Journal of Medical Microbiology (2016), 65, 1215 1224 DOI 10.1099/jmm.0.000347 In vitro activities of tedizolid compared with other antibiotics against Gram-positive pathogens associated with hospital-acquired pneumonia, skin and soft tissue infection and bloodstream infection collected from 26 hospitals in China Shuguang Li, 1 Yu Guo, 1 Chunjiang Zhao, 1 Hongbin Chen, 1 Bijie Hu, 2 Yunzhuo Chu, 3 Zhijie Zhang, 4 Yunjian Hu, 5 Zhiyong Liu, 6 Yan Du, 7 Qiaodi Gui, 8 Ping Ji, 9 Ji Zeng, 10 Bin Cao, 11 Quan Fu, 12 Rong Zhang, 13 Zhongxin Wang, 14 Chao Zhuo, 15 Xianju Feng, 16 Wei Jia, 17 Yan Jin, 18 Xuesong Xu, 19 Kang Liao, 20 Yuxing Ni, 21 Yunsong Yu, 22 Xiuli Xu, 23 Zhidong Hu, 24 Jin-e Lei, 25 Qing Yang 26 and Hui Wang 1 Correspondence Hui Wang wanghui@pkuph.edu.cn or whuibj@163.com 1 Department of Clinical Laboratory, Peking University People s Hospital, Beijing 100044, PR China 2 Zhongshan Hospital Fudan University, Shanghai 200032, PR China 3 The First Hospital of China Medical University, Shenyang 110001, PR China 4 Shengjing Hospital of China Medical University, Shenyang 110004, PR China 5 Beijing Hospital, Beijing 100730, PR China 6 Affiliated Xinan Hospital of Third Military Medical University, Chongqing 400038, PR China 7 First Affiliated Hospital of Kunming Medical University, Kunming 650032, PR China 8 Shanxi Provincial People s Hospital, Xi an 710068, PR China 9 The First Teaching Hospital of Xinjiang Medical University, Urumqi 830054, PR China 10 Affiliated Puai Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China 11 Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, PR China 12 The Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010000, PR China 13 The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, PR China 14 The First Affiliated Hospital of Anhui Medical University, Hefei 230022, PR China 15 The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510230, PR China 16 The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, PR China 17 General Hospital of Ningxia Medical University, Yinchuan 750004, PR China 18 Shandong Provincial Hospital, Jinan 250021, PR China 19 China-Japan Union Hospital of Jilin University, Changchun 130033, PR China Received 6 January 2016 Accepted 1 September 2016 20 First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, PR China 21 Rui Jin Hospital Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China These authors contributed equally to this work. Abbreviations: BSI, bloodstream infection; CoNS, coagulase-negative Staphylococcus; FDA, Food and Drug Administration; HAP, hospital-acquired pneumonia; MRCoNS, methicillin-resistant coagulase-negative Staphylococcus; MRSA, methicillin-resistant Staphylococcus aureus; MSCoNS, methicillinsensitive coagulase-negative Staphylococcus; MSSA, methicillin-sensitive Staphylococcus aureus; SSTI, skin and soft tissue infection. 000347 ã 2016 The Authors Printed in Great Britain 1215
S. Li and others 22 Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, PR China 23 Xijing Hospital, The Fourth Military Medical University, Xi an 710032, PR China 24 Tianjin Medical University General Hospital, Tianjin 300052, PR China 25 The First Affiliated Hospital of Xi an Jiaotong University, Xi an 710061, PR China 26 The First Affiliated Hospital, Zhejiang University, Hangzhou 310003, PR China To evaluate the in vitro antimicrobial activities of tedizolid, linezolid and other comparators against clinically significant Gram-positive cocci isolates from hospital-acquired pneumonia (HAP), skin and soft tissue infection (SSTI) and bloodstream infection (BSI), 2140 nonduplicate isolates (23.7 % isolated from HAP, 46.8 % from SSTI and 29.5 % from BSI) were consecutively collected in 26 hospitals in 17 cities across China during 2014. These pathogens included 632 methicillin-resistant Staphylococcus aureus, 867 methicillin-sensitive Staphylococcus aureus, 299 coagulase-negative Staphylococcus (CoNS), 104 Enterococcus faecalis, 99 Enterococcus faecium, 13 Streptococcus pneumoniae, 23 a-haemolytic Streptococcus and 103 b-haemolytic