Antimicrobial susceptibility of

Acta Veterinaria Hungarica 57 (3), pp. 357–367 (2009) DOI: 10.1556/AVet.57.2009.3.2

ANTIMICROBIAL SUSCEPTIBILITY OF PASTEURELLA MULTOCIDA ISOLATED FROM SWINE AND POULTRY Boglárka SELLYEI1, Zsuzsanna VARGA1, Katalin SZENTESI-SAMU2, Éva KASZANYITZKY2 and Tibor MAGYAR1* 1

Veterinary Medical Research Institute of the Hungarian Academy of Sciences, P.O. Box 18, H-1581 Budapest, Hungary; 2Central Agricultural Office, Veterinary Diagnostic Directorate, Budapest, Hungary (Received 13 January 2009; accepted 23 March 2009)

Pasteurella multocida causes infectious diseases in a wide range of animal species. Antimicrobial therapy is still an effective tool for treatment. Generally, P. multocida isolates are susceptible to most of the widely used commercial antimicrobial agents but their excessive and unjustified use accelerates the emergence of resistant strains. We defined the antimicrobial sensitivity pattern of 56 P. multocida strains isolated from poultry (20) and swine [16 P. multocida toxin (PMT) positive and 20 PMT negative] to 16 widely applied antibiotics (apramycin, cefquinome, chloramphenicol, colistin, doxycycline, enrofloxacin, erythromycin, florfenicol, flumequine, neomycin, oxolinic acid, penicillin, trimethoprim potentiated sulphamethoxazole, sulphonamide compounds, tetracycline, tulathromycin) by the disk diffusion method. The majority of the strains was susceptible to most of the antimicrobial agents tested. However, the resistance to sulphonamides, tetracyclines, first-generation quinolones and aminoglycosides was remarkable, and thus the use of these compounds for the treatment of infection caused by P. multocida is not recommended. On the other hand, the antimicrobial activity of the classical penicillin, the newer macrolide (tulathromycin), the third-generation fluoroquinolone (enrofloxacin) and the fourth-generation cephalosporin (cefquinome) proved to be satisfactory against this bacterium. Key words: Pasteurella multocida, swine, poultry, antibiotics

Pasteurella multocida is a natural inhabitant of the mucosal surfaces of vertebrates. It can survive in the upper part of the respiratory tract of clinically *

Corresponding author; E-mail: [email protected]; Phone: 0036 (1) 467-4092; Fax: 0036 (1) 467-4076 0236-6290/$ 20.00 © 2009 Akadémiai Kiadó, Budapest

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healthy animals and may occasionally cause disease. Among others, P. multocida is responsible for fowl cholera in poultry (Rimler and Rhoades, 1989), atrophic rhinitis in swine (Chanter and Rutter, 1989) and haemorrhagic septicaemia in cattle and buffaloes (Aalbaek et al., 1999). As a secondary invader, it frequently plays a major role in the progression to severe form of pleuropneumonia in swine and ruminants (Chanter and Rutter, 1989). Antimicrobial therapy is still the most effective tool for the treatment of infectious diseases caused by P. multocida. For appropriate therapy it is necessary to isolate the causative organism and define its in vitro antibiotic sensitivity. Due to the time-consuming nature of these laboratory procedures it is common to start antibiotic therapy against the supposed pathogen immediately after observing the clinical signs. With the widespread existence of antimicrobial resistance, the efficiency of these pre-diagnostic therapies is doubtful even if the choice of antibiotics is based on experience or expert opinions. The excessive and unjustified use of antimicrobial agents puts considerable selective pressure on genes encoding antibiotic resistance. For this reason, the data of national antimicrobial resistance monitoring programmes are important. However, such programmes concerning the genus Pasteurella are going on in a few European countries only (Kehrenberg et al., 2001). In the present study we determined the antimicrobial susceptibility patterns of P. multocida strains isolated from poultry and swine in Hungary. Since the antibiotic sensitivity pattern of a bacterium is useful for the general characterisation of the microorganism, some antibiotics not suitable for the treatment of diseases caused by P. multocida were also used. Materials and methods Bacterial strains Fifty-six P. multocida strains were studied (Table 1). The strains were collected from various geographic locations in Hungary from 2005 to 2008. Twenty strains were isolated from poultry [7 from geese, 7 from domesticated ducks (Anas species); 1 from Muscovy duck (Cairina moschata); 3 from turkeys, 1 from chicken and 1 from pheasant], while 36 strains were isolated from swine. Of the latter strains, 16 produced P. multocida toxin (PMT) whereas 20 were PMT negative. Of the strains of avian origin, 8 strains (5 from goose, 2 from turkey and 1 from pheasant) were isolated from cases of avian pasteurellosis, while 12 strains were isolated from cases of fowl cholera. Four PMT-negative and 8 PMT-positive strains were recovered from nasal swabs collected from swine herds where atrophic rhinitis had been suspected. Sixteen PMT-negative and 8 PMT-positive strains were isolated from swine suffering from pneumonia. The strains had been characterised for other phenotypic and genotypic features earlier (Varga et al., 2007; Sellyei et al., 2008). Acta Veterinaria Hungarica 57, 2009

