Denagard Performance

M. hyopneumoniae/in vitro studies

Denagard is highly active against M. hyopneumoniae

KEY POINTS
l Enzootic pneumonia, caused by Mycoplasma hyopneumoniae, is a common and costly disease of swine around the world. l In vitro studies conducted in various countries have shown that Denagard (tiamulin) is highly active against M. hyopneumoniae. l When Denagard (tiamulin) is combined with doxycycline, there is a synergistic activity against M. hyopneumonia.

Introduction
Enzootic pneumonia, caused by Mycoplasma hyopneumoniae, affects pigs around the world and is considered one of the most common and economically important diseases of swine. Economic losses are due to reduced rate of gain and poor feed efficiency 1. In vitro studies from several countries demonstrate that pleuromutilin antibiotics such as Denagard (tiamulin) and Econor (valnemulin) are highly active against M. hyopneumoniae. Denagard is a versatile antibiotic that can be administered in feed, water or by injection, while Econor is conveniently administered in feed. Pleuromutilins also minimize concern about the development of antibiotic resistant bacteria developing in people, an important concern among todays consumers. Pleuromutilins were developed solely for use in animals, not humans. In addition, studies show that resistance to pleuromutilins develops slowly, while resistance to some of the other antibiotics used against mycoplasma pathogens can develop rapidly.

Ulrich Klein Dr.med.vet

Global Technical Services Manager pig and poultry

United Kingdom
Since the development of resistance to antimicrobials is an important concern for pig producers attempting to control enzootic pneumonia, British investigators determined MIC values to demonstrate whether M. hyopneumoniae is likely to become resistant after repeated exposure to tiamulin and two other antibiotics 2. They used a J type strain obtained from a collection of type cultures and a recent field isolate known as MEVT G23. l Despite 10 passages, resistance to tiamulin was only slight in the type strain J and did not occur in the field strain. l There was marked resistance of both isolates to tylosin and moderate increases in resistance to oxytetracycline, as shown in Table 1. Their study, conclude the investigators, shows that resistance does not develop readily in vitro to tiamulin. In contrast, high resistance developed quickly to tylosin, an agent which has been in veterinary use for many years, they say.

Table 1. The results for two strains of M. hyopneumoniae passaged 10 times in vitro J Strain Before Tiamulin Tylosin Oxytetracycline 0.1 0.25 0.25 After 0.25 >500 1.0 Resistance Increase 2.5 >2000 4 Before 0.05 0.125 0.25 Field Strain (MEVT G23)) After 0.05 62.5 1.0 Resistance Increase 0 500 4

Canada
A literature review by a Canadian veterinarian points out that enzootic pneumonia does not always respond well to treatment 3. Hence, products with low MICs for M. hyopneumoniae should be favoured, the author says. Table 2 is adapted from the review and reflects three different studies summarizing the sensitivity results of M. hyopneumoniae to various antimicrobials. The investigator notes that fluoroquinolones have low MICs for M. hyopneumoniae and have been effective in treating enzootic pneumonia; however, because of their importance in human medicine and current concerns about antimicrobial resistance, particularly to drugs used in both animals and people, the number of countries that will allow or encourage the use of fluoroquinolones in swine is being limited.

Table 2. The average MIC of four antimicrobials tested against M. hyopneumoniae Reference Author/Year Yamamoto 86 Inamoto 945 Hannan 97
ND = Not determined
4

No. of M. hyopneumoniae strains Lincomycin 55 25 20 0.12 0.06 ND 0.74 1.2 1

MIC (g/ml) Oxytetracycline Tylosin 0.06 0.03 0.25 Tiamulin 0.03 0.02 0.05

Thailand
Investigators from Thailand determined MIC50 and MIC90 values for nine antimicrobials using 27 M. hyopneumoniae field isolates 6. They found that: l M. hyopneumoniae strains were very sensitive to tiamulin and valnemulin. For instance, the range for tiamulin, was <0.006-0.097. l Tiamulin was two times more active than lincomycin. l M. hyopneumoniae strains were only moderately susceptible to tilmicosin, which had a range of <0.024-3.125, and to chlortetracycline and oxytetracycline. l M. hyopneumoniae strains were less susceptible to spectinomycin, which had a range of <0.024-100.

