Please wait a minute...
Journal of Integrative Agriculture  2021, Vol. 20 Issue (7): 1921-1932    DOI: 10.1016/S2095-3119(20)63572-9
Special Issue: 动物医学合辑Veterninary Medicine
Animal Science · Veterinary Medicine Advanced Online Publication | Current Issue | Archive | Adv Search |
Susceptibility breakpoint for cefquinome against Escherichia coli and Staphylococcus aureus from pigs
ZHANG Hui-lin*, ZHAO Yi-yang*, ZHOU Zi-chong, DING Huan-zhong
Guangdong Key Laboratory for Veterinary Drug Development and Safety Evaluation, South China Agricultural University, Guangzhou 510000, P.R.China
Download:  PDF in ScienceDirect  
Export:  BibTeX | EndNote (RIS)      

头孢喹肟是动物专用的第四代头孢菌素类药物,对大肠杆菌和金黄色葡萄球菌均有较好的作用效果。本研究旨在建立头孢喹肟对大肠杆菌和金黄色葡萄球菌的野生型折点(wild-type cut-off, COWT)和药动/药效学折点(pharmacokinetic/pharmacodynamic, COPD),以期为临床细菌耐药性监测提供数据指导。采用微量肉汤稀释法测定2014至2018年期间广东省分离的210株猪源大肠杆菌和160株猪源金黄色葡萄球菌对头孢喹肟的最低抑菌浓度(minimum inhibitory concentration, MIC),结果表明头孢喹肟对大肠杆菌的MIC50(能抑制50%细菌生长的最低药物浓度和MIC90(能抑制90%细菌生长的最低药物浓度)分别是0.06 μg mL-1和0.25 μg mL-1;对金黄色葡萄球菌的MIC50和MIC90分别是0.5 μg mL-1 和1 μg mL-1。统计学分析方法和ECOFFinder程序计算结果表明头孢喹肟对大肠杆菌和金黄色葡萄球菌的野生型折点分别为0.125 μg mL-1和2 μg mL-1。大肠杆菌和金黄色葡萄球菌对头孢喹肟的耐药率分别为11.9%和6.25%。基于5000次循环的蒙特卡洛计算结果显示在临床推荐给药剂量下(2 mg kg-1,每天给药2次,连续给药3天),头孢喹肟对大肠杆菌和金黄色葡萄球菌的药动/药效学折点值均为0.25 µg mL-1,表明在当前推荐剂量下可对MIC ≤ 0.25 μg mL-1的大肠杆菌和金黄色葡萄球菌实现90%以上的有效治疗。当前的给药方案对金黄色葡萄球菌引起的感染不能取得理想的治疗效果,将头孢喹肟给药剂量调整为4.5 mg kg-1时,能对MIC90 = 1 μg mL-1的金黄色葡萄球菌引起的感染实现90%以上的有效治疗。本研究对于临床上头孢喹肟对猪源大肠杆菌和金黄色葡萄球菌的耐药性监测和用药指导有重要意义。

Cefquinome is the only fourth-generation cephalosporin used solely for veterinary applications.  In this study, we established the wild-type cut-off (COWT) and pharmacokinetic/pharmacodynamic cut-off (COPD) of cefquinome against Escherichia coli and Staphylococcus aureus.  A total of 210 E. coli and 160 S. aureus isolates were collected from pigs in Guangdong Province between 2014 and 2018.  The minimum inhibitory concentrations (MICs) were determined using a microdilution broth method.  MIC50 and MIC90 were 0.06 and 0.25 μg mL–1 for E. coli and 0.5 and 1 μg mL–1 for S. aureus, respectively.  Statistical analysis and the ECOFFinder Program showed that the COWT for cefquinome against E. coli and S. aureus were 0.125 and 2 µg mL–1, respectively.  The resistance rates were 11.9% for E. coli and 6.25% for S. aureus.  Based on a 5 000-subject Monte Carlo simulation, the COPD value for cefquinome against E. coil and S. aureus was 0.25 µg mL–1 under the recommended dose (2 mg kg–1, twice a day for 3 days), confirming that infections caused by strains with MIC≤0.25 μg mL–1 could be effectively treated.  Following adjustment of the dosing regimen to 4.5 mg kg–1, effective treatment (>90) was achieved for S. aureus infections with MIC90 1 μg mL–1.  This susceptibility breakpoint determination is significant for resistant surveillance and cefquinome dosage guidance against E. coli and S. aureus in pigs.