Streptococcus. MICs of routine clinical antibiotics were determined by broth microdilution method according to the Clinical and Laboratory Standards Institute guidelines 2015. Tedizolid, linezolid, vancomycin, daptomycin, teicoplanin and tigecycline showed high in vitro activity against Gram-positive pathogens (98.0 % susceptible), and tedizolid exhibited four- to eight fold greater activity than linezolid against the pathogens tested, with MIC 90 s of methicillinresistant Staphylococcus aureus, a-haemolytic Streptococcus and b-haemolytic Streptococcus (0.25 vs 2 µg ml 1 ); methicillin-sensitive Staphylococcusaureus, E. faecalis and E. faecium (0.5 vs 2 µg ml 1 ); methicillin-resistant CoNS and methicillin-sensitive CoNS (0.25 vs 1 µg ml 1 ); and Streptococcus pneumoniae (0.125 vs 0.5 µg ml 1 ). Tedizolid MIC 90 s associated with different infections did not show significant differences, and the drug exhibited excellent activity against surveyed Gram-positive pathogens associated with HAP, SSTI and BSI, including linezolid-nonsusceptible strains. These data suggest that tedizolid could be an alternative to linezolid for the treatment of infections caused by Gram-positive organisms. INTRODUCTION Gram-positive bacteria are common causes of hospitalacquired pneumonia (HAP), skin and soft tissue infections (SSTIs) and bloodstream infections (BSIs) in hospitalized patients worldwide and are associated with high morbidity and mortality (Rice, 2006; Sievert et al., 2013; Woodford & Livermore, 2009). Notably, the incidence rates of methicillin-resistant Staphylococcus aureus (MRSA), vancomycinintermediate Staphylococcus aureus, vancomycin-resistant Enterococcus and penicillin-nonsusceptible Streptococcus pneumoniae have been increasing, and these bacteria have become a serious challenge to clinical treatment (Hiramatsu et al., 1997; Leclercq et al., 1988; Stryjewski & Corey, 2014; Tsai et al., 2012; Winston et al., 1999). Vast quantities of antimicrobials are used in China, and the abuse of antibiotics continues to be an issue. The multi-centre surveillance network in China is important to monitor bacterial resistance levels in different regions and provide the basis for clinical infection control and rational drug usage. Tedizolid phosphate (TR-701) is a novel, second-generation oxazolidinone prodrug that is converted in the serum into the active drug tedizolid (TR-700) (Kanafani & Corey, 2012). Tedizolid exerts its broad-spectrum antibacterial activity against Gram-positive pathogens by binding to the 23S rrna of the 50S subunit, resulting in inhibition of protein synthesis (Kanafani & Corey, 2012; Moellering, 2003). Tedizolid has an increased potency compared with linezolid; this is due to structural differences in the C- and D- rings, resulting in additional hydrogen bonds with 23S rrna residues (Shaw et al., 2008). Tedizolid can be administered orally or intravenously in a once-daily dose (Prokocimer et al., 2011). Tedizolid has been shown to be effective and well tolerated in the treatment of acute bacterial skin and skin structure infections (Moran et al., 2014; Prokocimer et al., 2013) and was approved by the US Food and Drug Administration (FDA) in 2014 (Burdette & Trotman, 2015; Kisgen et al., 2014). Additionally, an ongoing global phase 3 study will investigate the efficacy and safety of tedizolid in the treatment of hospital-acquired or ventilator-associated bacterial pneumonia and concurrent bacteraemia (Burdette & Trotman, 2015; Kisgen et al., 2014). To support this, the current study aimed to evaluate the in vitro antimicrobial activities 1216 Journal of Medical Microbiology 65
