对动物饲料中禁用抗菌促生长剂的反思

doi:10.3864/j.issn.0578-1752.2015.03.18

摘要/Abstract

摘要： 欧盟国家对饲用抗菌促生长剂禁令的颁布引起了国际社会的广泛争议。文章综合动物源细菌耐药性监测数据和风险评估结果，对饲料中禁用抗菌促生长剂进行了反思，结果发现：（1）某些饲用抗菌促生长剂（如大环内酯类促生长剂泰乐菌素和链阳性菌素类促生长剂维吉尼亚霉素等）对人类健康的耐药性风险似乎被人为夸大，系统的风险评估结论认为，养殖动物中泰乐菌素等大环内酯类促生长剂的使用对人类弯曲杆菌耐药性的风险是可以忽略的，维吉尼亚霉素促生长剂的应用也几乎不会对人类肠球菌耐药性造成很大的风险；（2）“病原菌耐药性从农场到餐桌转移”的命题似乎缺乏科学证据，目前虽然有证据显示动物体耐药菌会直接传播给那些与动物密切接触的人群，但动物体耐药菌通过食物链环节传播给人的证据尚不充分；（3）禁用抗菌促生长剂并没有改变耐药模式，特别是禁用糖肽类阿伏帕星、氟喹诺酮类恩诺沙星和四环素类金霉素等促生长剂后，动物体和人体耐药菌数量仍然有增无减、持续上升，其原因可能归咎于万古霉素耐药屎肠球菌较强的传播特性和氟喹诺酮类耐药弯曲杆菌较强的适应性，而四环素类治疗用药的增加也必然增加肠道细菌的耐药性；（4）禁用抗菌促生长剂对动物养殖业带了一定的损失，比如，使产气荚膜梭菌引起的坏死性肠炎的发病率升高，使养殖动物治疗性抗生素的使用量增加，使养殖原料和场地相应增加等；（5）禁用抗菌促生长剂对动物源性食品安全和人类公共健康造成了一定的影响，比如，影响动物体肠道菌群发酵从而增加了有害气体的排放，提高了食品加工过程中的细菌污染几率从而增加了人体食源性病原菌的发病率。总而言之，决策的制定需要权衡利弊、因地因时制宜，综合考虑禁用抗菌促生长剂对耐药性风险的控制作用以及对动物养殖业和人类公共健康的影响。结合中国动物养殖业发展现状及全球动物性产品需要程度，需要开展深入的科学研究，寻找耐药性控制新措施；开展系统的风险评估，有的放矢地制定风险控制策略；加强政府监管力度，避免药物滥用，促进合理用药以延缓耐药性产生。

关键词: 动物饲料, 抗菌促生长剂, 禁用, 耐药性风险, 合理用药

Abstract: Withdrawal of antimicrobial growth promotants (AGPs) in animal feed issued by European Union (EU) countries caused widespread controversy in the international community. This paper comprehensively reviewed the antimicrobial resistance monitoring data from animal original bacteria and the risk assessment results of veterinary usage. After profoundly rethinking the ban of AGPs in animal feed, the results showed that (1) the risk of some AGPs (e.g. macrolide AGP of tylosin and streptogramin AGP of virginiamycin) seemed to be overstated. The risk of the usage of macrolide AGPs in food animals to emergence of macrolide resistant Campylobacter in human is negligible, and the use of virginiamycin as AGPs could hardly affect the treatment of human infections caused by Enterococcus; (2)There is a lack of scientific evidence for supporting the proposition of transmission of antimicrobial resistance from farm to dining table. Although there are some evidence that antimicrobial resistant bacteria could directly transmit from food animal to those persons who closely contacted with animals, there is no direct and sufficient evidents to support the transfer of antimicrobial resistant pathogens through food chain to persons; (3) Withdrawal of AGPs did not change the epidemiology of resistant pathogens, especially for the avoparcin in glycopeptides, enrofloxacin in fluoroquinolones and chlorotetracycline in tetracyclines. After ban of these three classes of AGPs, the number of resistant bacteria from both animal and human continued to increase. The reason may be attributed to the enhanced fitness of fluoroquinolone resistance in Campylobacter and the increase of the consumption of therapeutic tetracycline agents; (4) Withdrawal of the AGPs may brought a certain loss for the animal breeding industry. For example, it may increase the incidence of necrotizing enteritis caused by Clostridium, increase therapeutic use of antimicrobial agents in the farmed animals, and increase breeding materials and corresponding venues, etc.; (5) Withdrawal of the AGPs may cause a certain influence on animal food safety and human public health. For instance, it may affect the fermentation of animal intestinal flora and thereby increase the emissions of harmful gas. It may increase the chances of bacteria contamination during food processing and therefore increase the incidence of foodborne pathogens in human. Conclusively, the political decision must be developed based on the balance of pros and cons and the adjustment of spatial and temporal condition. It also need to comprehensively consider the function of withdrawal of AGPs on control of antimicrobial resistance and the influence of withdrawal of AGPs on the animal breeding industry and human public health. Face the development of animal breeding industry in China and the world food sustainable needs, it is necessary to conduct in-depth research and systemic risk assessment to find new and rational strategy to control resistance. It is also essential to strengthen the government supervision to avoid drug abuse and promote the rational use of antimicrobial agents in food animals.

