazolyl penicillin, except for two isolates where data were missing. Despite this, 7 patients (23%) received treatment with different antibiotic combinations, and only one of these patients had a prosthetic valve IE. Only one isolate was tested for penicillin G even though S. lugdunensis is known to have a conserved susceptibility to most antibiotics [5,12,20]. Recent research has suggested penicillin to be the preferred treatment of S. lugdunensis infections [12], and reliable methods for susceptibility testing are available [21].
The most important weakness of this study is the small number of S. lugdunensis IE cases. Given the few cases of S. lugdunensis IE, this study was underpowered to detect any small differences between the groups, and statistically significant differences have to be interpreted with caution. Even so, this is to our knowledge the largest S. lugdunensis IE cohort described, and the registry-based design of the study adds important knowledge about the clinical presentation of S. lugdunensis IE.

Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of interest.
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