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Glycopeptide minimum inhibitory concentration creep among meticillin-resistant Staphylococcus aureus from 2006–2011 in China
International Journal of Antimicrobial Agents 41 (2013) 578–581
Contents lists available at SciVerse ScienceDirect
International Journal of Antimicrobial Agents journal homepage: http://www.elsevier.com/locate/ijantimicag
Short communication
Glycopeptide minimum inhibitory concentration creep among meticillin-resistant Staphylococcus aureus from 2006–2011 in China Chao Zhuo a,∗ , Ying-chun Xu b , Shu-nian Xiao a , Guang-yan Zhang c , Nan-Shan Zhong a a b c
State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical College, Guangzhou, China Peking Union Medical College Hospital, Beijing, China Chengdu 7th People’s Hospital, Chengdu, China
a r t i c l e
i n f o
Article history: Received 30 April 2012 Accepted 11 February 2013 Keywords: Staphylococcus aureus Teicoplanin Vancomycin Linezolid Minimum inhibitory concentration Creep
a b s t r a c t Vancomycin minimum inhibitory concentration (MIC) creep has recently been demonstrated by many countries but is rarely reported in China. In this study, a total of 1411 meticillin-resistant Staphylococcus aureus (MRSA) isolates were collected from six hospitals in China during the period 2006–2011 and the MICs of vancomycin, teicoplanin and linezolid were determined by broth microdilution according to Clinical and Laboratory Standards Institute (CLSI) guidelines. MIC50 and MIC90 values (MICs required to inhibit the growth of 50% and 90% of organisms, respectively) as well as geometric mean (GM) MICs were calculated for all isolates in each year, and MIC creep for the drugs was evaluated. All of the MRSA isolates were susceptible to vancomycin and linezolid. Overall, the vancomycin GM MIC of MRSA isolates was 0.906, 0.952, 0.956, 0.947, 1.013 and 1.040 mg/L, with a significantly increasing trend over the years (P < 0.001). Percentages of MRSA isolates with a vancomycin MIC above 1 g/mL (2 g/mL ≥ MIC > 1 g/mL) were 26.0%, 23.5%, 21.6%, 27.8%, 30.6% and 42.8% from 2006–2011, respectively, and increased over time (P < 0.005). The teicoplanin GM MIC increased rapidly from 0.749 mg/L in 2008 to 0.973 mg/L in 2011, and ca. 5% of isolates were resistant to teicoplanin in the period according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria. MIC shifts were not found for linezolid (P > 0.05). In conclusion, a tendency towards decreasing susceptibility to glycopeptides in MRSA has emerged in China. © 2013 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
1. Introduction
2. Materials and methods
Glycopeptides such as vancomycin remain a front-line drug for the treatment of meticillin-resistant Staphylococcus aureus (MRSA) infections. However, loss of susceptibility, characteristically involving an increase in vancomycin minimum inhibitory concentrations (MICs) to above 1.5 mg/L, is associated with treatment failure [1]. Several studies have demonstrated that the mean vancomycin MIC in MRSA has increased in recent years, referred to as ‘MIC creep’ [2–5]. To the best of our knowledge, no studies have examined the MIC creep phenomenon in China, although the incidence of heterogeneous vancomycin-intermediate S. aureus (hVISA) correlating with an increase of vancomycin MIC was reported by Chen et al. in 2011 [6]. Thus, the aim of this study was to analyse the vancomycin MIC distribution in MRSA isolates obtained from six hospitals over a 6-year period in southern China and to determine MIC trends of these isolates to teicoplanin and linezolid.
2.1. Micro-organisms
∗ Corresponding author. Present address: 1 Kangda Road, Guangzhou 510230, China. Tel.: +86 20 3429 5505; fax: +86 20 3429 5505. E-mail addresses: chao [email protected], [email protected] (C. Zhuo).
