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Use of tylvalosin-medicated feed to control porcine proliferative enteropathy

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DOI: 10.1136/vr.165.12.342 · Source: PubMed

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Use of tylvalosin-medicated feed
to control porcine proliferative
enteropathy
R. M. C. Guedes, S. A. França, G. S. Machado, M. A. Blumer, E. C. da Costa Cruz Jr
The effect of an oral treatment with the tartrate
salt of tylvalosin on the development of proliferative
enteropathy in 60 experimentally challenged pigs
was studied. Thirty of the pigs were fed a diet
medicated with 50 ppm tylvalosin and 30 were fed
the unmedicated diet. The treated animals started
to receive the medicated feed the day before they
were inoculated, and continued to receive it for 14
days. The pigs’ bodyweight, feed consumption and
clinical signs were evaluated, and they were examined
postmortem 20 days after inoculation, and samples
of ileum were collected for immunohistochemistry
(IHC) for Lawsonia intracellularis. Clinical signs of
the disease were more evident in the untreated
group than in the treated group. The average daily
weight gain, average daily feed consumption and
feed conversion efficiency were better in the treated
group. The combined length of intestine with lesions
was 2847 cm in the untreated group and 183 cm
in the treated group. The tylvalosin treatment
significantly reduced the level of L intracellularis
infection; almost half of the treated pigs were IHC-
negative compared with 3·3 per cent of the untreated
pigs.
PROLIFERATIVE enteropathy (PE), also known as ileitis, is an infec-
tious enteric disease of growing-finishing pigs and other animal species
worldwide (Cooper and others 1997a, b, Tomanová and others 2003). It
is caused by the obligate intracellular bacterium Lawsonia intracellularis
(Lawson and Gebhart 2000).
Veterinary Record (2009) 165, 342-345
R. M. C. Guedes, DVM, MS, PhD, G. S. Machado, DVM, DrAnimSci,
S. A. França, DVM, MS, Integrall-Soluções em Produção
E. C. da Costa Cruz Jr, DVM, Animal, Belo Horizonte, 30310-040,
Department of Clinic and Surgery, Brazil
Veterinary School, Federal University M. A. Blumer, DVM,
of Minas Gerais, Avenid Antônio Sanphar Química e Farmacêutica,
Campinas, 13023-101, Brazil
Carlos 6627, PO Box 567, Belo
Horizonte, MG 31 270-901, Brazil
E-mail for correspondence:
guedes@vet.ufmg.br
the VETERINARY RECORD | September 19, 2009
PE has been diagnosed in all countries with significant pig pro-
duction, and causes significant losses at different stages of production
(Chang and others 1997, Chiriboga and others 1999, Stege and others
2000). The chronic form of the disease reduces the average daily weight
gain (ADG) and increases the incidence of diarrhoea in growing-fin-
ishing animals; the acute form results in the mortality of replacement
gilts, young boars and pigs close to market age; and the subclinical form
causes a significant decrease in performance but no evident diarrhoea
(Lawson and Gebhart 2000).
The disease can be controlled by the administration of antimicrobial
drugs, either in the animals’ feed or water and/or by injection. Recently,
a modified live vaccine has also become available for the control of
the disease (Kroll and others 2004). The tartrate salt of tylvalosin, the
active ingredient of Aivlosin (ECO Animal Health), is a macrolide.
Several macrolides have been shown to be effective against L intracellu-
laris, including tylosin (McOrist and others 1997, Lee and others 2001),
josamycin (Kyriakis and others 2002), leucomycin (Guedes and others
2006) and spiramycin (Tsinas and others 1998). Tylvalosin has been
used to prevent and control porcine PE in the field, but there have been
few published controlled experimental studies of its efficacy; Pommier
and others (2008) compared tylvalosin with tylosin for the control of
subclinical PE under field conditions.
This study was conducted to evaluate the efficacy of incorporating
tylvalosin into pigs’ feed at 50 ppm as the tartrate salt (42·5 ppm tylva-
losin base) for 14 days (the usual period of treatment in Brazil for grow-
ing-finishing pigs) for controlling PE in pigs experimentally infected
with L intracellularis.
Materials and methods
Animals, housing and feeding
The study was approved and conducted according to the Good Clinical
Practice guidelines of the ethics committee for animal experimentation
of the Universidade Federal de Minas Gerais.
Sixty commercial crossbred 35-day-old pigs of both sexes, weighing
between 8·4 and 13·0 kg, were used. They were purchased from a local
pig farm free of Mycoplasma hyopneumoniae, Actinobacillus pleuropneu-
moniae, toxigenic Pasteurella multocida, Brachyspira pilosicoli, Brachyspira
hyodysenteriae, suid herpesvirus type 1 (Aujeszky’s disease) and with no
clinical history of Salmonella, rotavirus, porcine circovirus type 2-associ-
ated disease or PE. Brazil is free of porcine reproductive and respiratory
syndrome (PRRS) virus and transmissible gastroenteritis virus.
Groups of six pigs were housed in an experimental barn in 10 nursery
pens measuring 1·4 x 1·4 m, with perforated plastic grating floors and
wire mesh pen dividers, and an artificial heating system, one nipple
drinker and a two-hole deposit feeder.
Study design
The pigs were identified by ear tags, weighed and allocated to the 10
pens, with feed and water ad libitum, two days before they were chal-
lenged. They were divided into two groups of 30 pigs, using a completely
random experimental design, balancing the groups by weight, as fol-
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lows: light pigs, moderately light, medium,