In vitro activities of tedizolid from hospitals in China of tedizolid, linezolid and other comparators against clinically significant Gram-positive cocci isolates associated with HAP, SSTI and BSI in different regions of China in 2014. METHODS Bacterial isolate collection. Clinically common Gram-positive cocci strains isolated from HAP, SSTI and BSI were consecutively collected in 26 hospitals in 17 cities across China during January to November 2014 (Fig. 1). Upon receiving the isolates, species identification was confirmed by colony morphology, routine biochemical tests and/or the Vitek 2 system (biomerieux) in Peking University People s Hospital (the Central Laboratory). All isolates were stored at 80 C until MICs were measured. Antimicrobial susceptibility testing. The MICs of routine clinical antibiotics were determined in the Central Laboratory, using broth microdilution method (tedizolid and daptomycin) or agar dilution method (agents other than tedizolid and daptomycin) according to the CLSI (2015) guidelines (M100-S25). Pathogens were then categorized into resistant, intermediate or susceptible. As there are no CLSI interpretive criteria for tedizolid and tigecycline, FDA prescribing information was used to determine the breakpoints of these two drugs. Tedizolid breakpoints are as follows (FDA, 2014): Staphylococcus aureus and coagulase-negative Staphylococcus (CoNS) (refer to Staphylococcus aureus), 0.5 µg ml 1 for susceptible category, with an intermediate breakpoint at 1 and 2 µg ml 1 for resistant category, and Enterococcus (refer to Enterococcus faecalis) and Streptococcus other than Streptococcus anginosus group (refer to Streptococcus pyogenes and Streptococcus agalactiae), 0.5 µg ml 1 for susceptible with no intermediate or resistant categories. The following strains were used as quality controls: Staphylococcus aureus ATCC 29213, E. faecalis ATCC 29212 and Streptococcus pneumoniae ATCC 49619. The software WHONET-5.6 was used in data analysis. RESULTS Distribution of the pathogens in 26 teaching hospitals In total, 2140 nonduplicate Gram-positive cocci isolates were collected; the numbers of strains from each hospital were between 33 and 100. The pathogens included 1499 Staphylococcus aureus, 299 CoNS, 203 Enterococcus (104 E. faecalis and 99 Enterococcus faecium) and 139 Streptococcus (13 Streptococcus pneumoniae, 23 a-haemolytic Streptococcus and 103 b-haemolytic Streptococcus). Of these, 507 (23.7 %) were isolated from HAP, 1001 (46.8 %) from SSTI and 632 (29.5 %) from BSI (detailed information of bacterium types and quantitative distributions in different infections is shown in Table 1). Beijing Urumchi Yinchuan Changchun Hohhot Tianjin Shenyang Jinan Xi'an Wuhan Zhengzhou Shanghai Hangzhou Chongqing Kunming Hefei Guangzhou Fig. 1. Distribution map of the investigative cities in China. The white regions represent provinces which have cities in survey, and the surveyed cites were shown as black dots or black star (Beijing); while the dark grey regions represent the unsurveyed provinces in this study. http://jmm.microbiologyresearch.org 1217
S. Li and others Table 1. Bacterium types and quantitative distributions in different infections Organism HAP SSTI BSI Total n % n % n % Staphylococcus aureus 463 30.9 776 51.8 260 17.3 1499 MRSA 284 44.9 242 38.3 106 16.8 632 MSSA 179 20.6 534 61.6 154 17.8 867 CoNS 15 5.0 64 21.4 220 73.6 299 MRCoNS 14 5.7 47 19.3 183 75.0 244 MSCoNS 1 1.8 17 30.9 37 67.3 55 Enterococcus 9 4.4 87 42.9 107 52.7 203 E. faecalis 6 5.8 50 48.1 48 46.1 104 E. faecium 3 3.0 37 37.4 59 59.6 99 Streptococcus 20 14.4 74 53.2 45 32.4 139 spn 11 84.6 1 7.7 1 7.7 13 ahs 1 4.3 9 39.1 13 56.5 23 bhs 8 7.8 64 62.1 31 30.1 103 Total 507 23.7 1001 46.8 632 29.5 2140 MSSA, methicillin-sensitive Staphylococcus aureus; MRCoNS, methicillin-resistant CoNS; MSCoNS, methicillin-sensitive CoNS; spn, Streptococcus pneumoniae; ahs, a-haemolytic Streptococcus; bhs, b-haemolytic Streptococcus. Antimicrobial activities of antibiotics against different pathogens The MIC values of antibiotics against the three control strains were all within the quality control ranges. For tedizolid, the quality control ranges were as follows (CLSI, 2015): Staphylococcus aureus ATCC 29213, 0.25 to 1 µg ml 1 ; E. faecalis ATCC 29212, 0.25 to 1 µg ml 1 ; and Streptococcus pneumoniae ATCC 49619, 0.12 to 0.5 µg ml 1. Staphylococcus aureus. All Staphylococcus aureus isolates were susceptible to tedizolid, linezolid, vancomycin, daptomycin, teicoplanin