Veterinary Medicines

Aivlosin [Tylvalosin] for Pigs, Chickens and Pheasants

Active substance / Generic: Tylvalosin

Scientific discussion

This medicine is approved for use in the European Union
Aivlosin is a veterinary medicinal product containing the macrolide antibiotic tylvalosin (previous name: acetylisovaleryltylosin) as active substance. The target species are pigs, chickens and pheasants.

The product is presented for pigs as a premix for medicated feedingstuff to be incorporated into meal feed or pelleted feed or as an oral powder to be added to meal feed. The oral powder is to be used in individual pigs on farms where only a small number of pigs are to receive the medicine while large groups of animals would be medicated with medicated feedingstuff containing the premix. In pigs, chickens and pheasants, the product is available as granules for use in drinking water. The granules are either mixed directly into the drinking water system or first mixed as a stock solution into a smaller amount of water, which is then added into the drinking water system.

In pigs, Aivlosin is indicated for the treatment and prevention of Swine Enzootic Pneumonia at a dosage of 2.125 mg tylvalosin per kg bodyweight per day in-feed for 7 consecutive days. The product has also been authorised for the treatment of Porcine Proliferative Enteropathy and for the treatment and prevention of Swine Dysentery at a dosage of 4.25 mg tylvalosin per kg bodyweight per day in-feed for 10 consecutive days. The product is also authorised for the treatment and prevention of Porcine Proliferative Enteropathy at a dose rate of 5 mg tylvalosin per kg bodyweight per day in drinking water for 5 consecutive days.

In chickens, Aivlosin is indicated for the treatment and prevention of respiratory disease associated with Mycoplasma gallisepticum at a dosage of 25 mg tylvalosin per kg bodyweight per day in drinking water for 3 consecutive days. When used as an aid in the prevention strategy (where infection in ovum with Mycoplasma gallisepticum is likely), chicks are to be medicated in their first three days of life and this is to be repeated at the period of risk, i.e. at times of management stress such as administration of vaccines (typically when birds are 2-3 weeks old).

In pheasants, Aivlosin is indicated for the treatment of respiratory disease associated with Mycoplasma gallisepticum at a dosage of 25 mg tylvalosin per kg bodyweight per day in drinking water for 3 consecutive days.

The withdrawal period is 2 days for meat and offal (pigs, chickens and pheasants); however, for the granules for use in drinking water for pigs, the withdrawal period for meat and offal is one (1) day. Aivlosin is not authorised for birds laying eggs for human consumption and should, therefore, not be used in laying birds or in the two weeks before birds are likely to start laying eggs for human consumption.

No side effects in pigs, chickens or pheasants have been reported during the clinical trials.

Due to the skin-sensitising potential of tylvalosin in laboratory animals, the product literature includes a user warning for people with known hypersensitivity to tylvalosin tartrate.

Aivlosin: Quality Assessment

Composition of the veterinary medicinal product

Aivlosin as a premix for medicated feeding stuff contains 42.5 mg/g or 8.5 mg/g of tylvalosin (as tylvalosin tartrate) as the active substance, in a carrier of wheat feed flour and magnesium trisilicate along with other conventional pharmaceutical excipients. The oral powder presentations are identical to the 8.5 mg/g and 42.5 mg/g premix for medicated feeding stuff presentations, containing 8.5 mg/g and 42.5 mg/g of tylvalosin, respectively.

The granules for use in drinking water for pigs, chickens and pheasants are identical and contain 625 mg/g tylvalosin (as tylvalosin tartrate) as the active substance and lactose monohydrate as excipient.

Clinical Trial Formula

Clinical trials in pigs have been conducted using the premix formulation containing 42.5 mg/g tylvalosin. For chickens, pigs and pheasants, clinical trials have been conducted using granules for use in drinking water, containing 625 mg/g tylvalosin.

Development pharmaceutics

Data on the development of the intermediate product (which is used to prepare the 8.5 mg/g premix and oral powder presentations) have been presented. The selection of the excipients and the granulation method are explained. Intra-bag homogeneity of the intermediate product has been examined following transportation. The results indicate that there is no tendency for segregation to occur.

For the premix, inert carriers, wheat feed flour and magnesium trisilicate are used as the diluents. Intra-bag homogeneity of the premix has also been examined following transportation. The results indicate that no segregation occurred in the bags. Dust studies demonstrated that the 42.5 mg/g premix and 8.5 mg/g premix were both classified as being of medium dustiness.

The 8.5 mg/g oral powder formulation is identical to the 8.5 mg/g premix formulation. No special development studies were originally performed but in response to questions the bulk density of the powder: tapped/un-tapped and pre/post transport have been examined. The differences observed were acceptable.

For the granules for use in drinking water, the selection of the excipient, the granulation method and the need for moisture resistant packaging are explained.

The dustiness and friability of the product was not evaluated, but since the complete sachet of the granules for use in drinking water will be used at once without measuring out, the absence of such data is acceptable.

Manufacturing Process

The 8.5 mg/g premix and oral powder formulations are manufactured via the intermediate product Aivlosin 17% Granules. Manufacturing formulae for the intermediate product and the final premix and oral powder are presented. The intermediate product is produced using a roller compaction granulation process. A conventional blending procedure is then employed to dilute the intermediate product. The 42.5 mg/g premix is manufactured by blending all of the formulation ingredients and then granulating the blend by roller compaction to produce the final product.

For the granules for use in drinking water, tylvalosin tartrate and lactose monohydrate are blended together and then transferred to a granulation system which uses a roller compaction process.

Satisfactory flow diagrams and detailed descriptions of the method of manufacture, including in-process controls, are presented for the all presentations of Aivlosin.

All of the above manufacturing processes have been validated.

Active substance

Tylvalosin tartrate is a white to light yellow powder and is not described in any pharmacopoeia. The specification for tylvalosin tartrate is based upon the monograph for this substance as set out in “The minimum requirements for pharmaceutical products not requiring approval for veterinary use in Japan”. Manufacture is via fermentation, using a genetically modified strain of Streptomyces thermotolerans. Tylvalosin is isolated from the fermentation broth and the tartrate salt is formed with the final material being spray dried. No organic solvents are employed during the manufacturing process.

In-process controls, their limits and methods, as performed during the fermentation, purification and spray drying stages are fully documented. Comprehensive specifications and linked test methods, and an indication of which tests are conducted on receipt, are presented for each of the materials used during production.

Satisfactory process validation data of the active substance are provided. The in-process results at various stages of manufacture of the active substance show consistency between batches. The final batch results demonstrate compliance with the authorised specification.

Stability data are presented according to CVMP-VICH guidelines on a number of batches of the active substance. A 9-month re-test period for the active substance was accepted.


The intermediate product is packed in four-layer aluminium laminated bags with an innermost layer of polyethylene. The 42.5 mg/g premix is packed in laminated bags (laminate composed of polyester, aluminium and low density polyethylene) containing 5 or 20 kg. The 8.5 mg/g premix and oral powder presentations are packed in polyethylene lined paper bags containing 5 or 20 kg for premix and 1 kg or 3 kg bags for the oral powder. Full specifications have been provided for the packaging.

For the oral powder presentation, polystyrene measuring scoops of 5 ml, 10 ml and 25 ml (for 8.5 mg/g) and 1 ml and 5 ml (for 42.5 mg/g) are supplied with each pack. The suitability of the scoops for food contact applications has been confirmed. Scoop accuracy and precision were satisfactory.

The granules for use in drinking water are packed in single, laminated sachets (laminate composed of polyester, aluminium and low density polyethylene).

For chicken, pack sizes of 40 g and 400 g are available, which would allow the treatment of a total of 1,000 kg or 10,000 kg bodyweight of chickens per sachet, respectively (e.g. 20,000 birds with average bodyweight of 50 g or 500 g, respectively). For pheasants, pack sizes of 16 g and 40 g are available, which would allow the treatment of a total of 400 kg or 1,000 kg bodyweight of pheasants per sachet, respectively (e.g. 1000 birds with an average bodyweight of 400 g or 20,000 birds with a bodyweight of 50 g, respectively). For pigs, pack sizes of 40 g and 160 g are available, which would allow the treatment of a total of 5,000 or 20,000 kg bodyweight of pigs per sachet, respectively (e.g. 250 pigs with an average bodyweight of 20 kg or 400 pigs with an average bodyweight of 50 kg, respectively). For treatment of smaller flocks or animal numbers, the preparation of a stock solution is required.

Overall Conclusion On Quality

The active substance is suitably controlled using validated methods. The specification limits for individual impurities have been justified in terms of batch data, stability data and safety.

The method of manufacture for the 42.5 mg/g premix is well defined. The premix is suitably controlled using validated methods. The shelf-life Finished Product Specification includes limits for four named degradation products and for total impurities and these limits have also been suitably justified in terms of batch data, stability data and safety.

Stability data are presented which confirm: the shelf-life for the intermediate product (24 months), the shelf-life for the 42.5 mg/g premix (18 months) and the in-feed shelf-life (1 month).

It has been demonstrated that the premix can be homogeneously incorporated into pig feed to give an in-feed concentration of 42.5 mg tylvalosin/kg feed. A specification was proposed for feed medicated with the premix.

The inclusion rate of the 42.5 mg premix in feed will be 0.1%. Since inclusion rates of less than 0.5% are not permitted in some EU Member States, an appropriate recommendation was included in the SPC and the product information: “Consideration should be given to official guidance on the incorporation of medicated premixes in final feeds.” In addition, the applicant confirmed to submit an application for a new presentation with a lower strength resulting in an inclusion rate of 0.5%.

The data presented subsequently for the lower strength premix (8.5 mg/g) premix are comprehensive. The 8.5 mg/g premix is prepared using an intermediate product unlike the 42.5 mg/g premix, which is prepared directly from its constituent ingredients. The intermediate product is simply subjected to a dilution step in order to produce the 8.5 mg/g premix. The data submitted for the 8.5 mg/g premix results in higher inclusion rate for the 8.5 mg/g premix in feed is in accordance with recommendations in the European Pharmacopoeia and national legislation in the EU concerning the medication of feed.

The 8.5 mg/g oral powder presentation is identical in formulation to the 8.5 mg/g premix presentation. However, as the oral powder is to be added to the feed of individual animals, the pack size is smaller and measuring scoops are supplied with each pack. Scoop accuracy and precision have been demonstrated. In view of the volumetric measurement of the dose, the bulk density of the oral powder is controlled.

An 18 month shelf life was initially agreed for the 8.5 mg/g premix and the oral powder when stored below 25°C; this was later extended to 3 years. The oral powder cannot be mixed thoroughly into pelleted feed; therefore, the use of the oral powder is restricted to dry, non-pelleted feed.

In 2006, the Marketing Authorisation Holder extended the indications to two further claims (Porcine Proliferative Enteropathy (ileitis) and Swine Dysentery) with a higher dosage resulting in higher inclusion rates for the premix in feed (85 mg/g tylvalosin/kg feed). Satisfactorily results from homogeneity and stability data were provided. However, low recoveries of the feed medicated with the premix which were attributed to the double pelleting process used by the feed mill resulted in slight changes in the wording of the SPC regarding the recommended pelleting conditions. Also, a new formula was introduced in the product literature to calculate the correct inclusion rate in feed. With regard to the oral powder presentation, an additional larger size scoop was requested.

In 2008, the marketing authorisation was extended to include a new pharmaceutical form, granules for use in drinking water for chickens. Satisfactory data were provided to demonstrate that the product is suitably formulated and quality-controlled. The solubility of the product has been investigated according to the relevant CVMP Guideline. In higher concentrations, presence of cloudiness was noted, which was demonstrated to be a very fine secondary precipitate without impact on the efficacy of the product. Appropriate instructions have therefore been included in the SPC. Stability studies have been presented confirming the proposed shelf-life of 3 years for the finished product. No stability data are provided for open sachets and opened sachets should not be stored. Sufficient data have been presented to demonstrate the stability of the diluted product in typical drinking water systems. In 2009, the marketing authorisation was further extended to allow the use of granules for use in drinking water for pigs and pheasants.

In 2009, the marketing authorisation was extended to include a 42.5 mg/g oral powder for pigs that is identical to 42.5 mg/g Premix containing 42.5 mg/g. No additional development studies were performed. However, as the oral powder is to be added to the feed of individual animals, the pack size is small and measuring scoops are supplied with each pack. Scoop accuracy and precision have been demonstrated. In view of the volumetric measurement of the dose, the bulk density of the oral powder is controlled.

Tylvalosin: Efficacy Assessment


Tylvalosin is a macrolide, which is mainly active against Gram-positive bacteria and mycoplasma. No other major pharmacological effects are known. The mode of action is to inhibit protein synthesis by reversibly binding to the 50S ribosome subunit.

Tylvalosin showed activity towards various gram-positive strains

(e.g. Staphylococcus, Micrococcus, Microbacterium, Bacillus, Corynebacterium, Aerococcus, Arthrobacter and Streptococcus, Campylobacter, Enterococcus and Clostridia). The substance was not active against most of the gram-negative strains (including Escherichia coli, Serratia, Klebsiella, Proteus, Salmonella, Shigella and Pseudomonas). The main metabolite, 3-O-acetyltylosin (3-AT), showed similar antimicrobial activity.

Target animal safety


Two tolerance studies were presented in pigs receiving up to 250 mg tylvalosin/kg feed (inclusion rate) over 10 days and in pigs receiving 500 mg tylvalosin/kg feed (inclusion rate) for 14 consecutive days (i.e. five-times the recommended dose for an extended treatment duration). Tylvalosin had no negative effect on the health of the pigs. There was no variation in food consumption between groups and no differences in body weight. No intolerance to the diet was observed. No necropsy findings could be attributable to tylvalosin administration.

It was concluded that tylvalosin administration via feed to growing pigs, was safe at up to five times the proposed dose.

In support of the extension application for granules for use in drinking water, the marketing authorisation holder provided in 2009 a new GLP-compliant target animal safety study in 6-week old pigs. The study was conducted in USA in 2006. As concentrations over 200 ppm cause palatability issues, most pigs were medicated by gavage. No adverse effects were observed and it was concluded that Aivlosin Granules for use in drinking water are safe when administered at up to 10 x the recommended dose level of 5 mg/kg for 3 x the recommended duration of treatment, and at up to 20 x the recommended dose level for the recommended duration of treatment.


Groups of chickens were medicated with doses of 30 mg, 90 mg or 150 mg tylvalosin/kg bodyweight for three days, or with 30 mg/kg bodyweight for 15 days, i.e. 5 x the recommended duration. The results demonstrated that the administration of high doses of tylvalosin had no adverse effect on the birds. Similar observations were made in the clinical studies. The CVMP concluded, therefore, that tylvalosin has a wide safety margin and is considered to be safe when administered at the proposed dose regimen in chickens as young as 1 day old.


As the proposed dose rate in pheasants is the same as for chickens, the CVMP agreed that the findings in chickens could be extrapolated to the minor species pheasant and that no extra tolerance data in pheasants were required.

Aivlosin: Benefit Risk Assessment

Tylvalosin is a macrolide antibiotic with in vitro activity against Gram-positive bacteria, mycoplasma and some Gram-negative bacteria, including Lawsonia intracellularis.

Benefit Assessment

Direct benefits

Aivlosin in different formulations (premix for medicated feeding stuff, oral powder, granules for use in drinking water) has been shown to be efficacious in the treatment and / or prevention of a number of indications in pigs, i.e. enzootic pneumonia, porcine proliferative enteropathy and swine dysentery; and in respiratory disease associated withMycoplasma gallisepticum in chickens and pheasants.

Efficacy of the proposed dose and duration in the treatment of the respective diseases has been demonstrated in a number of pre-clinical and clinical studies.

Indirect benefits

The Committee noted that the inclusion rate of active substance in the 42.5 mg/g premix in feed would be 0.1%. Since inclusion rates of less than 0.5% are not permitted in some EU Member States, the lower strength premix (8.5 mg/g premix for medicated feeding stuff), introduced as an extension in 2005 achieved higher inclusion rates in feed, which are in accordance with recommendations in the European Pharmacopoeia and national legislation in the EU concerning the medication of feed.

Granules for use in drinking water have the advantage that even animals with reduced appetite due to illness might still drink and receive medication via drinking water. Also, the inclusion rate can be adjusted daily according to water intake to achieve the correct dose. The oral powders permit treatment of individual animals where necessary.

Risk Assessment

Tylvalosin has a wide therapeutic margin in target animal safety studies. This is supported by the clinical studies (no serious adverse reactions). The risk of adverse effects is low and no special warnings are required in the SPC.

Safety of the product has not been established in pregnant or lactating pigs; however, these animals are not at high risk of developing the disease and are unlikely to be treated with the product. An appropriate warning in section 4.7 of the SPC addresses any potential risk.

