摘要
副猪嗜血杆菌(Haemophilus parasuis, HPS)是猪上呼吸道的一种常在菌或条件致病菌,1910年K.Glasser首先发现并报道该病原,该菌感染猪后可引发多发性浆膜炎、关节炎和脑膜炎。近年来,由副猪嗜血杆菌所引起的革拉瑟氏病已成为影响养猪业发展的一种重要细菌性疾病。发病后及时采用抗生素进行治疗可显著降低动物死亡率,同时在生产过程中适当添加抗生素也可在一定程度上降低该病的发生率。但随着大量抗菌药特别是广谱抗菌药在养猪业中的广泛使用,细菌对抗菌药物的耐药性问题日趋突出,与此同时也有研究资料表明亚抑制浓度的抗生素可以影响细菌的代谢过程而改变细菌的毒力或细菌对环境的适应能力等。
本研究围绕副猪嗜血杆菌对喹诺酮类药物的耐药机理、耐药质粒的分布情况及其与亚抑制浓度氟苯尼考相互作用进行研究,以了解副猪嗜血杆菌耐药情况、耐药机理及亚抑制浓度氟苯尼考对其转录谱的影响,为合理使用抗菌药物提供理论基础,主要研究内容、方法及结果如下：
1.副猪嗜血杆菌耐喹诺酮类药物的机制研究
副猪嗜血杆菌血清型众多,免疫预防往往因为疫苗交叉保护力低而致免疫失败,抗生素治疗便成为控制革拉瑟氏病的主要手段和措施。氟喹诺酮类药物因具有抗菌谱广、杀菌力强等优点而在养猪生产过程中得到广泛应用。研究表明细菌对喹诺酮类药产生耐药性主要通过编码旋转酶和拓扑异构酶的基因gyrA和parC发生突变而引起,同时也存在由质粒qnr及外排泵所介导的耐药。目前国外已围绕副猪嗜血杆菌的药物敏感性及耐药性等问题进行了大量研究,但国内的相关研究相对较少。
本研究首先采用特异性16S rRNA PCR方法对临床分离株进行鉴定,确认分离株是副猪嗜血杆菌后测定菌株对萘啶酸、环丙沙星和恩诺沙星的敏感性,然后用特异性PCR扩增副猪嗜血杆菌标准菌株和MIC值较高的临床分离株的gyrA和parC基因的喹诺酮耐药决定区(QRDR)并进行测序。采用Blast法对测序结果进行分析,包括副猪嗜血杆菌标准血清型间的比对及耐药株与敏感株之间的比对。在测MIC的同时添加外排泵抑制剂苯丙氨酸-精氨酸-β-萘酰胺以检测是否存在由外排泵介导的细菌对喹诺酮类药物的耐药性,同时还设计特异性引物以扩增质粒qnr以检测是否存在由质粒所介导的细菌对喹诺酮类药物的耐药性。
研究结果表明,副猪嗜血杆菌标准血清型的QRDR序列间具有高度的保守性,未发现有差异基因。而耐药株的gyrA和parC的QRDR区域存在数量不等、位置各异的突变位点,其中GyrA以83位和87位的突变为主,发生突变的主要方式为ser-83-phe和ser-83-tyr,asp-87-asn、asp-87-gly和asp-87-tyr。而ParC以73位和77位为主；GyrA的突变在副猪嗜血杆菌耐喹诺酮类药物的机理中占主导作用,而ParC的突变仅起次要作用,往往发生于GyrA突变之后。在所用的临床分离株中未发现由质粒和外排泵所介导的细菌对喹诺酮类药物的耐药性。研究结果可以为制定副猪嗜血杆菌对喹诺酮类药物的敏感性判定标准提供理论依据。
2.副猪嗜血杆菌耐药质粒的提取及功能分析
常见的耐药因子达数百种之多,其中部分耐药因子可通过染色体突变产生并可以垂直传播,部分耐药因子由质粒等可移动元件所介导,能够水平传播。目前CLSI尚未确定各种抗菌药物对副猪嗜血杆菌耐药性的判定标准,因此不能仅仅依据各种药物对副猪嗜血杆菌的MIC值大小确定菌株是否耐药,若直接用PCR等方法去检测耐药因子则效率较低。本研究通过从副猪嗜血杆菌临床分离株提取耐药质粒,以了解副猪嗜血杆菌临床分离株耐药质粒的流行情况及可能的耐药情况。
本研究用Qiagen公司质粒小提试剂盒对156株副猪嗜血杆菌临床分离株进行质粒提取,所获得的质粒先用合适的内切酶进行酶切,再与相应的载体连接后转化感受态细胞,挑阳性重组子进行测序、注释,进而获得质粒分离菌株的耐药情况。
本研究仅在1株临床分离株(A67)中分离出质粒,其大小约为4.2kb。内切酶Sau3AI可以将所分离出的质粒进行有效切割,获得大小分别为2.7kb和1.5kb的片段,将小片段与经内切酶BamHI进行酶切后的pUC19载体进行连接,连接产物成功转化BL21感受态细胞,挑选阳性重组子送上海生工生物有限公司用M13正、反向引物对插入序列进行测序。再根据所测得的小片段的碱基序列设计引物,以所提质粒为模板进行测序,直至测通。用DNAstar软件对测序所获得的序列进行拼接并删除重复序列,得到一闭合环状的质粒DNA,其大小为4248bp,其中主要包含有mobA、mobB和mobC等移动因子和sul2及strA两种耐药因子,质粒序列已保存至GenBank(No. FJ670543)。
对含有耐药质粒的菌株进行了链霉素和磺胺甲基异恶唑的药物敏感性试验,其MIC值大小分别为128和512μg/mL。所提取的质粒可以成功转化至多杀性巴氏杆菌,转化菌对上述两种药物也产生耐药性。研究结果表明,该质粒可以介导副猪嗜血杆菌对链霉素和磺胺类药物产生耐药性。
3.亚抑制浓度氟苯尼考对副猪嗜血杆菌转录谱的影响研究
不同浓度的抗生素对细菌会产生不同的作用,高浓度抗生素对细菌产生抑制或杀灭作用,而低浓度抗生素不但不能抑制或杀灭细菌,而且有可能作为一种信号物质对细菌的代谢过程进行调节,进而影响细菌的毒力和适应性等特性。
本研究选用我国养猪生产中广泛使用的广谱抗生素——氟苯尼考作为研究对象,探讨亚抑制浓度氟苯尼考对副猪嗜血杆菌转录谱的影响。根据GenBank所公布的副猪嗜血杆菌SH0165株全序列(CP001321)设计探针,由Agilent公司进行芯片的设计与制作。
将副猪嗜血杆菌临床分离株SH0165株分别于添加亚抑制浓度氟苯尼考(0.25μg/mL)和不添加药物的条件下培养16h,分别提取mRNA用于后续的芯片研究,每个处理组设3个生物学重复。以mRNA进行反转录获得cDNA及cRNA,并对cRNA进行荧光标记,点校进行检测而获得差异表达基因,用实时荧光定量PCR对差异表达基因进行验证。
经亚抑制浓度氟苯尼考作用后,副猪嗜血杆菌的转录谱较对照组发生较明显的改变,共有163个基因表达水平变化在1.5倍(p<0.05)以上,其中96个基因表达上调,另外67个基因表达下调。表达上调的基因主要包括参与碳水化合物代谢、铁离子摄取与利用、潜在毒力因子神经氨酸酶等,这些基因的表达上调可以增强细菌对环境的适应能力,同时也可能改变菌株的潜在毒力。而作为主要抑制蛋白质合成的抗生素,亚抑制浓度氟苯尼考对蛋白质合成的相关基因的抑制作用却很轻微。
本研究结果表明,临床上使用低剂量抗生素预防呼吸道细菌性感染时有必要考虑药物对细菌生理生化活动的影响,特别是要注意在抗生素的作用下细菌的毒力及适应性方面的改变。
H. parasuis is a ubiquitous, opportunistic pathogen of swine and the causative agent of Glasser's disease, which was first described by K. Glasser in1910as a bacillus found in the serous exudates of pigs. It is an early colonizer of the upper respiratory tract of pigs. It invades the surrounding mucosa and is disseminated systemically via the bloodstream. Finally resulting in disease is manifested as systemic inflammation of serous surfaces of pigs.