and tigecycline, while 94.9 % of MRSA and 97.8 % of methicillin-sensitive Staphylococcus aureus (MSSA) were susceptible to trimethoprim sulfamethoxazole (Table 2). For other antibiotics, i.e. gentamicin, levofloxacin, moxifloxacin, clindamycin, erythromycin and tetracycline, the susceptibility rates of MRSA were all lower than those for MSSA (Table 2). Interestingly, for trimethoprim sulfamethoxazole, levofloxacin, moxifloxacin, gentamicin and tetracycline, the susceptibility rates of MRSA isolated from HAP patients were the lowest, followed by susceptibility rates of isolates from BSI patients and then from SSTI patients. However, situations were just contrary for clindamycin and erythromycin. The incidence rates of MRSA among Staphylococcus aureus were 61.3 % (284/463), 31.2 % (242/776) and 40.8 % (106/ 260) in HAP, SSTI and BSI, respectively. The incidence rates of MRSA across the 17 study sites ranged from 13.8 to 66.7 %. Three cities, i.e. Guangzhou (66.7 %), Xi an (65.3 %) and Shanghai (61.3 %), had MRSA incidence rates higher than 60 %, while Kunming and Chongqing, on the other hand, had incidence rates lower than 20 %. CoNS. All CoNS were susceptible to tedizolid, vancomycin, daptomycin, teicoplanin and tigecycline. Susceptibility rates of methicillin-resistant CoNS (MRCoNS) were lower than that of methicillin-sensitive CoNS (MSCoNS) for the other tested antibiotics (Table 2). Interestingly, for levofloxacin, moxifloxacin, gentamicin and tetracycline, the susceptibility rates of MRCoNS isolated from HAP cases were the lowest, followed by higher susceptibility rates of isolates from SSTI cases and then by isolates from BSI cases. Of note, for two linezolid-resistant MRCoNS strains (Staphylococcus capitis subsp. capitis) collected from BSI, linezolid MICs were both 16 µg ml 1 ; however, both strains were susceptible to tedizolid (tedizolid MICs were both 0.25 µg ml 1 ). The incidence rates of MRCoNS among CoNS isolates were 93.3 % (14/15), 73.4 % (47/64) and 83.2 % (183/220) in HAP, SSTI and BSI, respectively, which were similar to those of MRSA across the three infection types; thus, compared with BSI and SSTI, Staphylococcus in HAP were more likely to be methicillin resistant. Overall, the incidence rates of CoNS across the studied institutions ranged from 57.9 to 100 % (CoNS were not collected from Jinan in this study). The cities with MRCoNS incidence rates higher than 90 % were Yinchuan (100 %), Shanghai (94.4 %), Wuhan (92.9 %) and Shenyang (90.0 %), while Xi an had the lowest incidence rate (57.9 %). Enterococcus. All Enterococcus isolates were susceptible to tedizolid, vancomycin, daptomycin and teicoplanin; however, the susceptibility rates of E. faecium to ampicillin, penicillin, levofloxacin and erythromycin were all lower than those of E. faecalis (Table 2). The susceptibility rates of Enterococcus collected in varied infections to erythromycin were all very low (0 10.4 %), with all Enterococcus from 1218 Journal of Medical Microbiology 65
In vitro activities of tedizolid from hospitals in China Table 2. Activity profile of tedizolid and comparator antibiotics against all evaluated isolates (n=2140) collected in China in 2014 (MIC, mg ml 1 ) Organism Agent MIC 50 MIC 90 Range S% MRSA (n=632) Tedizolid 0.25 0.25 0.064 0.5 100 Linezolid 2 2 0.5 4 100 Vancomycin 1 1 0.25 2 100 Daptomycin 0.25 0.5 0.125 1 100 Teicoplanin 2 4 0.032 8 100 Tigecycline 0.25 0.5 0.064 0.5 100 Trimeth/sulfa 0.125 1 0.016 64 94.9 Levofloxacin 32 64 0.064 64 25.2 Moxifloxacin 8 8 0.016 64 26.6 Gentamicin 32 128 0.064 256 31.4 Tetracycline 64 64 0.064 256 22.9 Clindamycin 256 256 0.016 256 38.4 Erythromycin 256 256 0.016 256 12.5 MSSA (n=867) Tedizolid 0.25 0.5 0.064 0.5 100 Linezolid 2 2 0.5 4 100 Vancomycin 1 1 0.25 2 100 Daptomycin 0.25 0.5 0.125 1 100 Teicoplanin 1 1 0.125 8 100 Tigecycline 0.125 0.25 0.064 0.5 100 Trimeth/sulfa 0.064 0.5 0.016 128 97.8 Levofloxacin 0.25 4 0.032 64 88.9 Moxifloxacin 0.064 2 0.016 32 88.8 Gentamicin 0.125 16 0.064 256 83.5 Tetracycline 0.25 32 0.064 128 81.4 Clindamycin 0.064 