Keywords:  cefquinome        Escherichia coli        Staphylococcus aureus        COWT        COPD  
Received: 15 July 2020   Accepted:
Fund: This work was supported by the National Natural Science Foundation of China (31972733).
Corresponding Authors:  Correspondence DING Huan-zhong, Tel/Fax: +86-20-85282562, E-mail:   
About author:  ZHANG Hui-lin, E-mail:; * These authors contributed equally to this study.

Cite this article: 

ZHANG Hui-lin, ZHAO Yi-yang, ZHOU Zi-chong, DING Huan-zhong. 2021. Susceptibility breakpoint for cefquinome against Escherichia coli and Staphylococcus aureus from pigs. Journal of Integrative Agriculture, 20(7): 1921-1932.

Ahmad I, Hao H, Huang L, Sanders P, Wang X, Chen D, Tao Y, Xie S, Xiuhua K, Li J, Dan W, Yuan Z. 2015. Integration of PK/PD for dose optimization of cefquinome against Staphylococcus aureus causing septicemia in cattle. Frontiers in Microbiology, 6, 588.
Alejandro H M, Matias L A, Javier L N, del Pilar Z M, Soledad A M, Julio D J. 2017. Pharmacokinetic/pharmacodynamic analysis by monte carlo simulation of cefquinome in llamas, following intravenous, intramuscular and subcutaneous administration in serum and tissue cage fluid. Small Ruminant Research, 149, 134–140.
Ambrose P G, Grasela D M. 2000. The use of Monte Carlo simulation to examine pharmacodynamic variance of drugs: fluoroquinolone pharmacodynamics against Streptococcus pneumoniae. Diagnostic Microbiology and Infectious Disease, 38, 151–157.
Ambrose P G, Quintiliani R. 2000. Limitations of single point pharmacodynamic analysis. The Pediatric Infectious Disease Journal, 19, 769.
Barton M D. 2014. Impact of antibiotic use in the swine industry. Current Opinion in Microbiology, 19, 9–15.
Belanger L, Garenaux A, Harel J, Boulianne M, Nadeau E, Dozois C M. 2011. Escherichia coli from animal reservoirs as a potential source of human extraintestinal pathogenic E. coli. FEMS Immunology and Medical Microbiology, 62, 1–10.
De la Calle C, Morata L, Cobos-Trigueros N, Martinez J A, Cardozo C, Mensa J, Soriano A. 2016. Staphylococcus aureus bacteremic pneumonia. European Journal of Clinical Microbiology and Infectious Diseases, 35, 497–502.
Canton E, Peman J, Hervas D, Iniguez C, Navarro D, Echeverria J, Martinez-Alarcon J, Fontanals D, Gomila-Sard B, Buendia B, Torroba L, Ayats J, Bratos A, Sanchez-Reus F, Fernandez-Natal I. 2012. Comparison of three statistical methods for establishing tentative wild-type population and epidemiological cut off values for echinocandins, amphotericin B, flucytosine, and six Candida species as determined by the colorimetric Sensititre YeastOne method. Journal of Clinical Microbiology, 50, 3921–3926.
Chan L C, Gilbert A, Basuino L, da Costa T M, Hamilton S M, Dos Santos K R, Chambers H F, Chatterjee S S. 2016. PBP4 mediates high-level resistance to new-generation cephalosporins in Staphylococcus aureus. Antimicrobial Agents and Chemotherapy, 60, 3934–3941.