Tylvalosin is of low toxicity and poses low risk to users of the product. However, people may be exposed to tylvalosin via inhalation, by accidental ingestión or by skin contact and hypersensitivity reactions are a possible effect of contact with the product. However, satisfactory user warnings are included in the SPC and product literature explaining how to avoid such contact.

The environmental risk assessment has demonstrated that the risk for the soil and aquatic environments is acceptable and it is concluded that the product will not pose a risk for the environment when used according to the recommended posology for pigs, chickens and pheasants.

MRLs for tylvalosin for pigs and poultry have been included in Annex I of Council Regulation (EEC) No. 2377/90. Based on the data provided and taking into account a sufficient safety span, a withdrawal period of 2 days was considered acceptable for chickens and pheasants, as well as for the premix and oral powder formulations for pigs, and 1 day for the granules for use in drinking water formulation for pigs.

Consumer safety is assured by a withdrawal period for meat and offal of 1 to 2 days for chickens, pheasants and pigs (depending on the different presentations).

Resistance may be a hazard. Tylvalosin has no activity against Salmonella spp. and variable activity against Campylobacter spp., and concentrations reached in the ileum and colon of pigs may be sufficient to lead to selection for resistant strains, which could be transferred to humans. An appropriate warning has been added to the SPC and product literature. The indication for the product advises that the presence of disease should be established in a herd before preventive use.

Evaluation Of The Benefit – Risk Balance

The product is considered to be appropriately formulated. It is manufactured and controlled in accordance with relevant EU and VICH quality guidelines and current scientific knowledge.

The indications for Aivlosin represent serious diseases in terms of the effect they have on pig, chicken and pheasant welfare and production losses (mortalities and reduced feed efficiency).

Dose determination and confirmation studies demonstrated the efficacy of Aivlosin in the treatment of clinical signs, improving performance and reducing mortality. The product has been shown to be efficacious for a number of indications.

The therapeutic margin for the product is very good, with no adverse reactions at up to 5 x of the recommended daily dose. Residues also deplete quickly, leading to practicable withdrawal periods. Sufficient warnings have been included in the SPC and product literature in relation to mitigation against the risk of resistance development and risk for the user.

The overall benefit-risk evaluation is deemed positive with a sufficiently clear and complete SPC and product literature.

Overall Conclusions

Based on the original and subsequent data presented, the Committee concluded that the quality, safety and efficacy of Aivlosin were considered to be in accordance with the requirements of Council Directive 2001/82/EC, as amended.

Veterinary Medicine


1. What is the typical signahnent for acute colitis?

• German shepherds and golden retrievers are the most commonly affected breeds.

• 1-4 years old is the most common age.

• Males are more commonly affected than females (3:2).

2. What are the common clinical signs of acute colitis?

• Diarrhea or soft stool (watery, mucus, fresh blood, frequent small amounts)

• Tenesmus

• Normal appetite with little or no weight loss

• Vomiting (30%)

• Abdominal pain

3. What is the typical scenario for a nosocomial clostridial infection?

Acute, bloody diarrhea beginning 1-3 days after exposure to a veterinary hospital.

4. What are the possible causes of acute colitis?

The cause of acute colitis is usually unknown, but the following possibilities should be considered:

1. Mucosal injury by a foreign body or trauma

2. Infection

• Parasitic (whipworms[Trichuris sp.])

• Bacterial (Salmonella, Campylobacter, Clostridium spp.)

• Fungal (histoplasmosis)

3. Systemic disease (especially uremia)

5. What differential diagnoses should be considered in patients suspected of acute colitis?

1. Other gastrointestinal problems

• Chronic colitis

• Neoplasia (adenocarcinoma, lymphoma, leiomyosarcoma, polyp)

• Ileocolic intussusception

• Cecal inversion

• Irritable colon (diagnosis by exclusion)

• Rectal stricture

• Perianal fistula

• Uremic ulcers

2. Painful abdomen

• Hemorrhagic gastroenteritis (HGE)

• Viral enteritis

• GI foreign bodies

• Bowel ischemia due to thrombi

• Intestinal volvulus

• Pancreatitis

• Hepatobiliary problems

• Urologic disorder (renal calculi, pyelonephritis, urinary tract infection)

• Peritonitis (ruptured abdominal organ, sepsis)

• Splenic torsion

• Genital problems (uterine torsion or rupture, testicular torsion, prostatic abscess)

3. Thoracolumbar pain

6. Which diagnoses are most commonly confused with acute colitis?

• Neoplasia (adenocarcinoma, lymphoma, leiomyosarcoma, polyps)

• Rectal stricture

7. What are the most common physical findings?

1. Physical examination is usually normal.

2. Deep palpation may or may not produce abdominal pain.

3. Rectal examination may be painful and show fresh blood and mucus.

8. How do you approach the diagnosis of acute colitis?

• Rectal examination

• Fecal flotation for ova or parasites

• Direct and stained fecal smears

• Fecal culture

• Routine laboratory evaluation (complete blood count, biochemical profile, urinalysis)

• Abdominal radiographs and barium enema

• Colonoscopy

• Mucosal biopsy via colonoscopy

9. Describe the appropriate symptomatic treatment.

1. Withhold food for 24-48 hours or until diarrhea resolves. If lymphocytic-plasmocytic enteritis is suspected, withholding food will not resolve the problem.

2. Give crystalloid fluids with potassium chloride.

3. Give medication to decrease fecal water and increase colonic motility (loperamide).

10. What cause-specific treatments may be used for acute colitis?

• Correction of underlying cause if known (e.g., foreign body removal)

• Reduction of clostridial overgrowth (tylosin preferred; also metronidazole)

• Treatment of inflammatory bowel disease (i.e., chronic colitis) with tylosin, mesalazine, sulfasalazine (oral, enema, or foam), or prednisone (antiinflammatory doses)

• High-fiber diet (often supplemented with Metamucil)


Clostridium perfringens

Clostridium perfringens: Cause

Clostridium perfringens is a gram-positive, spore-forming, obligate anaerobic rod-shaped bacterium that contributes to the rhicrobial ecology and nutrition of the colon in healthy dogs and cats. Under certain conditions, proliferation and sporulation of Clostridium perfringens permits enterotoxin A (or clostridium perfringens enterotoxin) production which may then induce mucosal damage, fluid secretion and large bowel-type diarrhea. Evidence for and against a role for Clostridium perfringens in the pathogenesis of large bowel diarrhea has been put forward. Enterotoxigenic Clostridium perfringens has been associated with canine nosocomial diarrhea, hemorrhagic enteritis, and acute and chronic large bowel diarrhea. On the other hand, many dogs harbor Clostridium perfringens and clostridium perfringens enterotoxin in the gastrointestinal tract without developing clinical signs. Until more definitive evidence is obtained, including the fulfillment of Koch’s postulates, Clostridium perfringens should probably be considered as a suspected pathogen in large bowel diarrhea.

Pathophysiology of Clostridium perfringens

The presumed pathogenicity of Clostridium perfringens requires an anaerobic environment, sporulation, and enterotoxin production. However, problems exist with this hypothesis: enterotoxin may be demonstrated in the feces without sporulation, and enterotoxin may be found in the feces of healthy dogs. Clostridium perfringens isolates are classified as one of five toxigenic types (A to E) based on the production of one or more of four major and seven minor toxins. Although all five types of Clostridium perfringens are capable of producing clostridium perfringens enterotoxin, the majority is produced by type A strains. As with enterotoxigenic E. coli (ETEC) strains, clostridium perfringens enterotoxin is believed to induce crypt epithelial cell secretion.

Clinical examination

Clostridium perfringens-associated colitis is believed to be a major cause of acute, nosocomial, chronic large bowel diarrhea. Acute nosocomial diarrhea often begins within 1 to 5 days of boarding or kenneling. Affected dogs develop diarrhea, often with blood pigments, mucous, and tenesmus. These diarrheas are usually self-limiting and may resolve with supportive care alone. Chronic large bowel diarrheas associated with Clostridium perfringens are similar to other large bowel-type diarrheas (i. e., chronic, intermittent, and recurring signs of colitis).

Diagnosis of Clostridium perfringens

No gold standard exists for the diagnosis of Clostridium perfringens -associated diarrhea. Ideally, the diagnosis would be made on the basis of positive test results with Gram staining, fecal culture, enzyme-linked immunosorbent assay enterotoxin (clostridium perfringens enterotoxin) assay, polymerase chain reaction enterotoxin (cpe) genotyping, and rule-out of other colonic diseases on colonoscopy and biopsy. Compared with normal dogs (without diarrhea), diarrheic dogs are more often clostridium perfringens enterotoxin enzyme-linked immunosorbent assay and cpe polymerase chain reaction positive, but many normal dogs are positive on both assays.

Treatment of Clostridium perfringens

Recent in vitro antimicrobial susceptibility testing suggests that Clostridium perfringens should be susceptible to ampicillin, erythromycin, metronidazole, and tylosin. These antibiotics have also been used in vivo with good success. It should be emphasized that many of the same patients respond to supportive care, including intravenous fluids, intestinal protectants, and bland or fiber-supplemented diets.

Prognosis of Clostridium perfringens

Affected animals usually respond to appropriate therapy within a matter of days. The prognosis for recovery is excellent.



Cause of Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) may be defined using clinical, histologic, immunologic, pathophysiologic, and genetic criteria.

Clinical criteria Inflammatory bowel disease has been defined clinically as a spectrum of gastrointestinal disorders of an unknown cause that is associated with chronic inflammation of the stomach, intestine, or colon. A clinical diagnosis of inflammatory bowel disease is considered only if affected animals have: (1) persistent (> 3 weeks in duration) gastrointestinal signs (anorexia, vomiting, weight loss, diarrhea, hematochezia, mucosy feces), (2) failure to respond to symptomatic therapies (parasiticides, antibiotics, gastrointestinal protectants) alone, (3) failure to document other causes of gastroenterocolitis by thorough diagnostic evaluation, and (4) histologic diagnosis of benign intestinal inflammation. Small bowel and large bowel forms of inflammatory bowel disease have been reported in both dogs and cats, although large bowel inflammatory bowel disease appears to be more prevalent in the dog.

Histologic criteria Inflammatory bowel disease has been defined histologically by the type of inflammatory infiltrate (neutrophilic, eosinophilic, lymphocytic, plasmacytic, granulomatous), associated mucosal pathology (villus atrophy, fusion, crypt collapse), distribution of the lesion (focal or generalized, superficial or deep), severity (mild, moderate, severe), mucosal thickness (mild, moderate, severe), and topography (gastric fundus, gastric antrum, duodenum, jejunum, ileum, cecum, ascending colon, descending colon). As with small intestinal inflammatory bowel disease, subjective interpretation of large intestinal inflammatory bowel disease lesions has made it difficult to compare tissue findings between pathologists. Subjectivity in histologic assessments has led to the development of several inflammatory bowel disease grading systems.

Immunologic criteria Inflammatory bowel disease (IBD) has been denned immunologically by the innate and adaptive response of the mucosa to gastrointestinal antigens. Although the precise immunologic events of canine and feline inflammatory bowel disease remain to be determined, a prevailing hypothesis for the development of inflammatory bowel disease is the loss of immunologic tolerance to the normal bacterial flora or food antigens, leading to abnormal T cell immune reactivity in the gut microenvironment. Genetically engineered animal models (e. g., IL-2, IL-10, T cell receptor knockouts) that develop inflammatory bowel disease involve alterations in T cell development, function, or both, suggesting that T cell populations are responsible for the homeostatic regulation of mucosal immune responses. Immunohistochemical studies of canine inflammatory bowel disease have demonstrated an increase in the T cell population of the lamina propria, including CD3+ cells and CD4+ cells, macrophages, neutrophils, and IgA-containing plasma cells. Many of the immunologic features of canine inflammatory bowel disease can be explained as an indirect consequence of mucosal T cell activation. Enterocytes are also likely involved in the immunopathogenesis of inflammatory bowel disease. Enterocytes are capable of behaving as antigen-presenting cells, and interleukins (e. g., IL-7, IL-15) produced by enterocytes during acute inflammation activate mucosal lymphocytes. Up-regulation of Toll-like receptor 4 (TLR4) and Toll-like receptor 2 (TLR2) expression contribute to the innate immune response of the colon. Thus the pathogenesis and pathophysiology of inflammatory bowel disease appears to involve the activation of a subset of CD4+ T cells within the intestinal epithelium that overproduce inflammatory cytokines with concomitant loss of a subset of CD4+ T cells and their associated cytokines, which normally regulate the inflammatory response and protect the gut from injury. Enterocytes, behaving as antigen-presenting cells, contribute to the pathogenesis of this disease.

Pathophysiologic criteria Inflammatory bowel disease (IBD) may be defined patho-physiologically in terms of changes in transport, blood flow, and motility. The clinical signs of inflammatory bowel disease, whether small or large bowel, have long been attributed to the pathophysiology of malabsorption and hypersecretion, but experimental models of canine inflammatory bowel disease have instead related clinical signs to the emergence of abnormality motility patterns.

Genetic criteria Inflammatory bowel disease (IBD) may be defined by genetic criteria in several animal species. Crohn’s disease and ulcerative colitis are more common in certain human genotypes, and a mutation in the NOD2 gene (nucleotide-binding oligomerization domain2) has been found in a subgroup of patients with Crohn’s disease. Genetic influences have not yet been identified in canine or feline inflammatory bowel disease, but certain breeds (e. g., German shepherds, boxers) appear to be at increased risk for the dis-

Inflammatory Bowel Disease: Pathophysiology

The pathophysiology of large intestinal inflammatory bowel disease is explained by at least two interdependent mechanisms: (1) the mucosal immune response and (2) accompanying changes in motility.

Immune responses A generic inflammatory response involving cellular elements (B and T lymphocytes, plasma cells, macrophages, and dendritic cells), secretomotor neurons (e. g., vasoactive intestinal polypeptide, substance P, cholinergic neurons), cytokines and interleukins, and inflammatory mediators (e. g., leukotrienes, prostanoids, reactive oxygen metabolites, nitric oxide (NO], 5-HT, IFN-γ, TNF-α, platelet-activating factor) is typical of canine and feline inflammatory bowel disease. Many similarities exist between the inflammatory response of the small and large intestine, but recent immunologic studies suggest that inflammatory bowel disease of the canine small intestine is a mixed Th 1 and Th2 response, whereas inflammatory bowel disease of the canine colon may be more of a Th 1 type response with elaboration of IL-2, IL-12, INF-γ, and TNF-α. Other studies of canine colonic inflammatory bowel disease have demonstrated increased numbers of mucosal IgA- and IgG-containing cells, nitrate, CD3+ T cells, NO, and inducible nitric oxide synthase (iNOS) in the inflamed colonic mucosa (Table Immunologic and Motility Abnormalities in Canine Large Bowel Inflammatory Bowel Disease). Increases in the CD3+ positive T cell population of the inflamed colon are consistent with changes reported in the inflamed canine intestine. Thus important similarities exist, as do differences between small and large bowel inflammatory bowel disease.

Immunologic and Motility Abnormalities in Canine Large Bowel Inflammatory Bowel Disease

Histolocic Findings Immunologic Abnormalities
Lymphocytic-plasmacytic colitis Increased nitric oxide and IgG in colonic lavage fluid
Lymphocytic-plasmacytic colitis Increased expression of inducible nitric oxide synthase mRNA
Lymphocytic-plasmacytic colitis Increases in T cells and B cells in lamina propria
Lymphocytic-plasmacytic colitis Increases in CD3+ T cells and in lgA+ and lgC+ plasma cells
Lymphocytic-plasmacytic colitis Increased IL-2 and TNF-α mRNA expression
Tissue / Cell Type Motility Abnormalities
Colon Loss of spontaneous phasic contractions
Decreased frequency of migrating motor complexes (MMCs)
Increased frequency of giant migrating contractions (CMCs)
Colonic circular smooth muscle cells Decreased amplitude and duration of the slow wave plateau potential
Shift from the M3 to M2 muscarinic receptor subtype
Reduced calcium influx through L-type calcium channel
Reduced L-type calcium channel expression
Decreased open probability of KCa channels
Down-regulation of PKC α, β, ξ expression and activation
Reduced phospholipase A2 expression
Increased NF-κB expression and activation
Colonic enteric neurons Sensitization to substance P during colonic inflammation
Colonic interstitial cells of Cajal Reduced density of interstitial cells
Cytoplasmic vacuolation and damage to cellular processes

IgG, Immunoglobulin G; IgA, immunoglobulin A; IL-2, interleukin-2; TNF-α, tumor necrosis factor alpha; PKC, protein kinase C; M, muscarinic; NF-κB, nuclear factor-icB; KCa, calcium-activated potassium channel.