256 0.016 256 72.7 Erythromycin 256 256 0.125 256 41.6 MRCoNS (n=244) Tedizolid 0.25 0.25 0.064 0.5 100 Linezolid 1 1 0.25 16 99.2 Vancomycin 1 2 0.25 4 100 Daptomycin 0.25 0.5 0.125 1 100 Teicoplanin 2 4 0.125 8 100 Tigecycline 0.25 0.5 0.016 0.5 100 Trimeth/sulfa 2 16 0.016 128 61.9 Levofloxacin 4 64 0.064 64 30.0 Moxifloxacin 2 16 0.032 64 31.6 Gentamicin 8 128 0.064 256 48.4 Tetracycline 1 128 0.064 256 70.5 Clindamycin 0.125 256 0.016 256 57.0 Erythromycin 256 256 0.032 256 11.5 MSCoNS (n=55) Tedizolid 0.25 0.25 0.064 0.5 100 Linezolid 1 1 0.25 2 100 Vancomycin 1 2 0.25 2 100 Daptomycin 0.25 0.5 0.125 0.5 100 Teicoplanin 0.5 4 0.125 8 100 Tigecycline 0.125 0.25 0.016 0.5 100 Trimeth/sulfa 0.064 8 0.016 32 81.8 Levofloxacin 0.125 4 0.016 64 85.5 Moxifloxacin 0.064 1 0.016 16 87.3 Gentamicin 0.064 2 0.064 16 94.5 Tetracycline 0.25 64 0.064 128 72.7 Clindamycin 0.064 256 0.016 256 83.6 http://jmm.microbiologyresearch.org 1219
S. Li and others Table 2. cont. Organism Agent MIC 50 MIC 90 Range S% Erythromycin 16 256 0.016 256 30.9 E. faecalis (n=104) Tedizolid 0.5 0.5 0.125 0.5 100 Linezolid 2 2 0.5 8 98.1 Vancomycin 1 2 0.5 2 100 Daptomycin 1 2 0.25 4 100 Teicoplanin 0.25 0.5 0.064 4 100 Tigecycline 0.125 0.25 0.032 0.5 99.0 Ampicillin 2 4 1 256 94.2 Penicillin 2 4 0.25 256 93.3 Levofloxacin 1 64 0.125 64 70.2 Erythromycin 128 256 0.125 256 6.7 E. faecium (n=99) Tedizolid 0.5 0.5 0.125 0.5 100 Linezolid 2 2 1 8 98.0 Vancomycin 0.5 1 0.25 2 100 Daptomycin 2 2 0.25 4 100 Teicoplanin 0.5 0.5 0.064 1 100 Tigecycline 0.064 0.125 0.032 0.25 100 Ampicillin 256 256 0.125 256 18.2 Penicillin 256 256 0.064 256 18.2 Levofloxacin 64 64 0.125 64 18.2 Erythromycin 256 256 0.125 256 5.1 Streptococcus pneumoniae (n=13) Tedizolid 0.125 0.125 0.032 0.125 100 Linezolid 0.5 0.5 0.25 1 100 Vancomycin 0.25 0.25 0.064 0.5 100 Tigecycline 0.125 0.125 0.016 0.125 100 Levofloxacin 1 1 0.5 1 100 Moxifloxacin 0.125 0.125 0.032 0.125 100 Penicillin (nonmeningitis) 0.5 4 0.004 4 76.9 Trimeth/sulfa 4 8 0.064 8 38.5 Clindamycin 128 256 0.016 256 23.1 Erythromycin 8 256 0.016 256 7.7 Tetracycline 32 32 2 32 7.7 ahs (n=23) Tedizolid 0.125 0.25 0.064 0.5 100 Linezolid 1 2 0.5 2 100 Vancomycin 0.25 0.5 0.25 1 100 Daptomycin 0.5 1 0.032 1 100 Tigecycline 0.25 0.25 0.125 0.25 100 Penicillin 0.032 2 0.004 32 68.2 Levofloxacin 1 32 0.125 32 56.5 Tetracycline 4 32 0.125 64 52.2 Clindamycin 64 256 0.016 256 34.8 Erythromycin 16 256 0.032 256 8.7 bhs (n=103) Tedizolid 0.25 0.25 0.032 0.5 100 Linezolid 1 2 0.25 2 100 Vancomycin 0.25 0.5 0.25 1 100 Daptomycin 0.5 0.5 0.032 1 100 Tigecycline 0.25 0.25 0.064 0.25 100 Penicillin 0.032 0.032 0.004 0.125 100 Levofloxacin 0.5 32 0.125 32 68.9 Tetracycline 32 64 0.125 256 31.1 Clindamycin 256 256 0.016 256 24.3 1220 Journal of Medical Microbiology 65
In vitro activities of tedizolid from hospitals in China Table 2. cont. Organism Agent MIC 50 MIC 90 Range S% Erythromycin 256 256 0.016 256 14.6 Trimeth/sulfa, trimethoprim sulfamethoxazole; ahs, a-haemolytic Streptococcus; bhs, b-haemolytic Streptococcus; S%, percentage of susceptibility rates. HAP being resistant to erythromycin. For ampicillin and penicillin, the susceptibility rates of E. faecalis isolates from HAP cases were the lowest, followed by the susceptibility rates of isolates from BSI cases and then from SSTI cases; for levofloxacin and erythromycin, the susceptibility rates of E. faecalis isolates from HAP cases was the lowest, and it was higher for isolates from SSTI cases and highest for isolates from BSI cases. While for ampicillin, penicillin and levofloxacin, the susceptible rates of E. faecium isolates from BSI cases were the lowest, followed by the susceptibility rates of isolates from SSTI cases and then from HAP cases. Notably, the linezolid MICs of two linezolid-resistant Enterococcus isolates (one E. faecalis from HAP and one E. faecium from BSI) were both 8 µg ml 1, while one E. faecalis and one E. faecium from BSI were intermediate to linezolid (linezolid MICs were both 4 µg ml 1 ). These four strains, however, were all susceptible to