A total of 1411 clinical MRSA isolates collected from six hospitals were submitted to the MOH National Antimicrobial Resistance Investigation Net (Mohnarin) programme from January 2006 to December 2011. Only the first isolate per patient was tested in this study. Isolates were recovered from various clinical sources, including the respiratory tract (n = 947), secretions (n = 212), blood (n = 106), pus and wounds (n = 54), drainage (n = 25), urine (n = 16), abdominal fluid (n = 15) and other sources (n = 36). All isolates were stored at −80 ◦ C until MIC testing was performed. 2.2. Antimicrobial susceptibility testing MICs were determined by the Clinical and Laboratory Standards Institute (CLSI) recommended broth microdilution testing method [7] with some modifications. For vancomycin and teicoplanin, the precise incremental dilutions method reported by Sader et al. [4] was used, comprising 15 dilution steps of vancomycin ranging from 0.125 mg/L to 8 mg/L (0.125, 0.25, 0.50, 0.625, 0.75, 0.875, 1, 1.125,
0924-8579/$ – see front matter © 2013 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. http://dx.doi.org/10.1016/j.ijantimicag.2013.02.014
C. Zhuo et al. / International Journal of Antimicrobial Agents 41 (2013) 578–581
579
Table 1 Susceptibility of meticillin-resistant Staphylococcus aureus (MRSA) in China, 2006–2011. Antimicrobial agent
Year
No. of isolates
MIC (mg/L)
Susceptibility (%)
GM
MIC50
MIC90
CLSI
EUCAST
0.25–2.0 0.25–2.0 0.25–2.0 0.375–2.0 0.375–2.0 0.125–2.0 0.125–2.0
100 100 100 100 100 100 100
100 100 100 100 100 100 100
1 2 2 2 2 2 2
0.5–2 0.5–4 0.5–4 0.5–4 0.5–4 0.5–4 0.5–4
100 100 100 100 100 100 100
100 100 96.4 96.8 95.0 94.5 96.8
2 2 4 2 2 2 2
0.5–4 0.5–4 0.5–4 0.5–4 0.5–4 0.125–4 0.125–4
100 100 100 100 100 100 100
100 100 100 100 100 100 100
Vancomycin
2006 2007 2008 2009 2010 2011 Total
192 284 305 187 242 201 1411
0.906 0.952 0.956 0.947 1.013 1.040 0.968
1 1 1 1 1 1 1
1.5 1.5 1.5 1.5 1.5 1.5 1.5
Teicoplanin
2006 2007 2008 2009 2010 2011 Total
192 284 305 187 242 201 1411
0.712 0.739 0.749 0.743 0.768 0.973 0.773
0.5 0.5 0.5 0.5 0.5 1 0.5
Linezolid
2006 2007 2008 2009 2010 2011 Total
192 284 305 187 242 201 1411
1.461 1.414 1.422 1.386 1.41 1.221 1.388
2 1 1 1 1 1 1
Range
MIC, minimum inhibitory concentration; GM, geometric mean; MIC50/90 , MICs required to inhibit the growth of 50% and 90% of organisms, respectively; CLSI, Clinical and Laboratory Standards Institute; EUCAST, European Committee on Antimicrobial Susceptibility Testing.