Motility changes Experimental studies of canine large intestinal inflammatory bowel disease have shown that many of the clinical signs (diarrhea, passage of mucus and blood, abdominal pain, tenesmus, and urgency of defecation) are related to motor abnormalities of the colon. Ethanol and acetic acid perfusion of the canine colon induces a large bowel form of inflammatory bowel disease syndrome indistinguishable from the natural condition. I Inflammation in this model suppresses the normal phasic contractions of the colon, including the migrating motility complex, and triggers the emergence of giant migrating contractions. The appearance of these giant migrating contractions in association with inflammation is a major factor in producing diarrhea, abdominal cramping, and urgency of defecation. Giant migrating contractions are powerful lumen-occluding contractions that rapidly propel pancreatic, biliary, and intestinal secretions in the fasting state (and undigested food in the fed state) to the colon to increase its osmotic load. Malabsorption results from direct injury to the epithelial cells and from ultrarapid propulsion of intestinal contents by giant migrating contractions so that sufficient mucosal contact time is not allowed for digestion and absorption to take place.

Inflammation impairs the regulation of the colonic motility patterns at several levels (i. e., enteric neurons, interstitial cells of Cajal, circular smooth muscle cells; summarized in Table Immunologic and Motility Abnormalities in Canine Large Bowel Inflammatory Bowel Disease). Inflammation-induced changes in the amplitude and duration of the smooth muscle slow wave plateau potentials contribute to the suppression of rhythmic phasic contractions. These alterations likely have their origin in structural and functional damage to the interstitial cells of Cajal. At the same time that inflammation suppresses the rhythmic phasic contractions, inflammation sensitizes the colon to the stimulation of giant migrating contractions by the neurotransmitter substance P. These findings suggest that SP increases the frequency of giant migrating contractions during inflammation and that selective inhibition of giant migrating contractions during inflammation may minimize the symptoms of diarrhea, abdominal discomfort, and urgency of defecation associated with these contractions.

Inflammation suppresses the generation of tone and phasic contractions in the circular smooth muscle cells through multiple molecular mechanisms (see Table Immunologic and Motility Abnormalities in Canine Large Bowel Inflammatory Bowel Disease). Inflammation shifts muscarinic receptor expression in circular smooth muscles from the M3 to the M2 subtype. This shift has the effect of reducing the overall contractility of the smooth muscle cell. Inflammation also impairs calcium influx” and down-regulates the expression of the L-type calcium channel, which may be important in suppressing phasic contractions and tone while concurrently stimulating giant migrating contractions in the inflamed colon. Changes in the open-state probability of the large conductance calcium-activated potassium channels (Kc) partially attenuate this effect. Inflammation also modifies the signal transduction pathways of circular smooth muscle cells. Phospholipase A2 and protein kinase C. (PKC) expression and activation are significantly altered by colonic inflammation, and this may partially account for the suppression of tone and phasic contractions. PKC α, β and ξ isoenzyme expression is down-regulated, PKC i and X isoenzyme expression is up-regulated, and the cytosol-to-membrane translocation of PKC is impaired. The L-type calcium channel, already reduced in its expression, is one of the molecular targets of PKC. Inflammation also activates the transcription factor NF-κB that further suppresses cell contractility.

Clinical Examination The clinical signs of large intestinal inflammatory bowel disease are those of a large bowel-type diarrhea (i. e., marked increased frequency, reduced fecal volume per defecation, blood pigments and mucous in feces, and tenesmus). Anorexia, weight loss, and vomiting are occasionally reported in animals with severe inflammatory bowel disease of the colon or concurrent inflammatory bowel disease of the stomach, small intestine, or both. Clinical signs usually wax and wane in their severity. A transient response to symptomatic therapy may occur during the initial stages of inflammatory bowel disease. As the condition progresses, diarrhea gradually increases in its frequency and intensity and may become continuous. In some cases the first bowel movement of the day may be normal or nearlv normal, whereas successive bowel movements are reduced in volume and progressively more urgent and painful. During severe episodes, mild fever, depression, and anorexia may occur.

There does not appear to be any sex predilection, but age may be a risk factor, with inflammatory bowel disease appearing more frequently in middle-aged animals (mean age approximately 6 years with a range of 6 months to 20 years). German shepherd and boxer dogs are at increased risk for inflammatory bowel disease, and pure-breed cats appear to be at greater risk. Cats more often have an upper gastrointestinal form of inflammatory bowel disease, whereas dogs are at risk for both small and large bowel inflammatory bowel disease.

Physical examination is unremarkable in most cases. Thickened bowel loops may be detected during abdominal palpation if the small bowel is concurrently involved. Digital examination of the anorectum may evoke pain or reveal irregular mucosa, and blood pigments and mucous may be evident on the examination glove.

Diagnosis of Inflammatory Bowel Disease

CBCs, serum chemistries, and urinalyses are often normal in mild cases of large bowel inflammatory bowel disease. Chronic cases may have one or more subtle abnormalities. One review of canine and feline inflammatory bowel disease reported several hematologic abnormalities including mild anemia, leukocytosis, neutrophilia with and without a left shift, eosinophilia, eosinopenia, lymphocytopenia, monocytosis, and basophilia. The same study reported several biochemical abnormalities including increased activities of serum alanine aminotransferase and alkaline phosphatase, hypoalbuminemia, hypoproteinemia, hyperamylasemia, hyperglobulinemia, hypokalemia, hypocholesterolemia, and hyperglvcemia. No consistent abnormality in the complete blood count or serum chemistry has been identified.

A scoring index for disease activity in canine inflammatory bowel disease was recently developed that relates severity of clinical signs to serum acute-phase protein (C-reactive protein (CRP], serum amyloid A) concentrations. The canine inflammatory bowel disease activity index (CIBDAI) assigns levels of severity to each of several gastroen-terologic signs (e. g., anorexia, vomiting, weight loss, diarrhea), and it appears to be a reliable index of mucosal inflammation in canine inflammatory bowel disease. Interestingly, both the activity index and serum concentrations of C-reactive protein improve with successful treatment, suggesting that serum C-reactive protein is suitable for the laboratory evaluation of therapy in canine inflammatory bowel disease. Other acute-phase proteins were less specific than C-reactive protein. One important caveat that should be emphasized is that altered CRP is not prima facie evidence of gastrointestinal inflammation. Concurrent infections or other inflammatory conditions could cause an acute-phase response, including C-reactive protein, in affected patients.

Treatment of Inflammatory Bowel Disease

Dietary therapy The precise immunologic mechanisms of canine and feline inflammatory bowel disease have not yet been determined, but a prevailing hypothesis for the development of inflammatory bowel disease is the loss of immunologic tolerance to the normal bacterial flora or food antigens. Accordingly, dietary modification may prove useful in the management of canine and feline inflammatory bowel disease. Several nutritional strategies have been proposed including novel proteins, hydrolyzed diets, antioxidant diets, medium chain triglyceride supplementation, low-fat diets, modifications in the omega-6 (ω-6) and omega-3 (ω-3) fatty acid ratio, and fiber supplementation. Of these strategies, some evidence-based medicine has emerged for the use of novel protein, hydrolyzed, and fiber-supplemented diets.

Food sensitivity reactions were suspected or documented in 49% of cats presented because of gastroenterologic problems (with or without concurrent dermatologic problems) in a prospective study of adverse food reactions in cats. Beef, wheat, and com gluten were the primary ingredients responsible for food sensitivity reactions in that study, and most of the cats responded to the feeding of a chicken- or venison-based selected protein diet for a minimum of 4 weeks. The authors concluded that adverse reactions to dietary staples are common in cats with chronic gastrointestinal problems and that they can be successfully managed by feeding selected protein diets. Further support for this concept comes from studies in which gastroenterologic or dermatologic clinical signs were significandy improved by the feeding of novel proteins.

Evidence is accruing that hydrolyzed diets may be useful in the nutritional management of canine inflammatory bowel disease. The conceptual basis of the hydrolyzed diet is that oligopeptides are of insufficient size and structure to induce antigen recognition or presentation. In one preliminary study, dogs with inflammatory bowel disease showed significant improvement after the feeding of a hydrolyzed diet, although they had failed to respond to the feeding of a novel protein. Clinical improvement could not be solely attributed to the hydrolyzed nature of the protein source because the test diet had other modified features (i. e., high digestibility, cornstarch rather than intact grains, medium-chain triglycerides, an altered ratio of ω-6 to ω-3 polyunsatu-rated fatty acids). Additional studies will be required to ascertain the efficacy of this nutritional strategy in the management of inflammatory bowel disease.

Fiber-supplemented diets may be useful in the management of irritable bowel syndrome (IBS) in the dog. IBS is a poorly defined syndrome in the dog that may or may not bear resemblance to IBS in humans. Canine irritable bowel syndrome has been defined as a chronic large bowel-type diarrhea without known cause and without evidence of colonic inflammation on colonoscopy or biopsy. Dogs fulfilling these criteria were successfully managed with soluble fiber (psyllium hydrophilic mucilloid) supplementation of a highly digestible diet.

Exercise Experimental inflammatory bowel disease (IBD) in the dog is accompanied by significant abnormalities in the normal colonic motility patterns. Physical exercise has been shown to disrupt the colonic MMCs and to increase the total duration of contractions that are organized as nonmigrating motor complexes during the fed state. Exercise also induces giant migrating contractions, defecation, and mass movement in both the fasted and fed states. The increased motor activity of the colon and extra giant migrating contractions that result from physical exercise may aid in normal colonic motor function.

Pharmacologic therapy Animals with mild to moderate forms of large bowel inflammatory bowel disease generally respond favorably to dietary modification alone, but pharmacologic therapy will be required with more severe forms of large bowel inflammatory bowel disease. Medical therapy includes anti-inflammatory (sulfasalazine and other 5-aminosalicylates, metronidazole, prednisone, budesonide), immunosuppressive (azathioprine, cyclosporine, chlorambucil), and motility-modifying (loperamide) drugs (Table Drug Index — Large Bowel Diarrhea).

Drug Index — Large Bowel Diarrhea

Drug Classification And Examples Dose Indication
Anthelmintic Drugs
Albendazole 25 mg / kg PO SID x 2 days Ciardia infection
Febantel 10 mg / kg PO SID x 3 days — adult dogs Trichuris infection
15 mg / kg PO SID x 3 days — puppies Trichuris infection
Fenbendazole 50 mg / kg PO SID x 3 days Trichuris, Ancylostoma, Ciardia infection
Ivermectin 200 μg / kg SQ once Larvicidal for Trichuris canis
Mebendazole 22 mg / kg PO SID x 3 days Trichuris infection
Metronidazole 25 mg / kg PO BID x 5 days Ciardia infection
Milbemycin oxime 0.5 mg / kg PO once per month Trichuris preventive
Praziquantel 44 mg / kg PO once Heterobilharzia
Pyrantel pamoate 5 mg / kg PO dog, 20 mg / kg cat Ancylostoma, Toxocara
Ampicillin 22mg / kg PO IV TID Salmonella, E. coli, Clostridium perfringens
Cefadroxil 22 mg / kg PO BID Salmonella, E. coli
Chloramphenicol 44 mg / kg PO TID — dogs Campylobacter
11 mg / kg PO BID — cats Campylobacter
Enrofloxacin 5 mg / kg PO IM SQ BID Salmonella, E. coli
Erythromycin 15-20 mg / kg PO TID Campylobacter, C. perfringens
Metronidazole 10-20 mg / kg PO BID-TID C. perfringens
Orbifloxacin 2.5-7.5 mg / kg PO SID Salmonella, E. coli
Trimethoprim sulfonamide 30 mg / kg PO IM SQ BID Salmonella
Tylosin 40-80 mg / kg PO SID Inflammatory bowel disease, C. perfringens
Antifungal Drugs
Amphotericin B 2-3 mg / kg IV QOD administered to a cumulative dose of 24-27 mg / kg Histoplasmosis, pythiosis, protothecosis
Itraconazole 5 mg / kg PO BID for several months Histoplasmosis, pythiosis, protothecosis
Ketoconazole 10-15 mg / kg PO BID several months Histoplasmosis, pythiosis. protothecosis
Anti-Inflammatory Drugs
Budesonide 1 mg / cat or 1 mg / dog PO SID Inflammatory bowel disease
Meselamine 10 mg / kg PO TID IBD
Metronidazole 10-20 mg / kg PO BID-TID for 4-6 weeks Inflammatory bowel disease
Olsalazine 5-10 mg / kg PO TID for 4-6 weeks IBD
Prednisolone 4.0-6.0 mg / kg PO SID for 4-6 weeks Feline eosinophilic colitis
Prednisone 1.0-2.0 mg / kg PO SID for 4-6 weeks IBD
Sulfasalazine 10-25 mg / kg PO TID for 4-6 weeks — dogs inflammatory bowel disease, ulcerative colitis
5-12.5 mg / kg PO TID for 2-4 weeks — cats Refractory IBD
Immunosuppressive Drugs
Azathioprine 2 mg / kg PO SID for 4-6 weeks — dogs Inflammatory bowel disease
Chlorambucil 2 mg / m PO every other day for 4-6 weeks IBD
Cyclosporine 3-7 mgAg PO BID for 4-6 weeks IBD
Motility-Modifying Drugs
Loperamide 0.08 mgAg PO TID-QID IBD, IBS
Propantheline 0.25 mg / kg PO BID-TID Irritable bowel syndrome
Aminopentamide 0.01-0.03 mg / kg PO BID-TID IBS
Enterococcus faecium (SF68) 5 x 10 colony-forming units / day IBD
Lactobacillus rhamnosus GC 1 x 10 to 5 x 10 colony-forming units / day Inflammatory bowel disease

PO, per os; SID, once per day; IV, intravenous; TID, three times per day; BID, twice per day; QOD, every other day.

Sulfasalazine Sulfasalazine is a highly effective prostaglandin synthetase inhibitor that has proven efficacy in the therapy of large bowel inflammatory bowel disease in the dog. Sulfasalazine is a compound molecule of 5-aminosalicylate (meselamine) and sulfapyridine linked in an azochemical bond. After oral dosing, most of the sulfasalazine is transported to the distal gastrointestinal tract where cecal and colonic bacteria metabolize the drug to its component parts. Sulfapyridine is largely absorbed by the colonic mucosa but much of the 5-aminosalicylate remains in the colonic lumen where it inhibits mucosal cyclooxygenase and the inflammatory cascade. Sulfasalazine has been recommended for the treatment of canine large bowel inflammatory bowel disease at doses of 10 to 25 mg / kg orally, three times a day for 4 to 6 weeks. With resolution of clinical signs, sulfasalazine doses are gradually decreased by 25% at 2-week intervals and eventually discontinued while maintaining dietary management. Salicylates are readily absorbed and induce toxicity in cats; therefore this drug classification should be used with great caution in cats. If used in cats, some authors have recommended using half of the recommended dog dose (i. e., 5 to 12.5 mg / kg orally, three times a day). Sulfasalazine use has been associated with the development of keratoconjunctivitis sicca in the dog, so tear production should be assessed subjectively (by the pet owner) and objectively (by the veterinarian) during use.

Other 5-aminosalicylates This drug classification was developed to reduce the toxicity of the sulfapyridine portion of the parent molecule (sulfasalazine) and to enhance the efficacy of the 5-aminosalicylate portion. Meselamine (Dipentum, Asachol) and dimeselamine (olsalazine) are available for use in the treatment of canine large bowel inflammatory bowel disease. Olsalazine has been used at a dose of 5 to 10 mg / kg orally, three times a day in the dog. Despite the formulation of sulfa-free 5-aminosalicylate preparations, instances of keratoconjunctivitis sicca have still been reported in the dog.

Metronidazole Metronidazole (10 to 20 mg / kg orally, twice a day to three times a day) has been used in the treatment of mild to moderate cases of large bowel inflammatory bowel disease in both dogs and cats. Metronidazole has been used either as a single agent or in conjunction with 5-aminosalicylates or glucocorti-coids. Metronidazole is believed to have several beneficial properties, including antibacterial, antiprotozoal, and immunomodulatory effects. Side effects include anorexia, hypersalivation, and vomiting at recommended doses and neurotoxicity (ataxia, nystagmus, head title, and seizures) at higher doses. Side effects usually resolve with discontinuation of therapy, but diazepam may accelerate recovery of individual patients.

