Denagard Performance

Mixed Respiratory Infections

Denagard (tiamulin) combined with tetracyclines offers excellent efficacy against mixed respiratory infections in swine
KEY POINTS
l Mixed respiratory infections in pigs remain a leading herd health problem for pig producers and cause major economic losses. l An experimental infection study strongly indicates that Denagard (tiamulin) combined with chlortetracycline in feed can effectively control Mycoplasma hyopneumoniae, Pasteurella multocida and Actinobacillus pleuropneumoniae, pathogens that are major components of mixed respiratory infections. l MIC studies support the use of Denagard (tiamulin) combined with chlortetracycline or doxycycline, which offers broad spectrum control against many of the varied pathogens involved in mixed respiratory infections.

Introduction
Respiratory disease in pigs has long been a cause of major economic loss for pork producers. In 1995, the National Animal Health Monitoring System reported that respiratory disease was the leading cause of mortality in nurseries and grower-finisher units. Data collected from 1990 to 1994 in high health herds showed the prevalence of pneumonia at slaughter was nearly 60%1. Respiratory infections are often due to multiple pathogens, resulting in the syndrome known as Porcine Respiratory Disease Complex (PRDC). An important contributor to PRDC is Mycoplasma hyopneumoniae, which predisposes pigs to other respiratory infections. On most farms with PRDC, one or two viruses, M. hyopneumoniae and several opportunistic bacteria combine to induce losses associated with respiratory disease2. Consequently, well-timed, targeted treatment of pigs exposed to PRDC with therapeutic doses of antimicrobials that inhibit both mycoplasma and bacteria is key to an effective PRDC control program3. Denagard (tiamulin) have been shown in several studies to be highly active against M. hyopneumoniae and other pathogens that may be involved in PRDC such as Pasteurella multocida and Actinobacillus pleuropneumoniae. Combining pleuromutilins with antibiotics such as chlortetracycline (CTC) or doxycycline provides even broader coverage against the range of pathogens seen in PRDC.

Ulrich Klein Dr.med.vet

International Technical Services Manager

Experimental infection study

In a comparative study, various in-feed medications were tested for treatment of 5- to 6week old specificpathogen-free (SPF) pigs that were infected on day 1 of the study with M. hyopneumoniae, on day 8 with P. multocida and on day 15 with A. pleuropneumoniae 3. Treatment was initiated on day 9 and continued for 12 consecutive days. Animals were examined on days 8, 15 and 22 and were also evaluated upon necropsy. Figure 1. The incidence of lung lesions was lower in the Denagard + CTC group compared to other treatment groups and controls.
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The medications tested included: Group 1: Denagard, 100 ppm plus CTC 400 ppm Group 2: Lincomycin 100 ppm plus CTC 400 ppm Group 3: Pulmotil (tilmicosin) 300 ppm Compared to an infected, untreated control group, the investigators found that:
l The Denagard + CTC group had a lower incidence of

macroscopic pathologic lung lesions (refer Figure 1) and a lower incidence of pneumonia than the other groups (refer Table 1).
l Nasal swabs and bacteriologic examination showed

60 Lung Lesion Score

that M. hyopneumoniae could not be recovered from the lungs of the Denagard + CTC group 12 days after treatment started.
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l There was no significant reduction in

44

40

M. hyopneumoniae isolates among the lincomycin + CTC and Pulmotil-treated groups.

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20

l Mycoplasmas could not be detected in lungs from the

14
0 Control Denagard/CTC Lincomycin/CTC Pulmotil

Denagard + CTC group.

l A. pleuropneumoniae could not be re-isolated from all

three treatment groups.

l Of these three groups, Denagard + CTC-treated pigs

Table 1. The occurrence of pneumonia in pigs experimentally infected with M. hyopneumoniae, P. multocida and A. pleuropneumoniae was lowest in the Denagard + CTC group. Treatment group Denagard + CTC Lincomycin + CTC Pulmotil Infected, untreated Occurrence of pneumonia 2/10 6/10 5/10 10/10 Isolation M.hyo 0/10 5/10 3/10 8/10 Isolation APP 1/10 2/10 1/10 6/10

had the best average daily gain. Feed conversion efficiency was excellent compared to the control group (refer Table 2).

Table 2. Body weight gain and feed conversion efficiency Treatment group Denagard + CTC Lincomycin + CTC Pulmotil Infected, untreated controls Average daily gain 10.1 8.65 9.95 8.85 Feed conversion efficiency 1.90 2.23 1.88 2.44

Tiamulin and Chlortetracycline

Three separate in vitro studies have shown that when Denagard is combined with CTC, there is synergistic activity against several of the various important respiratory pathogens involved in PRDC, including M. hyopneumoniae, P. multocida, A. pleuropneumoniae, Haemophilus parasuis and Bordetella bronchiseptica4,5,6. Table 3 summarizes the data from these investigations.