1.25, 1.375, 1.5, 1.75, 2.0, 4.0 and 8.0 mg/L) and 14 dilution steps of teicoplanin ranging from 0.06 mg/L to 16 mg/L (0.06, 0.12, 0.25, 0.50, 0.625, 0.75, 0.875, 1, 1.125, 1.25, 1.5, 2.0, 4.0 and 8.0 mg/L). For linezolid, the two-fold dilutions method with a concentration range of 0.25–16 mg/L in seven dilutions was employed. Differences in aggregate susceptibility were evaluated between 2010 European Committee on Antimicrobial Susceptibility Testing (EUCAST) and CLSI M100-S20 criteria [7,8]. Quality controls were performed by each testing site on each day of testing using S. aureus ATCC 29213 according to CLSI guidelines. 2.3. Data analysis MIC50 and MIC90 values (MICs required to inhibit the growth of 50% and 90% of organisms, respectively), the MIC range, the geometric mean (GM) MIC, MIC distribution, and percentage susceptible and resistant were evaluated using WHONET 5.4 software (http://www.who.int/drugresistance/whonetsoftware/en/). 2.4. Statistical analysis Statistical analysis was carried out using SPSS v.17.0 software (SPSS Inc., Chicago, IL). For analysis of MIC trends over time, nonparametric correlation (Spearman’s r) was used. For comparison of GM MICs among groups, the Kruskal–Wallis test was employed. Statistical significance was defined a priori as P < 0.05. 3. Results and discussion 3.1. Minimum inhibitory concentration population distribution of three antibiotics As shown in Table 1, the overall GM MICs were 0.968 mg/L for vancomycin, 0.773 mg/L for teicoplanin and 1.388 mg/L for linezolid. Vancomycin MICs were around 1 mg/L (range 0.75–1.25 mg/L) for 79.4% of the isolates, which is similar to a previous report in the USA [2], and the incidence of isolates with a MIC of 2 mg/L remained relatively low (<5%). Teicoplanin MICs were around 0.5 mg/L for 54.6% of the isolates. Linezolid MICs were
1 mg/L and 2 mg/L for 41.7% and 40.3% of the isolates, respectively, which is higher than 0.46 mg/L reported by Steinkraus et al. [2] and lower than 3.3 mg/L reported by Golan et al. [9]. All isolates were categorised as susceptible to vancomycin and linezolid according to EUCAST and CLSI breakpoints. For teicoplanin, all isolates were susceptible according to CLSI criteria and 96.8% of isolates were susceptible according to EUCAST criteria. 3.2. Assessment of minimum inhibitory concentration creep Two methods were employed to assess MIC creep for the three antibiotics. First, as seen from the annual change of GM MICs shown in Table 1, the GM MIC increased 1.15-fold over the study period for vancomycin, from 0.906 mg/L in 2006 to 1.040 mg/L in 2011 (P < 0.001). For teicoplanin, the GM MIC increased 1.37-fold from 0.712 mg/L in 2006 to 0.973 mg/L in 2011 (P < 0.001), whilst the GM MIC for linezolid decreased 0.84-fold from 1.461 mg/L in 2006 to 1.221 mg/L in 2011. Second, different MIC intervals shown in Fig. 1 were divided as described previously [2]. For vancomycin, there was a decrease in the percentage of isolates with a MIC ≤ 0.5 mg/L from 5.7% (11/192) in 2006 to 1.0% (2/201) in 2011, whilst there was a sharp increase in isolates in the MIC range >1.0 mg/L to ≤1.5 mg/L from 18.2% (35/192) in 2006 to 38.3% (77/201) in 2011; the percentage of isolates in the MIC range from >0.5 mg/L to ≤1.0 mg/L and the range from >1.5 mg/L to ≤2.0 mg/L remained relatively stable. For teicoplanin, there was a small fluctuation in the percentage of isolates with a MIC of 2 mg/L in the period 2006–2010, ranging from 7.9% to 10.2%, but there was a dramatic increase in 2011, up to 15.9%; moreover, there was a slow growth in the percentage of isolates with a MIC of 4 mg/L from 2006 to 2011. For linezolid, there were a downward trend in the percentages of isolates with a MIC of 1 mg/L and a MIC of 4 mg/L from 2006 to 2011, respectively. Vancomycin MIC creep has recently been reported worldwide, although relevant data in China are lacking. There are a number of factors accounting for the inconsistent results in the available literature [10]. For instance, the precise incremental dilution method, but not the doubling dilution method, has enabled differences in MICs to be more precisely assessed for susceptibility to
580
C. Zhuo et al. / International Journal of Antimicrobial Agents 41 (2013) 578–581
Fig. 1. Distribution of minimum inhibitory concentrations (MICs) of (A) vancomycin, (B) teicoplanin and (C) linezolid against meticillin-resistant Staphylococcus aureus from 2006 to 2011 in China.
glycopeptide antibiotics [4]. MIC creep may differ considerably by the analytical approaches on the basis of single or consecutive years. Pooled analysis of bacterial strains for consecutive years, a currently preferable approach, suggested that mean MIC increase with years (MIC creep) was misleading [5].