Glucocorticoids Anti-inflammatory doses of prednisone or prednisolone (1 to 2 mg / kg orally, once a day) may be used to treat inflammatory bowel disease in dogs that have failed to respond to dietary management, sulfasalazine, or metronidazole, and as adjunctive therapy to dietary modification in feline inflammatory bowel disease. Prednisone or prednisolone are used most frequendy, because both have short durations of action, are cost-effective, and are widely available. Equipotent doses of dexamethasone are equally effective but may have more deleterious effects on brush border enzyme activity. Prednisone should be used for 2 to 4 weeks depending upon the severity of the clinical signs. Higher doses of prednisone (e. g., 2 to 4 mg / kg orally, once a day) may be needed to control severe forms of eosinophilic colitis or hypereosinophilic syndrome in cats.

Combination therapy with sulfasalazine, metronidazole, or azathioprine may reduce the overall dose of prednisone needed to achieve remission of clinical signs. As with sulfasalazine, the dose of glucocorticoid may be reduced by 25% at 1- to 2-week intervals while (it is hoped) maintaining remission with dietary modification.

Because of steroid side effects and suppression of the hypothalamic-pituitary-adrenal axis, several alternative glucocorticoids have been developed that have excellent topical (i. e., mucosal) anti-inflammatory activity but are significantly metabolized during first pass hepatic metabolism. Budesonide has been used for many years as an inhaled medication for asthma, and an enteric-coated form of the drug is now available for treatment of inflammatory bowel disease in humans (and animals). Little clinical evidence supports of the use of this medication in canine or feline inflammatory bowel disease, but doses of 1 mg / cat or 1 mg / dog per day have been used with some success in anecdotal cases.

Azathioprine Azathioprine is a purine analog that, after DNA incorporation, inhibits lymphocyte activation and proliferation. It is rarely effective as a single agent and should instead be used as adjunctive therapy with glucocorticoids. Azathioprine may have a significant steroid-sparing effect in inflammatory bowel disease. Doses of 2 mg / kg orally, every 24 hours in dogs and 0.3 mg / kg orally every 48 hours in cats have been used with some success in inflammatory bowel disease. It may take several weeks or months of therapy for azathioprine to become maximally effective. Cats particularly should be monitored for side effects, including myelosuppression, hepatic disease, and acute pancreatic necrosis.

Cyclosporine Cyclosporine has been used in the renal transplantation patient for its inhibitory effect on T cell function. In more recent times, cyclosporine has been used in a number of immune-mediated disorders, including keratoconjunctivitis sicca, perianal fistula (anal furunculosis), and IMHA. Evidence-based medicine studies will be needed to establish efficacy, but anecdotal experience would suggest that cyclosporine (3 to 7 mg / kg orally, twice a day) may be useful in some of the more difficult or refractory cases of inflammatory bowel disease.

Chlorambucil Chlorambucil (2 mg / m orally, every other day) has been used in place of azathioprine in some difficult or refractory cases of feline inflammatory bowel disease.

Motility-modifying drugs The mixed μ, δ-opioid agonist, loperamide, stimulates colonic fluid and electrolyte absorption while inhibiting-colonic propulsive motility. Loperamide (0.08 mg / kg orally, three times a day to four times a day) may be beneficial in the treatment of difficult or refractory cases of large bowel-type inflammatory bowel disease.

Probiotic therapy Probiotics (see Table Drug IndexLarge Bowel Diarrhea) are living organisms with low or no pathogenicity that exert beneficial effects (e. g., stimulation of innate and acquired immunity) on the health of the host. The gram-positive commensal lactic acid bacteria (e. g., Lactobacilli) have many beneficial health effects, including enhanced lymphocyte proliferation, innate and acquired immunity, and anti-inflammatory cytokine production Lactobacillus rhamnosus GG, a bacterium used in the production of yogurt, is effective in preventing and treating diarrhea, recurrent Clostridia difficile infection, primary rotavirus infection, and atopic dermatitis in humans. Lactobacillus rhamnous GG and Lactobacillus acidophilus (strain DSM13241) have been safely colonized in the canine gastrointestinal tract, although probiotic effects in the canine intestine have not been firmly established. The probiotic organism, Enterococcus faecium (SF68), has been safely colonized in the canine gastrointestinal tract, and it has been shown to increase fecal IgA content and circulating mature B (CD21+ / MHC class 11+) cells in young puppies. It has been suggested that this probiotic may be useful in the prevention or treatment of canine gastrointestinal disease. This organism may, however, enhance Campybbacter jejuni adhesion and colonization of the dog intestine, perhaps conferring carrier status on colonized dogs. Two recent studies have shown that many commercial veterinary probiotic preparations are not accurately represented by label claims. Quality control appears to be deficient for many of these formulations. Until these products are more tightly regulated, veterinarians should probably view product claims with some skepticism.

Behavioral modification Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) very likely have underlying behavioral components. Abnormal personality traits and potential environmental stress factors were identified in 38% of dogs in one study. Multiple factors were present in affected households, including travel, relocation, house construction, separation anxiety, submissive urination, noise sensitivity, and aggression. The role of behavior in the pathogenesis and therapy of canine and feline gastrointestinal disorders remains largely unexplored.

Prognosis of Inflammatory Bowel Disease

Most reports indicate that the short-term prognosis for control of inflammatory bowel disease is good to excellent. After completion of drug therapy, many animals are able to maintain remission of signs with dietary management alone. Treatment failures are uncommon and are usually due to (1) incorrect diagnosis (it is especially important to rule out alimentary lymphosarcoma), (2) presence of severe disease such as histiocytic ulcerative colitis and protein-losing enteropathy or irreversible mucosa lesions such as fibrosis, (3) poor client compliance with appropriate drug and dietary recommendations, (4) use of inappropriate drugs or nutritional therapy, and (5) presence of concurrent disease such as small intestinal bacterial overgrowth or hepatobiliary disease. The prognosis for cure of inflammatory bowel disease is poor, and relapses should be anticipated.


Acute Small Intestinal Disease

Potential causes of acute diarrhea are listed in Table Causes of Acute Diarrhea, but whether a complete diagnosis is pursued and when therapy is instituted are clinical judgments. The diagnostic approach to acute diarrhea is discussed elsewhere.

Patients that are bright, alert, and not dehydrated may require no further investigation, because signs are often self-limiting. Further investigation of acute diarrhea is indicated under the following circumstances:

• The patient is dull or depressed, febrile, dehydrated, tachycardic or bradycardic or is having abdominal discomfort, melena, bloody mucoid stools, or frequent vomiting.

• Obvious physical abnormalities (e. g., intestinal masses, thickening, or plication) localize the problem to the small intestine, and diagnostic imaging, noninvasive biopsy, or surgery can define the cause.

• Systemic abnormalities are present, as defined by a minimum database and other clinicopathologic tests.

It is important that the patient be regularly re-evaluated to monitor the response to therapy and to detect any new abnormalities that may arise.

Causes of Acute Diarrhea

Causes Examples
Dietary Hypersensitivity (allergy), intolerance, sudden diet change, food poisoning (poor quality, spoiled foods / bacterial)
Toxic Food or other sources
Infectious Parvovirus, coronavirus, paramyxovirus, adenovirus, may or may not be feline leukemia virus / FIV related; also Salmonella, Campylobacter, Clostridium spp. (?) and Escherichia coli (?) 

Helminths; Coccidia, Ciardia spp.

Acute pancreatitis
Anatomic Intussusception
Metabolic Hypoadrenocorticism

FeLV, feline leukemia virus, FIV, feline immunodeficiency virus

Treatment of Acute Diarrhea

The initial management of acute diarrhea associated with systemic illness is symptomatic and supportive, and is commenced on the basis of clinical findings, in particular the presence of dehydration, while the results of the initial data base and further tests are pending.

Fluid therapy Oral fluid and electrolyte replacement therapy may be sufficient if acute diarrhea is associated with only mild or insignificant dehydration, and if vomiting is infrequent or absent, although its efficacy should still be monitored. However, when diarrhea is accompanied by significant vomiting or dehydration, parenteral fluids should be administered at a rate that replaces deficits, supplies maintenance needs and compensates for ongoing losses. Patients with marked hypovolemia require more aggressive support.

The type of fluid and requirement for potassium supplementation is best judged by performing a minimum data base and blood gas analysis. Parenteral fluids are usually best given intravenously. The intraosseous route can be used if venous access is unavailable, but subcutaneous administration of fluids is likely to be inadequate.

Diet Studies examining the role of diet in the treatment of acute diarrhea in dogs and cats are scarce. Current recommendations are based on common sense and anecdotal evidence Best practice generally is considered to be withholding food for 24 to 48 hours and then feeding a bland diet, given little and often, for 3 to 5 days. Thereafter the original diet is gradually reintroduced. In animals with no other significant clinical findings, this may be the only therapy required. Common choices of a bland, fat-restricted diet for dogs are boiled chicken or white fish or low-fat cottage cheese with boiled rice. Cats seem to have a lower tolerance to dietary starch and may benefit from a diet with a higher fat content. Little attention is paid to the overall nutritional adequacy of home-prepared bland diets when fed in the short term.

This dogma of intestinal rest has been challenged by studies that demonstrate that feeding human infants during diarrhea promotes recovery. The success of such feeding through diarrhea varies depending on the cause, with most benefit seen in secretory diarrhea. However, in dogs and cats, secretory diarrhea is less common, the increased volumes of diarrhea may be cosmetically unacceptable, and the frequently contemporaneous vomiting may preclude this approach. The inclusion of glutamine, a nutrient utilized preferentially by enterocytes, may also promote recovery and decrease bacterial translocatjon, although experimental proof of improved intestinal integrity in animals is lacking.

Theoretically, any intestinal disease may predispose the animal to the development of a food sensitivity, therefore feeding of a novel protein source during these periods may preclude the development of sensitivity to the staple diet. However, this concept of feeding of a sacrificial protein is supported only by circumstantial evidence.

Protectants and adsorbents Bismuth-subsalicylate, kaolin-pectin, montmorillonite, activated charcoal and magnesium, and aluminum and barium-containing products are often administered in acute diarrhea to bind bacteria and their toxins and to coat and protect the intestinal mucosa, but they may also have an antisecretory effect. Therapy for acute diarrhea with protectants, absorbents or motility modifying agents should not exceed 5 days.

Motility- and secretion-modifying agents Anticholinergics and opiates or opioids (loperamide, diphenoxylate) are frequently used for the symptomatic management of acute diarrhea, but anticholinergic agents can potentiate ileus and are not recommended. Opiate analgesics were thought to exert their effects by stimulating segmental motility, but they actually act mainly by decreasing intestinal secretion and promoting absorption and can be used in the short-term symptomatic management of acute diarrhea in dogs. They are contraindicated in cases involving obstruction or an infectious etiology.

Antimicrobial therapy Antimicrobials are indicated only in animals with a confirmed bacterial or protozoal infection, those in which a breach of intestinal barrier integrity is suspected from evidence of gastrointestinal bleeding, and hence in those at risk of sepsis. Leukopenia, neutrophilia, pyrexia, the presence of blood in the feces, and shock all are indications for prophylactic antibiotics in animals with diarrhea. Initial choices in these situations include ampicillin or a cephalosporin (effective against gram-positive and some gram-negative and anaerobic bacteria). If systemic translocation of enteric bacteria is suspected, antimicrobials effective against anaerobic organisms (e. g., metronidazole or clindamycin) and “difficult” gram-negative aerobes (e. g., an aminoglycoside or a fluoroquinolone) are indicated. Intravenous quinolones have been shown to reach therapeutic concentrations in the canine gut lumen and can be effective against enterococci, E. coli, and anaerobes. Oxytetracycline, tylosin, and metronidazole are suitable for the treatment of SIBO.

A four-quadrant, intravenous antibacterial regimen may be required if septicemia is likely, and suitable combinations would be a cephalosporin (or amoxicillin) or a fluoroquinolone (or amikacin) with metronidazole or clindamycin. However, aminoglycosides should not be given until the patient is volume-expanded.

Probiotics Traditionally, many practitioners have recommended feeding live yogurt as a way of repopulating the intestine with beneficial lactobacilli after an acute gastrointestinal upset. There is evidence in other species that probiotics do exert a positive effect on intestinal permeability and mucosal immune responses, although the effects may be species specific and present only while the probiotic is continuously administered. Probiotics are now available for use in dogs and cats, and emerging data exist to support their use.

Acute Diarrhea Induced by Diet, Drugs, or Toxins

Altered food intake, probably the most common cause of acute, self-limiting diarrhea in dogs, includes rapid diet change, dietary indiscretion, dietary intolerance, hypersensitivity, and food poisoning. Dietary hypersensitivity (food allergy) is probably rare. Ingestion of drugs (e. g., nonsteroidal anti-inflammatory drugs [NSAIDs] or antibacterials) or toxins (e. g., insecticides) also may cause vomiting and diarrhea. The history may allow an educated, presumptive diagnosis to be made. However, the exact cause often is never determined because the patient is not systemically unwell and responds to symptomatic therapy. The prognosis usually is excellent, and only if the diarrhea does not respond or the patient deteriorates is further investigation necessary.

Hemorrhagic Gastroenteritis

There are numerous potential causes of bloody vomiting and diarrhea, but hemorrhagic gastroenteritis (HGE) is the name given to a syndrome characterized by acute hemorrhagic diarrhea accompanied by marked hemoconcentration. The cause of the syndrome is unknown. It may represent an intestinal type 1 hypersensitivity reaction or could be a consequence of C. perfringens enterotoxin production.

Clinical findings Dogs present with acute hemorrhagic diarrhea, with small breed dogs most frequently affected. Pyrexia is unusual, but vomiting, depression, and abdominal discomfort are common. The onset may be peracute and can be associated with marked fluid shifts into the small intestine, leading to severe hypovolemic shock even before signs of dehydration (e. g., decreased skin turgor) appear.

Diagnosis A presumptive diagnosis of hemorrhagic gastroenteritis can be made on the basis of appropriate clinical findings associated with a packed cell volume (PCV) of 55% to 60% or more. Total protein is often normal or not as high relative to the packed cell volume. probably because ot intestinal plasma loss. Radiographs may demonstrate ileus. The absence of leukopenia and the presence of marked hemoconcentration help distinguish hemorrhagic gastroenteritis from parvovirus. Positive fecal tests may support a diagnosis of clostridiosis, but direct evidence of small intestine infection is rarely obtained.

Treatment Intravenous fluids are essential in treating patients with hemorrhagic gastroenteritis. Some patients become hypoproteinemic, and plasma or colloid support may be required. Parenteral antibiotics are often administered because of potential clostridial infection and the high risk of sepsis. Clinical improvement is usually noted within a few hours, though the diarrhea may take several days to resolve. Close patient monitoring is essential; patients that have not responded within 24 hours should be re-evaluated for parvovirus, intussusception, or foreign objects. Once the patient is in the recovery phase, standard dietary therapy for acute diarrhea can be instigated. The prognosis for most animals with hemorrhagic gastroenteritis is good, but if hemorrhagic gastroenteritis is complicated by severe hypoproteinemia or sepsis, the prognosis is more guarded.

Infectious and Parasitic Causes of Acute Diarrhea

Diarrhea caused by infectious and parasitic agents is considered common in animals that are young, immunologically naive or immunocompromised, housed in large numbers, or housed in unsanitary conditions. Parvovirus, Giardia, Salmonella, and Campylobacter spp., and some helminths can be significant causes of diarrhea. The importance of coronavirus, C. perfringens, and E. coli as causes of diarrhea has yet to be defined. The zoonotic potential of many of these infections has not been clearly elucidated, but basic hygienic precautions should always be adopted. Specific small intestine infections are discussed below, but the reader is referred elsewhere for detailed information on other viruses such as paramyxoviruses, adenoviruses, feline leukemia, and immunodeficiency viruses, which also cause diarrhea but affect many other organ systems apart from the gastrointestinal tract.


Chronic Enteropathies

Chronic Idiopathic Enteropathies

Chronic enteropathies have historically been defined by histologic description of the tissue, which provides little information as to the nature of the intestinal dysfunction or its etiology.

Furthermore, tissue samples collected from many cases have no obvious morphologic changes. In the future, new methods of investigation may better characterize functional and immunologic abnormalities.

Management of Chronic Enteropathies

The management of idiopathic enteropathies is essentially symptomatic if a specific diagnosis is made (e. g., lymphangiectasia, severe inflammatory bowel disease, lymphoma), specific treatment modalities can be used. However, in many circumstances the diagnosis is not obvious, often because of a lack of specific or marked histopathologic changes, and it usually is most appropriate to perform treatments sequentially. It is safest to commence with antiparasiticides, then a dietary trial, followed by an antibacterial trial, before finally attempting immunosup-pression. Such an approach may identify occult parasitism, antibiotic-responsive diarrhea (antibiotic-responsive diarrhea) and diet-responsive conditions. However, because different treatments also lack specific activities, caution should be exercised in using treatment trials for diagnosis without prior investigation.