TABLE 1: Mean (sd) weight, average daily weight gain (ADG), average daily feed consumption
moderately heavy and heavy. Five pens were (ADFC) and feed conversion rate (FCR) of 30 non-medicated pigs and 30 pigs fed a diet
randomly allocated to each treatment using medicated with 50 ppm tylvalosin tartrate
a random digit table (Moore and McCabe
Group of pigs Weight (kg) ADG (day –3 to 20) ADFC (day –1 to 20) FCR
1999). The treatments were feed with no Day –3 Day 20 (kg/day) (g/day) (kg feed/kg gain)
medication and feed containing 50 ppm
tylvalosin (Aivlosin; ECO Animal Health). Non-medicated 10·30 (1·17) 20·69 (1·73)a 0·451 (0·076)a 862 (96) 1·931 (0·199)a
Medicated 10·30 (1·17) 22·75 (2·24)b 0·541 (0·054)b 896 (90) 1·655 (0·017)b
They were fed from the day before the chal-
lenge (day –1) for 14 days, after which both a, b
Different letters in a column indicate a significant difference (P<0·05) between the groups
groups were fed non-medicated feed until the
end of the study on day 20.
Faecal samples were collected from all the pigs on the day before the least statistical difference test, with the pig being the experimental unit
challenge for PCR testing for L intracellularis (Jones and others 1993). for ADG and the pen being the experimental unit for ADFC and FCR.
The next day, they were inoculated intragastrically with a homogenate A Kruskal-Wallis one-way analysis of variance was used to analyse the
of intestinal mucosa from affected animals containing between 108 gross lesions, with the pig being the experimental unit. The crude meas-
and 1010 L intracellularis organisms. Three times a week, on Monday, urements of the length of the lesions were adjusted by multiplying them
Wednesday and Friday, the faeces of each pig were scored from 0 to 3 (0 by the severity of the lesions (graded from 0 to 4) in each segment of
Normal, 1 Pasty, 2 Watery with no blood, 3 Watery, blood-tinged and/ intestine (Guedes and Gebhart 2003a).
or with necrotic casts). The pigs were weighed on day 20 and their feed
consumption was recorded throughout the study. Results
On day 20 the pigs were humanely euthanased and the incidence, Inoculum and clinical findings
severity and length of the characteristic intestinal lesions of PE were The faecal samples collected before the pigs were inoculated were all
evaluated. Gross intestinal lesions were scored as follows: 0 Normal; 1 negative by PCR for L intracellularis. Each pig received 1·26 x 1010
Mild mesenteric and intestinal wall oedema and hyperaemia; 2 Mild L intracellularis organisms in the inoculum; no other pathogen was found
to moderate oedema and hyperaemia of the mesentery and intestinal in the inoculum used to challenge the pigs.
wall, and corrugated intestinal mucosa; 3 Severe mesenteric and intes- The course of the clinical disease, based on the consistency of the
tinal wall oedema and hyperaemia, and necrosis of the mucosal surface pigs’ faeces, is illustrated in Fig 1. Diarrhoea was mild and affected only
with formation of pseudodiphtheric membranes (necrotic enteritis); 4, a few of the pigs fed the medicated feed, but the pigs fed non-medicated
Moderate to severe oedema and hyperaemia of the mesentery and intes- feed had severe and frequent diarrhoea, mainly from days 13 to 20, and
tinal wall, thick and corrugated mucosa, and blood clots in the intestinal two of them had bloody diarrhoea, one only on day 13, and the other
lumen. Samples of ileum, taken 2 cm from the ileocaecal valve, were on days 16 and 18. Both of these were lethargic during that period,
fixed by immersion in 10 per cent neutral buffered formalin and proc- but the pig that developed diarrhoea on day 13 recovered, while the
essed for histology and immunohistochemistry (IHC). other progressed to lateral recumbency on day 19 and was euthanased
on day 20.
Inoculum
The inoculum was prepared from porcine intestines affected by histologi- Performance
cally confirmed PE by the method described by Winkelman and others The ADG of the medicated group was significantly greater than that of
(2002). Briefly, the scraped mucosa from the intestines of several pigs the non-medicated group (Table 1); by the end of the study the medi-
was blended with sucrose-potassium-glutamate solution, 1:1 w/v. Each cated pigs were 2 kg heavier than the non-medicated pigs (P<0·05).
pig received 37 ml of the inoculum. Samples of the inoculum were exam- There was no difference between the groups in ADFC, but the FCR of
ined bacteriologically at the Veterinary Diagnostic Laboratory of the the medicated group was significantly better than that of the control
Universidade Federal de Minas Gerais for enterotoxigenic Escherichia coli group (P<0·05).
and Salmonella species, and by direct examination and flotation for the
detection of any parasites or other enteropathogenic organisms. Pathology
The numbers of L intracellularis in the inoculum were established More of the non-medicated group had grossly detectable and more
using immunoperoxidase staining (K675; Dako) and a monoclonal anti- extensive lesions characteristic of porcine PE than the medicated group
body specific for L intracellularis organisms (Guedes and Gebhart 2003b). (Table 2), and the adjusted lesion length (lesion length x lesion score)
Serial 1:10 dilutions of the inoculum in sterile phosphate-buffered saline was significantly higher in the non-medicated group (63·0 v 36·2) (<0·05).
were prepared. A 15-well glass slide was coated with 10 µl of each dilu- Seventy-six per cent of the non-medicated pigs had characteristic gross
tion and dried at 37°C for 30 minutes. The slide was fixed with cold lesions postmortem, in contrast with only 30 per cent of the medicated pigs.
acetone, stained by immunoperoxidase, and the numbers of L intracel- In addition, the non-medicated pigs had more extensive lesions (P<0·05).
lularis were counted under a light microscope.