H. parasuis belong to the family of Pasteurellaceae, which currently includes at least10genera and more than50species of bacteria. Members of this family are polymorphic, G-cells ranging from coccobacilli to rod shaped, measuring<1.0μm in diameter. They are commonly isolated from vertebrates, especially mammals, birds, and their hosts. The genus Haemophilus are facultative anaerobes that are oxidase, catalase, and alkaline phosphatase positive. It includes fastidious organisms requiring complex media for growth. They have a strict requirement for X factor (protoporphyrin) and/or V factor (nicotinamide adenine dinucleotide) and grow optimally at35to37℃. H. parasuis forms smooth, gray colonies on chocolate agar or TSA growing to a diameter of approximately0.5mm. Some strains form capsules and tend to be coccobacillary whereas nonencapsulated strains tend to be filamentous in shape.
The onset of acute Glasser's disease is usually seen within2days of the first signs of disease, such as coughing and dyspnoea, pyrexia (40to41℃), anorexia, serous nasal discharge. Clinical signs are dependent on the localization of the pathogen within the host. When pathogen located in the joints, it usually results in swelling, lameness, and lateral recumbent. Other signs include cyanosis of the extremities caused by the failure of peripheral circulation, reddened conjunctivae, subcutaneous edema of the ears and eyelids, and abortion. While pathogen located in the brain, meninges, or spinal cord causes central nervous system disturbances such as posterior paresis, tremors, and incoordination.
Chronic disease in piglets can result in paleness, poor growth, and decreased feed efficiency. Chronic arthritis, intestinal obstruction, meningitis and peritonitis maybe observed in some cases. Survivors suffer chronic pericarditis and congestive cardiac failure which is frequently linked to sudden death. Acute disease may include arthritis, meningitis, pericarditis, polyserositis, pneumonia, and septicaemia. The mortality maybe reach50%if left untreated the acute disease and can have a potentially devastating economic impact on swine herds.
Based on history, clinical signs and the presence of characteristic lesions can diagnose Glasser's disease. The characteristic lesions contain serofibrinous exudates in the peritoneal cavity or petechial renal hemorrhages, pericardial sac, fibrinopurulent exudates of the brain, or multifocal lesions of the lung, and so on. Isolation of H. parasuis is required for confirmation of Glasser's disease. At the same time, H. parasuis also needs to be differentiated from similar pathogens such as Streptococcus suis and Pasteurella spp.. Recently, a number of molecular methods have been developed for the identification of H. parasuis as an alternative to culture.
Treatment with parenteral antibiotics may be effective after H. parasuis diagnosis is made. Reduction or elimination of stressful situations may also reduce outbreaks. In pig industry, transporting and handling of pigs is often necessary so that strategic administration of antimicrobials before, during, and after required transport has been used to reduce the occurrence of Glasser's and other stress-induced diseases. Limited cross-protection due to serovar heterogeneity and the existence of untypable isolates has meant that vaccine development is very difficult, although current understanding of the basis of immunity is rudimentary.
The objective of this research is,(1) To detected the susceptibility of H. parasuis clinical isolated strain to nalidixic acid, enrofloxacin and ciprofloxacin, and identify the molecular mechnasim of H. parasuis resistant to quinolone antibacterial.(2) Isolated plasmid from clinical strain and sequenced, annotate the genes in the plasmid and compared with plasmid isolated from other Pasteurellaceae family bacteria.(3) The transcriptional profile of H. parasuis to subinhibitory concentration of florfenicol was investigated using the H. parasuis microarray developed by Agilent Corporation.
1. Molecular mechanism of H. parasuis resistant to quinolone
This thesis examined molecular changes in the quinolone-resistance determining regions (QRDR) of the topoisomerase genes, gyrA and parC of H. parasuis and their contribution to quinolone resistance. H. parasuis isolates and standard serotype strain were confirmed by16S rRNA PCR and then investigated for quinolone (nalidixic acid, ciprofloxacin and enrofloxacin) susceptibility and mutation in QRDR by PCR and DNA sequence. Additionally, plasmid-mediated quinolone resistance (PMQR) determinants were determined by specific PCR.
Among156clinical isolated strains,21H. parasuis isolates showed higher MIC values of nalidixic acid, enrofloxacin and ciprofloxacin. No strains possessed qnrA, qnrB, qrnC, qnrS, aac(6')-Ib-cr and qepA plasmid and efflux pump mediated quinolone resistance. Mutation analysis of QRDRs showed that the lower susceptibility strains carried at least one mutation in GyrA (at codon83or87), mutation occurred in ParC(at codon73and77) followed by mutation in gyrA.
Key findings were that the initial QRDR changes always occurred in GyrA and were the predominant influence on phenotypic expression of quinolone resistant. QRDR alterations were acquired sequentially and two GyrA and two ParC changes represented the full complement of changes observed in H. parasuis. GyrA alterations at Ser-87in H. parasuis were pivotal for the development of further resistance. ParC changes required the presence of two GyrA alterations for any major impact on quinolone.
This thesis provides a comprehensive analysis of the relationship between QRDR alterations and quinolone resistance in H. parasuis and offers insights into the potential for quinolone development in H. parasuis.These data provide important insights into the mechanism of fluoroquinolone resistance in H. parasuis, thereby highlighting the usefulness of quinolones for the treatment and control of this infection.
2. Plasmid-borne antibacterial resistance in H. parasuis
H. parasuis isolate from pigs were investigated for the genetic basis of antibacterial resistance.156H. parasuis isolate strains were screened for plasmid content. A4.2kb plasmid, designated pHPS-A67, was extracted from strain A67.
R-plasmid isolated as described above was digested with Sau3AI according to the manufacturer's recommendations. Restriction fragments were purified using QIAquick Spin columns (Qiagen) and ligated into vector pUC19which previously digested with BamHI. Ligation reactions were used to transform E.coli BL21chemically competent cells. Recombinant plasmids were purified with QIAprep Spin columns (Qiagen) and inserts were sequenced using the vector's internal sequencing primers(M13forward and reverse primer). According to the sequence of inserts design primers used for further sequence of the whole sequence of the plasmid.