In this study, vancomycin and teicoplanin, when compared with linezolid, were associated with a significant increase in MICs. The dramatic increase in MICs of teicoplanin warrants being alert to MIC creep. It has been suggested by surveys conducted between 2008 and 2011 that 5% of isolates were resistant to teicoplanin based on
C. Zhuo et al. / International Journal of Antimicrobial Agents 41 (2013) 578–581
EUCAST criteria. This could have stemmed from the overuse and inappropriate use of teicoplanin and was supported by the evidence that 75% of patients without a clinical load dose of teicoplanin [11] readily resulted in reduced teicoplanin susceptibility, and that teicoplanin-non-susceptible Staphylococcus haemolyticus has also been detected in China [12]. This study has one limitation of sample origin, as 67% of the strains were from the lower respiratory tract and therefore may not represent the true picture of MRSA infection. More attention should be paid to learn MIC shifts of MRSA isolates from blood and wound and skin infections in a further study. In summary, this study describes increased vancomycin and teicoplanin MICs for MRSA isolates in China, which may portend the development of resistance and contribute to the diminishing effectiveness of glycopeptides in MRSA infections. Acknowledgments The authors thank the members of the six hospitals that submitted to the MOH National Antimicrobial Resistance Investigation Net (Mohnarin) programme, including Su Dan-hong, Chen Cha, Liang Kang, Wang Lu-xia, Li Hong-yu, Zhang Li-hua, and Xiao meng, for sending the clinical isolates. Funding: This work was funded by Pfizer IIR grant (WS 804350); a grant (No. 201002021) from the Special Fund for Health-scientific Research in the Public Interest: Research & application for the prevention & control of nosocomial infections caused by multi-drug resistant bacteria; and a grant (no. 2009A030301011) from the Key Foundation of Guangdong Province Bureau of Science and Technology. Competing interests: None declared. Ethical approval: Not required.
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References [1] Lodise TP, Graves J, Evans A, Graffunder E, Helmecke M, Lomaestro BM, et al. Relationship between vancomycin MIC and failure among patients with methicillin-resistant Staphylococcus aureus bacteremia treated with vancomycin. Antimicrob Agents Chemother 2008;52:3315–20. [2] Steinkraus G, White R, Friedrich L. Vancomycin MIC creep in non-vancomycinintermediate Staphylococcus aureus (VISA), vancomycin-susceptible clinical methicillin-resistant S. aureus (MRSA) blood isolates from 2001–05. J Antimicrob Chemother 2007;60:788–94. [3] Hawser SP, Bouchillon SK, Hoban DJ, Dowzicky M, Babinchak T. Rising incidence of Staphylococcus aureus with reduced susceptibility to vancomycin and susceptibility to antibiotics: a global analysis 2004–2009. Int J Antimicrob Agents 2011;37:219–24. [4] Sader HS, Fey PD, Limaye AP, Madinger N, Pankey G, Rahal J, et al. Evaluation of vancomycin and daptomycin potency trends (MIC creep) against methicillinresistant Staphylococcus aureus isolates collected in nine U.S. medical centers from 2002 to 2006. Antimicrob Agents Chemother 2009;53:4127–32. [5] Reynolds R, Hope R, Warner M, MacGowan AP, Livermore DM, Ellington MJ, et al. Lack of upward creep of glycopeptide MICs for methicillin-resistant Staphylococcus aureus (MRSA) isolated in the UK and Ireland 2001–07. J Antimicrob Chemother 2012;67:2912–18. [6] Chen H, Liu Y, Sun W, Chen M, Wang H. The incidence of heterogeneous vancomycin-intermediate Staphylococcus aureus correlated with increase of vancomycin MIC. Diagn Microbiol Infect Dis 2011;71:301–3. [7] Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing. Document M100-S20. Wayne, PA: CLSI; 2010. [8] European Committee on Antimicrobial Susceptibility Testing (EUCAST). Clinical breakpoints, v.3.1. 