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Acta Microbiologica Hellenica
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  • Communication
  • Open Access

8 December 2025

Prevalence of a Linezolid Minimum Inhibitory Concentration of 2 mg/L in Methicillin-Susceptible/Resistant Staphylococcus aureus, Staphylococcus argenteus, Coagulase-Negative Staphylococcus, and Mammaliicoccus

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1
Department of Social Medicine, Division of Hygiene, School of Medicine, Sapporo Medical University, Sapporo 060-8556, Japan
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Yangon Children’s Hospital, Yangon 11191, Myanmar
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Department of Medical Laboratory Technology, University of Medical Technology, Yangon 11011, Myanmar
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Division of Pediatric Dentistry, Department of Oral Growth and Development, School of Dentistry, Health Sciences University of Hokkaido, Hokkaido 061-0293, Japan
Acta Microbiol. Hell.2025, 70(4), 45;https://doi.org/10.3390/amh70040045
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Abstract

Linezolid (LZD) is an oxazolidinone antibiotic effective in the treatment of infection with Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). The decline in susceptibility to linezolid is a concern for antimicrobial chemotherapy. In this study, the prevalence of the LZD minimum inhibitory concentration (MIC) of 2 mg/L (LZD-MIC2), which represents a slightly high value within a range of susceptibility for S. aureus (≤4 mg/L), was investigated retrospectively for staphylococcal species from different sources. We collected the records of LZD MIC of Staphylococcus/Mammaliicoccus that had been obtained in our previous studies on isolates from patients, healthy individuals, and foodstuff. Prevalence of isolates showing LZD-MIC2 was analyzed depending on the type of staphylococcal species and S. aureus clones. In clinical isolates, methicillin-susceptible S. aureus (MSSA) and S. argenteus showed significantly higher LZD-MIC2 rates (20.0% and 21.5%, respectively) than MRSA (7.3%). Among clinical and colonizing isolates of MSSA, LZD-MIC2 was more commonly found in CC1 (ST188, ST2990, etc.), CC8, CC15, ST30, ST97, and ST121 than other lineages. In S. argenteus isolates, which were mostly methicillin-susceptible, there was no significant difference in the LZD-MIC2 prevalence among the three genotypes. The LZD-MIC2 was detected in 18.3% of coagulase-negative Staphylococci (CoNS), with S. saprophyticus, S. pasteuri, and M. sciuri showing higher prevalence (30–57%) than other species. The present study revealed that the prevalence of the LZD-MIC2 is different depending on staphylococcal species/types, as they are more common in specific MSSA lineages and some CoNS species.

1. Introduction

Linezolid is a synthetic antimicrobial agent belonging to the class of oxazolidinones and inhibits bacterial growth by disturbing protein synthesis via binding to the 50S ribosomal subunit. This antimicrobial has been used for severe infections due to Gram-positive bacteria, including methicillin-resistant/susceptible Staphylococcus aureus (MRSA/MSSA), vancomycin-resistant Enterococci (VRE), and some Streptococcus species [1]. Since its global use after the 2000s, linezolid exhibits excellent susceptibility to S. aureus clinical isolates as well as coagulase-negative staphylococci (CoNS) [2]. Resistance to linezolid has been more commonly described for Enterococcus, due to mutations in 23S rRNA or rplC/rplD gene, or expression of resistance determinants cfr, optrA, or poxtA [3,4]. Although the same mechanisms are involved in the linezolid resistance in staphylococci [5], still, the global prevalence of the resistance appears to be extremely low [6].
According to the definition by the Clinical Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST), linezolid minimum inhibitory concentration (MIC) of ≤4 mg/L is judged as susceptible, while the resistance breakpoint is ≥8 mg/L [7,8]. It has been noted that linezolid-susceptible Staphylococcus isolates show variable MICs depending on the isolate, which is equal to MIC of 4 mg/L or lower (≤0.25–4 mg/L). MICs that are required to inhibit 50% and 90% of S. aureus isolates (MIC50 and MIC90, respectively) are usually 1 or 2 mg/L [9,10,11,12]. However, recently, linezolid MIC creep, which represents a gradual reduction in the susceptibility to linezolid, has been recognized as a potential concern [9]. This was noticed by the increase in the rate of isolates showing MIC of higher value (2 or 4 mg/L) over the years, and reported in Japan [9], China [11], Taiwan [13], and India [14], while it was not evident in some studies [10,15]. A study in a single medical institution located in western Japan reported that the 24% LZD-MIC2 rate of S. aureus in 2008 increased to 63% in 2012, with the emergence of MIC of 4 mg/L in 2009 [9]. In Taiwan, the rate of linezolid MIC of ≥2 mg/L in MRSA increased from 4% in 2000–2001 to 65% in 2004–2005 [13].
In our previous studies on molecular epidemiology and antimicrobial resistance of Staphylococcus isolates from clinical specimens, healthy individuals, and foodstuff (ground meat), we noted that only a part of the isolates showed linezolid MIC of 2 mg/L (LZD-MIC2), while others showed lower MIC values [16,17,18,19,20,21,22,23]. Although the LZD-MIC2 does not represent resistance, it is possible to imply the linezolid MIC creep, or intrinsically reduced susceptibility to linezolid that is inherent to some clones of Staphylococcus. We conducted the present study to determine the prevalence of LZD-MIC2 in different groups of staphylococcal isolates, to detect possible association of LZD-MIC2 with any staphylococcal species or clonal groups.