tedizolid (MICs 0.5 µg ml 1 ). In HAP, SSTI and BSI, the incidence rates of ampicillinresistant E. faecalis were 16.7 % (1/6), 2.0 % (1/50) and 8.3 % (4/48), respectively, while the incidence rates of ampicillin-resistant E. faecium were 33.3 % (1/3), 81.1 % (30/37) and 84.7 % (50/59), respectively. In SSTI and BSI, the incidence rates of ampicillin-resistant E. faecalis were both significantly lower than ampicillin-resistant E. faecium (Pearson chi-square tests, both P<0.01). In this survey, no Enterococcus isolates were collected in Changchun, and only ampicillin-sensitive E. faecalis strains were collected in Hefei. In the other 15 cities, the incidence rates of ampicillin-resistant E. faecalis were between 0 and 33.3 %, and resistant isolates occurred only in Tianjin (33.3 %), Jinan (14.3 %), Xi an (12.5 %), Guangzhou (7.1 %) and Beijing (5.9 %). The incidence rates of ampicillin-resistant E. faecium were much higher than those for E. faecalis (33.3 100 %), and all E. faecium isolates were resistant to ampicillin in Kunming, Hohhot, Xi an and Zhengzhou. Streptococcus. All 13 Streptococcus pneumoniae isolates were susceptible to tedizolid, linezolid, vancomycin, tigecycline, levofloxacin and moxifloxacin, while the susceptibility rates of Streptococcus pneumoniae to penicillin (nonmeningitis), trimethoprim sulfamethoxazole, clindamycin, erythromycin and tetracycline were 76.9, 38.5, 23.1, 7.7 and 7.7 %, respectively (Table 2). For the 23 a-haemolytic Streptococcus, tedizolid, linezolid, vancomycin, daptomycin and tigecycline were the most active agents (100 % were susceptible to all these antibiotics), while the susceptibility rates of a-haemolytic Streptococcus to penicillin (nonmeningitis), levofloxacin, tetracycline, clindamycin and erythromycin were 68.2, 56.5, 52.2, 34.8 and 8.7 %, respectively (Table 2). All b-haemolytic Streptococcus isolates were susceptible to tedizolid, linezolid, vancomycin, daptomycin, tigecycline and penicillin, while for levofloxacin, tetracycline, clindamycin and erythromycin, the susceptibility rates of b-haemolytic Streptococcus were 68.9, 31.1, 24.3 and 14.6 %, respectively (Table 2). The susceptibility rates to levofloxacin and tetracycline were lowest for b-haemolytic Streptococcus isolates from BSI cases, higher for isolates from SSTI cases and highest for isolates from HAP cases, while the opposite trend in susceptibility rates was found for clindamycin. In HAP, SSTI and BSI, the incidence rates of erythromycinnonsusceptible b-haemolytic Streptococcus were 87.5 % (7/ 8), 89.1 % (57/64) and 77.4 % (24/31), respectively. No b- haemolytic Streptococcus isolates were collected in Hefei and Zhengzhou, and all b-haemolytic Streptococcus were nonsusceptible to erythromycin in Beijing, Changchun, Guangzhou, Jinan, Kunming, Shenyang, Yinchuan and Urumqi. Comparative analysis of the antibiotic activities of tedizolid and linezolid Antimicrobial activities of tedizolid and linezolid were comparatively analysed (Table 3). Tedizolid exhibited four- to eightfold greater in vitro activity than linezolid against all surveyed pathogens according to MIC 90 s of MRSA (0.25 vs 2 µg ml 1 ), MSSA (0.5 vs 2 µg ml 1 ), MRCoNS (0.25 vs 1 µg ml 1 ), MSCoNS (0.25 vs 1 µg ml 1 ), E. faecalis (0.5 vs 2 µg ml 1 ), E. faecium (0.5 vs 2 µg ml 1 ), Streptococcus pneumoniae (0.125 vs 0.5 µg ml 1 ), a-haemolytic Streptococcus (0.25 vs 2 µg ml 1 ) and b-haemolytic Streptococcus (0.25 vs 2 µg ml 1 ) (Table 3). Linezolid MICs for 55.8 % of all pathogens were >1 µg ml 1, while tedizolid MICs for all bacteria were 0.5 µg ml 1. Tedizolid MIC 90s for different organisms were identical in different infections, except for MRSA: MIC 90 s were 0.25, 0.5 and 0.5 µg ml 1 in HAP, SSTI and BSI, respectively (Streptococcus pneumoniae and a-haemolytic Streptococcus were not comparatively analysed in varied infections as the numbers were both less than 30). Tedizolid geometric mean MICs for different pathogens were varied in different hospitals and cities; however, the degree of differences has no relation with geographic distances; thus, there was no regional distribution pattern for tedizolid MICs in China (data not shown). In this study, six linezolid-nonsusceptible isolates were obtained, including two linezolid-resistant Staphylococcus http://jmm.microbiologyresearch.org 1221