Histology and immunohistochemistry 0·45 Non-medicated

The formalin-fixed ileum samples were processed routinely for histology, 0·40 Medicated
embedded in paraffin, and sectioned 5 µm thick. The sections of ileum 0·35
Mean faecal score

were also stained immunohistochemically by the labelled streptavidin 0·30

method (K675; Dako) with rabbit polyclonal antibodies (1999 PAB) 0·25
to L intracellularis (Guedes and Gebhart 2003c). The concentration of 0·20
positive antigen labelled in the sections was graded as follows: 0 No 0·15
positive antigen labelled; 1 One isolated focal area of antigen labelled; 0·10
2 Multifocal areas of antigen-labelled; 3 Majority of the mucosa (up to 0·05
75 per cent of the crypts) positive antigen labelled; 4 All of the mucosa 0
positive antigen-labelled. -1 2 4 6 9 11 13 16 18
Days before and after inoculation
Statistical analysis
FIG 1: Mean clinical scores, based on the characteristics of the
The ADG, average daily feed consumption (ADFC) and feed conver- faeces, of pigs challenged with Lawsonia intracellularis and either
sion rate (FCR) of the two groups were analysed using a one-way analy- non-medicated or medicated by the inclusion of 50 ppm tylvalosin
sis of variance in a completely random design, comparing means by the tartrate in the feed