Key words: animal feed, antimicrobial growth promotants, withdrawal, resistance risk, rational use of drugs

郝海红，程古月，戴梦红，王旭，王玉莲，黄玲利，刘振利，袁宗辉. 对动物饲料中禁用抗菌促生长剂的反思[J]. 中国农业科学, 2015, 48(3): 594-603.

HAO Hai-hong, CHENG Gu-yue, DAI Meng-hong, WANG Xu, WANG Yu-lian, HUANG Ling-li, LIU Zhen-li, YUAN Zong-hui. Rethinking the Withdrawal of Antimicrobial Growth Promotants in Animal Feed[J]. Scientia Agricultura Sinica, 2015, 48(3): 594-603.

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参考文献

[1] Dibner J J, Richards J D. Antibiotic growth promoters in agriculture: history and mode of action. Poultry Science, 2005, 84(4):634-643.

[2] Niewold T A. The nonantibiotic anti-inflammatory effect of antimicrobial growth promoters, the real mode of action? A hypothesis. Poultry Science, 2007, 86(4):605-609.

[3] Marshall B M, Levy S B. Food animals and antimicrobials: impacts on human health. Clinical Microbiology Reviews, 2011, 24(4): 718-733.

[4] FDV-CVM. Risk assessment of streptogramin resistance in enterococcus faecium attributable to the use of streptogramins in animals. “Virginiamycin Risk Assessment” In: Medicine FCfV, editor:http://www.fda.gov/downloads/animalveterinary/newsevents/cvmupdates/ucm054722.pd; 2004.

[5] Casewell M, Friis C, Marco E, McMullin P, Phillips I. The European ban on growth-promoting antibiotics and emerging consequences for human and animal health. The Journal of Antimicrobial Chemotherapy, 2003, 52(2):159-161.

[6] Phillips I, Casewell M, Cox T, De Groot B, Friis C, Jones R, Nightingale C, Preston R, Waddell J. Antibiotic use in animals. The Journal of Antimicrobial Chemotherapy, 2004, 53(5):885-886.

[7] Phillips I, Casewell M, Cox T, De Groot B, Friis C, Jones R, Nightingale C, Preston R, Waddell J. Does the use of antibiotics in food animals pose a risk to human health? A critical review of published data. The Journal of Antimicrobial Chemotherapy, 2004, 53(1):28-52.

[8] Turnidge J. Antibiotic use in animals--prejudices, perceptions and realities. The Journal of Antimicrobial Chemotherapy, 2004, 53(1): 26-27.

[9] Jones R N, Ballow C H, Biedenbach D J, Deinhart J A, Schentag J J. Antimicrobial activity of quinupristin-dalfopristin (RP 59500, Synercid) tested against over 28,000 recent clinical isolates from 200 medical centers in the United States and Canada. Diagnostic Microbiology and Infectious Disease, 1998, 31(3):437-451.

[10] McDonald L C, Yu H T, Yin H C, Hsiung C A, Hung C C, Ho M. Correlates of antibiotic use in Taiwan hospitals. Infect Control Hosp Epidemiol, 2001, 22(9):565-571.

[11] McDonald L C, Rossiter S, Mackinson C, Wang Y Y, Johnson S, Sullivan M, Sokolow R, DeBess E, Gilbert L, Benson J A, Hill B, Angulo F J. Quinupristin-dalfopristin-resistant Enterococcus faecium on chicken and in human stool specimens. The New England Journal of Medicine, 2001, 345(16):1155-1160.