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Agar disc diffusion method Sensitivity of the P. multocida strains was evaluated against 16 widely used antibiotics. Tulathromycin 30 µg antimicrobial discs were used from Pfizer (Karlsruhe, Germany), and the following antimicrobial discs were produced by Oxoid (Basingstoke, Hampshire, UK): apramycin 15 µg, cefquinome 10 µg, chloramphenicol 30 µg, colistin 10 µg, doxycycline 30 µg, enrofloxacin 5.0 µg, erythromycin 15 µg, florfenicol 30 µg, flumequine 30 µg, neomycin 30 µg, oxolinic acid 2.0 µg, penicillin 10 U, sulphamethoxazole / trimethoprim (19:1) 300 µg, sulphonamides compound 300 µg, tetracycline 30 µg. The tests were carried out according to the guidelines of the National Committee for Clinical Laboratory Standards (2003). The strains were grown on Columbia agar (Nebotrade, Biatorbágy, Hungary) plates supplemented with 5% sheep blood at 37 °C for 24 h. Then the bacterial growth was suspended in saline. The turbidity was adjusted to 0.5 on the scale of McFarland standards. The agar disc diffusion test was performed on Mueller-Hinton agar (Oxoid, Basingstoke, Hampshire, UK) plates supplemented with 5% sheep blood. The bacterial suspension was streaked evenly over the entire surface of the agar with a swab soaked into the suspension. The plates were allowed to dry for a few minutes and the antimicrobial discs were placed on the surface approximately 2 cm apart. Then they were incubated at 35 °C for 18 h. The inhibition zones were measured with a ruler to the nearest millimetre. The strains were classified as sensitive, intermediate or resistant, using the zone diameter standards of the National Committee for Clinical Laboratory Standards (2003). Results and discussion The results of the disc diffusion test are shown in Tables 2 and 3. Generally, P. multocida isolates were susceptible to most of the widely used commercial antimicrobial agents. Strains with different antimicrobial resistance patterns are always present in animal populations. Their number and types may vary according to host species, geographical origin and antimicrobial treatments previously applied in the given population. In our study, although the number of different resistance patterns was equal (9 each) in both host groups (Table 4), the rate of resistance was slightly higher in the P. multocida strains from poultry (60%) than in those from swine (42%). The range of resistance to different individual antimicrobial agents was more diverse among isolates from swine than among strains isolated from poultry (9 and 7, respectively). We paid special attention to PMT-producing P. multocida strains, the causative agent of atrophic rhinitis in swine. These strains possessed resistance only to sulphonamides and apramycin, and the overall rate of this resistance was notably low (19%).

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Table 1 Origin of the Pasteurella multocida strains used in the study ID

Host

Date

Place

Organ

Diagnosis

P531 P538 P547/1 P553/1 P559 P569 P598 P672 P676 P689 P746 P762 P773 P778 P811 P855 P856 P876 P891 P898

turkey duck duck chicken duck goose duck turkey Muscovy duck goose goose turkey duck duck pheasant goose goose goose duck goose

2005 2005 2005 2005 2005 2006 2006 2006 2006 2006 2007 2007 2007 2007 2007 2008 2008 2008 2008 2008

Dunatetétlen Pusztavacs Budapest Ásotthalom Gyula Rém Törtel Kübekháza Jászszentlászló Lajosmizse Cered Érsekcsanád Szakmár Tiszaalpár Sződ Jászalsószentgyörgy Kecskemét Mélykút Kiskunfélegyháza Tiszaföldvár

lung liver heart heart heart cerebral cavity heart heart liver heart heart joint heart heart heart liver heart heart heart phallus

fowl cholera fowl cholera fowl cholera fowl cholera fowl cholera avian pasteurellosis fowl cholera avian pasteurellosis fowl cholera fowl cholera avian pasteurellosis avian pasteurellosis fowl cholera fowl cholera avian pasteurellosis avian pasteurellosis fowl cholera avian pasteurellosis fowl cholera avian pasteurellosis

nose nose tonsil nose lung lung lung lung lung lung lung lung lung lung lung lung lung lung lung lung

