The in vitro activities of ceftaroline and tedizolid were compared against Staphylococcus aureus, Enterococcus faecalis, and Enterococcus faecium clinical isolates collected from the China Antimicrobial Surveillance Network. Ceftaroline demonstrated potent activity against S. aureus isolates (MIC50/90, ≤0.25/1 mg/liter). Tedizolid was also highly active against S. aureus (MIC50/90, 0.
KEYWORDS: ceftaroline, tedizolid, antimicrobial susceptibility testing, Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium
ABSTRACT
The in vitro activities of ceftaroline and tedizolid were compared against Staphylococcus aureus, Enterococcus faecalis, and Enterococcus faecium clinical isolates collected from the China Antimicrobial Surveillance Network. Ceftaroline demonstrated potent activity against S. aureus isolates (MIC50/90, ≤0.25/1 mg/liter). Tedizolid was also highly active against S. aureus (MIC50/90, 0.25/0.5 mg/liter) and Enterococcus (MIC50/90, 0.5/0.5 mg/liter) isolates. Our results support the clinical usefulness of ceftaroline and tedizolid in treating Gram-positive infections.
TEXT
Staphylococcus aureus and Enterococcus spp. represent the major Gram-positive pathogens causing bacteremia, infective endocarditis, and pneumonia, as well as bloodstream, skin and soft tissue, and urinary tract infections (1). According to data from the China Antimicrobial Surveillance Network (CHINET) (2), S. aureus accounted for 9.3% (23,323/249,758) of all clinical isolates, while Enterococcus faecalis and Enterococcus faecium accounted for 3.1% (7,676/249,758) and 4.2% (10,413/249,758), respectively. Ceftaroline, a novel broad-spectrum β-lactam cephalosporin, was approved in 2010 by the U.S. Food and Drug Administration (FDA) for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (3) due to its activity against methicillin-resistant S. aureus (MRSA). Tedizolid is an oxazolidinone antibacterial agent. In 2014, tedizolid was approved in the United States for the treatment of ABSSSI caused by susceptible strains of S. aureus, Streptococcus, and E. faecalis (4). Currently, the antimicrobial activity and spectrum of ceftaroline and tedizolid have not been studied extensively with clinical strains in China. Here, we compared the in vitro activities of ceftaroline, tedizolid, and other comparators against a large panel of clinical isolates with the purpose to support the clinical use of ceftaroline and tedizolid.
A total of 2,058 nonduplicate clinical isolates of S. aureus (n = 1,191), E. faecalis (n = 417), and E. faecium (n = 450) were collected from 44 hospitals in 26 provinces or cities across China in 2018, as part of CHINET. S. aureus ATCC 29213 and E. faecalis ATCC 29212 isolates were used as quality controls for antimicrobial susceptibility testing. MICs were determined by the reference broth microdilution method as recommended by the Clinical and Laboratory Standards Institute (CLSI) (5). The results were interpreted according to 2019 CLSI breakpoints for all the agents tested with the exception of tigecycline, for which CLSI criteria were not available (6). Tigecycline MICs were interpreted by FDA breakpoints for S. aureus (susceptible, ≤0.5 mg/liter) and E. faecalis (susceptible, ≤0.25 mg/liter) (7).
Ceftaroline inhibited 99.2% of the S. aureus strains at a concentration of 1 mg/liter (breakpoint for susceptibility), showing excellent activity against MRSA (MIC50/90, 0.5/1 mg/liter) and methicillin-susceptible S. aureus (MSSA) (MIC50/90, 0.25/0.5 mg/liter) strains (Table 1). Tedizolid inhibited 100% of the S. aureus strains at a concentration of 0.5 mg/liter (MIC50/90, 0.25/0.5 mg/liter). Nine (0.8%) strains of S. aureus were susceptible-dose dependent to ceftaroline (MIC, 2 to 4 mg/liter) (Table 1). Tedizolid was highly active (MIC50/90, 0.5/0.5 mg/liter) against Enterococcus isolates by inhibiting 100% of the 867 strains at a concentration of 2 mg/liter (Table 1).