[12] McDonald L C, Chen M T, Lauderdale T L, Ho M. The use of antibiotics critical to human medicine in food-producing animals in Taiwan. Journal of Microbiology, Immunology, and Infection, 2001, 34(2):97-102.

[13] Phillips G. Microbiological aspects of clinical waste. The Journal of Hospital Infection, 1999, 41(1):1-6.

[14] Sorensen T L, Blom M, Monnet D L, Frimodt-Moller N, Poulsen R L, Espersen F. Transient intestinal carriage after ingestion of antibiotic- resistant Enterococcus faecium from chicken and pork. The New England Journal of Medicine, 2001, 345(16):1161-1166.

[15] Hershberger E, Oprea S F, Donabedian S M, Perri M, Bozigar P, Bartlett P, Zervos M J. Epidemiology of antimicrobial resistance in enterococci of animal origin. The Journal of Antimicrobial Chemotherapy, 2005, 55(1):127-130.

[16] Smith D L, Johnson J A, Harris A D, Furuno J P, Perencevich E N, Jr Morris J G. Assessing risks for a pre-emergent pathogen: virginiamycin use and the emergence of streptogramin resistance in Enterococcus faecium. The Lancet Infectious Diseases 2003, 3(4):241-249.

[17] Hurd H S, Doores S, Hayes D, Mathew A, Maurer J, Silley P, Singer R S, Jones R N. Public health consequences of macrolide use in food animals: a deterministic risk assessment. Journal of Food Protection, 2004, 67(5):980-992.

[18] NARMS. Retail meat report-national antimicrobial resistance monitoring system. http://www.fda.gov/AnimalVeterinary/SafetyHealth/ AntimicrobialResistance/NationalAntimicrobialResistanceMonitoringSystem/default.htm, editor; 2010.

[19] Hao H, Yuan Z, Shen Z, Han J, Sahin O, Liu P, Zhang Q. Mutational and transcriptomic changes involved in the development of macrolide resistance in Campylobacter jejuni. Antimicrobial Agents and Chemotherapy, 2013, 57(3):1369-1378.

[20] Hao H, Dai M, Wang Y, Peng D, Liu Z, Yuan Z. 23S rRNA mutation A2074C conferring high-level macrolide resistance and fitness cost in Campylobacter jejuni. Microbial Drug Resistance (Larchmont, NY), 2009, 15(4): 239-244.

[21] Almofti Y A, Dai M, Sun Y, Haihong H, Yuan Z. Impact of erythromycin resistance on the virulence properties and fitness of Campylobacter jejuni. Microbial Pathogenesis, 2011, 50(6):336-342.

[22] Almofti Y A, Dai M, Sun Y, Hao H, Liu Z, Cheng G, Yuan Z. The physiologic and phenotypic alterations due to macrolide exposure in Campylobacter jejuni. International Journal of Food Microbiology, 2011, 151(1):52-61.

[23] SCAN. Opinion of the Scientific Committee for Animal Nutrition (SCAN) on the immediate and long-term risk to the value of streptogramins in human medicine posed by the use of virginiamycin as an animal growth promoter. Luxemburg; 1998.

[24] Cervantes H. Assessing The results of the EU Ban on antibiotic feed aAdditives. http://www.thepoultrysite.com/articles/471/assessing-the- results-of-the-eu-ban-on-antibiotic-feed-additives; 2005.

[25] Voss A, Loeffen F, Bakker J, Klaassen C, Wulf M. Methicillin- resistant staphylococcus aureus in pig farming. Emerging Infectious Diseases, 2005, 11(12):1965-1966.

[26] Alexander T W, Inglis G D, Yanke L J, Topp E, Read R R, Reuter T, McAllister T A. Farm-to-fork characterization of Escherichia coli associated with feedlot cattle with a known history of antimicrobial use. International Journal of Food Microbiology, 2010, 137(1):40-48.

[27] Dutil L, Irwin R, Finley R, Ng L K, Avery B, Boerlin P, Bourgault A M, Cole L, Daignault D, Desruisseau A, Demczuk W, Hoang L, Horsman G B, Ismail J, Jamieson F, Maki A, Pacagnella A, Pillai D R. Ceftiofur resistance in Salmonella enterica serovar Heidelberg from chicken meat and humans, Canada. Emerging Infectious Diseases, 2010, 16(1):48-54.