2. Materials and Methods

In this study, the linezolid MIC data were obtained from the original records in our previous studies on S. aureus and/or CoNS [16,17,18,19,20,21,22,23], in which all the isolates were described as susceptible to linezolid (MIC of ≤4 mg/L), and no isolates exhibited an MIC of 4 mg/L. MIC of linezolid had been measured by broth microdilution test using Dry Plate Eiken DP42 (Eiken Medical, Tokyo, Japan) within a limited range (≤0.25–≥8 mg/L), along with other antimicrobials in a single microtiter plate. Clinical isolates of S. aureus were derived from only blood samples [16,17] or various types of specimens, with pus/wound being the most common [18,19]. Colonizing isolates were recovered from the oral cavity and hand of systemically healthy individuals [21,22]. Isolates from foodstuffs were obtained from retail ground meat [23].
From the original data, the number of isolates showing 2 mg/L (LZD-MIC2) was counted in each category of staphylococcal isolates. In those studies, staphylococcal species were identified genetically by detection of the S. aureus-specific nuc gene by PCR or sequencing of 16S rRNA for CoNS. For genotyping of S. aureus and S. argenteus, multilocus sequence typing (MLST) was employed to determine sequence type (ST), which was further grouped into clonal complex (CC). Presence or absence of cfr, optrA, and poxtA was confirmed by PCR as described previously [24].
Study subjects, i.e., staphylococcal isolates of different categories and study settings, are summarized in Table 1. Clinical isolates of MRSA and MSSA were obtained from bloodstream infections in Hokkaido, northern main island of Japan (2019–2021, 2023) (a total of 580 isolates) [16,17], and from various specimens in Yangon, Myanmar (Yangon Children’s Hospital, YCH; Yangon General Hospital, YGH; 2020–2023) (a total of 455 isolates) [18,19]. S. argenteus was recovered from clinical specimens in Hokkaido, Japan (2020–2023) (n = 213) [20] and also in Yangon General Hospital (n = 15) [19]. Staphylococcal isolates derived from healthy individuals in Hokkaido, Japan, were mostly MSSA (n = 153) and CoNS (n = 348), with some isolates of MRSA and S. argenteus [21,22]. From ground meat specimens, most isolates were identified as CoNS (n = 112) [23]. Except for a methicillin-resistant (MR) S. argenteus clinical isolate in Japan, all S. argenteus and CoNS isolates were methicillin-susceptible (MS).
Table 1. Prevalence of Staphylococcus isolates with a LZD MIC of 2 mg/L.
The rates of LZD-MIC2 in different categories of Staphylococcus were analyzed statistically by Fisher’s exact test or chi-square test using the js-STAR XR+ 2.1.3 j software (https://www.kisnet.or.jp/nappa/software/star/index.htm) (accessed on 30 March 2025). A p-value <0.01 was considered statistically significant.