Chin N X, Gu J W, Fang W, Neu H C. 1992. In vitro activity of cefquinome, a new cephalosporin, compared with other cephalosporin antibiotics. Diagnostic Microbiology and Infectious, 15, 331–337.
Christiansen J G, Jensen H E, Johansen L K, Koch J, Koch J, Aalbaek B, Nielsen O L, Leifsson P S. 2013. Porcine models of non-bacterial thrombotic endocarditis (NBTE) and infective endocarditis (IE) caused by Staphylococcus aureus: A preliminary study. The Journal of Heart Valve Disease, 22, 368–376.
CLSI (Clinical and Laboratory Standards Institute). 2016. Performance Standards for Antimicrobial Susceptibility Testing. Twenty-Sixth Informational Supplement. Clinical and Laboratory Standards Institute Document M100-S26. Clinical and Laboratory Standards Institute, Wayne, PA.
CVMP (Committee for Veterinary Medical Products). 1999. Cefquinome (Extension to Pigs). Summary Report (2). EMEA/MRL/545/99-FINAL. European Agency for the Evaluation of Medicinal Products, London, UK.
DeRyke C A, Banevicius, M A, Fan H W, Nicolau D P. 2007. Bactericidal activities of meropenem and ertapenem against extended-spectrum-beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae in a neutropenic mouse thigh model. Antimicrobial Agents and Chemotherapy, 51, 1481–1486.
Gu M, Zhang N, Zhang L, Xiong M, Yang Y, Gu X, Shen X, Ding H. 2015. Response of a clinical Escherichia coli strain to repeated cefquinome exposure in a piglet tissue-cage model. BMC Veterinary Research, 11, 169.
Hao H, Pan H, Ahmad I, Cheng G, Wang Y, Dai M, Tao Y, Chen D, Peng D, Liu Z, Huang L, Yuan Z. 2013. Susceptibility breakpoint for enrofloxacin against swine Salmonella spp. Journal of Clinical Microbiology, 51, 3070–3072.
Huse H K, Miller S A, Chandrasekaran S, Hindler J A, Lawhon S D, Bemis D A, Westblade L F, Humphries R M. 2018. Evaluation of oxacillin and cefoxitin disk diffusion and MIC breakpoints established by the Clinical and Laboratory Standards Institute for detection of mecA-mediated oxacillin resistance in Staphylococcus schleiferi. Journal of Clinical Microbiology, 56, e01653-17.
Johnson J R, Russo T A. 2005. Molecular epidemiology of extraintestinal pathogenic (uropathogenic) Escherichia coli. International Journal of Medical Microbiology, 295, 383–404.
Kahlmeter G, Brown D F, Goldstein F W, MacGowan A P, Mouton J W, Osterlund A, Rodloff A, Steinbakk M, Urbaskova P, Vatopoulos A. 2003. European harmonization of MIC breakpoints for antimicrobial susceptibility testing of bacteria. The Journal of Antimicrobial Chemotherapy, 52, 145–148.
Li X S, Liu B G, Dong P, Li F L, Yuan L, Hu G Z. 2018. The prevalence of mcr-1 and resistance characteristics of Escherichia coli isolates from diseased and healthy pigs. Diagnostic Microbiology and Infectious Disease, 91, 63–65.
Limbert M, Isert D, Klesel N, Markus A, Seeger K, Seibert G, Schrinner E. 1991. Antibacterial activities in vitro and in vivo and pharmacokinetics of cefquinome (HR 111V), a new broad-spectrum cephalosporin. Antimicrobial Agents and Chemotherapy, 35, 14–19.
Lowy F D. 1998. Staphylococcus aureus infections. The New England Journal of Medicine, 339, 520–532.