TABLE 1.
MIC frequency distribution of ceftaroline and tedizolid against S. aureus, E. faecalis, and E. faecium
| Organisma | Antimicrobial agent | No. (cumulative %) of isolates at MIC (mg/liter) of: |
|||||
|---|---|---|---|---|---|---|---|
| 0.125 | 0.25 | 0.5 | 1 | 2 | 4 | ||
| S. aureus (n = 1,191) | Ceftaroline | 716 (60.1) | 299 (85.2) | 167 (99.2) | 8 (99.9) | 1 (100.0) | |
| Tedizolid | 22 (1.8) | 834 (71.9) | 335 (100) | ||||
| MRSA (n = 411) | Ceftaroline | 25 (6.1) | 225 (60.8) | 152 (97.8) | 8 (99.8) | 1 (100.0) | |
| Tedizolid | 9 (2.2) | 299 (74.9) | 103 (100.0) | ||||
| MSSA (n = 780) | Ceftaroline | 691 (88.6) | 74 (98.1) | 15 (100.0) | |||
| Tedizolid | 13 (1.7) | 535 (70.3) | 232 (100.0) | ||||
| Enterococcus spp. (n = 867) | Tedizolid | 5 (0.6) | 208 (24.6) | 623 (96.4) | 30 (99.9) | 1 (100.0) | |
| E. faecalis (n = 417) | Tedizolid | 4 (1.0) | 105 (26.1) | 283(94.0) | 25 (100.0) | ||
| E. faecium (n = 450) | Tedizolid | 1 (0.2) | 103 (23.1) | 340 (98.7) | 5 (99.8) | 1 (100.0) | |
MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-susceptible Staphylococcus aureus.
Overall, 99.2%, 100%, and 100% of the S. aureus strains tested were susceptible to ceftaroline, tedizolid, and linezolid, respectively, but had relatively lower susceptibility to the comparators erythromycin (31.7%), clindamycin (58.3%), gentamicin (77.8%), and levofloxacin (77.7%). In terms of susceptibility rates, vancomycin (100%), tedizolid (100%), linezolid (100%), tigecycline (98.2), and trimethoprim-sulfamethoxazole (95.6%) were similar to ceftaroline. Tedizolid and ceftaroline inhibited 100% and 97.8% of the MRSA isolates, respectively, which was much higher than erythromycin, clindamycin, gentamicin, and levofloxacin (14.1% to 67.2%). All MSSA strains were susceptible to ceftaroline, tedizolid, linezolid, tigecycline, and vancomycin and better than any other antibiotic tested (Table 2).
TABLE 2.
Activities of ceftaroline, tedizolid, and comparators against clinical isolates
| Organisma | Antimicrobial agent | MIC (mg/liter) |
Susceptibility (%)b
|
|||
|---|---|---|---|---|---|---|
| Range | 50% | 90% | Susceptible | Resistant | ||
| S. aureus (n = 1,191) | Ceftaroline | ≤0.25 to 4 | ≤0.25 | 1 | 99.2 | 0.8c |
| Tedizolid | 0.125 to 0.5 | 0.25 | 0.5 | 100 | 0 | |
| Linezolid | 0.5 to 4 | 2 | 2 | 100 | 0 | |
| Erythromycin | ≤0.5 to >16 | >16 | >16 | 31.7 | 66.1 | |
| Clindamycin | ≤0.5 to >16 | ≤0.5 | >16 | 58.3 | 40.2 | |
| Gentamicin | ≤1 to >32 | ≤1 | 32 | 77.8 | 20.3 | |
| Levofloxacin | ≤0.25 to >32 | ≤0.25 | 32 | 77.7 | 21.2 | |
| Trimethoprim-sulfamethoxazole | ≤0.25 to >8 | ≤0.25 | 1 | 95.6 | 4.4 | |
| Tigecycline | ≤0.06 to 2 | 0.125 | 0.25 | 98.2 | 0 | |