The plasmid is a4.2kb double DNA. It is comprised with mobA, mobB, mobC, sul2and strA genes. mobA, mobB and mobC coded the mobilization protein for plasmid transport, while sul2and strA coded protein mediated resistance to streptomycin and sulfonamide. Strain A67, which contained the isolated plasmid, has streptomycin and sulfonamide MIC128and512μg/mL, respectively.
The results of this study showed that a plasmid-borne sul2and strA gene was responsible for streptomycin and sulfonamide resistance in the swine respiratory tract pathogen. This is, to the best of our knowledge, the first report of an antibiotic resistance plasmid in H.parasuis from China.
3. Transcriptional responses of H. parasuis to subinhibitory concentration of florfenicol
The response of H. parasuis to subinhibitory concentration antibiotics is similar to mimic in vivo conditions encountered during infectious disease treatment. The transcriptional profile of H. parasuis to subinhibitory concentrations of florfenicol was investigated using the H. parasuis microarray developed by Agilent Corporation.
All experiments were carried out in biological triplicate. An overnight liquid culture was inoculated into TSB with and without0.25μg/mL florfenicol. The cells were harvested16h latter. RNA was extracted using a TRIzol Max bacterial RNA isolation kit (Qiagen) according to the manufacturer's instructions, and then DNase treated. A16S rRNA PCR amplification was carried out using0.5mL RNA as template to ensure there was no residual DNA.
Significantly regulated genes and operons were identified that are unique to or common between antibiotic stresses. The microarray chip demonstrate that a total of163genes were identified to be differentially regulated(FC>1.5, p<0.05),96of which were upregulated, and67down-regulated. Florfenicol-induced transcriptional changes mainly occurred in genes responsible for carbon utilization, ion uptake and virulence factor. The results reveal general changes in gene expression that are inconsistent with known mechanisms of action of florfenicol.
This study provides a starting point for detailed analyses of numerous genes whose expression is affected by florfenicol and may therefore be involved in adaptation to the host environment.
引文
白华,齐静,朱小玲,王庆艳,杜加法,刘玉庆,2009.恩诺沙星对大肠杆菌全基因组表达谱的影响.畜牧兽医学报,1537-1544.
蔡磊,赵青川,2007.差异表达基因的几种筛选方法.第四军医大学学报,286-288.
郭春燕,喻海忠,袁建芬,2010.FQ-PCR法检测耐喹诺酮类药物淋球菌的gyrA基因.临床检验杂志,430-431.
贾爱卿,李春玲,王贵平,杨冬霞,2010.副猪嗜血杆菌ERIC-PCR旨纹图谱多样性研究.中国兽医学报,337-339.
乐敏2010.副猪嗜血杆菌基因组学及毒力相关因子研究(武汉).华中农业大学学位论文,华中农业大学图书馆,武汉
吴娟,2006.副猪嗜血杆菌突变菌株的构建及生物学特性的研究.华中农业大学学位论文,华中农业大学图书馆,武汉.
熊萍萍,荣俊,2007.多杀性巴氏杆菌C48-16电转化条件的研究.长江大学学报(自科版)农学卷,62-64.
G塞德曼,F.R.E.1998.精编分子生物学实验指南[M].科学出版社,北京,23-24
Aarestrup, F.M., Seyfarth, A.M., Angen, O.,2004. Antimicrobial susceptibility of Haemophilus parasuis and Histophilus somni from pigs and cattle in Denmark. Vet Microbiol 101,143-146.
Abraham, E.P., Chain, E.,1988. An enzyme from bacteria able to destroy penicillin.1940. Rev Infect Dis 10,677-678.
Alvarez, A.I., Perez, M., Prieto, J.G., Molina, A.J., Real, R., Merino, G.,2008. Fluoroquinolone efflux mediated by ABC transporters. J Pharm Sci 97,3483-3493.
Amano, H., Shibata, M., Kajio, N., Morozumi, T.,1994. Pathologic observations of pigs intranasally inoculated with serovar 1,4 and 5 of Haemophilus parasuis using immunoperoxidase method. J Vet Med Sci 56,639-644.
Amano, H., Shibata, M., Takahashi, K., Sasaki, Y.,1997. Effects on endotoxin pathogenicity in pigs with acute septicemia of Haemophilus parasuis infection. J Vet Med Sci 59,451-455.
Aminimanizani, A., Beringer, P., Jelliffe, R.,2001. Comparative pharmacokinetics and pharmacodynamics of the newer fluoroquinolone antibacterials. Clin Pharmacokinet 40,169-187.
Angen, O., Oliveira, S., Ahrens, P., Svensmark, B., Leser, T.D.,2007. Development of an improved species specific PCR test for detection of Haemophilus parasuis. Vet Microbiol 119,266-276.
Angen, O., Svensmark, B., Mittal, K.R.,2004. Serological characterization of Danish Haemophilus parasuis isolates. Vet Microbiol 103,255-258.
Bak, H., Riising, H.J.,2002. Protection of vaccinated pigs against experimental infections with homologous and heterologous Haemophilus parasuis. Vet Rec 151,502-505.
Barber, M., Rozwadowska-Dowzenko, M.,1948. Infection by penicillin-resistant staphylococci. Lancet 2,641-644.
Barlow, M.,2009. What antimicrobial resistance has taught us about horizontal gene transfer. Methods Mol Biol 532,397-411.
Baumann, G., Bilkei, G.,2002. Effect of vaccinating sows and their piglets on the development of Glasser's disease induced by a virulent strain of Haemophilus parasuis serovar 5. Vet Rec 151,18-21.
Benveniste, R., Davies, J.,1973. Aminoglycoside antibiotic-inactivating enzymes in actinomycetes similar to those present in clinical isolates of antibiotic-resistant bacteria. Proc Natl Acad Sci U S A 70,2276-2280.
Biberstein, E.L., White, D.C.,1969, A proposal for the establishment of two new Haemophilus species. J Med Microbiol 2,75-78.
Bjedov, I., Tenaillon, O., Gerard, B., Souza, V., Denamur, E., Radman, M., Taddei, F., Matic, I.,2003. Stress-induced mutagenesis in bacteria. Science 300,1404-1409.
Blackall, P.J., Trott, D.J., Rapp-Gabrielson, V., Hampson, D.J.,1997. Analysis of Haemophilus parasuis by multilocus enzyme electrophoresis. Vet Microbiol 56, 125-134.
Blanco, I., Canals, A., Evans, G., Mellencamp, M.A., Cia, C., Deeb, N., Wang, L. Galina-Pantoja, L.,2008. Differences in susceptibility to Haemophilus parasuis infection in pigs. Can J Vet Res 72,228-235.
Brockmeier, S.L.,2004. Prior infection with Bordetella bronchiseptica increases nasal colonization by Haemophilus parasuis in swine. Vet Microbiol 99,75-78.
Burrack, L.S., Higgins, D.E.,2007. Genomic approaches to understanding bacterial virulence. Curr Opin Microbiol 10,4-9.
Cai, X.W., Chen, H.C., Blackall, P.J., Yin, Z.Y., Wang, L., Liu, Z.F., Jin, M.L.,2005. Serological characterization of Haemophilus parasuis isolates from China. Vet Microbiol 111,231-236.