Table 3. in vitro synergism between Tiamulin and CTC (MICs in g/ml) against respiratory pathogens Organism/(strains tested) Tiamulin CTC Combined Tiamulin/CTC Tiamulin M. hyopneumoniae A. pleuropneumoniae (9) P. multocida (8) H.parasuis (1) B.bronchiseptica (1) 0.13 3.9 15.8 0.9 250 2.0 0.9 12.8 1.9 0.45 0.016 1.1 2.9 0.45 0.45 CTC 1.0 0.22 3.2 0.45 0.22 Synergy factor (x) Tiamulin 8x 3.6x 5.4x 2x 555x CTC 2x 4x 4x 4.2x 2x

Tiamulin and Doxycycline

Recent sensitivity testing provides additional evidence that combined antibiotics exhibit synergistic activity that may provide clinically useful treatment for complex respiratory infections in pigs7. In this study, tiamulin and other antibiotics were combined with doxycycline, a second generation tetracycline. Hungarian field isolates for several pathogens seen in PRDC were isolated and used to determine MICs (g/ml), which were considered to be the lowest concentration of antibiotics needed to completely prevent the growth of bacteria. The synergistic effects of tiamulin combined with doxycycline are demonstrated by the results, shown in Table 4. The investigators point out that by using drug combinations, the concentrations of the drugs required to inhibit pathogens could be reduced significantly compared to the use of single drugs and that the combined use is clinically useful for treatment of complex respiratory infections.

Table 4. MIC averages for tiamulin and doxycycline alone and in combination and the synergistic factor for combined use Organism/(strains tested) Tiamulin Doxycycline Combined Tiamulin/DOXY Tiamulin M. hyopneumoniae (10) A. pleuropneumoniae (10) P. multocida (10) S. suis (10) B. bronchiseptica (10) 0.219 2.297 2.297 0.094 16.0 5.169 0.435 0.125 0.189 0.088 0.094 1.071 0.870 0.044 5.656 DOXY 0.659 0.088 0.016 0.025 0.017 Synergy factor (x) Tiamulin 2.3x 2.1x 2.6x 2.1x 2.8x DOXY 7.8x 4.9x 7.8x 7.6x 5.2x

Molecular action of Denagard and Tetracyclines: Denagard binds at the 50S ribosomal subunit and inhibits the protein formation8 while tetracyclines bind at the 30S subunit. Denagard and tetracyclines interfere with the protein production of bacteria cells at different ribosomal subunits which provides a better understanding of the synergistic effect of both against respiratory pathogens.

For further information or clinical data queries please email: ulrich.klein@novartis.com Visit our website: www.denagard.com

Summary
In an experimental infection study, Denagard combined with CTC proved to be superior treatment for mixed respiratory infections compared to lincomycin plus CTC and Pulmotil alone judging by factors such as lung lesions, the occurrence of pneumonia, the re-isolation of mycoplasmas and average daily weight gain. In vitro studies demonstrate that when Denagard is combined with CTC, there is synergistic activity against several of the various important respiratory pathogens involved in PRDC, including M. hyopneumoniae, P. multocida and A. pleuropneumoniae. In addition, recent sensitivity testing provides additional evidence that combined antibiotics such as Denagard and doxycycline, a second generation tetracycline, exhibit synergistic activity that may provide clinically useful treatment for complex respiratory infections in pigs.

References
1 US Department of Agriculture, Agricultural Research Service Project, Control of Porcine Respiratory Diseases of Complex Etiology. Annual Report. 2004. 2 Halbur, P. Emerging and Recurring Diseases in Growing Pigs. National Institute for Animal Agriculture Proceedings 2001. 3 Stipkovits L, et al. Treatment of pigs experimentally infected with Mycoplasma hyopneumoniae, Pasteurella multocida and Actinobacillus pleuropneumoniae with various antibiotics. Can. J. Vet. Res. 2001;65:213-222. 4 Miller DJS, et al. Recent advances in the control of enzootic pneumonia in pigs. Proceedings of the World Veterinary Congress 1991. 5 Burch DGS, et al. The synergistic activity of tiamulin and chlortetracycline: In-feed treatment of bacterially complicated enzootic pneumonia in fattening pigs. Vet. Rec. 1986;119:108-112. 6 Jones GT. IDL Reports, ER Squibb & Sons Ltd, Reeds Lane, Moreton, Wirral, England. IDL/MR/164. 1984. 7 Fodor L, et al. Sensitivity testing of respiratory pathogens of swine to antimicrobials. 18th International Pig Veterinary Society Congress, Hamburg, Germany 2004. 8 Inhibition of peptide bond formation by pleuromutilins: the structure of the 50S ribosomal subunit from Deinococcus radiodurans in complex with tiamulin; Frank Schlnzen, Erez Pyetan, Paola Fucini, Ada Yonath and Jrg N. Harms; Molecular Microbiology Volume 54 Page 1287 December 2004.

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