Viridans group streptococci (VGS) represent a diverse group of potentially pathogenic gram-positive cocci that form a part of the normal flora in the oropharynx, urogenital tract, and gastrointestinal tract. Doern and Burnham [1] commented that VGS are the "grab bag" that remains on exclusion of beta-hemolytic streptococci, enterococci, and pneumococci from the streptococci. Indeed, VGS includes various groups of streptococci such as Streptococcus mitis, S. salivarius, S. mutans, S. sanguinis, S. anginosus, and S. bovis [2].

Although VGS comprises diverse groups of the genus Streptococcus, they are grouped together owing to their shared status as potential pathogens. This concept, while underrated in the past has been gaining attention recently. VGS are known to be the most frequently isolated in infective endocarditis [3], and VGS bacteremia is being viewed as a serious cause of sepsis in neutropenic patients [4]. In addition, VGS could function as a reservoir of resistance genes, transferring resistance traits to S. pneumoniae or S. pyogenes [5].

Another VGS-related concern is the possibility of increased antimicrobial resistance to β-lactams and other such antimicrobial agents [4, 6]. We conducted a two-years study on the antimicrobial resistance of VGS isolated from various clinical specimens and compared the differences in the levels of antimicrobial resistance according to species. This study elucidates the antimicrobial resistance pattern of VGS isolated from various specimens.

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From May 2011 to April 2013, all cases showing VGS growth from any kind of specimen that was identified and reported for antimicrobial susceptibility at the Samsung Medical Center, Seoul, Korea were included in this study. The criteria for identification and antimicrobial resistance testing were determined as per the specimen. Growth of VGS in sources considered sterile was also included. Isolates from voided urine and indwelling urine catheter cultures were identified when the number of colonies exceeded 100,000 colony- forming unit (CFU)/mL. Isolates from straight or suprapubic urinary catheters were reported when the number of colonies exceeded 1,000 CFU/mL. Isolates from sites generally considered to harbor commensal flora were included when VGS were observed as being the dominantly growing group when cultured on a blood agar plate. VGS retrieved from bronchoalveolar lavage fluid or transtracheal aspiration, wound swabs, or bile fluid were identified and tested for antibiotic susceptibility. Isolates from specimens where VGS are considered the dominant flora, such as oral swabs, tissue samples from small intestinal tract, and specimens from female genitalia, were excluded from this study. The origin of all isolates is reported in Table 1. On the basis of the 1,448 isolates evaluated, blood was the most frequent source of VGS (412 isolates, 28.5%).

The isolates were identified by routine bacteriological methods and by using the automated VITEK 2 system (bioMérieux, Marcy l'Étoile, France). After pure cultures of the isolates were obtained, genus-, group-, or species-level identification was performed by using the VITEK2 GP identification system.

Antimicrobial resistance testing was performed by using two automated devices: the MicroScan MICroSTREP Plus Antimicrobial Panel (Siemens Healthcare Diagnostics, Erlangen, Germany) was utilized for testing specimens obtained between May 1, 2011 and April 13, 2012 and the VITEK 2 system was used for testing specimens obtained between April 14, 2012 and April 30, 2013.

Antimicrobial susceptibility was compared among the VGS groups by using the chi-square test. All statistical analyses were performed by using SPSS 21 (IBM Inc., Chicago, IL., USA). All statistical testing was conducted at the 0.05 level.

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In the past, VGS were considered to show little resistance to penicillin. However, strains showing penicillin resistance were reported to be isolated from the gingival flora of patients receiving penicillin prophylaxis for rheumatic fever in 1962 [7]. The virulence of penicillin-resistant VGS was further reported in S. anginosus [8], S. mitis [9, 10], and S. intermedius [10]. There were also speculations that this resistance was associated with the emergence of penicillin-resistant pneumococci [11]. Streptococci develop resistance to penicillin owing to an alteration in the penicillin-binding protein; thus, it was speculated that penicillin resistance could be translated into resistance to other β-lactams, all of which depend on penicillin-binding proteins to exert their activity [12]. This mechanism was described in S. pneumoniae [13], and it was theorized that VGS might exhibit a similar phenomenon regarding acquisition of resistance, since S. pneumoniae was suggested to have acquired its resistance from S. mitis [14].

