Staphylococcus aureus is an important human pathogen that causes infections at diverse sites in the body (Rasigade and Vandenesch, 2014), it is also the most frequently isolated Gram-positive bacterial species from burn patients (Song et al., 2001; Bayram et al., 2013). In recent years, S. aureus has attracted particular attention because of the prevalence of methicillin-resistant S. aureus (MRSA), which poses a serious public health risk (Cheng et al., 2013; Carrel et al., 2015). The concern is even greater in patients suffering burn-associated infections, since the isolation rate for MRSA in burn wards is much higher than in the general hospital population and the resistance to antimicrobials is more dangerous (Bahemia et al., 2015; Motallebi et al., 2016). Multiple molecular typing based on MRSA detection, staphylococcal cassette chromosome mec (SCCmec) typing, multilocus sequence typing (MLST), spa typing, and agr grouping was usually used in molecular epidemiological investigation for S. aureus (Cheng et al., 2013). In China, ST239-MRSA-III-t030-agrI is the most prevalent and persistent MRSA clone, and is a major challenge to clinical anti-infection therapy (Cheng et al., 2013; Li et al., 2013). Several factors contribute to its successful adaptation and survival. The clone often carries the portable SCCmec III, which can transfer drug resistance genes (Cheng et al., 2013). In addition, the ST239 clone may have adaptations that confer enhanced antimicrobial resistance (Cha et al., 2005; Chen et al., 2014), and ST239-MRSA is more likely to be classified as a heterogeneous vancomycin-intermediate S. aureus (hVISA) (Hu et al., 2015).

S. aureus bacteremia (SAB) is a common and severe infection (Naber, 2009). It is associated with high mortality and represents a major burden to both the patient and the health care system, especially when life-threatening complications such as infective endocarditis and metastatic infections occur (Naber, 2009). Due to susceptible factors such as loss of the skin barrier, immune deficiency, and the use of invasive catheters and monitoring devices, SAB in burn patients occurs more frequently, and is extremely serious in cases involving MRSA-associated SAB (Gang et al., 2000; Bahemia et al., 2015).

Vancomycin, a glycopeptide antimicrobial, has been in clinical use globally for over 50 years, and still serves as a first-line drug for treatment of SAB caused by MRSA (Choo and Chambers, 2016). However, many recent studies have documented an increase in the minimum inhibitory concentration (MIC) for vancomycin over time (“MIC creep”) (Steinkraus et al., 2007; Chang et al., 2015). Because vancomycin MIC creep is thought to be a potential contributor to increased treatment failure and mortality, new agents for effective therapy against MRSA are urgently needed (Chang et al., 2015; Choo and Chambers, 2016). In the USA, daptomycin, a lipopeptide class antimicrobial, is available as an effective alternative for invasive MRSA infection (Humphries et al., 2013). Daptomycin is seldom used in China primarily because its high cost is not reimbursed by medical insurance. Although the drug may have a promising market and widespread application in China, several studies have reported a correlation between vancomycin and daptomycin MICs, suggesting that decreased vancomycin susceptibility is linked to decreased susceptibility to daptomycin (Hsieh et al., 2016; San-Juan et al., 2016). If this is indeed the case, it will restrict the utility of daptomycin in China in the future. Teicoplanin is another glycopeptide antimicrobial used for serious infections caused by MRSA (Choo and Chambers, 2016). While having not been approved for use in the USA, it is used as commonly as vancomycin in Europe and many hospitals in China, and exhibits an efficacy comparable to vancomycin (Chang et al., 2012; Choo and Chambers, 2016). Decreased teicoplanin susceptibility has also been suggested as a contributor to treatment failure of MRSA infections (Chang et al., 2012). Because MIC creeps may affect the prognosis of MRSA-associated SAB (Chang et al., 2012, 2015), for clinical MRSA isolates, the evaluation of MICs for glycopeptides and daptomycin over time is a high priority.