[28] Barber M. Methicillin-resistant staphylococci. Journal of Clinical Pathology, 1961, 14:385-393.

[29] Wenzel R P. The emergence of methicillin-resistant Staphylococcus aureus. Annals of Internal Medicine, 1982, 97(3):440-442.

[30] Haley R W, Hightower A W, Khabbaz R F, Thornsberry C, Martone W J, Allen J R, Hughes J M. The emergence of methicillin-resistant Staphylococcus aureus infections in United States hospitals. Possible role of the house staff-patient transfer circuit. Annals of Internal Medicine, 1982, 97(3):297-308.

[31] Pan E S, Diep B A, Charlebois E D, Auerswald C, Carleton H A, Sensabaugh G F, Perdreau-Remington F. Population dynamics of nasal strains of methicillin-resistant Staphylococcus aureus and their relation to community-associated disease activity. The Journal of Infectious Diseases, 2005, 192(5):811-818.

[32] Maree C L, Daum R S, Boyle-Vavra S, Matayoshi K, Miller L G. Community-associated methicillin-resistant Staphylococcus aureus isolates causing healthcare-associated infections. Emerging Infectious Diseases, 2007, 13(2):236-242.

[33] Labandeira-Rey M, Couzon F, Boisset S, Brown E L, Bes M, Benito Y, Barbu E M, Vazquez V, Hook M, Etienne J, Vandenesch F, Bowden M G. Staphylococcus aureus Panton-Valentine leukocidin causes necrotizing pneumonia. Science, 2007, 315(5815):1130-1133.

[34] Catry B, Van Duijkeren E, Pomba M C, Greko C, Moreno M A, Pyorala S, Ruzauskas M, Sanders P, Threlfall E J, Ungemach F, Torneke K, Munoz-Madero C, Torren-Edo J. Reflection paper on MRSA in food-producing and companion animals: epidemiology and control options for human and animal health. Epidemiology and Infection, 2010, 138(5):626-644.

[35] Holmes M A, Zadoks R N. Methicillin resistant S. aureus in human and bovine mastitis. Journal of Mammary Gland Biology and Neoplasia, 2011, 16(4):373-382.

[36] Verkade E, Kluytmans J. Livestock-associated Staphylococcus aureus CC398: Animal reservoirs and human infections. Infect Genet Evology, 2014, 21:523-530.

[37] Loncaric I, Kubber-Heiss A, Posautz A, Stalder G L, Hoffmann D, Rosengarten R, Walzer C. Characterization of methicillin-resistant Staphylococcus spp. carrying the mecC gene, isolated from wildlife. The Journal of Antimicrobial Chemotherapy, 2013, 68(10):2222-2225.

[38] Hower S, Phillips M C, Brodsky M, Dameron A, Tamargo M A, Salazar N C, Jackson C R, Barrett J B, Davidson M, Davis J, Mukherjee S, Ewing R Y, Gidley M L, Sinigalliano C D, Johns L, Johnson F E, Adebanjo O, Plano L R. Clonally related methicillin- resistant Staphylococcus aureus isolated from short-finned pilot whales (Globicephala macrorhynchus), human volunteers, and a bayfront cetacean rehabilitation facility. Microbial Ecology, 2013, 65(4): 1024-1038.

[39] Haenni M, Saras E, Chatre P, Medaille C, Bes M, Madec J Y, Laurent F. A USA300 variant and other human-related methicillin-resistant Staphylococcus aureus strains infecting cats and dogs in France. The Journal of Antimicrobial Chemotherapy, 2012, 67(2):326-329.

[40] Ewers C, Bethe A, Semmler T, Guenther S, Wieler L H. Extended- spectrum beta-lactamase-producing and AmpC-producing Escherichia coli from livestock and companion animals, and their putative impact on public health: a global perspective. Clinical Microbiology and Infection, 2012, 18(7):646-655.

[41] Guenther S, Ewers C, Wieler L H. Extended-spectrum Beta- Lactamases producing E. coli in wildlife, yet another form of environmental pollution? Frontiers in Microbiology, 2011, 2:246.

[42] Dolejska M, Frolkova P, Florek M, Jamborova I, Purgertova M, Kutilova I, Cizek A, Guenther S, Literak I. CTX-M-15-producing Escherichia coli clone B2-O25b-ST131 and Klebsiella spp. isolates in municipal wastewater treatment plant effluents. The Journal of Antimicrobial Chemotherapy, 2011, 66(12):2784-2790.