| Vancomycin | ≤0.12 to 2 | 1 | 1 | 100 | 0 | |
| MRSA (n = 411) | Ceftaroline | ≤0.25 to 4 | 0.5 | 1 | 97.8 | 2.2c |
| Tedizolid | 0.125 to 0.5 | 0.25 | 0.5 | 100 | 0 | |
| Linezolid | 0.5 to 4 | 2 | 2 | 100 | 0 | |
| Erythromycin | ≤0.5 to >16 | >16 | >16 | 14.1 | 83.5 | |
| Clindamycin | ≤0.5 to >16 | >16 | >16 | 34.3 | 63.5 | |
| Gentamicin | ≤1 to >32 | ≤1 | >32 | 67.2 | 31.6 | |
| Levofloxacin | ≤0.25 to >32 | 0.5 | >32 | 59.1 | 40.1 | |
| Trimethoprim-sulfamethoxazole | ≤0.25 to >8 | ≤0.25 | 0.5 | 97.6 | 2.5 | |
| Tigecycline | ≤0.06 to 2 | 0.125 | 0.5 | 94.6 | 0 | |
| Vancomycin | ≤0.12 to 2 | 1 | 1 | 100 | 0 | |
| MSSA (n = 780) | Ceftaroline | ≤0.25 to 1 | ≤0.25 | 0.5 | 100 | 0 |
| Tedizolid | 0.125 to 0.5 | 0.25 | 0.5 | 100 | 0 | |
| Linezolid | 0.5 to 4 | 2 | 2 | 100 | 0 | |
| Erythromycin | ≤0.5 to >16 | >16 | >16 | 41 | 56.9 | |
| Clindamycin | ≤0.5 to >16 | ≤0.5 | 32 | 70.9 | 27.9 | |
| Gentamicin | ≤1 to >32 | ≤1 | 16 | 83.5 | 14.4 | |
| Levofloxacin | ≤0.25 to >32 | ≤0.25 | 4 | 87.6 | 11.3 | |
| Trimethoprim-sulfamethoxazole | ≤0.25 to >8 | ≤0.25 | 1 | 94.6 | 5.4 | |
| Tigecycline | ≤0.06 to 0.5 | 0.125 | 0.25 | 100 | 0 | |
| Vancomycin | ≤0.12 to 2 | 1 | 1 | 100 | 0 | |
| Enterococcus spp. (n = 867) | Tedizolid | 0.125 to 2 | 0.5 | 0.5 | 96.4 | 3.6c |
| Linezolid | ≤0.06 to >8 | 2 | 2 | 95.5 | 3.8 | |
| Ampicillin | ≤1 to >64 | 4 | >64 | 51.6 | 48.4 | |
| Nitrofurantoin | 2 to >256 | 32 | 256 | 54.2 | 28.4 | |
| Levofloxacin | ≤0.25 to >32 | 32 | >32 | 34.5 | 62.6 | |
| Erythromycin | ≤0.5 to >16 | >16 | >16 | 5.2 | 79.8 | |
| Tigecycline | ≤0.06 to 2 | 0.125 | 0.25 | 99.1 | 0 | |
| Vancomycin | ≤0.12 to >8 | 1 | 2 | 97.1 | 0 | |
| E. faecalis (n = 417) | Tedizolid | 0.125 to 1 | 0.5 | 0.5 | 94.0 | 6.0c |
| Linezolid | ≤0.06 to 8 | 2 | 2 | 92.1 | 6.5 | |
| Ampicillin | ≤1 to >64 | ≤1 | 2 | 98.1 | 1.9 | |
| Nitrofurantoin | 2 to 128 | 8 | 16 | 98.8 | 0.5 | |
| Levofloxacin | ≤0.25 to >32 | 2 | 32 | 64 | 34.3 | |
| Erythromycin | ≤0.5 to >16 | >16 | >16 | 5.3 | 72.2 | |
| Tigecycline | ≤0.06 to 0.25 | ≤0.06 | 0.125 | 100 | 0 | |
| Vancomycin | ≤0.12 to >8 | 1 | 2 | 99.8 | 0 | |
| E. faecium (n = 450) | Tedizolid | 0.125 to 2 | 0.5 | 0.5 | 98.7 | 1.3c |
| Linezolid | 0.5 to >8 | 2 | 2 | 98.7 | 1.3 | |
| Ampicillin | ≤1 to >64 | >64 | >64 | 8.4 | 91.6 | |
| Nitrofurantoin | 8 to >256 | 128 | 256 | 12.9 | 54.2 | |
| Levofloxacin | 0.5 to >32 | >32 | >32 | 7.1 | 88.9 | |
| Erythromycin | ≤0.5 to >16 | >16 | >16 | 5.1 | 86.9 | |
| Tigecycline | ≤0.06 to 2 | 0.125 | 0.25 | 98.2 | 0 | |
| Vancomycin | 0.25 to >8 | 1 | 2 | 94.7 | 0 | |
MRSA, methicillin-resistant S. aureus; MSSA, methicillin-susceptible S. aureus.