Luppi A, Bonilauri P, Dottori M, Gherpelli Y, Biasi G, Merialdi G, Maioli G, Martelli P. 2015. Antimicrobial resistance of F4+ Escherichia coli isolated from swine in Italy. Transboundary and Emerging Diseases, 62, 67–71.
Maglio D, Kuti J L, Nicolau D P. 2005. Simulation of antibiotic pharmacodynamic exposure for the empiric treatment of nosocomial bloodstream infections: A report from the OPTAMA program. Clinical Therapeutics, 27, 1032–1042.
Nesta B, Pizza M. 2018. Vaccines against Escherichia coli. Current Topics in Microbiology and Immunology, 416, 213–242.
Perez-Trallero E, Marimon J M, Gonzalez A, Vicente D, Garcia-Arenzana J M. 2004. Spectrum of antibiotic resistance of the Spain14-5 Streptococcus pneumoniae clone over a 22 year period. The Journal of Antimicrobial Chemotherapy, 53, 620–625.
Sabath L D. 1982. Mechanisms of resistance to beta-lactam antibiotics in strains of Staphylococcus aureus. Annals of Internal Medicine, 97, 339–344.
Shan Q, Wang J. 2017. Activity of cefquinome against extended-spectrum beta-lactamase-producing Klebsiella pneumoniae in neutropenic mouse thigh model. Journal of Veterinary Pharmacology and Therapeutics, 40, 392–397.
Sheldon I M, Bushnell M, Montgomery J, Rycroft A N. 2004. Minimum inhibitory concentrations of some antimicrobial drugs against bacteria causing uterine infections in cattle. The Veterinary Record, 155, 383–387.
Sun J, Xiao X, Huang R J, Yang T, Chen Y, Fang X, Huang T, Zhou Y F, Liu Y H. 2015. In vitro dynamic pharmacokinetic/pharmacodynamic (PK/PD) study and COPD of marbofloxacin against Haemophilus parasuis. BMC Veterinary Research, 11, 293.
Tan C, Tang X, Zhang X, Ding Y, Zhao Z, Wu B, Cai X, Liu Z, He Q, Chen H. 2012. Serotypes and virulence genes of extraintestinal pathogenic Escherichia coli isolates from diseased pigs in China. Veterinary Journal, 192, 483–488.
Tian Y, Sun W, Bian Q, Liu Y, Cheng Q, Wang P, Liu Y. 2016. Application of new ƒ%T>MIC calculation method in determination of PK/PD cut-off. Chinese Journal of Antibiotics, 41, 305–308. (in Chinese)
Turnidge J, Kahlmeter G, Kronvall G. 2006. Statistical characterisation of bacterial wild-type MIC value distributions and the determination of epidemiological cut-off values. Clinical Microbiology and Infection, 12, 418–425.
Turnidge J, Paterson D L. 2007. Setting and revising antibacterial susceptibility breakpoints. Clinical Microbiology Reviews, 20, 391–408.
VanderWaal K, Deen J. 2018. Global trends in infectious diseases of swine. Proceedings of the National Academy of Sciences of the United States of America, 115, 11495–11500.
Wang J, Shan Q, Ding H, Liang C, Zeng Z. 2014. Pharmacodynamics of cefquinome in a neutropenic mouse thigh model of Staphylococcus aureus infection. Antimicrobial Agents and Chemotherapy, 58, 3008–3012.
Wisselink H J, Veldman K T, Van den Eede C, Salmon S A, Mevius D J. 2006. Quantitative susceptibility of Streptococcus suis strains isolated from diseased pigs in seven European countries to antimicrobial agents licensed in veterinary medicine. Veterinary Microbiology, 113, 73–82.
Xiong M, Wu X, Ye X, Zhang L, Zeng S, Huang Z, Wu Y, Sun J, Ding H. 2016. Relationship between cefquinome PK/PD parameters and emergence of resistance of staphylococcus aureus in rabbit tissue-cage infection model. Frontiers in Microbiology, 7, 874.