Calabrese, E.J., Baldwin, L.A.,2002. Defining hormesis. Hum Exp Toxicol 21,91-97.
Canton, R.,2009. Antibiotic resistance genes from the environment:a perspective through newly identified antibiotic resistance mechanisms in the clinical setting. Clin Microbiol Infec,20-25.
Cardenas, M., Barbe, J., Llagostera, M., Miro, E., Navarro, F., Mirelis, B., Prats, G., Badiola, I.,2001. Quinolone resistance-determining regions of gyrA and parC in Pasteurella multocida strains with different levels of nalidixic acid resistance. Antimicrob Agents Chemother 45,990-991.
Cardoso, K., Gandra, R.F., Wisniewski, E.S., Osaku, C.A., Kadowaki, M.K., Felipach-Neto, V., Haus, L.F., Simao, R.C.,2010. DnaK and GroEL are induced in response to antibiotic and heat shock in Acinetobacter baumannii. J Med Microbiol 59,1061-1068.
Chang, C.F., Yeh, T.M., Chou, C.C., Chang, Y.F., Chiang, T.S.,2002. Antimicrobial susceptibility and plasmid analysis of Actinobacillus pleuropneumoniae isolated in Taiwan. Vet Microbiol 84,169-177.
Charland, N., D'Silva, C.G., Dumont, R.A., Niven, D.F.,1995. Contact-dependent acquisition of transferrin-bound iron by two strains of Haemophilus parasuis. Can J Microbiol 41,70-74.
Choi, H., Lee, H.J., Lee, Y.,1998. A mutation in QRDR in the ParC subunit of topoisomerase IV was responsible for fluoroquinolone resistance in clinical isolates of Streptococcus pneumoniae. Yonsei Med J 39,541-545.
CLSI,2008. Performance Standards for Antimicrobial Disk and Dilution Susceptibility Tests for Bacteria Isolated From Animals; Approved Standard-Third Edition CLSI document M31-A3 (ISBN 1-56238-659-X). Clinical and Laboratory Standards Institute.
Conway, T., Schoolnik, G.K.,2003. Microarray expression profiling:capturing a genome-wide portrait of the transcriptome. Mol Microbiol 47,879-889.
Courvalin, P.,2008. Predictable and unpredictable evolution of antibiotic resistance. J Intern Med 264,4-16.
Crofton, J., Mitchison, D.A.,1948. Streptomycin resistance in pulmonary tuberculosis. Br MedJ2,1009-1015.
Crosa, J.H., Walsh, C.T.,2002. Genetics and assembly line enzymology of siderophore biosynthesis in bacteria. Microbiol Mol Biol Rev 66,223-249.
Dantas, G., Sommer, M.O., Oluwasegun, R.D., Church, G.M.,2008. Bacteria subsisting on antibiotics. Science 320,100-103.
Davies, J.,2006, Are antibiotics naturally antibiotics? J Ind Microbiol Biotechnol 33, 496-499.
Davies, J., Spiegelman, G.B., Yim, G.,2006, The world of subinhibitory antibiotic concentrations. Curr Opin Microbiol 9,445-453.
Davies, J.E.,1997, Origins, acquisition and dissemination of antibiotic resistance determinants. Ciba Found Symp 207,15-27,27-35.
D'Costa, V.M., McGrann, K.M., Hughes, D.W., Wright, G.D.,2006. Sampling the antibiotic resistome. Science 311,374-377.
De Ley, J., Mannheim, W., Mutters, R., Piechulla, K., Tytgat, R., Segers, P., Bisgaard, M., Frederiksen, W., Hinz, K.H., Vanhoucke, M.,1990. Inter-and intrafamilial similarities of rRNA cistrons of the Pasteurellaceae. Int J Syst Bacteriol 40,126-137.
De, F.A., Tucker, A.W., Navas, J., Blanco, M., Morris, S.J., Gutierrez-Martin, C.B.,2007. Antimicrobial susceptibility patterns of Haemophilus parasuis from pigs in the United Kingdom and Spain. Vet Microbiol 120,184-191.
Del, R.M., Gutierrez, C.B., Ferri, E.F.,2003. Value of indirect hemagglutination and coagglutination tests for serotyping Haemophilus parasuis. J Clin Microbiol 41, 880-882.
Del, R.M., Gutierrez-Martin, C.B., Rodriguez-Barbosa, J.I., Navas, J., Rodriguez-Ferri, E.F.,2005. Identification and characterization of the TonB region and its role in transferrin-mediated iron acquisition in Haemophilus parasuis. Ferns Immunol Med Mic 45,75-86.
Delcour, A.H.,2009. Outer membrane permeability and antibiotic resistance. Bba-Proteins Proteom 1794,808-816.
Depardieu, F., Podglajen, I., Leclercq, R., Collatz, E., Courvalin, P.,2007. Modes and modulations of antibiotic resistance gene expression. Clin Microbiol Rev 20,79-114.
Deslandes, V., Denicourt, M., Girard, C, Harel, J., Nash, J.H., Jacques, M.,2010. Transcriptional profiling of Actinobacillus pleuropneumoniae during the acute phase of a natural infection in pigs. BMC Genomics 11,98.
DJ, D.2004. In the matter of enrofloxacin for poultry:withdrawal of approval of Bayer Corporation's new animal drug application 1 ((NADA)).
EMEA, E.A.F.T.1999. European Agency for the Evaluation of Medical Products (EMEA), Antibiotic resistance in the European union associated with therapeutic use of veterinary medicines. Report and qualitative risk assessment..
Fabrega, A., Sanchez-Cespedes, J., Soto, S., Vila, J.,2008. Quinolone resistance in the food chain. Int J Antimicrob Agents 31,307-315.
Fajardo, A., Martinez, J.L.,2008. Antibiotics as signals that trigger specific bacterial responses. Curr Opin Microbiol 11,161-167.
Freiberg, C., Fischer, H.P., Brunner, N.A.,2005. Discovering the mechanism of action of novel antibacterial agents through transcriptional profiling of conditional mutants. Antimicrob Agents Chemother 49,749-759.
Ginsberg, A.M.,2010, Drugs in development for tuberculosis. Drugs 70,2201-2214.
Guo, L., Zhang, J., Xu, C., Zhao, Y., Ren, T., Zhang, B., Fan, H., Liao, M.,2011, Molecular characterization of fluoroquinolone resistance in Haemophilus parasuis isolated from pigs in South China. J Antimicrob Chemother 66,539-542.
Hjarre, A.W.G.1943. uber die fibrinose Serosa-Gelenkentzundung (Glasser) beim Schwein. Zeitschrift fur Infektionskrankheiten, p.60.
Holt, J.G.1994. Bergey's manual of determinitive bacteriology, Krieg, N.R., ed. (U.S.A, Williams & Wilkins), p.279.
Homma, T., Hori, T., Sugimori, G., Yamano, Y.,2007. Pharmacodynamic assessment based on mutant prevention concentrations of fluoroquinolones to prevent the emergence of resistant mutants of Streptococcus pneumoniae. Antimicrob Agents Chemother 51,3810-3815.