Antiparasiticides An appropriate trial of an antiparasiticide should eliminate the possibility of parasitic diseases, such as chronic giardiasis, that are difficult to diagnose. Fenbendazole (50 mg / kg given orally every 24 hours for 3 days) is the most appropriate drug for these circumstances, although alternatives exist (e. g., metronidazole or a febantel / pyrantel / praziquantel combination). Given the highly infectious nature of Giardia organisms, all in-contact animals may need to be treated concurrendy or reinfection may occur, which might suggest apparent treatment failure.

Dietary management Dietary management is a very important treatment modality in most chronic enteropathies and can be used in different ways. For diagnosis and treatment of adverse food reactions, an antigen-limited exclusion diet is most appropriate. Dietary management also can be important in the symptomatic management of many idiopathic enteropathies. The ideal diet is highly digestible, moderately fat restricted, lactose free, gluten free, not markedly hypertonic, nutritionally balanced, and palatable.

Inclusion of moderately fermentable fiber (e. g., psyllium, ispaghula) is known to promote colonic health, and soluble fiber also promotes small intestinal health. However, because dietary fiber can delay intestinal transit, its inclusion may be contraindicated for some intestinal diseases. Feeding the daily requirement in divided meals (usually between two and four) reduces the load on a compromised intestine. Feeding more frequendy is unnecessary, because the rate of gastric emptying imposes natural trickle feeding of the intestine.

Additional supplements include prebiotics such as fructo-oligosaccharides (FOS) and mannanoligosaccharides. FOS has been shown to alter the constituents of the fecal flora, but the effect on the small intestine flora is limited.

Antibacterials Antibacterials are indicated for specific conditions in which a bacterial pathogen has been documented (see above), in the treatment of antibiotic-responsive diarrhea or secondary SIBO, and in other chronic enteropathies, such as inflammatory bowel disease, in which modulation of the flora may be required. The drugs most commonly used in these circumstances are oxytetracycline, metronidazole, and tylosin. The beneficial effects of such drugs may go beyond their antibacterial activity, with potential effects on the mucosal immune system.

Immunosuppressive medication Immunosuppressive or anti-inflammatory drugs are indicated when evidence of mucosal inflammation is present and no underlying cause is found. However, given that immunosuppression may lead to clinical deterioration in some cases, the diagnosis should be reviewed before institution of such therapy, especially if the diagnosis was made on the basis of endoscopic biopsy alone.


Small Intestinal Bacterial Overgrowth

Normally the bacterial population of the small intestine is controlled by a number of mechanisms (see above). Bacterial overgrowth is the uncontrolled proliferation of these bacteria and, in humans, occurs secondary to a number of underlying disorders that interfere with the control mechanisms. Although the existence of small intestinal bacterial overgrowth in humans is not disputed, the subject is a source of controversy in small animal gastroenterology. In dogs, small intestinal bacterial overgrowth is best considered a clinical sign or a pathogenetic mechanism rather than a diagnosis. Historically, the term idiopathic small intestinal bacterial overgrowth was used to describe an antibiotic-responsive condition of large breed (especially German shepherd) dogs for which no underlying cause could be recognized. However, given concerns as to whether a true overgrowth exists in these cases, the alternative name of antibiotic-responsive diarrhea has been suggested. Although cats might feasibly suffer from secondary SIBO, an idiopathic antibiotic-responsive condition similar to that seen in German shepherds has not been documented in this species.


Genuine bacterial overgrowth is defined by an increase in the absolute number of bacteria in the upper small intestine during the fasted state (i. e., the number of colony-forming units cultured per milliliter of duodenal juice (CFU / mL]). The upper limit for normal bacterial numbers was defined in humans, and that number has been extrapolated to dogs. Controversy exists as to its validity, however, because the original work used a small number of dogs and questionable bacteriologic techniques. Subsequent studies with different collection methods and improved anaerobic culture techniques have demonstrated that a count equal to or greater than 107 CFU / mL total bacteria is commonly found in asymptomatic dogs. Therefore, although a genuine bacterial overgrowth may exist in conditions equivalent to those in humans, defining the presence of small intestinal bacterial overgrowth based on the original numeric limit is flawed. In this chapter, cases with a documented underlying cause are defined as secondary SIBO, and the term idiopathic antibiotic-responsive diarrhea is used for idiopathic antibiotic-responsive conditions without an obvious underlying cause.

Etiology and Pathogenesis

Secondary small intestinal bacterial overgrowth SIBO can occur secondary to (1) diseases that result in excess substrate in the intestinal lumen (e. g., EPI, motility disorder, blind loop), (2) diseases that affect the clearance of bacteria (e. g., partial obstruction, abnormal motility), or (3) morphologic or functional derangement of the mucosa (Box Causes of Secondary Small Intestinal Bacterial Overgrowth). Increased numbers of bacteria in the upper small intestine cause malabsorption and diarrhea through several mechanisms. First, bacteria compete for nutrients; for example, by binding cobalamin and reducing its availability for absorption. Second, bacterial metabolism of nutrients can create products that provoke diarrhea (e. g., hydroxylated fatty acids and deconjugated bile salts), leading to diarrhea from fat malabsorption and stimulation of colonocyte secretion. Finally, the bacterial flora may damage the mucosal brush border, and alterations in enzyme activity, which reverse on antibiotic treatment, can be detected.

Causes of Secondary Small Intestinal Bacterial Overgrowth


  • Spontaneous (atrophic gastritis)
  • Acid blockers

Exocrine pancreatic insufficiency

Partial intestinal obstruction

  • Chronic intussusception
  • Stricture
  • Tumor

Abnormal anatomy

  • Surgical resection of ileocolic valve
  • Blind loop

Motility disorder

  • Primary
  • Hypothyroidism

Mucosal disease

  • Latent primary pathogens (?)
  • Inflammatory bowel disease (cause or effect?)
  • Chronic giardiasis

Dietary sensitivity (?)

Idiopothic antibiotic-responsive diarrhea A number of hypotheses exist as to the cause of idiopathic antibiotic-responsive diarrhea. Historically, hypotheses were based on the belief that a genuine increase in small intestine bacterial numbers was present and therefore pathogenesis was related to the mechanisms described above. An underlying defect allowing overgrowth was not obvious, and suggested mechanisms such as abnormal intestinal motility or achlorhydria were not proved.

Given that recent studies have questioned whether a genuine increase in bacterial numbers occurs, recent hypotheses now focus on host-bacterial interactions. As was suggested for mouse models of enteric inflammation, antibiotic-responsive diarrhea may develop secondary to defects in the mucosal barrier, aberrant mucosal immune responses, qualitative changes in the enteric bacterial flora, or a combination of these mechanisms. Defects in the mucosal barrier are supported by studies documenting abnormal permeability and the presence of brush border enzyme defects. A possible underlying selective IgA deficiency in the German shepherd breed has been postulated. German shepherds with intestinal disease have defective small intestinal IgA production, although mucosal IgA+ plasma cell numbers in affected dogs are either normal or increased. The cause of this IgA deficiency is not clear, but a complex defect is likely, involving abnormalities either in the production and release of IgA from the plasma cell or in the pathway of translocation of IgA across the epithelium during secretion.

Studies demonstrate that dogs with antibiotic-responsive diarrhea have increased lamina propria CD4+ T cells and increased expression of certain cytokines. It therefore is tempting to speculate that this represents immune dysregulation and perhaps a loss of tolerance toward endogenous bacterial antigens. Such a hypothesis is supported by the fact that antibacterials lead to resolution of clinical signs and decreased cytokine expression but not to a decline in bacterial numbers. The fact that the most effective antibacterials are those with immune-modulating properties (e. g., oxytetracycline, metronidazole, tylosin) may support this hypothesis.

An alternative hypothesis is that an unidentified pathogen is involved; candidates include intestinal Helicobacter spp. or enteropathogenic E. coli. The predisposition of German shepherds to this syndrome could therefore be explained by genetic susceptibility to infection as a result of MHC II antigen expression.

Clinical Presentation

Idiopathic antibiotic-responsive diarrhea Idiopathic antibiotic-responsive diarrhea is most commonly recognized in young German shepherds, although cases have been reported in other dog breed? (but not in cats). Affected dogs show signs of chronic intermittent diarrhea accompanied by weight loss and / or stunting. Intermittent, watery diarrhea, often associated with excessive gas production (manifested as borborygmi and flatus), is seen most frequently. However, vomiting and signs of colitis are sometimes reported, and occasionally dogs are stunted yet do not have diarrhea. Activity levels are normal, and appetite is variable; most affected dogs have polyphagia, pica, or coprophagia, but few are anorectic. A positive response to antibiotics is expected, and the clinical condition may deteriorate if corticosteroids are given. The major differential diagnoses are exocrine pancreatic insufficiency and inflammatory bowel disease, both of which are common in German shepherds.

Secondary small intestinal bacterial overgrowth SIBO may occur secondary to numerous primary conditions (see Box Causes of Secondary Small Intestinal Bacterial Overgrowth), and clinical signs usually relate to the underlying condition. However, signs of secondary small intestinal bacterial overgrowth also can been seen and are indistinguishable from those of idiopathic antibiotic-responsive diarrhea, with diarrhea predominating. When small intestinal bacterial overgrowth develops secondary to a partial obstruction or focal dysmotility, bacterial numbers can exceed 109 CFU / mL. Clinical signs may be noted intermittently, because recurrent diarrhea can temporarily flush out the overgrowth.

Using the historical numeric cutoff of 105 CFU / mL total bacteria, secondary small intestinal bacterial overgrowth was considered common in chronic enteropathies. In reality, true secondary small intestinal bacterial overgrowth is uncommon, with the exception of small intestinal bacterial overgrowth secondary to EPI. An increase in small intestine bacterial numbers has been documented in experimentally induced EPI, although bacterial numbers decrease upon treatment of exocrine pancreatic insufficiency with enzyme replacement. Therefore in many cases the small intestinal bacterial overgrowth itself is of no significance. However, a proportion of naturally occurring exocrine pancreatic insufficiency cases respond suboptimally to pancreatic enzyme supplementation alone and may require concurrent antibiotic therapy. Given that the majority of dogs affected with exocrine pancreatic insufficiency are German shepherds, it is not clear whether this is the result of secondary small intestinal bacterial overgrowth or of a concurrent idiopathic antibiotic-responsive diarrhea.


The diagnosis of small intestinal bacterial overgrowth and antibiotic-responsive diarrhea is controversial. In all cases it is critical that a thorough investigation be conducted to eliminate causes of secondary small intestinal bacterial overgrowth before the patient is treated with antibacterials. In this regard, diagnostic imaging, especially ultrasonography, is useful for ruling out partial intestinal obstructions. Systemic disorders should be ruled out with a minimum database, and exocrine pancreatic insufficiency is eliminated by serum TLI assay. Fecal examination for parasitic and bacterial diseases is also mandatory.

Idiopathic antibiotic-responsive diarrhea Although both direct and indirect tests were previously advocated for idiopathic SIBO, recent studies have suggested that they are all of limited value. One recent study demonstrated that neither indirect biochemical markers (folate, cobalamin, unconjugated bile acids) nor quantitative bacterial culture could reliably identify cases of antibiotic-responsive diarrhea. Therefore the only available diagnostic test for antibiotic-responsive diarrhea is response to an antibacterial trial. However, such a diagnostic modality is appropriate only after thorough diagnostic investigations have eliminated all other causes of an antibacterial responsiveness.

Secondary small intestinal bacterial overgrowth Although numerous tests are available to document secondary overgrowth, in practice it is more important to identify the underlying cause.

Duodenal juice culture Quantitative aerobic and anaerobic culture of duodenal juice previously formed the gold standard for diagnosis. For dogs, increases in either total or anaerobic bacteria above the upper cutoff (105 CFU / mL total bacteria or 104 CFU / mL anaerobic bacteria) were considered diagnostic. However, the validity of these cutoffs has been questioned. A count of 107 CFU / mL total duodenal bacteria has been documented commonly in healthy dogs, and numbers as high as 109 CFU / mL have been found occasionally in cats and asymptomatic dogs. Some of the discrepancies may reflect difficulties and differences in the methodology, because numbers vary widely when individual animals are repeatedly sampled. Use of an inappropriately low cutoff value leads to overdiagnosis of SIBO, which probably explains why it has been reported in 50% of dogs with chronic intestinal disease. Culture of endoscopic biopsies has not been shown to be of greater diagnostic utility.

The flora present in idiopathic antibiotic-responsive diarrhea may be comprised predominantly of either aerobic or anaerobic bacteria, but it tends to be a mixed population, with staphylococci, streptococci, coliforms, enterococci, and corynebacteria and anaerobes such as bacteroids, fusobacteria, and clostridia. These bacteria generally are commensals found normally in the oropharynx, small intestine, and large intestine. However, culture of fecal bacteria cannot be correlated with small intestine bacterial numbers and cannot be used to diagnose this condition.

Indirect tests for small intestinal bacterial overgrowth / antibiotic-responsive diarrhea Indirect tests include serum biochemical markers and breath hydrogen analysis.

Serum folate and cobalamin concentrations Bacteria synthesize folate and bind cobalamin, preventing its absorption. Therefore small intestinal bacterial overgrowth would be predicted to be associated with an increased serum folate concentration or a decreased cobalamin concentration, or both. Although such results would be expected in cases of genuine small intestinal bacterial overgrowth (e. g., secondary SIBO), no studies have specifically assessed the usefulness of these tests in those diseases. Alterations of serum folate and cobalamin noted in exocrine pancreatic insufficiency may reflect pancreatic dysfunction rather than secondary SIBO.

Furthermore, recent studies have demonstrated that these tests are of limited value in the diagnosis of idiopathic antibiotic-responsive diarrhea. This poor performance may be related to dietary factors, the presence of concurrent disease, or the use of drugs that alter serum vitamin concentrations. The other possibility (for idiopathic antibiotic-responsive diarrhea) is that disease pathogenesis is not related to genuine increases in bacterial numbers. Although these tests are often the only tests available to practitioners, they are generally unhelpful in the diagnosis of idiopathic antibiotic-responsive diarrhea.

Serum unconjugated bile acids Bile acids are synthesized and conjugated in the liver and excreted into the intestine via the biliary tract. Some small intestine bacterial species can deconjugate bile acids, which then are absorbed passively by the small intestine. Studies in humans have suggested that increased serum unconjugated bile acid (SUBA) concentrations are an indirect indicator of SIBO. A preliminary study in dogs suggested that SUBA concentrations increased in SIBO. However, these results have been contradicted by another recent study, which demonstrated that SUBA concentrations were neither sensitive nor specific for diagnosis of idiopathic antibiotic-responsive diarrhea. Further work may be required to clarify the diagnostic value of SUBA concentrations in dogs.

Other biochemical tests Measurement of increased amounts of a bacterial product made either naturally or after oral administration of a test substance could be used to diagnose SIBO, but none of these are reliable.

Breath hydrogen excretion Bacterial fermentation in the intestinal tract releases hydrogen which, after systemic absorption, is exhaled and can be measured in breath samples. Theoretically, small intestinal bacterial overgrowth can result in a high resting breath hydrogen concentration or an early (or double) hydrogen peak after ingestion of a test meal. However, increased breath hydrogen can also be seen with carbohydrate malabsorption or decreased orocecal transit time. Given these problems with interpretation and the fact that protocols have not been standardized, breath hydrogen testing has not been widely adopted.

Intestinal permeability Intestinal permeability, as measured by 51Cr-EDTA and differential sugar absorption, can be abnormal in small intestinal bacterial overgrowth and can improve after antibiotic treatment. However, such findings are not pathognomonic for either secondary small intestinal bacterial overgrowth or idiopathic antibiotic-responsive diarrhea.

Lack of histologic changes on intestinal biopsy Histopathologic examination of intestinal biopsies is most often normal or demonstrates only subde abnormalities. However, such findings are not pathognomonic, because other conditions yield similar results. Despite the lack of histologic evidence of inflammation, disturbances in immune cell populations have been noted, most notably increases in IgA+ plasma cells and CD4+ cells. However, such techniques have not been applied for routine diagnostic purposes.

Empiric response to antibiotics Currendy, the best diagnostic test for idiopathic antibiotic-responsive diarrhea is, logically, the response to empirical therapy. However, a response to antibacterials is not specific and indeed may be beneficial in inflammatory bowel disease, infectious diarrhea, and even a range of nonenteric diseases such a portovascular anomalies. Furthermore, response to antibiotic therapy does not discriminate idiopathic antibiotic-responsive diarrhea from secondary SIBO. Therefore an empirical response to antibiotics is valid only after thorough diagnostic investigations have eliminated other possible causes.