3. Results

The rate of LZD-MIC2 in clinical isolates of MRSA ranged from 4.2 to 12.2% in the four studies, and the overall rate was 7.3% (Table 1). In contrast, MSSA and S. argenteus clinical isolates showed the overall rates of 20% and 21.5%, respectively, which were higher than those of MRSA. The higher rate of MSSA than MRSA was found in three studies in Japan and Myanmar [17,18,19]. In the MSSA from healthy individuals, the LZD-MIC2 rate was 32%, which was comparable to or higher than that in clinical MSSA isolates. CoNS from healthy individuals and foodstuff showed significantly different rates of LZD-MIC2 (13.2% and 33.9%, respectively). The overall rate of LZD-MIC2 in CoNS was 18.3% (84/460). cfr, fexA, optrA, and poxtA were not detected in all the isolates with LZD-MIC2. In the present study, the number of isolates in some categories (i.e., colonizing S. argenteus, and a part of S. aureus STs and CoNS species) was too low to determine the exact prevalence of LZD-MIC2 rate. Therefore, only the rates obtained for >10 isolates in individual categories are described as findings in this study.
When the prevalence was compared among S. aureus/S. argenteus genotypes (STs/CCs), more responsible clones for LZD-MIC2 were evident (Table 2). In clinical isolates of MRSA in Japanese studies, CC1 (ST1/ST2725/ST2764) accounted for 69% (22/32) of LZD-MIC2 isolates, showing a higher LZD-MIC2 rate than other CCs (CC5, CC8), though the incidence rate of total CC1 isolates was 40–50% of MRSA. In contrast, among MSSA, LZD-MIC2 was detected at higher rates (29–39%) in several different STs/CCs with incidence of >10 isolates, i.e., ST188 (CC1), ST8 (CC8), ST15 (CC15), ST30 (CC30), and ST97 (CC97). In MSSA clinical isolates in Myanmar, a higher incidence and rate of LZD-MIC2 were noted in CC88 and ST121 (CC121) in YCH, and ST2990 (CC1) and ST121 (CC121) in YGH. Among the colonizing MSSA isolates, CC1 (ST188, ST7182), CC15, CC30, and CC97 were common (>10 isolates) and showed LZD-MIC2 rates of 27–43%. In the three STs (ST1223, ST2198, ST2250) of S. argenteus, LZD-MIC2 was detected at similar rates (18–24%), despite the difference in isolate numbers of each ST. Clinical isolates with LZD-MIC2 were derived from various specimens, including pus/wound, sputum, urine, and blood, while no particular specimen with evidently higher frequency or rate of LZD-MIC2 was found.
Table 2. Prevalence of S. aureus and S. argenteus isolates with a LZD MIC of 2 mg/L in each ST/CC.
Species of CoNS from healthy individuals and foodstuffs are listed in Table 3 with their frequencies of isolates and LZD-MIC2 rates. Although identified species in these two CoNS groups were different, S. pasteuri, S. saprophyticus, and S. warneri were commonly isolated and showed higher rates of LZD-MIC2 (overall rates of 29.6%, 43.6%, and 21%, respectively). M. sciuri, which was mostly derived from ground meat samples, had 57% of LZD-MIC2 isolates. The more frequent species from healthy individuals, i.e., S. capitis, S. caprae, S. haemolyticus, S. lugdunensis, and S. epidermidis, had fewer LZD-MIC2 isolates, showing an overall rate of 3.6% (n = 6 in total; 6/169).
Table 3. Species of CoNS/Mammaliicoccus isolates with an LZD MIC of 2 mg/L derived from healthy individuals (dental patients/staff) and foodstuff (ground meat).