September 19, 2009 | the VETERINARY RECORD

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TABLE 2: Numbers of pigs and length and severity of gross lesions
characteristic of porcine proliferative enteropathy observed in 30
non-medicated pigs and the 30 pigs fed a diet medicated with 50 ppm
tylvalosin tartrate
Gross lesion score*
Number of animals Range of length of
Group of pigs 0 1 2 3 with lesions intestinal lesions (cm)
Non-medicated 7 23 0 0 23 9-366
Medicated 21 9 0 0 9 7-43
* 0 Normal, 1 Thickened mucosa, 2 Thickened and necrotic mucosa, 3 Thickened
mucosa associated with blood clots in the lumen
TABLE 3: Intensity of infection with Lawsonia intracellularis based on
immunohistochemistry (IHC) labelling in fragments of ileum from
groups of 30 pigs that were non-medicated or medicated with 50 ppm
tylvalosin tartrate in feed, 20 days postinfection
Score of L intracellularis
antigen labelling by IHC*
Group of pigs 0 1 2 3 4 Number (%) of infected animals by IHC
Non-medicated 1 3 4 18 4 29 (96·7)a
Medicated 14 5 8 3 0 16 (53·3)b
* 0 No positive antigen labelled, 1 One isolated focal area of antigen labelled,
2 Multifocal areas of antigen labelled, 3 Majority of the mucosa has positive antigen
labelling, 4 All of the mucosa has positive antigen labelling
a, b
Different letters in the same column indicate a significant difference (P<0·05)
between groups
The pig from the non-medicated group that had bloody diarrhoea on days
16 and 18 had typical intestinal lesions 220 cm in length and graded 3 by
IHC, and the pig that recovered from bloody diarrhoea had 170 cm of typi-
cal intestinal lesions graded 4 by IHC. The length of the intestinal lesions
ranged from 9 to 366 cm in the non-medicated pigs and from 7 to 43 cm in
the medicated pigs. In the non-medicated group, 96·7 per cent of the pigs
were infected, in comparison with 53·3 per cent of the medicated group,
and 75·9 per cent of the non-medicated pigs had lesions graded 3 or 4 by
IHC, compared with 18·7 per cent of the medicated pigs.
All the non-medicated pigs had positive antigen labelling for L intra-
cellularis in the sections of ileum stained by IHC (Table 3), but only 53·3
per cent of the medicated pigs were IHC- positive. One sample of ileum
from the non-medicated pigs was lost and not analysed.
Discussion
A well-established challenge model (Winkelman and others 2002,
Guedes and Gebhart 2003a) was used in this study to test the effect of
tylvalosin in controlling PE in pigs. The 60 pigs were inoculated experi-
mentally with the same dose of a homogenate of intestinal mucosa from
affected pigs containing a high concentration of L intracellularis on the
same day, to provide the same challenge to all of them. The clinical
signs and gross and microscopic findings observed in the non-medicated
animals showed that the disease had been reproduced successfully. The
observation of bloody diarrhoea is not a common finding in this type of
challenge model, although it has been described by Jordan and others
(2004), and it indicates the potency of the inoculum. An increased inci-
dence of diarrhoea from day 11 to 18 after inoculation (Fig 1) has been
reported in studies using either a pure culture or an intestinal homogenate
(Guedes and others 2002, Guedes and Gebhart 2003a, Collins and Love
2007), and can be explained by the fact that the third week after infec-
tion has been observed to be the period of peak infection in the intestine
(MacIntyre and others 2003, Gebhart and Guedes 2004).
Performance results are a secondary but still important measure of
the efficacy of an antimicrobial agent for controlling the chronic and
subclinical forms of PE (McOrist and Gebhart 2006). During the study,
the medicated group of pigs gained weight more quickly, even though
the ADFC of the two groups was similar, and the FCR of the medi-
cated animals was significantly better (Table 1), showing that tylvalosin
included in the diet of the pigs on the day before they were challenged
effectively improved their performance.
the VETERINARY RECORD | September 19, 2009
The efficacy of tylvalosin was expected, on the basis of the proper-
ties of other molecules in the pharmacological group, and preliminary
reports by Winkelman and Tasker (2002) and Tasker and others (2004)
and a study by Pommier and others (2008), which demonstrated that
85 ppm tylvalosin in the feed for 10 days at the start of the fattening
period reduced the number of days to slaughter in subclinically affected
pigs, compared with 100 ppm tylosin. Macrolides, including tylvalosin,
can be bacteriostatic or bactericidal depending on the dose. They are
liposoluble and have a great capacity to penetrate cell membranes. As
a result, tylvalosin can pass through the eukaryotic lipid cell membrane
and accumulate in the cytosol (Tulkens 1991), an important charac-
teristic for its efficacy against L intracellularis, an obligate intracellular
bacterium. A large proportion of macrolide molecules are absorbed from
the intestine and excreted in its active form in the bile, and part of the
dose is reabsorbed from the intestine and eliminated in the faeces; these
are important characteristics for controlling enteropathogenic agents
(McOrist and others 1997, Plumb 2002).
Acknowledgements
The study was supported by Sanphar Química e Farmacêutica and by
Capes (Próequipamentos 01/2007). RMCG is supported by a fellow-
ship from CNPq (National Council for the Development of Research,
Brasília, Brazil).
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