2013-02-11. http://eucast.org/clinical breakpoints [accessed 06.03.13]. [9] Golan Y, McDermott L, Perry L, Snydman DR. Changes in linezolid susceptibility among consecutive MRSA bacteremia isolates. In: 46th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Washington, DC: American Society for Microbiology; 2006. p. 127. Abstract C2-1157. [10] Holmes NE, Johnson PD, Howden BP. Relationship between vancomycinresistant Staphylococcus aureus, vancomycin-intermediate S. aureus, high vancomycin MIC, and outcome in serious S. aureus infections. J Clin Microbiol 2012;50:2548–52. [11] Dong YL, Dong HY, Hu SS, Wang X, Wei YX, Wang MY, et al. An assessment of teicoplanin use and monitoring serum levels in a Chinese teaching hospital. Int J Clin Pharmacol Ther 2011;49:14–22. [12] Ma XX, Wang EH, Liu Y, Luo EJ. Antibiotic susceptibility of coagulase-negative staphylococci (CoNS): emergence of teicoplanin-non-susceptible CoNS strains with inducible resistance to vancomycin. J Med Microbiol 2011;60:1661–8.
Contents lists available at SciVerse ScienceDirect
International Journal of Antimicrobial Agents journal homepage: http://www.elsevier.com/locate/ijantimicag
Short communication
Glycopeptide minimum inhibitory concentration creep among meticillin-resistant Staphylococcus aureus from 2006–2011 in China Chao Zhuo a,∗ , Ying-chun Xu b , Shu-nian Xiao a , Guang-yan Zhang c , Nan-Shan Zhong a a b c
State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical College, Guangzhou, China Peking Union Medical College Hospital, Beijing, China Chengdu 7th People’s Hospital, Chengdu, China
a r t i c l e
i n f o
Article history: Received 30 April 2012 Accepted 11 February 2013 Keywords: Staphylococcus aureus Teicoplanin Vancomycin Linezolid Minimum inhibitory concentration Creep
a b s t r a c t Vancomycin minimum inhibitory concentration (MIC) creep has recently been demonstrated by many countries but is rarely reported in China. In this study, a total of 1411 meticillin-resistant Staphylococcus aureus (MRSA) isolates were collected from six hospitals in China during the period 2006–2011 and the MICs of vancomycin, teicoplanin and linezolid were determined by broth microdilution according to Clinical and Laboratory Standards Institute (CLSI) guidelines. MIC50 and MIC90 values (MICs required to inhibit the growth of 50% and 90% of organisms, respectively) as well as geometric mean (GM) MICs were calculated for all isolates in each year, and MIC creep for the drugs was evaluated. All of the MRSA isolates were susceptible to vancomycin and linezolid. Overall, the vancomycin GM MIC of MRSA isolates was 0.906, 0.952, 0.956, 0.947, 1.013 and 1.040 mg/L, with a significantly increasing trend over the years (P < 0.001). Percentages of MRSA isolates with a vancomycin MIC above 1 g/mL (2 g/mL ≥ MIC > 1 g/mL) were 26.0%, 23.5%, 21.6%, 27.8%, 30.6% and 42.8% from 2006–2011, respectively, and increased over time (P < 0.005). The teicoplanin GM MIC increased rapidly from 0.749 mg/L in 2008 to 0.973 mg/L in 2011, and ca. 5% of isolates were resistant to teicoplanin in the period according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria. MIC shifts were not found for linezolid (P > 0.05). In conclusion, a tendency towards decreasing susceptibility to glycopeptides in MRSA has emerged in China. © 2013 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
1. Introduction
2. Materials and methods