NA NA NA NA pneumonia pneumonia pneumonia pneumonia pneumonia pneumonia pneumonia pneumonia pneumonia pneumonia pneumonia pneumonia pneumonia pneumonia pneumonia pneumonia

PMT-negative swine strains P476 P477 P479 P480 P535 P677 P693 P706 P719 P723 P733 P740 P802 P833 P839 P863 P881 P885 P892 P903

swine swine swine swine swine swine swine swine swine swine swine swine swine swine swine swine swine swine swine swine

2005 2005 2005 2005 2005 2006 2006 2006 2006 2006 2007 2007 2007 2007 2007 2008 2008 2008 2008 2008

Table 1 continued on next page.


Bábolna Bábolna Bábolna Bábolna Kéleshalom Cegléd Dávod Szajk Pásztó Besnyő Borota Kisköre Verseg Küngős Ács Fehérvárcsurgó Jászladány Kiskunmajsa Budapest Bölcske


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Table 1 continued ID

Host

Date

Place

Organ

Diagnosis

lung lung lung lung nose nose nose lung lung lung nose lung nose nose nose nose

pneumonia pneumonia pneumonia pneumonia NA NA NA pneumonia pneumonia pneumonia NA pneumonia NA NA NA NA

PMT-positive swine strains P688 P711/1 P711/2 P738 P752/1 P752/2 P753 P758 P760 P806 P824 P849 P870 P871 P873 P874

swine swine swine swine swine swine swine swine swine swine swine swine swine swine swine swine

2006 2006 2006 2007 2007 2007 2007 2007 2007 2007 2007 2007 2008 2008 2008 2008

Bácsalmás Budapest Budapest Solt Rábakecöl Rábakecöl Rábakecöl Rábakecöl Gyomaendrőd Seregélyes Döbrököz Mócsa Borota Hódmezővásárhely Tiszavasvári Tiszavasvári

NA = not applicable

Multiple drug resistance in P. multocida was reported by Chang and Carter (1976) and Hirsh et al. (1985). Plasmids encoding streptomycin, sulphonamides and/or tetracycline resistance were responsible for this phenomenon (Hirsh et al., 1985; Coté et al., 1991). During their continuous use for decades, these antibiotics promoted the survival of resistant isolates, especially under industrial housing conditions. We examined the antibiotic resistance of our isolates to sulphonamides and tetracycline but not to streptomycin. The rate of sulphonamide resistance was relatively high in our strains from both poultry (20%) and swine (17%). This resistance was present, although in a much lower percentage (6%), among the PMT-producing isolates as well. Sulphonamide-resistant P. multocida strains have increasingly been causing substantial problems in poultry flocks since the 1980s (Hirsh et al., 1985; Shivachandra et al., 2004). The incidence of this resistance was 25% among P. multocida strains isolated from swine at the beginning of the 1990s (Coté et al., 1991), and it reached 50% by the end of that decade (von Altrock, 1998). Besides the remarkable resistance to sulphonamides, resistance to the sulphamethoxazole / trimethoprim (SXT) combination was also present in a high percentage (20%) among our strains isolated from poultry, indicating that this powerful combination is losing its efficacy against P. multocida. On the other hand, SXT resistance was still remarkably lower (3%) than sulphonamide resistance (17%) in strains isolated from swine. The SXT was a good choice for the treatment of P. multocida infections during the 1990s, but subsequently SXT resistance started to spread quickly among P. multocida strains (Hörmansdorfer and Bauer, 1998; Lizarazo et al., 2006; Kaspar et al., 2007). Acta Veterinaria Hungarica 57, 2009

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Table 2 Antimicrobial susceptibility pattern of 56 Pasteurella multocida strains isolated from poultry and swine and tested with the disc diffusion method Antimicrobial agent

Apramycin Cefquinome Chloramphenicol Colistin Doxycycline Enrofloxacin Erythromycin Florfenicol Flumequine Neomycin Oxolinic acid Penicillin SXT* Sulphonamides Tetracycline Tulathromycin