Hormansdorfer, S., Bauer, J.,1998. Resistance of bovine and porcine Pasteurella to florfenicol and other antibiotics. Berl Munch Tierarztl Wochenschr 111,422-426.
Hutter, B., Schaab, C., Albrecht, S., Borgmann, M., Brunner, N.A., Freiberg, C., Ziegelbauer, K., Rock, C.O., Ivanov, I., Loferer, H.,2004. Prediction of mechanisms of action of antibacterial compounds by gene expression profiling. Antimicrob Agents Chemother 48,2838-2844.
Ishii, H., Fukuyasu, T., Iyobe, S., Hashimoto, H.,1993. Characterization of newly isolated plasmids from Actinobacillus pleuropneumoniae. Am J Vet Res 54,701-708.
Ishii, H., Hayashi, F., Iyobe, S., Hashimoto, H.,1991. Characterization and classification of Actinobacillus (Haemophilus) pleuropneumoniae plasmids. Am J Vet Res 52, 1816-1820.
Ito, H., Ishii, H., Akiba, M.,2004. Analysis of the complete nucleotide sequence of an Actinobacillus pleuropneumoniae streptomycin-sulfonamide resistance plasmid, pMS260. Plasmid 51,41-47.
Jacoby, G.A., Walsh, K.E., Mills, D.M., Walker, V.J., Oh, H., Robicsek, A., Hooper, D.C.,2006. qnrB, another plasmid-mediated gene for quinolone resistance. Antimicrob Agents Chemother 50,1178-1182.
Jayaraman, R.,2008. Bacterial persistence:some new insights into an old phenomenon. J Biosci 33,795-805.
Jin, H., Zhou, R., Kang, M.S., Luo, R., Cai, X.W., Chen, H.C.,2006. Biofilm formation by field isolates and reference strains of Haemophilus parasuis. Vet Microbiol 118, 117-123.
Jung, K., Ha, Y., Kim, S.H., Chae, C.,2004. Development of polymerase chain reaction and comparison with in situ hybridization for the detection of Haemophilus parasuis in formalin-fixed, paraffin-embedded tissues. J Vet Med Sci 66,841-845.
K., G.1910. Die fibrinose Serosen-und Gelenkentzundung der Ferkel (Die Krankheiten des Schweines. M.& H. Schaper, Hannover), pp.122-125.
Karg, G., Bilkei, G.,2002. The effect of season and vaccination for Glasser's disease and post-weaning Colibacillosis in an outdoor pig unit endemically infected with virulent strain of Haemophilus Parasuis serotype 5 and pathogenic Escherichia coli. J Vet Med B Infect Dis Vet Public Health 49,464-468.
Kehrenberg, C., Carry, B., Haesebrouck, F., de Kruif, A., Schwarz, S.,2005, Novel spectinomycin/streptomycin resistance gene, aadA14, from Pasteurella multocida. Antimicrob Agents Chemother 49,3046-3049.
Kehrenberg, C., Schulze-Tanzil, G., Martel, J.L., Chaslus-Dancla, E., Schwarz, S.,2001, Antimicrobial resistance in pasteurella and mannheimia:epidemiology and genetic basis. Vet Res 32,323-339.
Kehrenberg, C., Schwarz, S.,2005. dfrA20, A novel trimethoprim resistance gene from Pasteurella multocida. Antimicrob Agents Chemother 49,414-417.
Kehrenberg, C., Tham, N.T., Schwarz, S.,2003. New plasmid-borne antibiotic resistance gene cluster in Pasteurella multocida. Antimicrob Agents Chemother 47,2978-2980.
Kehrenberg, C., Werckenthin, C., Schwarz, S.,1998. Tn5706, a transposon-like element from Pasteurella multocida mediating tetracycline resistance. Antimicrob Agents Chemother 42,2116-2118.
Kielstein, P., Rapp-Gabrielson, V.J.,1992. Designation of 15 serovars of Haemophilus parasuis on the basis of immunodiffusion using heat-stable antigen extracts. J Clin Microbiol 30,862-865.
Kim, H.B., Park, C.H., Kim, C.J., Kim, E.C., Jacoby, G.A., Hooper, D.C.,2009. Prevalence of plasmid-mediated quinolone resistance determinants over a 9-year period. Antimicrob Agents Chemother 53,639-645.
Kirkwood, R.N., Rawluk, S.A., Cegielski, A.C., Otto, A.J.,2001. Effect of pig age and autogenous sow vaccination on nasal mucosal colonization of pigs by Haemophilus parasuis. J Swine Health Prod 9,77-80.
Lancashire, J.F., Terry, T.D., Blackall, P.J., Jennings, M.P.,2005. Plasmid-encoded tet B tetracycline resistance in Haemophilus parasuis. Antimicrob Agents Ch 49, 1927-1931.
Levin, B.R., Rozen, D.E.,2006, Non-inherited antibiotic resistance. Nat Rev Microbiol 4, 556-562.
Levy, S.B.,1992. Active efflux mechanisms for antimicrobial resistance. Antimicrob Agents Chemother 36,695-703.
Levy, S.B., Marshall, B.,2004. Antibacterial resistance worldwide:causes, challenges and responses. Nat Med 10, S122-S129.
Li, J.X., Jiang, P., Wang, Y., Li, Y.F., Chen, W., Wang, X.W., Li, P.,2009. Genotyping of Haemophilus parasuis from diseased pigs in China and prevalence of two coexisting virus pathogens. Prev Vet Med 91,274-279.
Li, X.Z.,2005. Quinolone resistance in bacteria:emphasis on plasmid-mediated mechanisms. Int J Antimicrob Agents 25,453-463.
Li, X.Z., Nikaido, H.,2004. Efflux-mediated drug resistance in bacteria. Drugs 64, 159-204.
Li, X.Z., Nikaido, H.,2009. Efflux-mediated drug resistance in bacteria:an update. Drugs 69,1555-1623.
Lichtensteiger, C.A., Vimr, E.R.,1997. Neuraminidase (sialidase) activity of Haemophilus parasuis. Ferns Microbiol Lett 152,269-274.
Lichtensteiger, C.A., Vimr, E.R.,2003. Purification and renaturation of membrane neuraminidase from Haemophilus parasuis. Vet Microbiol 93,79-87.
Linares, J.F., Gustafsson, I., Baquero, F., Martinez, J.L.,2006. Antibiotics as intermicrobial signaling agents instead of weapons. Proc Natl Acad Sci U S A 103, 19484-19489.
Little, T.W.,1970. Haemophilus infection in pigs. Vet Rec 87,399-402.
Lu, Q., Wei, W., Kowalski, P.E., Chang, A.C., Cohen, S.N.,2004. EST-based genome-wide gene inactivation identifies ARAP3 as a host protein affecting cellular susceptibility to anthrax toxin. Proc Natl Acad Sci U S A 101,17246-17251.
Luis Martinez, J., Fajardo, A., Garmendia, L., Hernandez, A., Francisco Linares, J., L., Blanca Sanchez, M.,2009. A global view of antibiotic resistance. Fems Microbiol Rev 33,44-65.