Glycopeptides such as vancomycin remain a front-line drug for the treatment of meticillin-resistant Staphylococcus aureus (MRSA) infections. However, loss of susceptibility, characteristically involving an increase in vancomycin minimum inhibitory concentrations (MICs) to above 1.5 mg/L, is associated with treatment failure [1]. Several studies have demonstrated that the mean vancomycin MIC in MRSA has increased in recent years, referred to as ‘MIC creep’ [2–5]. To the best of our knowledge, no studies have examined the MIC creep phenomenon in China, although the incidence of heterogeneous vancomycin-intermediate S. aureus (hVISA) correlating with an increase of vancomycin MIC was reported by Chen et al. in 2011 [6]. Thus, the aim of this study was to analyse the vancomycin MIC distribution in MRSA isolates obtained from six hospitals over a 6-year period in southern China and to determine MIC trends of these isolates to teicoplanin and linezolid.
2.1. Micro-organisms
∗ Corresponding author. Present address: 1 Kangda Road, Guangzhou 510230, China. Tel.: +86 20 3429 5505; fax: +86 20 3429 5505. E-mail addresses: chao [email protected], [email protected] (C. Zhuo).
A total of 1411 clinical MRSA isolates collected from six hospitals were submitted to the MOH National Antimicrobial Resistance Investigation Net (Mohnarin) programme from January 2006 to December 2011. Only the first isolate per patient was tested in this study. Isolates were recovered from various clinical sources, including the respiratory tract (n = 947), secretions (n = 212), blood (n = 106), pus and wounds (n = 54), drainage (n = 25), urine (n = 16), abdominal fluid (n = 15) and other sources (n = 36). All isolates were stored at −80 ◦ C until MIC testing was performed. 2.2. Antimicrobial susceptibility testing MICs were determined by the Clinical and Laboratory Standards Institute (CLSI) recommended broth microdilution testing method [7] with some modifications. For vancomycin and teicoplanin, the precise incremental dilutions method reported by Sader et al. [4] was used, comprising 15 dilution steps of vancomycin ranging from 0.125 mg/L to 8 mg/L (0.125, 0.25, 0.50, 0.625, 0.75, 0.875, 1, 1.125,
0924-8579/$ – see front matter © 2013 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. http://dx.doi.org/10.1016/j.ijantimicag.2013.02.014
C. Zhuo et al. / International Journal of Antimicrobial Agents 41 (2013) 578–581
579
Table 1 Susceptibility of meticillin-resistant Staphylococcus aureus (MRSA) in China, 2006–2011. Antimicrobial agent
Year
No. of isolates
MIC (mg/L)
Susceptibility (%)
GM
MIC50
MIC90
CLSI
EUCAST
0.25–2.0 0.25–2.0 0.25–2.0 0.375–2.0 0.375–2.0 0.125–2.0 0.125–2.0
100 100 100 100 100 100 100
100 100 100 100 100 100 100
1 2 2 2 2 2 2
0.5–2 0.5–4 0.5–4 0.5–4 0.5–4 0.5–4 0.5–4
100 100 100 100 100 100 100
100 100 96.4 96.8 95.0 94.5 96.8
2 2 4 2 2 2 2
0.5–4 0.5–4 0.5–4 0.5–4 0.5–4 0.125–4 0.125–4
100 100 100 100 100 100 100
100 100 100 100 100 100 100
Vancomycin
2006 2007 2008 2009 2010 2011 Total
192 284 305 187 242 201 1411
0.906 0.952 0.956 0.947 1.013 1.040 0.968
1 1 1 1 1 1 1
1.5 1.5 1.5 1.5 1.5 1.5 1.5
Teicoplanin
2006 2007 2008 2009 2010 2011 Total
192 284 305 187 242 201 1411
0.712 0.739 0.749 0.743 0.768 0.973 0.773
0.5 0.5 0.5 0.5 0.5 1 0.5
Linezolid
2006 2007 2008 2009 2010 2011 Total
192 284 305 187 242 201 1411
1.461 1.414 1.422 1.386 1.41 1.221 1.388
2 1 1 1 1 1 1
Range
MIC, minimum inhibitory concentration; GM, geometric mean; MIC50/90 , MICs required to inhibit the growth of 50% and 90% of organisms, respectively; CLSI, Clinical and Laboratory Standards Institute; EUCAST, European Committee on Antimicrobial Susceptibility Testing.