Previously, Alcaide et al. [15] investigated the difference in penicillin resistance among stains isolated from VGS bacteremia. They revealed that the most frequently isolated species among VGS were S. mitis, S. anginosus, and S. sanguinis. It was also observed that antimicrobial resistance to penicillin differed among these species; 41.5% of S. mitis, 41.7% of S. sanguinis, 28.1% of S. salivarius, and 14% of S. anginosus (P<0.01) showed intermediate or high resistance to penicillin. Their findings are in concordance with our findings, in that S. mitis, S. anginosus, and S. sanguinis were the most frequently isolated species. The penicillin resistance patterns exhibited by the various species were also similar to those observed in this study; isolates from the S. anginosus group showed the greatest susceptibility to penicillin, while a large number of isolates of both S. mitis and S. sanguinis groups were resistant to penicillin. However, our investigation shows a high portion of resistance or intermediate resistance of S. salivarius to penicillin (79% non-susceptible, n=57), which is in contrast to the 28.1% resistance reported by Alcaide et al. [15]. It must be noted that the number of isolates in our study was relatively smaller compared with that in the former study. Another different finding from the former study is that compared to S. sanguinis, S. mitis is distinctly more resistant to penicillin (60.3% vs. 40.2%, P<0.001). It was noticed that the rise of penicillin resistant strains was mostly observed in the S. mitis and S. sanguinis groups, whereas the S. anginosus group remains mostly susceptible to penicillin. It was also observed that some studies disregarded the difference in antimicrobial susceptibility among species when investigating VGS bacteremia [16, 17, 18]. We suggest that this premise can be misleading, since our data clearly shows that there is such a difference, specifically among the resistant strains of the different species.

The percentage of strains resistant to penicillin is seen to differ from region to region. Lower resistance rates were reported in Germany [19] compared with the rates observed in our study or that observed in the study from Spain [15]. Such geological variance has also been noted in a surveillance program that covered multiple hospitals from the United States, Canada, and Latin America [12]. β-Lactam-resistant VGS are particularly prevalent in regions with high-incidence of penicillin-resistant pneumococci, which, in turn, correlated with outpatient sales of β-lactams [20].

Also, our previous study that was conducted 10 yr ago showed a non-susceptibility of 32% in VGS isolated from blood cultures [6]. When comparing the rates of penicillin alone, this shows no significant difference compared to the non-susceptibility rate of 40% (35% when including isolates from blood cultures only) seen in our study. However, our data show that the rate of cefotaxime-resistant VGS has tripled in the last 10 yr. In addition, when considering non-susceptibility to antibiotic agents other than β-lactams, a comparison with our previous results showed no significant difference [6]. Considering the mechanism behind the resistance to other antimicrobial agents being different from that involved in resistance to penicillin, this finding is not surprising.

Multiple sources have demonstrated that our chosen identification method shows results that are similar to those obtained using other methods with regards to the genus Streptococcus [16, 21, 22]. However, it should also be noted that the identification of alpha-hemolytic streptococci to the species level is one of the limitations of the VITEK2 system [23]. The large number of isolates that were identified simply as VGS without mention of specific species type reflects such limitations.

Overall, our study displays antimicrobial resistance in VGS in a large collection of isolates obtained from various specimens. We show that while the percentage of penicillin-resistant isolates may have not increased substantially, our focus should shift to other β-lactams. There is also a significant difference in antimicrobial resistance pattern among species; this must be taken into consideration when isolating and identifying VGS in order to decide the first-line empirical antimicrobial therapy. We suggest that the practice of reporting isolates simply as VGS may not be sufficient in a clinical setting and recommend identification up to the species level.

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