Ma, J., Zeng, Z., Chen, Z., Xu, X., Wang, X., Deng, Y., Lu, D., Huang, L., Zhang, Y., Liu, J., Wang, M.,2009. High prevalence of plasmid-mediated quinolone resistance determinants qnr, aac(6')-Ib-cr, and qepA among ceftiofur-resistant Enterobacteriaceae isolates from companion and food-producing animals. Antimicrob Agents Chemother 53,519-524.
MacInnes, J.I., Paradis, M.A., Vessie, G.H., Slavic, L., Watson, S., Wilson, J.B., Aramini, J.J., Dick, C.P.,2003. Efficacy of prophylactic tilmicosin in the control of experimentally induced Haemophilus parasuis infection in pigs. J Swine Health Prod 11,174-180.
Marshall, C.G., Lessard, I.A., Park, I., Wright, G.D.,1998. Glycopeptide antibiotic resistance genes in glycopeptide-producing organisms. Antimicrob Agents Chemother 42,2215-2220.
Martinez, J.L., Baquero, F.,2000. Mutation frequencies and antibiotic resistance. Antimicrob Agents Chemother 44,1771-1777.
Martinez, J.L., Baquero, F., Andersson, D.I.,2007. Predicting antibiotic resistance. Nat Rev Microbiol 5,958-965.
Martinez, J.L., Rojo, F.,2011, Metabolic regulation of antibiotic resistance. Ferns Microbiol Rev 35,768-789.
Martinez-Martinez, L., Pascual, A., Jacoby, G.A.,1998. Quinolone resistance from a transferable plasmid. Lancet 351,797-799.
McVicker, J.K., Tabatabai, L.B.,2006. Isolation and characterization of the P5 adhesin protein of Haemophilus parasuis serotype 5. Prep Biochem Biotechnol 36,363-374.
Metcalf, D.S., MacInnes, J.I.,2007. Differential expression of Haemophilus parasuis genes in response to iron restriction and cerebrospinal fluid. Can J Vet Res 71, 181-188.
Miniats, O.P., Smart, N.L., Ewert, E.,1991. Vaccination of gnotobiotic primary specific pathogen-free pigs against Haemophilus parasuis. Can J Vet Res 55,33-36.
Miniats, O.P., Smart, N.L., Rosendal, S.,1991. Cross protection among Haemophilus parasuis strains in immunized gnotobiotic pigs. Can J Vet Res 55,37-41.
Monnet, D.L., Ferech, M., Frimodt-Moller, N., Goossens, H.,2005. The more antibacterial trade names, the more consumption of antibacterials:a European study. Clin Infect Dis 41,114-117.
Morozumi, T., Nicolet, J.,1986. Morphological variations of Haemophilus parasuis strains. J Clin Microbiol 23,138-142.
Mosher, R.H., Camp, D.J., Yang, K., Brown, M.P., Shaw, W.V., Vining, L.C.,1995. Inactivation of chloramphenicol by O-phosphorylation. A novel resistance mechanism in Streptomyces venezuelae ISP5230, a chloramphenicol producer. J Biol Chem 270,27000-27006.
Moyed, H.S., Bertrand, K.P.,1983, hipA, a newly recognized gene of Escherichia coli K-12 that affects frequency of persistence after inhibition of murein synthesis. J Bacteriol 155,768-775.
Narita, M., Kawashima, K., Matsuura, S., Uchimura, A., Miura, Y.,1994. Pneumonia in pigs infected with pseudorabies virus and Haemophilus parasuis serovar 4. J Comp Pathol 110,329.
Nodwell, J.R.,2007. Novel links between antibiotic resistance and antibiotic production. J Bacteriol 189,3683-3685.
Ohlsen, K., Ziebuhr, W., Koller, K.P., Hell, W., Wichelhaus, T.A., Hacker, J.,1998. Effects of subinhibitory concentrations of antibiotics on alpha-toxin (hla) gene expression of methicillin-sensitive and methicillin-resistant Staphylococcus aureus isolates. Antimicrob Agents Chemother 42,2817-2823.
Oliveira, S., Batista, L., Torremorell, M., Pijoan, C.,2001. Experimental colonization of piglets and gilts with systemic strains of Haemophilus parasuis and Streptococcus suis to prevent disease. Can J Vet Res 65,161-167.
Oliveira, S., Blackall, P.J., Pijoan, C.,2003. Characterization of the diversity of Haemophilus parasuis field isolates by use of serotyping and genotyping. Am J Vet Res 64,435-442.
Oliveira, S., Galina, L., Pijoan, C.,2001. Development of a PCR test to diagnose Haemophilus parasuis infections. J Vet Diagn Invest 13,495-501.
Oliveira, S., Pijoan, C.,2004a. Haemophilus parasuis:new trends on diagnosis, epidemiology and control. Vet Microbiol 99,1-12.
Oliveira, S., Pijoan, C.,2004b. Computer-based analysis of Haemophilus parasuis protein fingerprints. Canadian J. Vet Res-Revue Canadienne De Recherche Veterinaire 68, 71-75.
Olliver, A., Valle, M., Chaslus-Dancla, E., Cloeckaert, A.,2005. Overexpression of the multidrug efflux operon acrEF by insertional activation with IS1 or IS 10 elements in Salmonella enterica serovar typhimurium DT204 acrB mutants selected with fluoroquinolones. Antimicrob Agents Chemother 49,289-301.
Olvera, A., Calsamiglia, M., Aragon, V.,2006. Genotypic diversity of Haemophilus parasuis field strains. Appl Environ Microbiol 72,3984-3992.
Olvera, A., Cerda-Cuellar, M., Mentaberre, G., Casas-Diaz, E., Lavin, S., Marco, I., Aragon, V.,2007. First isolation of Haemophilus parasuis and other NAD-dependent Pasteurellaceae of swine from European wild boars. Vet Microbiol 125,182-186.
Olvera, A., Segales, J., Aragon, V.,2007, Update on the diagnosis of Haemophilus parasuis infection in pigs and novel genotyping methods. Vet J 174,522-529.
Parker, C., Becker, E., Zhang, X., Jandle, S., Meyer, R.,2005, Elements in the co-evolution of relaxases and their origins of transfer. Plasmid 53,113-118.
Perichon, B., Courvalin, P., Galimand, M.,2007. Transferable resistance to aminoglycosides by methylation of G1405 in 16S rRNA and to hydrophilic fluoroquinolones by QepA-mediated efflux in Escherichia coli. Antimicrob Agents Ch 51,2464-2469.
Philips, J.A., Rubin, E.J., Perrimon, N.,2005. Drosophila RNAi screen reveals CD36 family member required for mycobacterial infection. Science 309,1251-1253.
Pijoan, C., Morrison, R.B., Hilley, H.D.,1983. Dilution technique for isolation of Haemophilus from swine lungs collected at slaughter. J Clin Microbiol 18,143-145.
Rafiee, M., Bara, M., Stephens, C.P., Blackall, P.J.,2000. Application of ERIC-PCR for the comparison of isolates of Haemophilus parasuis. Aust Vet J 78,846-849.
Rafiee, M., Blackall, P.J.,2000. Establishment, validation and use of the Kielstein-Rapp-Gabrielson serotyping scheme for Haemophilus parasuis. Aust Vet J 78,172-174.