4. Discussion

The proportions of LZD-MIC2 of blood isolates shown in the present study (e.g., 11% in MRSA and 31% in MSSA, 2023 [17]) were lower than those reported in western Japan previously (63% in 2012) [9]. However, in our previous studies on hospital-acquired and community-acquired MRSA in Hokkaido, Japan (2011–2014), all the isolates showed linezolid MIC of <0.25 mg/L, using the previous version of microdilution test kit (Dry Plate Eiken DP32) (unpublished data) [25,26]. Therefore, it is suggested that the linezolid MIC creep might have also occurred in our study site, northern Japan, though the LZD-MIC2 rate may be different depending on the area or medical facilities studied.
In the present study, we described the difference in prevalence of LZD-MIC2 depending on species, MR/MS status, and clones/lineages of S. aureus/S. argenteus. It was notable that the LZD-MIC2 rates were higher in MSSA than in MRSA, as commonly seen in studies in Japan and Myanmar. A similar finding was described in a study in Japan showing a higher rate of linezolid MIC of >1 mg/L in MSSA [9], and in China, pointing out the higher geometric mean MIC and MIC50 value of MSSA [11], compared with those of MRSA. Although the reason for the reduced susceptibility to linezolid in MSSA compared with MRSA is not clear, it is presumable that the composition ratio of different clones in MSSA and MRSA may be related to it. It was deemed in the present study that several STs/CCs, including CC1, might be more linked to LZD-MIC2 and found more commonly in MSSA.
A linezolid-resistant MRSA mediated by mutations in 23S rRNA, and/or acquisition of cfr, optrA has been reported to date in several lineages, i.e., ST36-MRSA-SCCmec II (ST36-MRSA-II) [27], ST22-MRSA-IV [28], ST9 and ST764 MRSA [29], and CC5-MRSA-IV [30], which were derived from human patients or carriers, and animals (pig, chicken, duck, dog). Regarding the linezolid-resistant MSSA, one study reported that cfr-positive clinical isolates from a hospital belonged to eight STs, with ST188 (CC1) and ST965 (CC5) being the most common [31]. In contrast, there is a dearth of information on the clone/lineage of linezolid-susceptible isolates with LZD-MIC2, while one study described ST5-MRSA-II, ST59-MRSA-IV, and ST239/241-MRSA-III that showed linezolid MIC ≥2 mg/L [13]. Our present study revealed the higher LZD-MIC2 rate in several S. aureus clones/lineages, i.e., CC1 (ST1, ST188, ST2990), CC8, CC15, ST30, ST97, and ST121. These genotypes/groups of LZD-MIC2 S. aureus seem to be distinct from those listed for linezolid-resistant isolates, except for ST188 (CC1). In a report by Li and coworkers [31], LZD-MIC2 was seen in some cfr-positive ST188 and ST965 MSSA isolates with a mutation in 23S rRNA. Moreover, it was revealed that the intrinsic susceptibility to linezolid in S. aureus may be associated with mutations in various genes other than 23S rRNA [32]. Therefore, it is possible that the reduced susceptibility to linezolid in the S. aureus isolates was caused by mutations or intrinsic diversity in certain gene(s), including 23S rRNA, which is presumably prone to occur in a specific clone/lineage.
Similarly to MSSA, S. argenteus isolates in our study, which were mostly MS, showed a higher LZD-MIC2 rate than MRSA. S. argenteus is genetically distinct from S. aureus and S. epidemidis, with genomic identity of approximately 87% and 77%, respectively [33,34]. In the present study, three STs that constitute S. argenteus isolates showed similar LZD-MIC2 rates, while the isolate numbers of these STs were different. This may suggest that S. argenteus has a stable, inherent property of being less susceptible to linezolid at a constant proportion in the three lineages (ST1223, ST2198, ST2250).
Linezolid resistance has also been detected in several CoNS species, including S. capitis, S. epidermidis, S. haemolyticus, and S. cohnii, with S. capitis being most frequently reported [35,36,37,38,39,40,41]. The resistance mechanism commonly described for CoNS is a mutation in 23S rRNA, while the acquisition of cfr was also found. In a study on an in vitro-selected linezolid-resistant S. epidermidis strain without 23S rRNA mutation, the decreased uptake of linezolid was presumed to be a resistance mechanism [42]. In contrast, in our present study, LZD-MIC2 was more commonly found in S. saprophyticus, S. pasteuri, S. warneri, and also M. sciuri, while the LZD-MIC2 rates were lower in S. capitis, S. hemolyticus, and S. epidermidis. It may be suggested that the staphylococcal species with a higher LZD-MIC2 rate detected in the present study (e.g., S. saprophyticus) may be prone to be intrinsically less susceptible to linezolid, apart from the ability to easily acquire the obvious resistance to linezolid that is typically observed for S. capitis.
As a limitation of this study, a potential heterogeneity might be involved in the prevalence of LZD-MIC2 in staphylococcal species, because the isolates studied were derived from different countries, hospitals, populations, or foodstuffs, though general trends might be elicited. Accordingly, the study design and settings and subjects should be specified appropriately for further verification of the LZD-MIC2 trend in a certain staphylococcal species.

5. Conclusions

The present study described the presumptive association between LZD-MIC2 and specific lineages/strains of S. aureus (e.g., MSSA, CC1), S. argenteus, as well as CoNS species (e.g., S. saprophyticus). Though it is not certain whether LZD-MIC2 could develop to a higher resistance level to linezolid, its growing rate in S. aureus in patients and carriers may be a potential concern for the efficacy of antimicrobial chemotherapy. Nevertheless, since there is currently no direct clinical evidence linking MIC of 2 mg/L (within the susceptible range) to treatment failure, LZD-MIC2 may be regarded as a theoretical concern based on MIC trends. Hence, further attention is required for the MIC values of linezolid in Staphylococcus, along with clinical observations, and continuous monitoring of LZD-MIC2 may be recommended.

Author Contributions

Conceptualization, M.S.A. and N.K.; methodology, M.S.A. and N.K.; investigation, M.S.A., N.U., M.K., N.O., T.S., W.K.K., M.H. and M.O.; data curation, M.S.A. and N.K.; resources, M.I.; writing—original draft preparation, M.S.A.; writing—review and editing, M.S.A. and N.K.; funding acquisition, M.S.A. and N.K.; supervision and project administration, N.K. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded partly by JSPS (Japan Society for the Promotion of Science) KAKENHI Grant Numbers JP19K10450, JP21K10401, and JP20H03933.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

The raw data supporting the conclusions of this article will be made available by the authors on request.

Conflicts of Interest

Author Masahiko Ito was employed by the company Sapporo Clinical Laboratory, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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West Nile Virus: Insights into Microbiology, Epidemiology, and Clinical Burden
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