In this study, we first analyzed the molecular epidemiological characteristics of clinical S. aureus isolates from SAB and non-SAB patients in our center. Since our result suggested that SAB patients presented significantly more ST239-MRSA-III-t030-agrI infections, we determined MICs for all the MRSA isolates from SAB patients using E-tests, and evaluated antimicrobial MICs of these isolates according to their collection dates and sources. The tested antimicrobials included vancomycin and teicoplanin, the two most commonly used glycopeptides in our center. Daptomycin, which is never used in our hospital, was also tested to analyze the correlation of MICs amongst the three antimicrobials.

Multiple molecular typing of S. aureus is an important tool in epidemiological studies and is useful for the monitoring and control of infection (Cheng et al., 2013). In this work, we first analyzed S. aureus isolates from SAB and non-SAB patients in our burn center over a 5-year period. We found that the overall prevalence rate of MRSA in our center was high (92.28%). This result was similar to burn survey reports by Song et al. (98%) from Korea (Song et al., 2001), Khosravi et al. (87.4%), and Parhizgari et al. (86.4%) from Iran (Khosravi et al., 2012; Parhizgari et al., 2016), but higher than that reported by Chen et al. (55.3%) from southeast China (Chen et al., 2012). In contrast to the molecular typing results of other common bacteria from burn patients, such as Acinetobacter baumannii and Pseudomonas aeruginosa, which often display diverse molecular types (Huang et al., 2016; de Almeida Silva et al., 2017), the molecular types of S. aureus in burn wards were typically simple according to previous studies (Chen et al., 2012; Parhizgari et al., 2016). In our center, almost all the MRSA strains carried SCCmec III (96.23%), which is a characteristic of nosocomial MRSA strains and is associated with the capacity to resist antimicrobials (Cheng et al., 2013). The dominant MLST type was ST239 [91.89%, (162+76)/259], suggesting its strong ability to adapt and persist, as mentioned previously (Table 2) (Cha et al., 2005; Chen et al., 2014). The circulation of limited number of S. aureus clones in burn wards may be due mainly to the compromised skin barrier, poor conditions of burn patients, and the strong adaptability of specific S. aureus clones. This underscores the importance of placing more emphasis on disinfection of burn wards and patients to eradicate or restrict circulating bacteria.

According to our results, SAB patients were significantly more likely to be infected by MRSA (P = 0.0031) and clone ST239-MRSA-III-t030-agrI (P < 0.0001) (Table 2). The latter is considered the most prevalent hospital-acquired MRSA clone in China, and is closely associated with antimicrobial resistance (Cheng et al., 2013; Li et al., 2013). Its presence places burn patients with SAB at greater risk, and makes it more difficult to cure SAB infections. Moreover, if MIC creeps occurs, the situation may get worse (Chang et al., 2015; Choo and Chambers, 2016). MIC creeps to glycopeptides and daptomycin have been widely reported. Chang et al. found that the percentage of isolates with a vancomycin MIC of 1 mg/L increased significantly from 2006 (37.0%) to 2010 (75.7%) in a Chinese hospital, and the high vancomycin MIC was associated with a higher failure rate of anti-infection therapy in these patients (Chang et al., 2015). Increased vancomycin MICs to MRSA were also reported by Steinkraus et al. (2007) and Wang et al. (2006) in their 5-year studies in the USA. Hsieh et al. also observed MIC creeps of MRSA to vancomycin, teicoplanin, and daptomycin in an 11-year period study (Hsieh et al., 2016). However, some studies did not find an upward MIC creep. Sancak et al. demonstrated that the distribution of MICs for vancomycin and daptomycin was stable in an 11-year period (Sancak et al., 2013). Reynolds et al. did not find an upward creep for vancomycin or teicoplanin in the UK and Ireland (Reynolds et al., 2012). To our best knowledge, decreasing MIC trends were rarely reported by now. Steinkraus et al. reported that daptomycin MICs to MRSA significantly decreased from 2001 to 2005 in a medical center (Steinkraus et al., 2007). Lu et al. found that vancomycin MICs among MRSA isolates in a Chinese tertiary hospital decreased in a 12-year period (Lu et al., 2016). However, drug usage information was not mentioned or could not be acquired in the two studies. In this study, vancomycin and teicoplanin were used in almost all the MRSA-SAB patients in our center, while daptomycin was never used. Our results showed that, all the three antimicrobials exhibited significant MICs decreases during the 5-year period, especially teicoplanin (P < 0.0001). These results suggest that long-term use of glycopeptides (vancomycin and teicoplanin) does not necessarily lead to upward MIC creeps for glycopeptides or daptomycin, which are consistent with Lu et al.'s (2016) and Steinkraus et al.'s (2007) studies, but contrast to most other studies. Infection types, enforcement of guidelines for the reasonable use of antimicrobials, time and dosage for antimicrobials administration may contribute to the MIC trends. More detailed and in-depth investigation is needed to explain why different MIC trends were observed in different studies, and this will provide greatly useful guidance for antimicrobials administration.