S. Li and others Table 3. MIC distribution and susceptibility of 2140 Gram-positive cocci isolates to linezolid and tedizolid 1 Organism No. Agent Cumulative percentage of isolates inhibited at MIC (mg ml ): MIC range (mg ml 1 ) 1 MIC50 (mg ml ) 1 MIC90 (mg ml ) S% 0.032 0.064 0.125 0.25 0.5 1 2 4 8 16 All 2140 Linezolid 0.4 9.0 44.2 99.0 99.8 99.9 100 0.25 16 2 2 NA Tedizolid 0.1 2.3 8.9 83.3 100 0.032 0.5 0.25 0.5 NA MRSA 632 Linezolid 2.1 44.2 99.4 100 0.5 4 2 2 100 Tedizolid 1.6 5.1 90.0 100 0.064 0.5 0.25 0.25 100 MSSA 867 Linezolid 0.5 23.0 98.6 100 0.5 4 2 2 100 Tedizolid 2.3 5.4 84.2 100 0.064 0.5 0.25 0.5 100 MRCoNS 244 Linezolid 0.4 43.8 96.2 98.4 99.2 99.2 100 0.25 16 1 1 99.2 Tedizolid 2.5 14.4 96.3 100 0.064 0.5 0.25 0.25 100 MSCoNS 55 Linezolid 3.6 47.2 92.7 100 0.25 2 1 1 100 Tedizolid 5.5 20.0 98.2 100 0.064 0.5 0.25 0.25 100 E. faecalis 104 Linezolid 1.9 24 98.0 99.0 100 0.5 8 2 2 98.1 Tedizolid 1.0 25.0 100 0.125 0.5 0.5 0.5 100 E. faecium 99 Linezolid 39.4 98.0 99.0 100 1 8 2 2 98.0 Tedizolid 1.0 33.3 100 0.125 0.5 0.5 0.5 100 Streptococcus pneumoniae 13 Linezolid 38.5 92.3 100 0.25 1 0.5 0.5 100 Tedizolid 7.7 23.1 100 0.032 0.125 0.125 0.125 100 a-haemolytic 23 Linezolid 26.1 82.6 100 0.5 2 1 2 100 Streptococcus Tedizolid 17.4 56.5 95.7 100 0.064 0.5 0.125 0.25 100 b-haemolytic 103 Linezolid 1 22.4 81.6 100 0.25 2 1 2 100 Streptococcus Tedizolid 1 2.9 35.9 97.1 100 0.032 0.5 0.25 0.25 100 1222 Journal of Medical Microbiology 65
In vitro activities of tedizolid from hospitals in China capitis subsp. capitis (MRCoNS, linezolid MICs were both 16 µg ml 1, while tedizolid MICs were both 0.25 µg ml 1 ), one linezolid-resistant E. faecalis (linezolid and tedizolid MICs were 8 and 0.5 µg ml 1, respectively), one linezolidresistant E. faecium (linezolid and tedizolid MICs were 8 and 0.5 µg ml 1, respectively), one linezolid-intermediate E. faecalis (linezolid and tedizolid MICs were 4 and 0.25 µg ml 1, respectively) and one linezolid-intermediate E. faecium (linezolid and tedizolid MICs were 4 and 0.5 µg ml 1, respectively); these strains, however, were all susceptible to tedizolid. DISCUSSION In the resistance surveillance of Gram-positive pathogens associated with HAP, SSTI and BSI in 26 hospitals from 17 cities across China in 2014, Staphylococcus aureus was the most frequently isolated pathogen (70.0 %, 1499/2140). The incidence rate of MRSA was 42.2 % (632/1499), which showed no significant difference with surveillance in 2011 (43.7 %, 222/508; among 14 hospitals in 9 cities), 2012 (43.6 %, 264/605, 16 hospitals in 10 cities) or 2013 (39.7 %, 229/576, 15 hospitals in 10 cities) from China (Guo et al., 2012, 2013, 2015) and surveillance in 2011 to 2012 from the USA and Europe (39.3 %, 1770/4499) (Sahm et al., 2015). The incidence rates of MRSA were varied in different infections (31.2 61.3 %) and cities (13.8 66.7 %). Tedizolid, linezolid, vancomycin, daptomycin, teicoplanin and tigecycline demonstrated high in vitro activity against all Staphylococcus aureus isolates (100 % susceptible). For other antibiotics, the susceptibility rates of MRSA were all lower than MSSA. CoNS accounted for 14.0 % (299/2140) of all pathogens, and the incidence rate of MRCoNS was 81.6 % (244/299), which showed no significant difference to rates in 2011 (85.6 %, 214/250), 2012 (75.7 %, 227/300) or 2013 (80.6 %, 224/278) (Guo et al., 2012, 2013, 2015). The incidence rate of MRCoNS varied in different infections (73.4 93.3 %) and cities (57.9 100 %). All CoNS were susceptible to tedizolid, vancomycin, daptomycin, teicoplanin and tigecycline. The susceptibility rates of MRCoNS were all lower than MSCoNS for other antibiotics. Enterococcus accounted for 9.5 % (203/2140) of all pathogens. The incidence rate of ampicillin-resistant E. faecalis was 5.8 % (6/104), which