Tedizolid breakpoints for Staphylococcus spp.: susceptible, ≤0.5 mg/liter; intermediate, 1 mg/liter; resistant, ≥2 mg/liter; for Enterococcus spp.: susceptible, ≤0.5 mg/liter. Ceftaroline breakpoints for S. aureus: susceptible, ≤1 mg/liter; susceptible-dose dependent, 2 to 4 mg/liter; resistant, ≥8 mg/liter. Linezolid breakpoints for S. aureus: susceptible, ≤4 mg/liter; resistant, ≥8 mg/liter; for Enterococcus spp.: susceptible, ≤2 mg/liter; intermediate, 4 mg/liter; resistant, ≥8 mg/liter.
Nonsusceptible.
Tedizolid inhibited most of the Enterococcus strains, similar to linezolid, tigecycline, and vancomycin (95.5% to 99.1%) and better than all of the other antibiotics tested. More E. faecalis strains than E. faecium strains were susceptible to ampicillin (98.1% versus 8.4%), nitrofurantoin (98.8% versus 12.9%), levofloxacin (64% versus 7.1%), tigecycline (100% versus 98.2%), and vancomycin (99.8% versus 94.7%) (Table 2).
Gram-positive pathogens develop resistance to virtually all antimicrobials currently available in clinical practice because of an immense pool of resistant genes (8). Data from the CHINET program showed that S. aureus and Enterococcus strains were the most frequently isolated Gram-positive pathogens (2, 9, 10).
Sader et al. (11) reported the activity of ceftaroline against 21,056 clinical strains of S. aureus isolated from 42 medical centers in the United States, showing MIC50/90 values of 0.25/0.25 mg/liter against MSSA (100% susceptible) and 0.5/1 mg/liter against MRSA (97.2% susceptible). This is consistent with our results (modal MIC, 0.25 mg/liter). Andrey et al. (12) reported that 24% of the strains were resistant to ceftaroline (MIC, ≥2 mg/liter) according to EUCAST breakpoints. We found a much lower incidence (0.8%, 9/1,191) of ceftaroline-nonsusceptible S. aureus (MIC, 2 to 4 mg/liter). The percentage of ceftaroline resistance should be interpreted cautiously because the collection of clinical strains and the breakpoints are different.
The MIC values of tedizolid in our study were similar to those in previous reports, e.g., MIC50/90 values of 0.25/0.5 mg/liter against 1,839 strains of MRSA collected from the Asia Pacific region (13). Most (96.4%) of the Enterococcus isolates were susceptible to tedizolid, with a modal MIC of 0.5 mg/liter, which was 4- to 8-fold lower than that of linezolid. In this study, we found that 3.6% of Enterococcus strains were nonsusceptible to tedizolid (MIC, 1 to 2 mg/liter), and all of these strains were not susceptible to linezolid (data not shown).
In summary, ceftaroline and tedizolid have demonstrated good activity against clinical isolates of Gram-positive organisms in our surveillance program. Both drugs have shown promise for treatment of Gram-positive pathogens.