% of poultry strains

% of swine strains

Sensitive

Intermediate

Resistant

Sensitive

Intermediate

Resistant

45 100 100 100 95 100 60 100 60 85 60 100 80 80 80 100

40 – – – 5 – 40 – – – – – – – 5 –

15 – – – – – – – 40 15 40 – 20 20 15 –

55.5 100 97 100 97 100 53 97 97 83 100 100 97 80 94 100

14 – – – – – 44 – – 17 – – – 3 – –

30.5 – 3 – 3 – 3 3 3 – – – 3 17 6 –

*

SXT = Sulphamethoxazole / trimethoprim (19:1) Table 3

Antimicrobial susceptibility pattern of 36 Pasteurella multocida strains [16 P. multocida toxin (PMT) positive and 20 PMT negative] isolated from swine and tested with the disc diffusion method Antimicrobial agent

Apramycin Cefquinome Chloramphenicol Colistin Doxycycline Enrofloxacin Erythromycin Florfenicol Flumequine Neomycin Oxolinic acid Penicillin SXT* Sulphonamides Tetracycline Tulathromycin

% of PMT-negative swine strains Sensitive

35 100 95 100 95 100 40 95 95 70 100 100 95 70 90 100

*

Intermediate

Resistant

20 – – – – – 55 – – 30 – – – 5 – –

SXT = Sulphamethoxazole / trimethoprim (19:1)


45 – 5 – 5 – 5 5 5 – – – 5 25 10 –

% of PMT-positive swine strains Sensitive

81.25 100 100 100 100 100 68.75 100 100 100 100 100 100 93.75 100 100

Intermediate

Resistant

6.25 – – – – – 31.25 – – – – – – – – –

12.5 – – – – – – – – – – – – 6.25 – –


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Table 4 Patterns of antimicrobial resistance of Pasteurella multocida isolates from poultry and swine No. of isolates

No. of antimicrobial agents

Resistance pattern

Poultry

8 2 1 1 1 3 1 1 1 1

0 1 1 1 1 2 4 5 6 7

– APR UB OA TE UB, OA UB, OA, SXT, S3 UB, OA, N, SXT, S3 UB, OA, N, SXT, S3, TE APR, UB, OA, N, SXT, S3, TE

Swine (non-toxic isolates)

8 4 1 1 1 1 1 1 1 1

0 1 1 1 2 2 2 3 3 4

– APR S3 TE APR, S3 APR, FFC C, S3 APR, SXT, S3 APR, UB, S3 APR, DO, E, TE

(toxic isolates)

13 2 1

0 1 1

– APR S3

Isolates from

Abbreviations: APR – apramycin, C – chloramphenicol, DO – doxycycline, E – erythromycin, FFC – florfenicol, UB – flumequine, OA – oxolinic acid, N – neomycin, SXT – sulphamethoxazole/ trimethoprim 19:1, S3 – sulphonamides compound, TE – tetracycline

Over the past forty years, tetracyclines have widely been used not only as therapeutic agents in veterinary medicine but also as growth promoters in animal husbandry. This is the most likely reason why an increased resistance to tetracyclines appeared in the P. multocida isolates from swine (15%) and poultry (40%) (Bousquet et al., 1997; Shivachandra et al., 2004). In our study, in conformity with data of the literature, the rate of tetracycline resistance was more than double among strains from poultry (15%) than in those from swine (6%). In the strains from poultry we could detect resistance to tetracycline only, while in the strains from swine a resistance to doxycycline also occurred, although at a lower rate (3%). In 10% of the strains from poultry, tetracycline resistance went hand in hand with resistances to sulphonamides and SXT. Nowadays the use of these Acta Veterinaria Hungarica 57, 2009