The suggested criteria for a diagnosis of idiopathic antibiotic-responsive diarrhea are (1) a positive response to the antibiotic trial based on resolution of relevant clinical signs; (2) relapse of signs upon withdrawal of treatment; (3) remission on reintroduction of antibiotics; and (4) elimination of other etiologic causes based on the results of other diagnostic tests and histopathologic assessment.


Secondary small intestinal bacterial overgrowth Although antibacterial therapy improves clinical signs, appropriate treatment for the underlying condition is preferable. For EPI, pancreatic enzyme supplementation can reduce bacterial numbers because exogenous proteases have antibacterial properties.

Idiopathic antibiotic-responsive diarrhea No cure is available for idiopathic antibiotic-responsive diarrhea, but signs can be controlled with antibacterials. A broad-spectrum antibiotic is indicated; suitable choices include oxytetracycline (10 to 20 mg / kg given orally every 8 hours), metronidazole (10 to 20 mg / kg given orally every 8 hours), and tylosin (20 mg / kg given orally every 8 or every 12 hours). Oxytetracycline (OTC) is cheap, and because systemic absorption is not required, it can be given with food. It cannot be used before permanent tooth eruption because it causes staining of tooth enamel. Some authors have criticized the use of oxytetracycline because it is associated with rapid development of plasmid-mediated antibiotic resistance. However, given that long-term efficacy is maintained in most cases, oxytetracycline may not be acting through its antibacterial properties, because it does not significantly reduce small intestine bacterial numbers. Rather, it may provide a selective pressure on the intestinal flora, encouraging the establishment of less harmful bacteria, or it may exert immunomodulatory effects, which this antibiotic group has. Immunomodulatory activity has also been suggested for other antibacterials commonly used to treat antibiotic-responsive diarrhea, namely metronidazole and tylosin.

Whichever antibacterial is chosen, a 4- to 6-week course is appropriate initially, although the antibiotic should be changed after 2 weeks if the response has been suboptimal. In some cases, premature cessation of treatment can lead to relapse, and prolonged therapy often is necessary. In some animals a delayed relapse occurs several months after cessation of antibiotics, and such cases require either repeated courses or indefinite therapy. Efficacy is often maintained despite a reduction in dosage frequency from three times to even once daily. Dogs may also “outgrow” the problem with age, either as a result of a decrease in caloric intake or because of developing maturity of the mucosal immune system. It has also been suggested that idiopathic antibiotic-responsive diarrhea in German shepherds may predispose some of these dogs to inflammatory bowel disease later in life, but currently no direct evidence supports this supposition.

Ancillary treatments Dietary manipulation can be a useful adjunct to the treatment both of idiopathic antibiotic-responsive diarrhea and of secondary SIBO. In general, a highly digestible, low-fat diet is desired to reduce the substrate available for bacterial use. Addition of FOS has been advocated to reduce small intestine bacterial numbers, although evidence of efficacy is conflicting. Administration of probiotics has not been thoroughly assessed in idiopathic antibiotic-responsive diarrhea. Finally, if low cobalamin concentrations are documented, parenteral cobalamin therapy is warranted.


Inflammatory Bowel Disease

Inflammatory bowel disease is a collective term that describes a group of disorders characterized by persistent or recurrent gastrointestinal signs and histologic evidence of intestinal inflammation on biopsy material. The disease bears little resemblance to inflammatory bowel disease (Crohn’s disease and ulcerative colitis) of humans, and indiscriminate use of the term “IBD” is no more useful than a dermatologist making a diagnosis of “chronic dermatitis. Although a number of recognized diseases are associated with chronic intestinal inflammation (Box Causes of Chronic Small Bowel Inflammation), the cause of idiopathic inflammatory bowel disease is, by definition, unknown. Variations in the histologic appearance of the inflammation suggest that idiopathic inflammatory bowel disease is not a single disease entity, and the nomenclature reflects the predominant cell type present. Lymphocytic-plasmacytic enteritis (lymphocytic-plasmacytic enteritis) is the most common form reported; eosinophilic (gastro-) enteritis (EGE) is less common; and granulomatous enteritis is rare. Neutrophilic infiltration is a feature of human inflammatory bowel disease but is infrequent in idiopathic inflammatory bowel disease of dogs and cats.

Causes of Chronic Small Bowel Inflammation

Chronic infection

  • Giardia sp.
  • Histoplasma sp.
  • Toxoplasma sp.
  • Mycobacteria sp.
  • Protothecosis
  • Pythiosis
  • Pathogenic bacteria (Campylobacter, Salmonella spp., pathogenic Escherichia coli)

Food allergy

Small bowel inflammation associated with other primary gastrointestinal diseases

  • Lymphoma
  • Lymphangiectasia

Idiopathic causes

  • Lymphocytic-plasmacytic enteritis (lymphocytic-plasmacytic enteritis)
  • Eosinophilic gastroenterocolitis (EGE)
  • Granulomatous enteritis (same as regional enteritis?)

Clinical Presentation

Idiopathic inflammatory bowel disease is a common cause of chronic vomiting and diarrhea in dogs and cats, but its true incidence is unknown. In reality it is often overdiagnosed because of difficulties in interpretation of histopathologic specimens and failure to eliminate adequately other causes of mucosal inflammation. No apparent gender predisposition occurs in dogs and cats, but in both species inflammatory bowel disease is most common in middle-aged animals. gastrointestinal signs, which may have been variably controlled by dietary manipulation, are sometimes seen from an earlier age. Although inflammatory bowel disease can potentially occur in any dog or cat breed, certain predispositions are recognized, such as lymphocytic-plasmacytic enteritis in German shepherds and Siamese cats, lymphoproliferative enteropathy in basenjis, and protein-losing enteropathy / protein-losing nephropathy (protein-losing enteropathy / PLN) in soft-coated wheaten terriers. Shar Peis often have a severe lymphocytic-plasmacytic enteritis with hypoproteinemia and extremely low serum cobalamin concentrations. In cats an association, called triaditis, has been reported for inflammatory bowel disease, lymphocytic cholangitis, and chronic pancreatitis.

Clinical Signs Associated with Inflammatory Bowel Disease

Vomiting of bile with or without hair in cats and grass in dogs


Small intestinal — type diarrhea

  • Large volume
  • Watery
  • Melena

Thickened bowel loops

Large intestinal — type diarrhea

  • Hematochezia
  • Mucoid stool
  • Frequency and tenesmus

Abdominal discomfort / pain

Excessive borborygmi and flatus

Weight loss

Altered appetite

  • Polyphagia
  • Decreased appetite / anorexia
  • Eating grass

Hypoproteinemia / ascites

Vomiting and diarrhea are the most common clinical signs, but an individual case may show some or all of the signs in Box Clinical Signs Associated with Inflammatory Bowel Disease.Sometimes an obvious precipitating event (e. g., stress, dietary change) is present in the history, but clinical signs may wax and wane. The nature of signs crudely correlates with the region of the gastrointestinal tract affected: gastric signs are more common if gastric or upper small intestine inflammation is present; in cats, vomiting is often the predominant sign of small intestinal IBD; and Li-type diarrhea may be the result of colonic inflammation or may result from prolonged small intestine diarrhea. The presence of blood in the vomit or diarrhea is associated with more severe disease, especially eosinophilic inflammatory infiltrates. Severe disease is associated with weight loss and protein-losing enteropathy, with consequent hypoproteinemia and ascites. Appetite is variable; polyphagia may be present in the face of significant weight loss, whereas anorexia occurs with severe inflammation. Milder inflammation may not affect appetite, although postprandial pain can be significant even without other signs. Systemic consequences of inflammatory bowel disease can occur, although reports are sparse.

Etiology and Pathogenesis

The underlying etiology of small animal inflammatory bowel disease is unknown, and comparisons have been made with similar human conditions. In this regard, the breakdown of immunologic tolerance to luminal antigens (bacteria and dietary components) is thought to be critical, perhaps resulting from disruption of the mucosal barrier, dysregulation of the immune system, or disturbances in the intestinal microflora. Therefore antigens derived from the endogenous microflora are likely to be important in disease pathogenesis, and a potential role for diet-related factors is suggested by the clinical benefit of dietary therapy in some cases of canine inflammatory bowel disease.

Genetic factors are likely to contribute to the pathogenesis of inflammatory bowel disease, and in humans the strongest associations are with genes of the human MHC (human leukocyte antigen [HLA]). Furthermore, some human patients with Crohn’s disease have a mutation in the NOD2 gene on chromosome 16. This gene’s product detects bacterial lipopolysac-charide and can activate the proinflammatory transcription factor NF-kB. Such a link may explain the development of aberrant immune responses to bacteria in certain individuals. Genetic factors are also likely in dogs, given the recognized breed predispositions, although studies are lacking


Intestinal biopsy is necessary for a definitive diagnosis of inflammatory bowel disease, although the clinical signs and physical findings may be suggestive (see Box Clinical Signs Associated with Inflammatory Bowel Disease). The term idiopathic inflammatory bowel disease is limited to cases in which histologic evidence of inflammation is found without an obvious underlying cause. All other etiologies, including infectious, diet-responsive, and antibacterial-responsive conditions, should be excluded. Therefore before intestinal biopsy is undertaken, laboratory evaluation and diagnostic imaging are performed. Such tests cannot provide a definitive diagnosis of inflammatory bowel disease, but they can help eliminate the possibility of anatomic intestinal disease (e. g., tumor, intussusception), extraintestinal disease (e. g., pancreatitis), and known causes of intestinal inflammation. Furthermore, by determining whether focal or diffuse intestinal disease is present, the clinician can choose the most appropriate method of intestinal biopsy.

Hematology Occasionally neutrophilia, with or without a left shift, is noted. Eosinophilia may suggest EGE, but it is neither pathognomonic nor invariably present. Anemia may reflect chronic inflammation or chronic blood loss.

Serum biochemistry No pathognomonic changes are seen in 1BD, but diseases of other organ systems should be recognized and excluded. Hypoalbuminemia and hypoglobulinemia” are characteristic of protein-losing enteropathy, whereas hypocholesterolemia may suggest malabsorption. Intestinal inflammation in dogs may cause a “reactive hepatopathy, ” with mild elevations in liver enzymes (alanine aminotransferase (ALT] and alkaline phosphatase [ALP]). In contrast, because of the shorter half-lives of liver enzymes in cats, increases are more likely to be the result of hepatocellular or cholestatic disease.

Fecal examination Fecal examination is most important for eliminating other causes of mucosal inflammation, such as nematodes (e. g., Trichuris, Uncinaria, Ancylostoma, and Strongyloides spp.), Giardia infection, and bacterial infection (e. g., Salmonella or Campylobacter spp. or clostridia). Given that fecal parasitology may not always detect Giardia organisms, empirical treatment with fenbendazole is recommended in all cases.

Increased fecal alphap1-PI concentrations would be expected in dogs with inflammatory bowel disease, as well as significant intestinal protein loss even before hypoproteinemia develops (see above).

Folate and cobalamin Serum concentrations of both these vitamins are affected by intestinal absorption, therefore proximal, distal, or diffuse inflammation can result in subnormal folate concentrations (proximal inflammation) or cobalamin concentrations (distal inflammation) or both (diffuse inflammation). Although such alterations are not pathognomonic for inflammatory bowel disease, deficiencies may require therapeutic correction. Measurement of serum folate and cobalamin is now commercially available for cats, and cobalamin deficiency associated with inflammatory bowel disease has been documented. Cobalamin deficiency has systemic metabolic consequences, and anecdotal evidence suggests that deficient cats with inflammatory bowel disease require parenteral supplementation to respond optimally to immunosuppression.

Diagnostic imaging Imaging studies document whether focal or diffuse disease is present and whether other abdominal organs are affected. Such information, in conjunction with specific clinical signs, allows the clinician to choose the most appropriate method of biopsy. Plain radiographs may be useful for detecting anatomic intestinal disease; contrast studies rarely add further information. Ultrasonographic examination is superior to radiography for documenting focal anatomic intestinal disease and is particularly useful in cats with inflammatory bowel disease. Ultrasonography permits evaluation of intestinal wall thickness and can document mesenteric lymphadenopathy. Ultrasound-guided fine needle aspiration (FNA) can provide samples for cytologic analysis, which may aid in diagnosis.

Intestinal biopsy Intestinal biopsy is necessary to document intestinal inflammation. Endoscopy is the easiest method of biopsy, but it has limitations, because samples are superficial and in m6st cases can be collected only from the proximal small intestine. In some cases exploratory laparotomy and full-thickness biopsy are necessary, although the procedures are more invasive and can be problematic if severe hypoproteinemia is present. These techniques may be more suitable for cats, given the tendency in this species for multiorgan involvement.

Histopathologic assessment of biopsy material remains the gold standard for inflammatory bowel disease diagnosis, and the pattern of histopathologic change depends on the type of inflammatory bowel disease present. However, the limitations of histopathologic interpretation of intestinal biopsies are recognized. The quality of specimens can vary, agreement between pathologists is poor, and differentiation between normal specimens and those showing inflammatory bowel disease and even lymphoma can be difficult. Grading schemes for the histopathologic diagnosis of inflammatory bowel disease have been suggested, but these have not yet been widely adopted.

IBD activity index In humans, activity indices are used to quantify the severity of inflammatory bowel disease; this helps practitioners to assess the response to treatment and to make a prognosis by allowing comparisons between published studies in the literature. Recently an activity index was suggested for canine inflammatory bowel disease, and this may aid disease classification in the future.

Other diagnostic investigations Given the limitations of histopathology, other modalities are required. One approach would be the use of immunohistochemistry or flow cytometry to analyze immune cell subsets. However, such techniques are labor intensive and poorly standardized and are unlikely to be generally available in the foreseeable future.


Whatever the type of inflammatory bowel disease, treatment usually involves a combination of dietary modification and antibacterial and immunosuppressive therapy. Unfortunately, objective information on efficacy is lacking, and most recommendations are based on individual experience. The authors usually recommend a staged approach to therapy whenever possible; initial treatment involves antiparasiticides to eliminate the possibility of occult endoparasite infestation. Thereafter, sequential treatment trials with an exclusion diet and anlibacterials are pursued; immunosuppressive medication is used only as a last resort. However, in some cases, clinical signs or mucosal inflammation is so severe that early intervention with immunosuppressive medication is essential. If clinical signs are intermittent, the owners should keep a diary to provide objective information as to whether treatments produce genuine improvement.

Dietary modification The diets recommended for patients with inflammatory bowel disease are antigen limited, based on a highly digestible, single-source protein preparation. An exclusion diet trial should be undertaken to eliminate the possibility of an adverse food reaction, and most clients are happy to try this, given concerns over the side effects of immunosuppressive drugs. An easily digestible diet decreases the intestinal antigenic load and thus reduces mucosal inflammation. Such diets may also help resolve any secondary sensitivities to dietary components that may have arisen from disruption of the mucosal barrier. After the inflammation has resolved, the usual diet often can be reintroduced without fear of an acquired sensitivity.

Well-cooked rice is the preferred carbohydrate source because of its high digestibility, but potato, corn starch, and tapioca are also gluten free. Fat restriction reduces clinical signs associated with fat malabsorption. Modification of the n3 to n6 fatty acid ratio may also modulate the inflammatory response and may have some benefit both in treatment and in maintenance of remission, as in human inflammatory bowel disease. However, no direct studies have been done to prove a benefit in canine inflammatory bowel disease. Supplementation with oral folate and parenteral cobal-amin is indicated if serum concentrations are subnormal.

Antibacterial therapy Treatment with antimicrobials can be justified in inflammatory bowel disease, partly to treat secondary small intestinal bacterial overgrowth and partly because of the importance of bacterial antigens in the pathogenesis of inflammatory bowel disease. Ciprofloxacin and metronidazole are often used in human inflammatory bowel disease, and metronidazole is the preferred drug for small animals. The efficacy of metronidazole may not be related just to its antibacterial activity, because it may exert immunomodulatory effects on cell-mediated » immunity. Furthermore, other antibacterials (e. g., tylosin) may also have immunomodulatory effects and have efficacy in canine inflammatory bowel disease.

Immunosuppressive drugs The most important treatment modality in idiopathic inflammatory bowel disease is immunosuppression, although this should be used only as a last resort. In human inflammatory bowel disease, glucocorticoids and thiopurines (e. g., azathioprine, 6-mercaptopurine) are used most widely. In dogs, glucocorticoids are used most frequendy, and prednisone and prednisolone are the drugs of choice. Dexamethasone should be avoided, because it may have deleterious effects on enterocytes. In severe inflammatory bowel disease, prednisolone can be administered parenterally, because oral absorption may be poor. The initial dosage of 1 to 2 mg / kg given orally every 12 hours is given for 2 to 4 weeks and then tapered slowly over the subsequent weeks to months. In some cases therapy can be either completely withdrawn or at least reduced to a low maintenance dose given every 48 hours.