Rani, S.A., Pitts, B., Beyenal, H., Veluchamy, R.A., Lewandowski, Z., Davison, W.M., Buckingham-Meyer, K., Stewart, P.S.,2007. Spatial patterns of DNA replication, protein synthesis, and oxygen concentration within bacterial biofilms reveal diverse physiological states. J Bacteriol 189,4223-4233.
Rapp-Gabrielson, V.J., Gabrielson, D.A.,1992. Prevalence of Haemophilus parasuis serovars among isolates from swine. Am J Vet Res 53,659-664.
Rapp-Gabrielson, V.J., Gabrielson, D.A., Schamber, G.J.,1992, Comparative virulence of Haemophilus parasuis serovars 1 to 7 in guinea pigs. Am J Vet Res 53,987-994.
Reece, R.J., Maxwell, A.,1991, DNA gyrase:structure and function. Crit Rev Biochem Mol Biol 26,335-375.
Riising, H.J.,1981, Prevention of Glasser's disease through immunity to Haemophilus parasuis. Zentralbl Veterinarmed B 28,630-638.
Riley, M., Abe, T., Arnaud, M.B., Berlyn, M.K., Blattner, F.R., Chaudhuri, R.R., Glasner, J.D., Horiuchi, T., Keseler, I.M., Kosuge, T., Mori, H., Perna, N.T., Plunkett, G.R., Rudd, K.E., Serres, M.H., Thomas, G.H., Thomson, N.R., Wishart, D., Wanner, B.L., 2006. Escherichia coli K-12:a cooperatively developed annotation snapshot--2005. Nucleic Acids Res 34,1-9.
Robicsek, A., Strahilevitz, J., Jacoby, G.A., Macielag, M., Abbanat, D., Park, C.H., Bush, K., Hooper, D.C.,2006. Fluoroquinolone-modifying enzyme:a new adaptation of a common aminoglycoside acetyltransferase. Nat Med 12,83-88.
Rogers, P.D., Liu, T.T., Barker, K.S., Hilliard, G.M., English, B.K., Thornton, J., Swiatlo, E., McDaniel, L.S.,2007. Gene expression profiling of the response of Streptococcus pneumoniae to penicillin. J Antimicrob Chemother 59,616-626.
Ruiz, A., Oliveira, S., Torremorell, M., Pijoan, C.,2001. Outer membrane proteins and DNA profiles in strains of Haemophilus parasuis recovered from systemic and respiratory sites. J Clin Microbiol 39,1757-1762.
San, M.A., Escudero, J.A., Catalan, A., Nieto, S., Farelo, F., Gibert, M., Moreno, M.A., Dominguez, L., Gonzalez-Zorn, B.,2007. Beta-lactam resistance in Haemophilus parasuis Is mediated by plasmid pB1000 bearing blaROB-1. Antimicrob Agents Chemother 51,2260-2264.
Sandegren, L., Lindqvist, A., Kahlmeter, G., Andersson, D.I.,2008. Nitrofurantoin resistance mechanism and fitness cost in Escherichia coli. J Antimicrob Chemother 62,495-503.
Schreiber, A.W., Baumann, U.,2007. A framework for gene expression analysis. Bioinformatics 23,191-197.
Schumacher, M.A., Piro, K.M., Xu, W., Hansen, S., Lewis, K., Brennan, R.G.,2009, Molecular mechanisms of HipA-mediated multidrug tolerance and its neutralization by HipB. Science 323,396-401.
Schwarz, S., Kehrenberg, C., Doublet, B., Cloeckaert, A.,2004. Molecular basis of bacterial resistance to chloramphenicol and florfenicol. Ferns Microbiol Rev 28, 519-542.
Scortti, M., Lacharme-Lora, L., Wagner, M., Chico-Calero, I., Losito, P., Vazquez-Boland, J.A.,2006. Coexpression of virulence and fosfomycin susceptibility in Listeria:molecular basis of an antimicrobial in vitro-in vivo paradox. Nat Med 12,515-517.
Segales, J., Domingo, M., Balasch, M., Solano, G.I., Pijoan, C.,1998. Ultrastructural study of porcine alveolar macrophages infected in vitro with porcine reproductive and respiratory syndrome (PRRS) virus, with and without Haemophilus parasuis. J Comp Pathol 118,231-243.
Segales, J., Domingo, M., Solano, G.I., Pijoan, C.,1997, Immunohistochemical detection of Haemophilus parasuis serovar 5 in formalin-fixed, paraffin-embedded tissues of experimentally infected swine. J Vet Diagn Invest 9,237-243.
Seminati, C., Mejia, W., Mateu, E., Martin, M.,2005. Mutations in the quinolone-resistance determining region (QRDR) of Salmonella strains isolated from pigs in Spain. Vet Microbiol 106,297-301.
Shaw, K.J., Miller, N., Liu, X., Lerner, D., Wan, J., Bittner, A., Morrow, B.J.,2003. Comparison of the changes in global gene expression of Escherichia coli induced by four bactericidal agents. J Mol Microbiol Biotechnol 5,105-122.
Sheng, W.H., Lin, Y.C., Wang, J.T., Chen, Y.C., Chang, S.C., Hsia, K.C., Wu, R.J., Li, S.Y.,2009. Identification of distinct ciprofloxacin susceptibility in Acinetobacter spp. by detection of the gyrA gene mutation using real-time PCR. Mol Cell Probes 23, 154-156.
Simone Oliveira, C.P.,2002. Diagnosis of Haemophilus parasuis in affected herds and use of epidemiological data to control disease. J Swine Health Prod 10,221-225.
Sindelar, G., Zhao, X., Liew, A., Dong, Y., Lu, T., Zhou, J., Domagala, J., Drlica, K., 2000. Mutant prevention concentration as a measure of fluoroquinolone potency against mycobacteria. Antimicrob Agents Chemother 44,3337-3343.
Solano, G.I., Bautista, E., Molitor, T.W., Segales, J., Pijoan, C.,1998, Effect of porcine reproductive and respiratory syndrome virus infection on the clearance of Haemophilus parasuis by porcine alveolar macrophages. Canadian journal of veterinary research 62,251.
Solano, G.I., Segales, J., Collins, J.E., Molitor, T.W., Pijoan, C.,1997, Porcine reproductive and respiratory syndrome virus (PRRSV) interaction with Haemophilus parasuis. Vet Microbiol 55,247-257.
Solano-Aguilar, G.I., Pijoan, C., Rapp-Gabrielson, V., Collins, J., Carvalho, L.F., Winkelman, N.,1999. Protective role of maternal antibodies against Haemophilus parasuis infection. Am J Vet Res 60,81-87.
Spigaglia, P., Carattoli, A., Barbanti, F., Mastrantonio, P.,2010. Detection of gyrA and gyrB mutations in Clostridium difficile isolates by real-time PCR. Mol Cell Probes 24,61-67.
Spoering, A.L., Lewis, K.,2001. Biofilms and planktonic cells of Pseudomonas aeruginosa have similar resistance to killing by antimicrobials. J Bacteriol 183, 6746-6751.
Sundin, G.W., Bender, C.L.,1996, Dissemination of the strA-strB streptomycin-resistance genes among commensal and pathogenic bacteria from humans, animals, and plants. Mol Ecol 5,133-143.