1.25, 1.375, 1.5, 1.75, 2.0, 4.0 and 8.0 mg/L) and 14 dilution steps of teicoplanin ranging from 0.06 mg/L to 16 mg/L (0.06, 0.12, 0.25, 0.50, 0.625, 0.75, 0.875, 1, 1.125, 1.25, 1.5, 2.0, 4.0 and 8.0 mg/L). For linezolid, the two-fold dilutions method with a concentration range of 0.25–16 mg/L in seven dilutions was employed. Differences in aggregate susceptibility were evaluated between 2010 European Committee on Antimicrobial Susceptibility Testing (EUCAST) and CLSI M100-S20 criteria [7,8]. Quality controls were performed by each testing site on each day of testing using S. aureus ATCC 29213 according to CLSI guidelines. 2.3. Data analysis MIC50 and MIC90 values (MICs required to inhibit the growth of 50% and 90% of organisms, respectively), the MIC range, the geometric mean (GM) MIC, MIC distribution, and percentage susceptible and resistant were evaluated using WHONET 5.4 software (http://www.who.int/drugresistance/whonetsoftware/en/). 2.4. Statistical analysis Statistical analysis was carried out using SPSS v.17.0 software (SPSS Inc., Chicago, IL). For analysis of MIC trends over time, nonparametric correlation (Spearman’s r) was used. For comparison of GM MICs among groups, the Kruskal–Wallis test was employed. Statistical significance was defined a priori as P < 0.05. 3. Results and discussion 3.1. Minimum inhibitory concentration population distribution of three antibiotics As shown in Table 1, the overall GM MICs were 0.968 mg/L for vancomycin, 0.773 mg/L for teicoplanin and 1.388 mg/L for linezolid. Vancomycin MICs were around 1 mg/L (range 0.75–1.25 mg/L) for 79.4% of the isolates, which is similar to a previous report in the USA [2], and the incidence of isolates with a MIC of 2 mg/L remained relatively low (<5%). Teicoplanin MICs were around 0.5 mg/L for 54.6% of the isolates. Linezolid MICs were
1 mg/L and 2 mg/L for 41.7% and 40.3% of the isolates, respectively, which is higher than 0.46 mg/L reported by Steinkraus et al. [2] and lower than 3.3 mg/L reported by Golan et al. [9]. All isolates were categorised as susceptible to vancomycin and linezolid according to EUCAST and CLSI breakpoints. For teicoplanin, all isolates were susceptible according to CLSI criteria and 96.8% of isolates were susceptible according to EUCAST criteria. 3.2. Assessment of minimum inhibitory concentration creep Two methods were employed to assess MIC creep for the three antibiotics. First, as seen from the annual change of GM MICs shown in Table 1, the GM MIC increased 1.15-fold over the study period for vancomycin, from 0.906 mg/L in 2006 to 1.040 mg/L in 2011 (P < 0.001). For teicoplanin, the GM MIC increased 1.37-fold from 0.712 mg/L in 2006 to 0.973 mg/L in 2011 (P < 0.001), whilst the GM MIC for linezolid decreased 0.84-fold from 1.461 mg/L in 2006 to 1.221 mg/L in 2011. Second, different MIC intervals shown in Fig. 1 were divided as described previously [2]. For vancomycin, there was a decrease in the percentage of isolates with a MIC ≤ 0.5 mg/L from 5.7% (11/192) in 2006 to 1.0% (2/201) in 2011, whilst there was a sharp increase in isolates in the MIC range >1.0 mg/L to ≤1.5 mg/L from 18.2% (35/192) in 2006 to 38.3% (77/201) in 2011; the percentage of isolates in the MIC range from >0.5 mg/L to ≤1.0 mg/L and the range from >1.5 mg/L to ≤2.0 mg/L remained relatively stable. For teicoplanin, there was a small fluctuation in the percentage of isolates with a MIC of 2 mg/L in the period 