Denagard Performance

Mixed Respiratory Infections

Denagard® (tiamulin) combined with tetracyclines offers excellent

efficacy against mixed respiratory infections in swine

KEY POINTS

lM
 ixed respiratory infections in pigs remain a leading herd health problem for pig producers and cause major
economic losses.

lA
 n 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.

lM
 IC 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 Denagard® (tiamulin) have been shown in several studies
economic loss for pork producers. In 1995, the National Animal to be highly active against M. hyopneumoniae and other
Health Monitoring System reported that respiratory disease was pathogens that may be involved in PRDC such as Pasteurella
the leading cause of mortality in nurseries and grower-finisher multocida and Actinobacillus pleuropneumoniae. Combining
units. Data collected from 1990 to 1994 in high health herds pleuromutilins with antibiotics such as chlortetracycline (CTC)
showed the prevalence of pneumonia at slaughter was or doxycycline provides even broader coverage against the
nearly 60%1. range of pathogens seen in PRDC.
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 Ulrich Klein Dr.med.vet
respiratory infections. On most farms with PRDC, one or two International Technical
viruses, M. hyopneumoniae and several opportunistic bacteria Services Manager
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.
 Experimental infection study
In a comparative study, various in-feed medications
were tested for treatment of 5- to 6–week old specific-
pathogen-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.
80
60
Lung Lesion Score
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
that M. hyopneumoniae could not be recovered from
the lungs of the Denagard + CTC group 12 days after
treatment started.

58
l There was no significant reduction in
40
44
M. hyopneumoniae isolates among the lincomycin
+ CTC and Pulmotil-treated groups.
20
23
l Mycoplasmas could not be detected in lungs from the
14
Denagard + CTC group.
0
l A. pleuropneumoniae could not be re-isolated from all
Control Denagard/CTC Lincomycin/CTC Pulmotil
three treatment groups.
l Of these three groups, Denagard + CTC-treated pigs
had the best average daily gain. Feed conversion
Table 1. The occurrence of pneumonia in pigs experimentally infected with
efficiency was excellent compared to the control
M. hyopneumoniae, P. multocida and A. pleuropneumoniae was lowest in
group (refer Table 2).
the Denagard + CTC group.
Occurrence of Isolation Isolation
Treatment group
pneumonia M.hyo APP
Table 2. Body weight gain and feed conversion efficiency
Denagard + CTC 2/10 0/10 1/10
Average Feed conversion
Lincomycin + CTC 6/10 5/10 2/10 Treatment group
daily gain efficiency
Pulmotil 5/10 3/10 1/10
Denagard + CTC 10.1 1.90
Infected, untreated 10/10 8/10 6/10
Lincomycin + CTC 8.65 2.23

Pulmotil 9.95 1.88

Infected, untreated controls 8.85 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 µg/ml) against respiratory pathogens

Combined Synergy
Organism/(strains tested) Tiamulin CTC
Tiamulin/CTC factor (x)

Tiamulin CTC Tiamulin CTC

M. hyopneumoniae 0.13 2.0 0.016 1.0 8x 2x

A. pleuropneumoniae (9) 3.9 0.9 1.1 0.22 3.6x 4x
P. multocida (8) 15.8 12.8 2.9 3.2 5.4x 4x
H.parasuis (1) 0.9 1.9 0.45 0.45 2x 4.2x
B.bronchiseptica (1) 250 0.45 0.45 0.22 555x 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 (µg/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

Combined Synergy
Organism/(strains tested) Tiamulin Doxycycline
Tiamulin/DOXY factor (x)

Tiamulin DOXY Tiamulin DOXY

M. hyopneumoniae (10) 0.219 5.169 0.094 0.659 2.3x 7.8x

A. pleuropneumoniae (10) 2.297 0.435 1.071 0.088 2.1x 4.9x
P. multocida (10) 2.297 0.125 0.870 0.016 2.6x 7.8x
S. suis (10) 0.094 0.189 0.044 0.025 2.1x 7.6x
B. bronchiseptica (10) 16.0 0.088 5.656 0.017 2.8x 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 Schlünzen, Erez
Pyetan, Paola Fucini, Ada Yonath and Jörg N. Harms; Molecular
Microbiology Volume 54 Page 1287 – December 2004.

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