Tadjine, A., Mittal, K.R., Bourdon, S., Gottschalk, M.,2004. Development of a new serological test for serotyping Haemophilus parasuis isolates and determination of their prevalence in north America. J Clin Microbiol 42,839-840.
Talukder, K.A., Khajanchi, B.K., Islam, M.A., Islam, Z., Dutta, D.K., Rahman, M., Watanabe, H., Nair, G.B., Sack, D.A.,2006. Fluoroquinolone resistance linked to both gyrA and parC mutations in the quinolone resistance-determining region of Shigella dysenteriae type 1. Curr Microbiol 52,108-111.
Tang, X., Zhao, Z., Hu, J., Wu, B., Cai, X., He, Q., Chen, H.,2009. Isolation, antimicrobial resistance, and virulence genes of Pasteurella multocida strains from swine in China. J Clin Microbiol 47,951-958.
Tran, J.H., Jacoby, G.A.,2002, Mechanism of plasmid-mediated quinolone resistance. Proc Natl Acad Sci U S A 99,5638-5642.
Turni, C., Blackall, P.J.,2005. Comparison of the indirect haemagglutination and gel diffusion test for serotyping Haemophilus parasuis. Vet Microbiol 106,145-151.
Turni, C., Blackall, P.J.,2007. Comparison of sampling sites and detection methods for Haemophilus parasuis. Aust Vet J 85,177-184.
Turni, C., Pyke, M., Blackall, P.J.,2009. Validation of a real-time PCR for Haemophilus parasuis. J Appl Microbiol.
Vahle, J.L., Haynes, J.S., Andrews, J.J.,1997. Interaction of Haemophilus parasuis with nasal and tracheal mucosa following intranasal inoculation of cesarean derived colostrum deprived (CDCD) swine. Can J Vet Res 61,200-206.
Vanier, G., Szczotka, A., Friedl, P., Lacouture, S., Jacques, M., Gottschalk, M.,2006, Haemophilus parasuis invades porcine brain microvascular endothelial cells. Microbiol-Sgm 152,135-142.
Vashist, J., Vishvanath, Kapoor, R., Kapil, A., Yennamalli, R., Subbarao, N., Rajeswari, M.R.,2009. Interaction of nalidixic acid and ciprofloxacin with wild type and mutated quinolone-resistance-determining region of DNA gyrase A. Indian J Biochem Biophys 46,147-153.
Waddell, S.J., Stabler, R.A., Laing, K., Kremer, L., Reynolds, R.C., Besra, G.S.,2004. The use of microarray analysis to determine the gene expression profiles of Mycobacterium tuberculosis in response to anti-bacterial compounds. Tuberculosis (Edinb) 84,263-274.
Waksman, S.A., Woodruff, H.B.,1940. The Soil as a Source of Microorganisms Antagonistic to Disease-Producing Bacteria. J Bacteriol 40,581-600.
Webber, M.A., Talukder, A., Piddock, L.J.,2005, Contribution of mutation at amino acid 45 of AcrR to acrB expression and ciprofloxacin resistance in clinical and veterinary Escherichia coli isolates. Antimicrob Agents Chemother 49,4390-4392.
Weir, E.K., Martin, L.C., Poppe, C., Coombes, B.K., Boerlin, P.,2008. Subinhibitory concentrations of tetracycline affect virulence gene expression in a multi-resistant Salmonella enterica subsp. enterica serovar Typhimurium DT104. Microbes Infect 10, 901-907.
Willson, P.J., Deneer, H.G., Potter, A., Albritton, W.,1989. Characterization of a streptomycin-sulfonamide resistance plasmid from Actinobacillus pleuropneumoniae. Antimicrob Agents Chemother 33,235-238.
Wilson, M., DeRisi, J., Kristensen, H.H., Imboden, P., Rane, S., Brown, P.O., Schoolnik, G.K.,1999. Exploring drug-induced alterations in gene expression in Mycobacterium tuberculosis by microarray hybridization. Proc Natl Acad Sci U S A 96, 12833-12838.
Wissing, A., Nicolet, J., Boerlin, P.,2001. [The current antimicrobial resistance situation in Swiss veterinary medicine]. Schweiz Arch Tierheilkd 143,503-510.
Wright, C.L., Strugnell, R.A., Hodgson, A.L.,1997. Characterization of a Pasteurella multocida plasmid and its use to express recombinant proteins in P. multocida. Plasmid 37,65-79.
Wright, G.D.,2007. The antibiotic resistome:the nexus of chemical and genetic diversity. Nat Rev Microbiol 5,175-186.
Xu, Z., Yue, M., Zhou, R., Jin, Q., Fan, Y., Bei, W., Chen, H.,2011. Genomic characterization of Haemophilus parasuis SH0165, a highly virulent strain of serovar 5 prevalent in China. PLoS One 6, e19631.
Yamamoto, J., Sakano, T., Shimizu, M.,1990. Drug resistance and R plasmids in Pasteurella multocida isolates from swine. Microbiol Immunol 34,715-721.
Yeh, P.J., Hegreness, M.J., Aiden, A.P., Kishony, R.,2009. SYSTEMS MICROBIOLOGY-OPINION Drug interactions and the evolution of antibiotic resistance. Nature reviews microbiology 7,460-466.
Yim, G., Wang, H.H., Davies, J.,2006. The truth about antibiotics. Int J Med Microbiol 296,163-170.
Yoshida, H., Bogaki, M., Nakamura, M., Nakamura, S.,1990, Quinolone resistance-determining region in the DNA gyrase gyrA gene of Escherichia coli. Antimicrob Agents Chemother 34,1271-1272.
Yue, L., Jiang, H.X., Liao, X.P., Liu, J.H., Li, S.J., Chen, X.Y., Chen, C.X., Lu, D.H., Liu, Y.H.,2008. Prevalence of plasmid-mediated quinolone resistance qnr genes in poultry and swine clinical isolates of Escherichia coli. Vet Microbiol 132,414-420.
Yue, M., Yang, F., Yang, J., Bei, W., Cai, X., Chen, L., Dong, J., Zhou, R., Jin, M., Jin, Q., Chen, H.,2009. Complete genome sequence of Haemophilus parasuis SH0165. J Bacteriol 191,1359-1360.
Zapun, A., Contreras-Martel, C., Vernet, T.,2008. Penicillin-binding proteins and beta-lactam resistance. Ferns Microbiol Rev 32,361-385.
Zhang, X., Zhang, T., Fang, H.H.P.,2009. Antibiotic resistance genes in water environment. Appl Microbiol Biot 82,397-414.
Zhao, J., Chen, Z., Chen, S., Deng, Y., Liu, Y., Tian, W., Huang, X., Wu, C, Sun, Y., Sun, Y., Zeng, Z., Liu, J.H.,2010. Prevalence and dissemination of oqxAB in Escherichia coli isolates from animals, farmworkers, and the environment. Antimicrob Agents Chemother 54,4219-4224.
Zhou, X., Xu, X., Zhao, Y., Chen, P., Zhang, X., Chen, H., Cai, X.,2009, Distribution of antimicrobial resistance among different serovars of Haemophilus parasuis isolates. Vet Microbiol.141.168-730.