2006–2010, ranging from 7.9% to 10.2%, but there was a dramatic increase in 2011, up to 15.9%; moreover, there was a slow growth in the percentage of isolates with a MIC of 4 mg/L from 2006 to 2011. For linezolid, there were a downward trend in the percentages of isolates with a MIC of 1 mg/L and a MIC of 4 mg/L from 2006 to 2011, respectively. Vancomycin MIC creep has recently been reported worldwide, although relevant data in China are lacking. There are a number of factors accounting for the inconsistent results in the available literature [10]. For instance, the precise incremental dilution method, but not the doubling dilution method, has enabled differences in MICs to be more precisely assessed for susceptibility to
580
C. Zhuo et al. / International Journal of Antimicrobial Agents 41 (2013) 578–581
Fig. 1. Distribution of minimum inhibitory concentrations (MICs) of (A) vancomycin, (B) teicoplanin and (C) linezolid against meticillin-resistant Staphylococcus aureus from 2006 to 2011 in China.
glycopeptide antibiotics [4]. MIC creep may differ considerably by the analytical approaches on the basis of single or consecutive years. Pooled analysis of bacterial strains for consecutive years, a currently preferable approach, suggested that mean MIC increase with years (MIC creep) was misleading [5].
In this study, vancomycin and teicoplanin, when compared with linezolid, were associated with a significant increase in MICs. The dramatic increase in MICs of teicoplanin warrants being alert to MIC creep. It has been suggested by surveys conducted between 2008 and 2011 that 5% of isolates were resistant to teicoplanin based on
C. Zhuo et al. / International Journal of Antimicrobial Agents 41 (2013) 578–581
EUCAST criteria. This could have stemmed from the overuse and inappropriate use of teicoplanin and was supported by the evidence that 75% of patients without a clinical load dose of teicoplanin [11] readily resulted in reduced teicoplanin susceptibility, and that teicoplanin-non-susceptible Staphylococcus haemolyticus has also been detected in China [12]. This study has one limitation of sample origin, as 67% of the strains were from the lower respiratory tract and therefore may not represent the true picture of MRSA infection. More attention should be paid to learn MIC shifts of MRSA isolates from blood and wound and skin infections in a further study. In summary, this study describes increased vancomycin and teicoplanin MICs for MRSA isolates in China, which may portend the development of resistance and contribute to the diminishing effectiveness of glycopeptides in MRSA infections. Acknowledgments The authors thank the members of the six hospitals that submitted to the MOH National Antimicrobial Resistance Investigation Net (Mohnarin) programme, including Su Dan-hong, Chen Cha, Liang Kang, Wang Lu-xia, Li Hong-yu, Zhang Li-hua, and Xiao meng, for sending the clinical isolates. Funding: This work was funded by Pfizer IIR grant (WS 804350); a grant (No. 201002021) from the Special Fund for Health-scientific Research in the Public Interest: Research & application for the prevention & control of nosocomial infections caused by multi-drug resistant bacteria; and a grant (no. 2009A030301011) from the Key Foundation of Guangdong Province Bureau of Science and Technology. Competing interests: None declared. Ethical approval: Not required.
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