In burn patients with SAB, wound infection was considered as the major cause of invasive infection into the bloodstream (Pruitt et al., 1998), but previous studies did not evaluate the MICs of SAB isolates from different sites of the body. The present study showed that strains isolated from different sites in SAB patients present different susceptibility profiles to glycopeptides and daptomycin. In our results, MRSA isolates from the bloodstream exhibited decreased susceptibility to both vancomycin and daptomycin, compared to those isolated from catheters or wounds. Intriguingly, teicoplanin MICs showed an opposite trend. MIC values (P < 0.0001), and the number of isolates with MIC ≥ 1 mg/L (P < 0.0001), were both significantly lower in bloodstream isolates (Table 4). Our results suggest that teicoplanin may be a better choice for MRSA infections from the bloodstream. To efficiently defeat MRSA infections, clinicians should select drugs based on the susceptibility tests of bacteria isolated from different sites in the patient.

The correlations amongst MICs for vancomycin, teicoplanin, and daptomycin have been reported previously (Shoji et al., 2015; Hsieh et al., 2016; San-Juan et al., 2016). Hsieh et al. found that the vancomycin MIC was significantly correlated with teicoplanin, daptomycin, and teicoplanin MICs (Hsieh et al., 2016). Shoji et al. also observed that the vancomycin MIC was significantly correlated with MICs for both teicoplanin and daptomycin (Shoji et al., 2015). San-Juan et al. found a correlation between high MICs for vancomycin (>1.5 mg/L) and daptomycin (>0.5 mg/L) (San-Juan et al., 2016). These correlations may restrict the use of related drugs when one drug becomes less susceptible. In our results, although the three antimicrobials presented similar MIC trends over time, no significant correlation was found except between vancomycin and daptomycin in group BB (P = 0.024) (Table 5). Interestingly, consistent with this result, most previously reported correlations amongst these drugs were found in bloodstream isolates (Shoji et al., 2015; San-Juan et al., 2016). Our data suggest that decreased vancomycin susceptibility probably restricts the usage of daptomycin in anti-MRSA therapy, but only for bloodstream-associated infections.

In conclusion, we found that MRSA infections are serious in the center and ST239-MRSA-III-t030-agrI clone is significantly dominated in SAB patients. In contrast with most other reports, although vancomycin and teicoplanin are frequently used in our center, the increasing susceptibility to the two glycopeptides and daptomycin over time was observed, suggesting that the application of glycopeptides does not necessarily lead to MIC creeps. SAB-MRSA isolates from different body sites presented different susceptibility profiles, indicating antimicrobials selection in anti-infection therapy should be considered comprehensively. MICs correlation was found only between vancomycin and daptomycin amongst bloodstream MRSA isolates, suggesting that the usage of daptomycin may be restricted in treating MRSA-associated bloodstream infections if decreased vancomycin susceptibility occurs.

YP and YG conceived and designed this study. BJ, SY, and BY carried out the experiments, collected and analyzed the data. GH, ZiY, YZ, YC, and JC helped with the data interpretation. ZhY, XR, and XH drafted the manuscript. All authors have read and approved the final manuscript.