ACKNOWLEDGMENTS
We gratefully acknowledge the contribution of the members of CHINET for collection of the isolates in this study: Yingchun Xu and Xiaojiang Zhang from Peking Union Medical College Hospital; Zhaoxia Zhang and Ping Ji from the First Affiliated Hospital of Xinjiang Medical University; Mei Kang and Chao He from West China Hospital, Sichuan University; Chuanqing Wang and Leiyan He from Children’s Hospital of Fudan University; Yuanhong Xu and Ying Huang from the First Affiliated Hospital of Anhui Medical University; Zhongju Chen and Ziyong Sun from Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology; Yuxing Ni and Jingyong Sun from Ruijin Hospital, Shanghai Jiaotong University School of Medicine; Yunzhuo Chu and Sufei Tian from the First Affiliated Hospital of China Medical University; Zhidong Hu and Jin Li from Tianjin Medical University General Hospital; Yunsong Yu and Jie Lin from Sir Run Run Shaw Hospital, Zhejiang University School of Medicine; Bin Shan and Yan Du from the First Affiliated Hospital of Kunming Medical University; Sufang Guo and Yanyan Wang from the First Affiliated Hospital of Inner Mongolia Medical University; Lianhua Wei and Xin Wang from Gansu Provincial Hospital; Hong Zhang and Chun Wang from Children’s Hospital of Shanghai; Yunjian Hu and Xiaoman Ai from Beijing Hospital; Chao Zhuo and Danhong Su from the First Affiliated Hospital of Guangzhou Medical University; Ruizhong Wang and Hua Fang from Pudong New Area People’s Hospital; Bixia Yu from Zhejiang Ningbo Zhenhai Longsai Hospital; Ping Gong and Miao Song from the People’s Hospital of Zigui, Hubei Province; Dawen Guo and Jinying Zhao from the First Affiliated Hospital of Harbin Medical University; Wen’en Liu and Yanming Li from Xiangya Hospital, Central South University; Yan Jin and Yueling Wang from Shandong Provincial Hospital; Kaizhen Weng and Yirong Zhang from Jinjiang Municipal Hospital; Xuesong Xu and Chao Yan from China-Japan Union Hospital, Jilin University; Xiangning Huang and Hua Yu from Sichuan Provincial People’s Hospital; Yi Li and Shanmei Wang from Henan Provincial People’s Hospital; Lixia Zhang and Juan Ma from Shaanxi Provincial People’s Hospital; Shuping Zhou and Jiangwei Ke from Jiangxi Provincial Children’s Hospital; Lei Zhu and Jinhua Meng from Children’s Hospital of Shanxi; Wenqi Song and Fang Dong from Beijing Children’s Hospital, Capital Medical University; Han Shen and Wanqing Zhou from Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing; Gang Li and Wei Jia from General Hospital of Ningxia Medical University; Jinsong Wu and Yuemei Lu from Shenzhen People’s Hospital; Jihong Li from the Second Hospital of Hebei Medical University; Jiangshan Liu from Jinchang Hospital of integrated traditional Chinese and Western Medicine; Longfeng Liao from the People’s Hospital of Ganxian; Hongqin Gu from Guangrao County People's Hospital; Lin Jiang from the People’s Hospital of Huixian, Henan Province; Wen He from Central Hospital of Yingkou Development Zone, Liaoning Province; Shunhong Xue from Huzhu County People's Hospital, Qinghai Province; Jiao Feng from the People’s Hospital of Linshui, Sichuan Province; Rui Dou from Lixin County People's Hospital; and Chunlei Yue from Jiutai People's Hospital.
The study protocol was approved by the Institutional Review Board of Huashan Hospital, Fudan University (no. 2018-408).
This work was supported by National Mega-project for Innovative Drugs (2019ZX09721001-006-004), the National Natural Science Foundation of China (grant no. 81902100 to Y.G.), the Science and Technology Innovation Action Plan of Shanghai Science and Technology Committee (grant no. 17DZ1910403 to Y.G.), and China Antimicrobial Surveillance Network (grant no. WI207259).
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
We have no conflicts of interest to declare.
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