Yang Y, Zhang Y, Li J, Cheng P, Xiao T, Muhammad I, Yu H, Liu R, Zhang X. 2019. Susceptibility breakpoint for danofloxacin against swine Escherichia coli. BMC Veterinary Research, 15, 51.
Zhang J, Sun W, Lu L, Zhu J, Tang J, Tian Y, Cheng Q. 2017 PK/PD cut-off calculation method for sequential administration of time-dependent antibiotics. Chinese Journal of Antibiotics, 42, 435–440. (in Chinese)
Zhang L, Wu X, Huang Z, Kang Z, Chen Y, Shen X, Cai Q, Ding H. 2019. Pharmacokinetic/pharmacodynamic integration of cefquinome against Pasteurella Multocida in a piglet tissue cage model. Journal of Veterinary Pharmacology and Therapeutics, 42, 60–66.
Zhang L, Wu X, Huang Z, Zhang N, Wu Y, Cai Q, Shen X, Ding H. 2018. Pharmacokinetic/pharmacodynamic assessment of cefquinome against Actinobacillus pleuropneumoniae  in a piglet tissue cage infection model. Veterinary Microbiology, 219, 100–106.
Zhang P, Hao H, Li J, Ahmad I, Cheng G, Chen D, Tao Y, Huang L, Wang Y, Dai M, Liu Z, Yuan Z. 2016. The epidemiologic and pharmacodynamic cutoff values of tilmicosin against Haemophilus parasuis. Frontiers in Microbiology, 7, 385.
Zhang W, Zhao M, Ruesch L, Omot A, Francis D. 2007. Prevalence of virulence genes in Escherichia coli strains recently isolated from young pigs with diarrhea in the US. Veterinary Microbiology, 123, 145–152.
Zhao D H, Wang X F, Wang Q, Li L D. 2017. Pharmacokinetics, bioavailability and dose assessment of cefquinome against Escherichia coli in black swans (Cygnus atratus). BMC Veterinary Research, 13, 226.
[1] DAI Chao-hui, CAO Yue, GAO Zhong-cheng, ZHU Guo-qiang, WU Sheng-long, BAO Wen-bin. The tissue expression level of BPI gene in piglets from newborn to weaning and its relationship with Gram-negative bacterial infection[J]. >Journal of Integrative Agriculture, 2020, 19(12): 3065-3073.
[2] YANG Feng, ZHANG Shi-dong, SHANG Xiao-fei, WANG Xu-rong, WANG Ling, YAN Zuo-ting, LI Hong-sheng. Prevalence and characteristics of extended spectrum β-lactamaseproducing Escherichia coli from bovine mastitis cases in China[J]. >Journal of Integrative Agriculture, 2018, 17(06): 1246-1251.
[3] WEN Jie, LI Jiu-sheng, LI Yan-feng. Wetting patterns and bacterial distributions in different soils from a surface point source applying effluents with varying Escherichia coli concentrations[J]. >Journal of Integrative Agriculture, 2016, 15(7): 1625-1637.
[4] YANG Feng, WANG Qi, WANG Xu-rong, WANG Ling, LI Xin-pu, LUO Jin-yin, ZHANG Shi-dong, LI Hong-sheng. Genetic characterization of antimicrobial resistance in Staphylococcus aureus isolated from bovine mastitis cases in Northwest China[J]. >Journal of Integrative Agriculture, 2016, 15(12): 2842-2847.
[5] LI Ya-fei, WANG Lin, GU Xiao-yan, ZENG Zhen-ling, HE Li-min, YANG Fan, YUAN Bo, SHU Jianhua , DING Huan-zhong. Pharmacokinetics and Residues of Cefquinome in Milk of Lactating Chinese Dairy Cows After Intramammary Administration[J]. >Journal of Integrative Agriculture, 2014, 13(12): 2750-2757.
No Suggested Reading articles found!