[43] Guenther S, Grobbel M, Lubke-Becker A, Goedecke A, Friedrich N D, Wieler L H, Ewers C. Antimicrobial resistance profiles of Escherichia coli from common European wild bird species. Veterinary Microbiology, 2009, 144(1/2):219-225.

[44] Guenther S, Grobbel M, Beutlich J, Guerra B, Ulrich R G, Wieler L H, Ewers C. Detection of pandemic B2-O25-ST131 Escherichia coli harbouring the CTX-M-9 extended-spectrum beta-lactamase type in a feral urban brown rat (Rattus norvegicus). The Journal of Antimicrobial Chemotherapy, 2010, 65(3):582-584.

[45] Kirst H A, Thompson D G, Nicas T I. Historical yearly usage of vancomycin. Antimicrobial Agents and Chemotherapy, 1998, 42(5): 1303-1304.

[46] Acar J, Casewell M, Freeman J, Friis C, Goossens H. Avoparcin and virginiamycin as animal growth promoters: a plea for science in decision-making. Clinical Microbiology and Infection, 2000, 6(9): 477-482.

[47] Werner G, Coque T M, Hammerum A M, Hope R, Hryniewicz W, Johnson A, Klare I, Kristinsson K G, Leclercq R, Lester C H, Lillie M, Novais C, Olsson-Liljequist B, Peixe LV, Sadowy E, Simonsen G S, Top J, Vuopio-Varkila J, Willems R J, Witte W, Woodford N. Emergence and spread of vancomycin resistance among enterococci in Europe. Euro Surveillance, 2008, 13(47): pii 19046.

[48] Garcia-Migura L, Liebana E, Jensen L B, Barnes S, Pleydell E. A longitudinal study to assess the persistence of vancomycin-resistant Enterococcus faecium (VREF) on an intensive broiler farm in the United Kingdom. FEMS Microbiology Letters, 2007, 275(2):319-325.

[49] DANMAP. DANMAP 2010 - Use of antimicrobial agents and occurrence of antimicrobial resistance in bacteria from food animals, food and humans in Denmark. http://www.danmap.org, editor; 2010.

[50] Nilsson O, Greko C, Top J, Franklin A, Bengtsson B. Spread without known selective pressure of a vancomycin-resistant clone of Enterococcus faecium among broilers. The Journal of Antimicrobial Chemotherapy, 2009, 63(5):868-872.

[51] FDA. Freedom of Information Summary NADA 1412068. 1998, http://www.fda.gov/cvm/foi/942.html.

[52] FDA. Final decision of the Commissioner Docket No. 2000N21571 with drawal of approval of the new animal drug application for enrofloxacin in poultry [EB/OL]. http://www.fda.gov/oc/antimicrobial/ baytri. html]; 2002.

[53] Nelson J M, Chiller T M, Powers J H, Angulo F J. Fluoroquinolone- resistant Campylobacter species and the withdrawal of fluoroquinolones from use in poultry: a public health success story. Clinical Infectious Disease, 2007, 44(7):977-980.

[54] JVARM. A report on the Japanese veterinary antimicrobial resistance monitoring system 2002-2007. 2008.

[55] CIPARS. Canadian integrated program for antimicrobial resistance surveillance annual report 2008. http://www.phac-aspc.gc.ca/cipars- picra/2008/index-eng.php, editor; 2008.

[56] Zeitouni S, Collin O, Andraud M, Ermel G, Kempf I. Fitness of macrolide resistant Campylobacter coli and Campylobacter jejuni. Microbial Drug Resistance, 2012, 18(2):101-108.

[57] Luo N, Pereira S, Sahin O, Lin J, Huang S, Michel L, Zhang Q. Enhanced in vivo fitness of fluoroquinolone-resistant Campylobacter jejuni in the absence of antibiotic selection pressure//Proceedings of the National Academy of Sciences of the United States of America, 2005, 102(3):541-546.

[58] Prescott J F. Antibiotics: miracle drugs or pig food? The Canadian Veterinary, 1997, 38(12):763-766.

[59] Aarestrup F M, Nielsen E M, Madsen M, Engberg J. Antimicrobial susceptibility patterns of thermophilic Campylobacter spp. from humans, pigs, cattle, and broilers in Denmark. Antimicrobial Agents and Chemotherapy, 1997, 41(10):2244-2250.