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antimicrobial agents is limited in order to try to slow down the emergence of bacterial resistance, and this measure may explain the fact that there is only a minor increase in resistance to tetracyclines (Lizarazo et al., 2006). Chloramphenicol resistance has rarely been detected in P. multocida. Among our isolates from swine, the proportion of chloramphenicol and florfenicol resistant isolates was only 3% each. Chloramphenicol had been an extensively used antibiotic in veterinary therapy over three decades before its use was restricted because of its toxicity. In Europe, its use in food-producing animals was finally banned in 1994. At that time, the ratio of chloramphenicol resistant strains was about 10–15% (Yamamoto et al., 1990; Hörmansdorfer and Bauer, 1998; Mevius and Hartman, 2000). Its fluorinated derivative, florfenicol, has been licensed in Europe for the control of respiratory pathogens in cattle and swine (Kehrenberg and Schwarz, 2005). In those days, most of the strains had been susceptible to this antimicrobial agent (Mevius and Hartman, 2000; Shin et al., 2005; Lizarazo et al., 2006). None of the tested P. multocida strains had shown resistance to either chloramphenicol or florfenicol until 2005 (Kehrenberg and Schwarz, 2005). The growing rate of resistance to sulphonamides, tetracycline and chloramphenicol led to the more and more widespread use of quinolones, a group of antibiotics having a novel structure. This group includes nalidixic acid and its synthetic analogues, as well as the quinolones and their fluorinated derivatives. Very little is known about quinolone resistance in P. multocida. Few reports have described quinolone-resistant isolates exhibiting different levels (2–16%) of resistance to nalidixic acid (Cardenas et al., 2001; Wallmann, 2006) or to flumequine (Pijpers et al., 1989; Mevius and Hartman, 2000). Enrofloxacin proved to be the most active fluoroquinolone against P. multocida (only 0–0.2% resistance: Lizarazo et al., 2006; Wallmann, 2006) except for strains from poultry (43% resistance: Jonas et al., 2001; 29% resistance: Shivachandra et al., 2004). This phenomenon was also noticed among our strains. The strains of porcine origin were susceptible to different quinolone derivatives with the exception of one flumequine-resistant isolate (3%). The strains of avian origin possessed a substantial rate of resistance to oxolinic acid (40%) and flumequine (40%). On the other hand, they were susceptible to enrofloxacin. Aminoglycosides are generally efficiently applicable for the treatment of infection caused by Gram-negative bacteria. However, their activity against P. multocida is relatively low and the rate of intermediate susceptibility is high (Karaivanov, 1983; Yosimura et al., 2001). Among our strains the number of strains intermediately or fully resistant to aminoglycosides (apramycin, neomycin) was considerable, irrespective of the host species. The distribution of resistance was not uniform. Apramycin resistance was frequent (30.5%) in the strains from swine. Among the poultry isolates, the ratio of strains resistant to apramycin and neomycin was equally 15%. The rate of intermediate susceptibility to apramycin was high in strains isolated from poultry and swine (40% and 14%, respectively). Strains showing moderate resistance to neomycin were present Acta Veterinaria Hungarica 57, 2009


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only among isolates from swine (17%). Apramycin resistance was remarkable (12.5%) while intermediate susceptibility to apramycin was lower (6.25%) among the PMT-producing isolates. Macrolide antibiotics became available from the 1950s. Erythromycin is the most widely used agent of this class. P. multocida strains are generally susceptible to erythromycin. The rate of resistance to that compound is only 2–4% (Lizarazo et al., 2006). Most of our isolates except one strain from swine (3%) were susceptible to erythromycin to some extent. However, intermediate susceptibility to erythromycin was equally high among strains from poultry (40%) as well as among PMT-negative (55%) and PMT-positive (31%) strains from swine. In contrast, all strains were susceptible to tulathromycin. The semisynthetic macrolide derivatives have the same antibacterial spectrum as erythromycin, the older representative of this class of antimicrobial agents; however, they proved to be more potent against pathogenic P. multocida especially in swine (Nanjiani et al., 2005). Therefore, semi-synthetic macrolides have gained wide acceptance for the treatment of dermatitis as well as upper and lower respiratory tract infections caused by P. multocida. Our data illustrate that the range of eligible antimicrobial agents against P. multocida is still wide. Although the level of resistance to commercial antibiotics is generally low, the use of sulphonamides, SXT, tetracyclines, aminoglycosides and first-generation quinolones against strains of avian origin and that of apramycin against isolates from swine are not recommended. The majority of the tested P. multocida strains proved to be susceptible to aminoglycosides (apramycin 52%; neomycin 84%) and erythromycin (55%) in a certain degree; however, the category of intermediate susceptibility (23%, 11% and 43%, respectively) was remarkably represented among the strains. Chloramphenicols are effective and resistance to them is rare in P. multocida. We found the classical penicillin, the newer macrolide (tulathromycin), the third-generation fluoroquinolone (enrofloxacin) and the fourth-generation cephalosporin (cefquinome) to be the most active antimicrobial agents against P. multocida. References Aalbaek, B., Eriksen, L., Rimler, R. B., Leifsson, P. S., Basse, A., Christiansen, T. and Eriksen, E. (1999): Typing of Pasteurella multocida from haemorrhagic septicaemia in Danish fallow deer (Dama dama). Acta Pathol. Microbiol. Immunol. Scand. 107, 913–920. Bousquet, E., Morvan, H., Aitken, I. and Morgan, J. H. (1997): Comparative in vitro activity of doxycycline and oxytetracycline against porcine respiratory pathogens. Vet. Rec. 141, 37–40. Cardenas, M., Barbé, J., Llagostera, M., Miró, E., Navarro, F., Mirelis, B., Prats, G. and 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.


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