Signs of iatrogenic hyperadrenocorticism are common when the highest glucocorticoid dose is administered. However, signs are transient and resolve as the dosage is reduced. If clinical signs of inflammatory bowel disease consistently recur when the dosage is reduced, other drugs can be added to provide a steroid-sparing effect. Budesonide, an enteric-coated, locally active steroid that is destroyed 90% first-pass through the liver, has been successful in maintaining remission in human inflammatory bowel disease with minimal hypothalamic-pituitary-adrenal suppression. A preliminary study showed apparent efficacy in dogs and cats, but limited information is available on the use of this drug.

In dogs, azathioprine (2 mg / kg given orally every 24 hours) is commonly used in combination with prednisone / prednisolone when the initial response to therapy is poor or when glucocorticoid side effects are marked. However, azathioprine may have a delayed onset of activity (up to 3 weeks) and, given its myelosuppressive potential, regular monitoring of the hemogram is necessary. Azathioprine is not recommended for cats; chlorambucil (2 to 6 rag / m given orally every 24 hours until remission, followed by drug tapering) is a suitable alternative. Other immunosuppressive drugs are methotrexate, cyclophosphamide, and cyclosporine. Methotrexate is effective in the treatment of human Crohn’s disease, but it is not widely used in companion animals; it often causes diarrhea in dogs. Cyclophosphamide has few advantages over azathioprine and is rarely used. However, cyclosporine may show promise for the future, given its T lymphocyte-specific effects and efficacy in canine anal furunculosis. Unfortunately, it is expensive, and studies in human inflammatory bowel disease have shown variable efficacy and toxicity.

Novel therapies for inflammatory bowel disease Novel therapies are increasingly used for human inflammatory bowel disease in an attempt to target more accurately the underlying pathogenetic mechanisms. These therapies include new immunosuppressive drugs, monoclonal antibody therapy, cytokines and transcription factors, and dietary manipulation (Table Novel Therapies for Human Inflammatory Bowel Disease). In the future, such therapies may be adopted for small animal inflammatory bowel disease.

Novel Therapies for Human Inflammatory Bowel Disease

Therapy Mechanism Of Action
Drug Therapy
Tacrolimus Immunosuppressant macrolide
Mycophenolate Inhibits lymphocyte proliferation; reduces IFN-gamma production
Leukotriene antagonists (zileuton, verapamil) Inhibit arachidonic acid cascade
Prostaglandin (PG) targeting agents Mucosal protection from PC analogs; anti-inflammatory effects from PC antagonists
Thromboxane synthesis inhibitors Anti-inflammatory effects
Oxpentifylline Inhibits TNF-αlpha expression
Thalidomide Inhibits TNF-αlpha and IL-12 expression; reduces leukocyte migration; impairs angiogenesis
Bone Marrow and Stem Cell Transplantation
Bone marrow grafts Unknown; immunomodulation (?)
Dietary Manipulation
Protein hydrolysate diets “Hypoallergenic”
Fish oil therapy Diverts eicosanoid metabolism to LTB5 and PGE3
Short chain fatty acid therapy
Butyrate Provides nutrition for enterocytes
Probiotics and prebiotics Antagonize pathogenic bacteria; immunomodulatory effects
Cytokine Manipulation
Systemic IL-10 Down-modulatory cytokine
Anti-IL-2 monoclonal antibody (MAb) Counteracts proinflammatory effects
Anti-IL-2R (CD25) MAb Inhibits IL-2 effects
Anti-IL-12 MAb Counteracts proinflammatory effects
Anti-IL-11 MAb Downregulates TNF-alpha and IL-1beta
Recombinant IFN-alpha Anti-inflammatory; antiviral (?)
Anti-IFN-gamma MAb Immunomodulatory effect on Th 1 cells
Anti-TNF-αlpha MAb Counteracts proinflammatory effects; induces inflammatory cell apoptosis
Endothelial Cell Adhesion Molecules and Their Manipulation
ICAM-1 (antisense oligonucleotide) Reduces immune cell trafficking
Anti-alpha4 / beta7 MAb Reduces immune cell trafficking
Other Immune System Modulations
Intravenous immunoglobulin Saturates Fc receptors; other (?)
T-cell apheresis Immunomodulation
Anti-CD4 antibodies Immunomodulation
Transcription Factors
NF-kB antisense oligonucleotide Inhibits proinflammatory cytokine expression
ICAM-1 antisense oligonucleotide Reduces immune cell trafficking

IFN, interferon; IL, interleukin; ICAM, intercellular adhesion molecule; LTB, leukotriene B; MAb, monoclonal antibody; PG, prostaglandin; PGE, prostaglandin E; Th 1, T helper 1; TNF, tumor necrosis factor

Mycophenolate mofetil recently has been used to treat human inflammatory bowel disease, although its efficacy is variable. Drugs that target TNF-α (e. g., thalidomide and oxpentifylline) may be suitable for the treatment of canine inflammatory bowel disease because of the importance of this cytokine in disease pathogenesis. Human open-label trials have demonstrated a beneficial effect for thalidomide in refractory Crohn’s disease. Oxpentifylline has shown efficacy in studies in vitro, but clinical results have been less rewarding. Anti-TNF-alpha monoclonal antibody therapy, which has also undergone trials in human inflammatory bowel disease, has the additional beneficial effect of inducing apoptosis in inflammatory cells. Species-specific monoclonal antibodies will be needed for canine and feline inflammatory bowel disease.

Finally, modulation of the enteric flora with probiotics or prebiotics may have benefits in targeting the pathogenesis of inflammatory bowel disease. A probiotic is an orally administered living organism that exerts health benefits beyond those of basic nutrition. In addition to having direct antagonistic properties against pathogenic bacteria, they modulate mucosal immune responses by stimulating either innate (e. g., phagocytic activity) or specific ( e. g., secretory IgA) immune responses. However, care should be taken to select the most appropriate organisms, which are likely to vary between host species.

Prebiotics are selective substrates used by a limited number of “beneficial” species, which therefore cause alterations in the luminal microflora. The most frequently used prebiotics are nondigestible carbohydrates, such as lactulose, inulin, and FOS. Both probiotics and prebiotics can reduce intestinal inflammation in mouse models of inflammatory bowel disease. Preliminary placebo-controlled trials with probiotics and prebiotics in human inflammatory bowel disease patients have shown promising results, although similar trials in canine and feline inflammatory bowel disease are still awaited.

Lymphocytic-Plasmacytic Enteritis

Basenji Enteropathy

A severe, hereditary form of lymphocytic-plasmacytic enteritis has been well characterized in basenjis, although the mode of inheritance is unclear. It has been likened to immunoproliferative small intestinal disease (IPSID) in humans, because both conditions involve intense intestinal inflammation. However, IPSID is characterized by an associated gammopathy (alpha heavy chain disease) and a predisposition to lymphoma. Affected basenjis often have hyper-globulinemia but not alpha heavy chain disease and may be predisposed to lymphoma. The intestinal lesions in basenjis are characterized by increases in CD4+ and CD8+T cells.

Clinical Signs

Signs of chronic intractable diarrhea and emaciation are most rommon Lymphocytic-plasmacytic paslritis, with hypergasirmemia and mucosal hyperplasia, may be seen in addition to the enteropathy. Protein-losing enteropathy often occurs, with consequent hypoalbuminemia, although edema and ascites are not common. Clinical signs are usually progressive, and spontaneous intestinal perforation may occur.


The approach to diagnosis is the same as before, and ultimately depends on histopathological examination of biopsy specimens.


Treatment generally is unsuccessful, with dogs dying within months of diagnosis. However, early, aggressive combination treatment with prednisolone, antibiotics, and dietary modification may achieve remission in some cases.

Familial Protein-Losing Enteropathy and Protein-Losing Nephropathy in Soft-Coated Wheaten Terriers

Recendy a clinical syndrome unique to soft-coated wheaten terriers was characterized. Affected dogs present with signs of protein-losing enteropathy or PLN or both. A genetic basis is likely, and although the mode of inheritance is not yet clear, pedigree analysis of 188 dogs has demonstrated a common male ancestor. The disease is probably immune mediated, given the presence of inflammatory cell infiltration. A potential role for food hypersensitivity has been suggested, because affected dogs have demonstrated adverse reactions during provocative food trials and alterations in antigen-specific fecal IgE concentrations.

Clinical Signs

Signs of protein-losing enteropathy tend to develop at a younger age than PLN. Clinical signs of the protein-losing enteropathy include vomiting, diarrhea, weight loss, and pleural and peritoneal effusions. Occasionally, thromboembolic disease may occur.


Preliminary laboratory investigations, as in most dogs with protein-losing enteropathy, demonstrate panhypoproteinemia and hypocholesterolemia. In contrast, hypoalbuminemia, hypercholesterolemia, proteinuria, and ultimately azotemia are seen with PLN, Histopathologic examination of intestinal biopsy material reveals evidence of intestinal inflammation, villus blunting, and epithelial erosions, as well as dilated lymphatics and lipogranulomatous lymphangitis.

Treatment and Prognosis

The treatment for protein-losing enteropathy is similar to that described for general inflammatory bowel disease, but the prognosis is usually poor.

Eosinophilic Enteritis

Other Forms of Inflammatory Bowel Disease

Granulomatous Enteritis

Granulomatous enteritis is a rare form of inflammatory bowel disease characterized by mucosai infiltration with macrophages, resulting in the formation of granulomas. The distribution of inflammation can be patchy. This condition is probably the same as “regional enteritis,” in which ileal granulomas have been reported. Granulomatous enteritis has some histologic features in common with human Crohn’s disease, but obstruction, abscessation, and fistula formation are not noted. Conventional therapy is not usually effective, and the prognosis is guarded, although a combination of surgical resection and anti-inflammatory treatment was reported to be successful in one case. In cats, a pyogranulomatous transmurai inflammation has been associated with FIPV infection.

Proliferative Enteritis

Proliferative enteritis is characterized by segmental mucosal hypertrophy of the intestine. Although many species can be affected, the condition is most common in pigs. A similar but rare condition has been reported in dogs. There have been suggestions of an underlying infectious etiology, and Lawsonia intracellularis has been implicated, although this has not yet been proved. Other infectious agents with a proposed link are Campylobacter spp. and Chlamydia organisms



Definition and Cause

Intestinal lymphangiectasia is characterized by marked dilatation and dysfunction of intestinal lymphatics. Abnormal lymphatics leak protein-rich lymph into the intestinal lumen, ultimately causing protein-losing enteropathy and hypoproteinemia. Lymphangiectasia may be a primary disorder or can develop secondary to lymphatic obstruction.

Primary lymphangiectasia usually is limited to the intestine, although it may be part of a more widespread lymphatic abnormality involving, for example, chylothorax. It is considered congenital, although clinical signs are not usually present from birth. The development of associated lipogranulomatous lymphangitis, superimposed on the congenital abnormalities, is one reason for a progressive disorder. The disease is most commonly seen in small terrier breeds (e. g., Yorkshire, Maltese) and the Norwegian lundehund, suggesting a genetic predisposition.

Secondary lymphangiectasia is caused by intestinal lymphatic obstruction. Underlying causes include (1) infiltration or obstruction of lymphatics by an inflammatory, fibrosing, or neoplastic process; (2) possibly obstruction of the thoracic duct; and (3) right heart failure due to congestive heart failure or cardiac tamponade. Lipogranulomatous lymphangitis is sometimes reported in association with lymphangiectasia, but it is not clear which is the primary event; lymphangitis could cause lymphatic obstruction, or leakage of lymph could cause granuloma formation.

History and Clinical Signs

The clinical manifestations of lymphangiectasia are largely attributable to the effects of the enteric loss of lymph. Other intestinal functions remain intact, and hypoproteinemia may be present without diarrhea. Diarrhea, steatorrhea, profound weight loss, and polyphagia are more typical, and vomiting, lethargy, and anorexia are reported occasionally. Signs may have an insidious onset and an intermittent pattern. Ascites or subcutaneous edema may develop if hypoproteinemia is marked. The ascitic fluid usually is a pure transtidate, but if right heart failure causes secondary lymphangiectasia, a modified transudate develops through portal hypertension. Lymphangiectasia has been associated with granulomatous hepatopathy and in lundehunds with chronic gastritis and gastric carcinoma.


Given that lymph is rich in lipoproteins and lymphocytes, laboratory analysis often shows panhypoproteinemia, hypo-cholesterolemia, and lymphopenia. Hypocalcemia and hypo-magnesemia have been reported. The hypocalcemia is the result not only of hypoalbuminemia, but also of the development of ionized hypocalcemia. Therefore other mechanisms, including vitamin D and calcium malabsorption, may be involved. Protein-losing enteropathy can be documented by measuring Cr-albumin leakage or fecal concentrations of alpha1-PI. In affected lunde-hunds, increased permeability has been documented by both methods, and the increases in the fecal alpha1-PI concentration were seen before changes in serum proteins.

Gross findings at endoscopy include the presence of white lipid droplets or prominent mucosal blebs, which are likely the result of villus tip distension with chyle. Endoscopic biopsies may be supportive of the diagnosis, but full-thickness biopsies may be required to make a definitive diagnosis. At exploratory laparotomy, most dogs show gross abnormalities, including thickened small intestine, dilated lymphatics (in the mesentery and intestinal serosa), and occasionally adhesions. Mesenteric lymph nodes may also be enlarged, and yellow-white nodular masses (1 to 3 mm in diameter) are often observed in and around the mesenteric and serosal lymphatics. The nodules are lipogranulomas, consisting of accumulations of lipid-laden macrophages, and result from perilymphatic extravasation of chyle or are associated with a lymphangitis.

Characteristic histopathologic changes include “ballooning dilatation” of lymphatics, not only in the mucosa but also in the submucosa. This true lymphangiectasia must be distinguished both from normal postprandial dilatation of lacteals and from the secondary lacteal dilatation occasionally noted in other enteropathies (e. g., IBD). Genuine cases are less common than currently believed, and failure to recognize an underlying inflammatory cause may explain the success of steroid treatment in some cases. Assessment of the degree of inflammatory cell infiltrate in the lamina propria is subjective, and if edema is present, the lamina propria cell density may be underestimated.


Secondary lymphangiectasia is managed by specific treatment of underlying disease, such as pericardiocentesis or pericardectomy for cardiac tamponade. The aim of treatment of primary lymphangiectasia is to decrease the enteric loss of plasma protein, resolve associated intestinal or lymphatic inflammation, and control any edema or effusions. Dietary manipulation and glucocorticoids are the most important treatment modalities.

The ideal diet for cases of lymphangiectasia is markedly fat restricted, calorie dense, and highly digestible. Weight reduction diets, although low in fat, are inappropriate, because patients require a high level of nutrition. Previously, administration of medium chain triglycerides (MCT) was recommended, because these lipids were thought to be absorbed direcdy into the portal blood. However, this theory was recendy contradicted. Supplementation with fat-soluble vitamins is advised, and there are anecdotal reports of improvement with glutamine supplementation.

Glucocorticoid therapy (prednisolone, 1 to 2 mg / kg given orally divided daily and then tapered) may be beneficial in some cases, especially if associated lymphangitis, lipogranulomas, and a lymphocytic-plasmacytic infiltrate are present in the lamina propria. Unfortunately, not all cases respond to such therapy. The use of antimicrobials such as tylosin or metronidazole has not shown any obvious success. Diuretics are indicated in the management of effusions, and combinations of diuretics are preferred (e. g., furosemide and spironolactone); administration of plasma or colloid may also help if hypoproteinemia is marked. The response to treatment is unpredictable, but cessation of clinical signs may be achieved temporarily, with remissions of months to several years. However, die overall long-term prognosis is poor, and patients eventually succumb to severe malnutrition, incapacitating effusions, and intractable diarrhea.

Veterinary Drugs

Drugs acting on FEET

Disorders of the feet are typically characterised by lameness, although sometimes other clinical signs such as swelling, inflammation, and discharge may be seen. In farm livestock, lameness is both a major economic and a welfare problem and in horses performance can be seriously impaired.

Conditions affecting horses. Thrush in horses can result from poor hoof care, unhygienic stabling, poor foot conformation, and incorrect shoeing; Fusobacterium necrophorum is usually found in the lesion. Thrush is characterised by areas of necrotic frog exuding black, foul smelling discharge. Treatment includes debridement of necrotic tissue and improved stable hygiene. The diseased area can be dressed with anti-infective agents such as povidone-iodine 1% solution, sulfanilamide powder, tetracycline spray, or zinc sulfate 10% solution. It may be necessary to bandage severe cases for a short time. Attention should be paid to foot balance.