Hungary
One of the most recent MIC studies of M. hyopneumoniae strains was performed in Hungary 8. Ten strains of M. hyopneumoniae were isolated from swine lungs and used to test the efficacy of several antimicrobials. The investigators also tested combinations of antimicrobials and determined both MIC50 and MIC90 values. l Isolates were most susceptible to tiamulin. See Table 3 for the MIC ranges. l When tiamulin was combined with doxycycline, there was synergistic activity (Table 4) against M. hyopneumoniae pathogens. Table 3. MIC ranges and MIC 90 of antibiotics tested for M. hyopneumoniae Antimicrobial MIC range 0.06-1.0 0.5-32.0 0.25-16.0 0.25-8.0 4.0-32.0 0.125-2.0 MIC 90 1.0 16.0 16.0 8.0 32.0 2.0

Korea
Minimum inhibitory concentrations (MICs) were determined for different antimicrobials used to treat M. hyopneumoniae 7. MICs (g/ml) were defined as the lowest concentration of antibiotics at which complete inhibition of growth occurs. The seven isolates used for testing antimicrobials in the study were taken from Korean pigs ages 20 to 24 weeks old. Key findings follow: l All M. hyopneumoniae isolates were highly susceptible to tiamulin. l All isolates were moderately susceptible to tylosin, lincospectin and norfloxacin.

Tiamulin Doxycycline Tylosin Lincomycin Chlortetracycline Tilmicosin

Table 4. Average MIC values alone and in combination with doxycycline Organism Tiamulin Doxycycline Combined Tia/Doxy Tia M. hyopneumoniae 0.219 5.169 Doxy 0.094 0.659 Synergy Factor Tia 2.3 Doxy 7.8

The investigators conclude that the mycoplasma strains they tested showed a high susceptibility to tiamulin, and that the trial results prove the synergistic activity of tiamulin against mycoplasma pathogens when used in combination with doxycycline. The synergistic activity of Denagard with other tetracyclines like chlortetracycline and oxytetracycline against mycoplasmal pathogens was demonstrated in previous studies by Miller and Stipkovits in 19919 and Koh et al in 1994.

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

Summary
In vitro studies highlight the high susceptibility of M. hyopneumoniae strains to tiamulin. Denagard offers pig producers an effective agent for controlling enzootic pneumonia due to M. hyopneumoniae. The trial results also demonstrate the synergistic activity of Denagard when used in combination with doxycycline.

References
1 Ross RF. Mycoplasma disease. In: Diseases of Swine, ed 7. 1992;537-551. Edited by Leman AD, et al. State University Press, Ames, Iowa USA. 2 Hannan PC, et al. In vitro susceptibilities of recent field isolates of Mycoplasma hyopneumoniae and Mycoplasma hyosynoviae to valnemulin (Econor), tiamulin and enrofloxacin and in the in vitro development of resistance to certain antimicrobial agents in Mycoplasma hyopneumoniae. Res. Vet. Sci. 1997;63:157-160. 3 Desrosiers R. A review of some aspects of the epidemiology, diagnosis, and control of Mycoplasma hyopneumoniae infections. J. Swine Health Prod. 2001;9(5):233-237. 4 Yamamoto K, et al. In vitro susceptibility of Mycoplasma hyopneumoniae to antibiotics. Jpn. J. Vet. Sci. 1986;48:1-5. 5 Inamoto T, et al. Antibiotic susceptibility of Mycoplasma hyopneumoniae isolated from swine. J. Vet. Med. Sci. 1994;56:393-394. 6 Thongkamkoon P, et al. In vitro susceptibility test of Mycoplasma hyopneumoniae to antimicrobial agents. 17th International Pig Veterinary Society Congress, Des Moines, Iowa, USA 2002. Proceedings, p44. 7 Koh HB, et al. Minimum inhibitory concentrations of tiamulin and oxytetracycline in combination in field isolates of Mycoplasma hyopneumoniae. 13th International Pig Veterinary Society Congress, Bangkok, Thailand 1994. Proceedings, p353. 8 Stipkovits L, et al. Sensitivity testing of mycoplasma pathogens to antimicrobials. Proceedings of the 18th International Pig Veterinary Society Congress, Hamburg, Germany 2004. Volume 2, p518. 9 Miller DJS and Stipkovits L. Recent advances in the control of enzootic pneumonia. In: Proc. World Veterinary Congress, Rio de Janeiro, Brasil 1991.

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