is lower than that in 2011 (8.8 %, 13/148), 2012 (16.0 %, 26/162) and 2013 (9.2 %, 14/153) (Guo et al., 2012, 2013, 2015). The incidence rate of ampicillin-resistant E. faecium, on the other hand, was 81.8 % (81/99), which is higher than that in 2011 (78.3 %, 94/120), 2012 (76.8 %, 116/ 151) and 2013 (73.9 %, 102/138) (Guo et al., 2012, 2013, 2015). The incidence rates of ampicillin-resistant Enterococcus varied in different infections (E. faecalis, 2.0 16.7 %; E. faecium, 33.3 84.7 %) and cities (E. faecalis, 0 33.3 %; E. faecium, 33.3 100 %). Tedizolid, vancomycin, daptomycin and teicoplanin were very active against all Enterococcus (100 % susceptible); however, the susceptibility rates of E. faecium for ampicillin, penicillin, levofloxacin and erythromycin were much lower than that of E. faecalis. Streptococcus pneumoniae accounted for only 0.6 % (13/ 2140) of all pathogens, and all strains were sensitive to tedizolid, linezolid, vancomycin, tigecycline, levofloxacin and moxifloxacin, while 76.9 % (10/13) of isolates were sensitive to penicillin (nonmeningitis), which is lower than in 2011 (84.5 %, 202/239) but higher than in 2012 (65.7 %, 205/ 312) and in 2013 (69.5 %, 191/275) (Guo et al., 2012, 2013, 2015). For 23 a-haemolytic Streptococcus isolates, tedizolid, linezolid, vancomycin, daptomycin and tigecycline were the most active agents (100 % of isolates susceptible). b-haemolytic Streptococcus accounted for 4.8 % (103/2140) of all pathogens, and the incidence rate of erythromycin-nonsusceptible strains was 85.4 % (88/103), which was higher than in 2011 (76.0 %, 165/217), 2012 (74.2 %, 193/260) and 2013 (74.8 %, 181/242) (Guo et al., 2012, 2013, 2015). The incidence rates of erythromycin-nonsusceptible b-haemolytic Streptococcus varied in different infections (77.4 89.1 %) and cities (50.0 100 %). Tedizolid, linezolid, vancomycin, daptomycin, tigecycline and penicillin were the most effective agents against b-haemolytic Streptococcus (100 % of isolates were susceptible). Tedizolid has been approved by the FDA after studies demonstrated that it was noninferior to linezolid for the treatment of acute bacterial skin and skin structure infections. In addition, an ongoing study investigates the potency, efficacy and safety of tedizolid in nosocomial pneumonia and secondary bacteraemia. The safety of tedizolid in special patient populations (e.g. elderly, adolescents, renally impaired and hepatic impairment) has also been evaluated in a series of phase 1 trials, which indicate that dose adjustments were not necessary on the basis of age or clearance organ function (Das et al., 2014). However, there are still a few limitations to this agent, such as cross-resistance to other antibiotics (e.g. b-lactams and glycopeptides), the limitation in maximum recommended time of treatment (up to 6 days), higher cost compared to vancomycin and the inadequately evaluated safety and efficacy in patients with neutropenia (neutrophil counts <1000 cells mm 3 ) (Douros et al., 2015; Zhanel et al., 2015). As this is the first multi-centre surveillance network of tedizolid in Mainland China, we paid close attention to the efficacy comparison of tedizolid and linezolid, the susceptible ratio of different pathogens to tedizolid and the susceptibility differences for organisms isolated from HAP, SSTI and BSI in different regions. The current study showed that, according to the respective MIC 90 s, tedizolid exhibited four- to eightfold greater in vitro activity than linezolid against surveyed Gram-positive cocci isolates, including linezolid-nonsusceptible pathogens. Tedizolid MICs showed no significant difference among different infection types. Thus, tedizolid may be an alternative to linezolid for the treatment of serious infections such as SSTI, HAP and BSI caused by Grampositive organisms. In the following study, we would do in vivo clinical trials and pay more attention to the safety of tedizolid in nosocomial infections in China. http://jmm.microbiologyresearch.org 1223
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