Canker is a severe hypertrophic pododermatitis usually affecting the frog, but sometimes extending to the wall. Treatment consists of resection of the abnormal tissue followed by application of metronidazole and bandaging. Pathogens involved in suppurative hoof lesions include F. necrophorum, Actinomyces pyogenes, Bactemides spp., and Escherichia coli. Foot abscesses in horses should be carefully drained and poulticed. Tetanus antitoxin or a booster dose of tetanus toxoid should be administered as necessary. As the tissues heal, iodine-based spray and magnesium sulfate paste may be applied before bandaging to keep the area dry and clean. Antibacterials are generally not indicated for the treatment of subsolar abscesses. Deep penetrating wounds to the foot with sepsis involving the pedal bone, navicular bone, navicular bursa, or distal interphalangeal joint require surgical debridement, lavage, and appropriate antibacterial therapy. Laminitis in horses can present with a spectrum of clinical signs ranging from mild lameness to severe disease with loss of the hoof capsule. Although the precise pathogenesis of the disease is uncertain, there appears to be decreased laminar perfusion, with varying degrees of inflammation and necrosis of the sensitive laminae. Causes include carbohydrate overload, endotoxaemia (such as caused by gastrointestinal disease, septic metritis and pleuritis), excessive work, and hyperadrenocorticism (Cushing’s syndrome). The management of laminitis usually involves both physical support of the distal phalanx, and treatment of laminar pain and inflammation. Initial therapy should be aimed at removing the inciting cause if possible. Heparin at a dose of 25 to 100 micrograms/kg three times daily by subcutaneous injection has been shown to reduce the prevalence of laminitis associated with small intestinal disease and endotoxaemia. Heparin is only effective when administered before any clinical signs of laminitis are apparent.

NSAIDs, such as flunixin, ketoprofen, meclofenamic acid, and phenylbutazone, are used to manage pain and control laminar inflammation, especially during the acute phases of the disease. Systemic administration of dimethyl sulfoxide (100 mg to 1 g/kg by intravenous injection two to three times daily) has also been used to reduce inflammation and reperfusion injury in the laminae. Maintenance of laminar blood flow is important to reduce some of the deleterious effects of acute laminitis. Peripheral vasodilation has been attempted by use of the alpha-adrenergic blockers such as acepromazine. These drugs may help to reduce the hypertension associated with acute laminitis, although the efficacy of these treatments is unproven. Isoxsuprine has also been used as a peripheral vasodilator in laminitis ♦ at a dose of 0.6 to 4 mg/ kg orally twice daily.

Heparin and aspirin have been used to reduce inappropriate intravascular coagulation and to maintain perfusion in the laminar capillary network. Aspirin, given at a dose of 20 mg/kg orally daily, blocks thromboxane-mediated platelet aggregation. Heparin has an anticoagulant effect by enhancing the activity of antithrombin III and prolonging blood clotting times and also a potential beneficial effect on the laminar basement membrane. It is given at a dose of 40 to 100 units/kg by subcutaneous injection three times daily. Nitric oxide donors have been used in an attempt to increase laminar blood flow. Glyceryl trinitrate ointment applied locally to the coronary band or the digital arteries has been shown to increase the laminar blood flow and to reduce the bounding digital pulse in acute laminitis. A dose of 2.5 cm of 2% ointment applied to each digital vessel of affected feet is applied topically. Virginiamycin (Founderguard, distributed by Vetsearch International, Aust.) suppresses the activity of D-lactic acid producing gut flora thereby reducing the production of lactic acid, which can increase the risk of laminitis. The product is available only under a Special treatment Authorisation from the VMD. The STA application must include the details of the horse including its body-weight, a calculation to indicate the amount of product required, and the owner’s details.

Corrective trimming and shoeing are essential components of the treatment of acute laminitis. Frog pads or styrofoam pads apply support to the frog and deeper structures of the foot. The use of special shoes, such as heart bar shoes, and dorsal wall resection may be helpful in some cases. In advanced cases and unresponsive cases, deep digital flexor tenotomy may be performed to reduce the rotational forces on the distal phalanx.

Conditions affecting cattle. Sole ulcers and white line disorders (haemorrhage, separation, and abscessation), are associated with inflammatory changes within the foot, namely laminitis or more correctly coriosis. In some animals clinical signs of acute coriosis may be seen and include pain, altered gait, and heat in the hooves. However it is the sequelae of chronic coriosis (ulcers, white line disease, and hoof abnormalities) which cause most of the lameness. The cow seems to have an inherent phase of coriosis at parturition, although it is only when other factors that predispose the animal to coriosis occur that severe disease is seen. These factors include nutritional imbalance, excessive standing, poor cow comfort, and inadequate management during the periparturient period. The sole of the hoof is 5 to 10 mm thick and as horn grows at approximately 5 mm per month, it takes at least 4 to 8 weeks for the damaged horn, produced at the time of parturition and immediately afterwards, to grow to the surface. Therefore peak incidence of lameness is seen 6 to 14 weeks after calving. Many hoof lesions are essentially of a physical nature and treatment of uncomplicated cases involves paring away under-run horn, draining abscesses, and allowing the corium to regenerate new horn. ‘Blocks’, for example Cowslip (Giltspur) or Demotec (Demotec Hoof Care Products), may be applied to the sound claw to remove weight-bearing from the affected digit. This reduces lameness and improves the rate of healing of the damaged hoof.

Other lesions of the bovine hoof include foreign body penetration, vertical and horizontal fissures (‘sandcracks’), ‘false soles’, and growth abnormalities, the most common of which is overgrowth. Laminitis/coriosis, leading to increased pressure within the foot, can produce growth distortions such as ‘hardship grooves’ (concentric horizontal grooves encircling the anterior hoof wall) and a dorsal rotation of the toe, producing a concave anterior wall. Severe coriosis resulting from, for example, a toxic mastitis or metritis, can produce a total, but temporary, cessation of horn formation and may result in a complete horizontal fissure. This can cause lameness 6 to 8 months later when the distal fragment of hoof moves over the corium at the toe. Dietary supplementation with biotin (20 mg/cow daily) has been shown to decrease the incidence of white line disease and vertical fissures, especially in older animals.

The main lesions affecting the skin of the bovine claw are interdigital necrobacillosis (‘foul’), digital dermatitis, inter-digital skin hyperplasia (‘corns’, ‘growths), and mud fever. ‘Foul’ is a necrotising bacterial infection of the dermis caused by Fusobacterium necrophorum, Porphyromonas spp., and Prevotella spp. (Bacteroides melaninogenicus). The possible presence of an interdigital foreign body should be eliminated before using parenteral antibacterials for the treatment of ‘foul’. Concurrent topical treatment reduces the spread of infection. The peracute condition of ‘super foul’ appears to involve the same organisms, although more prompt, prolonged, and aggressive antibacterial therapy is required. The local application of antibacterials such as clindamycin, has also been suggested. ‘Super foul’ is most commonly seen in herds infected with digital dermatitis.

Digital dermatitis is a superficial erosive epidermitis caused by a spirochaete of the Treponema genus, the full identity of which has yet to be determined. There are probably three subtypes, two in cattle and one affecting sheep and cattle. A reservoir of infection persists in the interdigital pouch (at the rear of the interdigital cleft) and the typical lesion radiates circumferentially from this pouch. Other common sites for dermatitis include the interdigital cleft, the anterior aspect of the hoof (where infection may involve the coronary band and produce a vertical fissure), and the bulbs of the heels. Lesions in the interdigital cleft may be specifically referred to as ‘interdigital dermatitis’; Dichelobacter nodosus may be involved in these lesions. Chronic neglected lesions of the heel develop a proliferative epidermitis known as ‘hairy warts’. Treatment of individual animals is by topical antibacterial aerosol spray, usually oxytetracycline. Herd treatments involve the use of an antibacterial foot bath; oxytetracycline ♦ (200 g to 600 g/100 litres), lincomycin (100 g/100 litres), lincomycin and spectinomycin Linco-Spectin 100, Pfizer (150 g of powder/150 litres), and erythromycin (46 g/100 litres) have all been used. Lincomycin is rapidly degraded in the environment and may be preferred. Maximum benefit is obtained if the heels are washed with a pressure hose before entering the foot bath, or if two foot baths are used in series, the first containing water to wash the feet, remove superficial debris, and allow better penetration of the antibacterial. Control of digital dermatitis is achieved by attention to environmental hygiene and regular footbaths with formaldehyde solution (= 40% formaldehyde) diluted to maximum 5 to 10% in water. Cows should be footbathed daily for one week, repeated on alternate weeks. Formaldehyde solution should not be used where raw open lesions are present.

Interdigital skin hyperplasia may be a sequel to chronic inflammatory conditions such as low-grade ‘foul’ or digital dermatitis, although there is also a hereditary predisposition. Early lesions may resolve spontaneously after dishing the axial hoof wall to minimise compression of the lesion during locomotion; more advanced lesions required amputation. Regular footbathing helps in control.

Mud fever is uncommon in cattle. Extremely muddy and damp conditions are required. Treatment involves washing affected limbs with antiseptic and spraying with iodine teat disinfectants containing an emollient. Parenteral antibacterials may also be used.

Lesions within the foot mainly affect the pedal bone, for example fractures and necrosis, or are infections secondary to ulcers, white line abscesses , or ‘foul’.

Conditions affecting sheep and goats. Footrot, a bacterial infection caused by Dichelobacter nodosus (Bacteroides nodosus), is the main cause of lameness in sheep and goats. Footrot is highly contagious and, if possible, treated sheep should not be returned to infected ground for at least one week. Recent outbreaks of peracute disease, in some cases leading to total shedding of the hoof, have also implicated an organism similar to the spirochaete causing digital dermatitis. A dermatitis affecting the interdigital cleft (‘scald’, ‘strip’) is thought to be caused by the same organism and can be treated with topical antibacterial aerosol spray (usually oxytetracycline). Typical lesions lead to separation of the horn wall from the underlying corium. For treatment, all under-run wall must be removed and the area sprayed with antibacterial or disinfectant. Parenteral antibacterials, such as oxytetracycline, can also be used and promote healing. D. nodosus is a strict anaerobe and exposing the lesion to air facilitates healing. Neglected lesions, leading to secondary joint infections with organisms such as A. pyogenes, require more protracted parenteral antibacterial therapy. A proliferative dermatitis extending dorsally from the skin of the heel bulbs is often referred to as ‘strawberry footrot’ because of the nature of the lesion. A combination of the orf virus and Dermatophilus congolensis may be involved and is exacerbated by wet muddy conditions under foot. Cleaning the lesion, in addition to topical and parenteral antibacterials facilitates healing.

Conditions affecting pigs. In the first week of life the feet of piglets are highly susceptible to bruising, especially when concrete floors are rough, damp, or poorly bedded. The junction of the abaxial wall with the bulb of the heel is a particularly common site of injury and often leads to a secondary bacterial infection of the foot, requiring parenteral antibacterial therapy. Similar lesions occur in sows and are again associated with rough floors, wet conditions under foot (leading to soft horn), and sudden foot movements (for example from aggression) leading to physical separation of the wall from the heel bulb. The ideal treatment is to lift the foot and remove all under-run horn. Unfortunately few farmers do this and a large number of cases develop secondary infections, leading to a swollen foot with a chronic discharge. These cases are known as ‘bush foot’.

Haemorrhages and fissures in the anterior hoof wall have been attributed to biotin deficiency and biotin is often added to pig rations in an attempt to prevent lameness and to reverse hoof problems. Joint infections caused by Mycoplasma hyosynoviae or Erysipelothrix rhusiopathiae may occur. M. hyosynoviae is common and responds well to treatment with lincomycin or tiamulin. The other major causes of lameness and leg weakness in sows are conditions affecting the bones and joints of the upper leg and spine.

Conditions affecting dogs and cats. See site for information on dogs and cats.

Conditions affecting chickens. In poultry, the majority of causes of lameness are associated with bone and joint abnormalities of the limb and do not involve the feet. The most common foot lesion is erosion of the foot pad caused by wet litter. Dietary changes resulting in scouring are often implicated. The high fat content of partially digested faeces seems to be particularly erosive. Insufficient litter in high humidity, poorly insulated, and poorly ventilated buildings in the winter can also be contributory factors. Under such conditions, long-standing erosions and other causes of skin damage predispose to a deeper infection of the footpads, often known as ‘bumble foot’ and commonly involving staphylococcal species.

In domestically-housed chickens, mange caused by Cnemidocoptes mutans can be a problem, leading to ‘scaly leg’. Occasionally osteopetrosis (leucosis virus infection) may occur and is characterised by foot and leg swelling; there is no treatment.

General treatment of foot conditions.

Lesions of the hoof should be treated by removing all under-run horn, thereby exposing the underlying healthy corium. In most cases the corium will be covered by a layer of germinative epidermis and growth of new horn is rapid. Sole ulcers are the exception to this, because the corium itself will have been damaged. Opinions vary concerning the value of dressings. In cattle there is a risk that they will be left on for too long, impede drainage, and therefore retard rather than improve healing. In addition, the presence of a dressing may make the affected claw the major weight-bearing area. Fixing a block to the sole of the sound claw, thereby removing weight bearing from the affected claw, is excellent practice and promotes both healing and comfort. Blocks may be nailed on or glued on. A glue-on PVC shoe (Cowslip Plus, Giltspur) gives excellent support. With such support there is often no longer a need to house lame cows separately, although this is good practice while lameness persists because lame cows may find cubicles especially difficult to use.

Topical antibacterials are commonly applied to sheep lesions such as scald and footrot, and lesions involving the digital skin of cattle such as digital dermatitis and ‘foul’. Disinfectants and antiseptics may also be used, although single applications are of limited value against digital dermatitis because the causative organism is sited below the surface of the epidermis: disinfectants (and particularly formaldehyde) ‘seal’ the surface of the skin and although surface contamination may be eliminated, the infection persists deeper within the epidermis. Prolonged footbathing with disinfectants may be beneficial.

Parenteral antibacterials help to resolve sheep footrot lesions and long-acting oxytetracycline preparations are frequently used. They are becoming increasingly common as part of the standard treatment, even where no secondary infection exists. A wide range of antibacterials is effective against ‘foul’ in cattle, with long-acting penicillin or oxytetracycline usually used in younger stock. Tilmicosin is widely used for footrot and ‘foul’ in many countries. Ceftiofur is often used in lactating dairy cows because of its nil milk withholding period; cefalexin, cefquinome, or tylosin may also be used. Mycoplasmal arthritis in pigs generally responds well to lincomycin or tiamulin. Ideally, deep-seated lesions in all species which involve the tendon sheaths, navicular bursa or even the pedal joint require drainage in addition to prolonged and aggressive antibacterial therapy such as high doses for 7 to 14 days. Again a wide range of antibacterials is used including oxytetracycline, tylosin, and lincomycin. High concentrations of tylosin and lincomycin are achieved in joints following parenteral administration.

A vaccine is available for footrot in sheep.

Anti-infective foot preparations

Hoof care preparations

Many preparations are said to assist in maintaining the integrity of hoof horn, although the efficacy of some is difficult to assess.

Beneficial effects on hoof structure have been demonstrated when supplementary biotin is added to the diet. A daily dose of 20 mg biotin per cow has been shown to reduce the incidence of white line lameness in the UK, and vertical fissures (sand cracks) in beef cattle in North America. In pigs, biotin at a dose of 500 to 1500 mg/tonne is often added to the feed in an attempt to prevent lameness due to poor hoof horn quality. In extreme cases up to 3000 mg/tonne has been used to reverse hoof problems. Biotin has been shown to be beneficial in horses that are not biotin deficient. Long-term biotin supplementation in horses may improve hoof quality and certain hoof deficits when given either alone or in combination with additional calcium and good quality protein.

Zinc is often promoted as reducing lameness, and while it is known to improve the rate of healing of skin lesions, its effect on the feet of livestock has yet to be proven. Chelated or organic mineral complexes may give better absorption and improve the effectiveness of mineral supplementation.

Methionine also appears to assist in improving horse hoof horn integrity but its efficacy is better when given in combination with biotin. Compound preparations containing vitamins and minerals are available.

Application of vegetable oil-based products to the horse hoof will improve appearance of the hoof but the efficacy of these preparations is unproven and may even cause deteri-ation of the horn.

Tar or Stockholm tar, which has antiseptic properties, may be used following treatment of an infected frog in horses or footrot in cattle and sheep. It is used alone or with a packing material to fill defects in the wall, sole, or frog and helps to prevent entry of gravel and reinfection.