[60] Anjum M F, Choudhary S, Morrison V, Snow L C, Mafura M, Slickers P, Ehricht R, Woodward M J. Identifying antimicrobial resistance genes of human clinical relevance within Salmonella isolated from food animals in Great Britain. The Journal of Antimicrobial Chemotherapy, 2011, 66(3):550-559.

[61] Drouin E. Helicobacter pylori: novel therapies. Canadian Journal of Gastroenterology, 1999, 13(7):581-583.

[62] Rose N, Beaudeau F, Drouin P, Toux J Y, Rose V, Colin P. Risk factors for Salmonella enterica subsp. enterica contamination in French broiler-chicken flocks at the end of the rearing period. Preventive Veterinary Medicine, 1999, 39(4):265-277.

[63] Lovland A, Kaldhusdal M. Severely impaired production performance in broiler flocks with high incidence of Clostridium perfringens- associated hepatitis. Avian Pathology, 2001, 30(1):73-81.

[64] Jensen G B, Hansen B M, Eilenberg J, Mahillon J. The hidden lifestyles of Bacillus cereus and relatives. Environmental Microbiology, 2003, 5(8):631-640.

[65] DANMAP. DANMAP 2000 - Use of antimicrobial agents and occurrence of antimicrobial resistance in bacteria from food animals, food and humans in Denmark. http://www.danmap.org, editor; 2000.

[66] Mahews K. Antimicrobial drug use and veterinary costs in U.S. Livestock Production, 2001, 766: 761-768 .

[67] DANMAP. DANMAP 2003 - Use of antimicrobial agents and occurrence of antimicrobial resistance in bacteria from food animals, food and humans in Denmark. http://www.danmap.org, editor; 2003.

[68] IFAH-EuroP. IFAH-Europe annual report 2005; 2005.

[69] Hook S E, Wright A D, McBride B W. Methanogens: methane producers of the rumen and mitigation strategies. Archaea, 2010, 945785.

[70] Jones C M. The effects of selected antibiotics on nitrogen uptake by Spirodela punctata[D]. Arcata: Humboldt State University, 2010.

[71] Poduval R D, Kamath R P, Corpuz M, Norkus E P, Pitchumoni C S. Clostridium difficile and vancomycin-resistant enterococcus: the new nosocomial alliance. The American Journal of Gastroenterology, 2000, 95(12):3513-3515.

[72] Jones R L. Clostridial enterocolitis. The Veterinary Clinics of North America, 2000,16(3):471-485.

[73] Tice A. Outpatient parenteral antimicrobial therapy (OPAT): a global perspective. Introduction Chemotherapy, 2001, 47( Suppl 1):1-4.

[74] Russell S M. The effect of airsacculitis on bird weights, uniformity, fecal contamination, processing errors, and populations of Campylobacter spp. and Escherichia coli. Poultry Science, 2003, 82(8):1326-1331.

[75] Heuer O E, Pedersen K, Andersen J S, Madsen M. Prevalence and antimicrobial susceptibility of thermophilic Campylobacter in organic and conventional broiler flocks. Letters in Applied Microbiology, 2001, 33(4):269-274.

[76] Hurd H S. Risk-Risk Assessment of Antibiotic Use in Food Animals. 2011; COEX, Seoul, Korea. www.isaar.org.

[77] Hurd H S, Yaeger M J, Brudvig J M, Taylor D D, Wang B. Lesion severity at processing as a predictor of Salmonella contamination of swine carcasses. American Journal of Veterinary Research, 2012, 73(1):91-97.

[78] Cook R. EU ban on four antibiotic growth promoters. The Veterinary Record, 1999, 144(6):158.

[79] Ferran A A, Toutain P L, Bousquet-Melou A. Impact of early versus later fluoroquinolone treatment on the clinical; microbiological and resistance outcomes in a mouse-lung model of Pasteurella multocida infection. Veterinary Microbiology, 2011, 148(2-4):292-297.

[80] Ferran A A, Kesteman A S, Toutain P L, Bousquet-Melou A. Pharmacokinetic/pharmacodynamic analysis of the influence of inoculum size on the selection of resistance in Escherichia coli by a quinolone in a mouse thigh bacterial infection model. Antimicrobial Agents and Chemotherapy, 2009, 53(8):3384-3390.