While the Food and Drug Administration, Purina and Milo’s Kitchen assure consumers that the antibiotic drug residues found in the recalled treats are not a health risk to dogs, research dating back decades contradicts that claim.  There is a reason drug residues are not allowed in food-producing animals in the U.S.

Chemical residues in animals slaughtered for human and animal consumption are carefully regulated to minimize or eliminate their presence to safety levels based on FDA-established tolerance levels.  The possibility that chemical additives, drugs and their metabolites (drug residues) could cause allergic reactions or disease is not taken lightly by the public or by health care professionals.

Residues of drugs or their metabolites in food products from treated food animals are major considerations in the safety of drugs approved for use in food animals.  Residues, usually from animal drugs, can cause allergic reactions and antimicrobials can contribute to antibiotic resistance to certain “superbugs.”

Sulfonamide Hypersensitivity

Sulfonamide-containing antibiotics are the second most frequent cause of allergic drug reactions. Sulfonamide hypersensitivity occurs in both humans and dogs. Adverse drug reactions are common, but only 6% to 10% of dogs are immunologically mediated allergic reactions to antimicrobials, in particular sulfonamides. The concern is for the small percentage of dogs hypersensitive to sulfa drugs.  Hypersensitive dogs could have an allergic reaction to sulfa drugs even in trace amounts — the same amounts found in the contaminated dog treats.

Unpredictable Reactions

However, not all dogs will experience severe symptoms.  Unlike most adverse drug reactions, allergic drug reactions are unpredictable. Concentrations of residual veterinary drugs in foods may not be not high enough to cause an initial hypersensitive reaction, but may cause such an effect in a dog that has already become sensitized to the drug.  Idiosyncratic reactions, which mean their occurrence has nothing to do with the amount given but instead, are about an unpredictable dog’s sensitivity to any dose.

Sulfonamide-Induced Reactions in Canines

Dogs are considered unable to acetylate sulfonamides to any significant degree.  Therefore, dogs have a particular sensitivity to sulfonamides known as a species mediated sensitivity.  Because dogs do not produce acetylated metabolites, they may be susceptible to these adverse effects. Idiosyncratic sulfonamide toxicosis can occur in any breed of dog, but it has been reported more frequently in certain breeds than in other breeds.

It is not at all uncommon for antibiotic sensitivities or reactions to happen days after the dog have been exposed to the drug.  In some dogs, within 24 hours you will notice something is wrong, with others it may be up to 8 to 20 days before you notice the symptoms.

Although effects that are more serious may not accompany the initial reactions, re-exposure can provoke this life-threatening reaction.  These reactions appear to be immediate-type immune-mediated reactions that are associated with the presence antibodies toward the sulfonamide.

Sulfonamides also induce a delayed-type reaction that appears to be immune-mediated.  These reactions are generally manifested 8 to 20 days after exposure to a sulfonamide and are believed to be caused either by an immune-mediated syndrome or by an idiosyncratic reaction in dogs, perhaps due to toxic metabolites of the sulfonamide.

Sulfonamide Induced Acute Renal Failure

The nephrotoxic potential of sulfonamides has long been recognized.  The most common cause of interstitial nephritis (or tubulo-interstitial nephritis) is by an allergic reaction to a drug.  Over 70% to 90% of cases are a reaction to medication such as antibiotics, including sulfonamides.

Nephrotoxic reactions including interstitial nephritis and tubular necrosis, which may result in renal failure, have been attributed to hypersensitivity to sulfamethoxazole, one of the drug residues found in the pet treats. Fanconi syndrome Type 2-Proximal renal tubular acidosis is associated with exposure to sulfonamides. An idiosyncratic hypersensitivity-type reaction as a cause of acute renal injury is the principal cause of renal adverse effects of sulfonamides.

One Gram per Ton

As little as one gram of a sulfonamide per ton of animal feed would cause a high incidence of residues in the liver of the food-producing animal.  8 grams of a sulfonamide per ton in feed was required before a violative level of sulfa occurred in the muscle of the animal.

Withdrawal periods of veterinary drugs in food-producing animals, ranging from a few days to a few weeks, are recommended for approved animal drugs for meat to be free of drug residues above the tolerance level.

However, a recent year-long investigation into poultry facilities in China revealed that multiple drugs, including many that are illegal in the U.S., are used right up until the time of slaughter causing violative amounts of drugs to appear in their tissue.

Drugs Found

Sulfaclozine is a synthetic sulfonamide antimicrobial.  Immune reactions resulting in pyrexia and depression or bone marrow suppression are occasionally reported and are thought to be more common in cats, Dobermans, German Shepherds, and Rottweiler’s.  The FDA revoked all approved sub-therapeutic uses of sulfonamide drugs in animal feed in 1975.

Sulfaquinoxaline is an antibacterial sulfonamide drug FDA approved for veterinary medicine.  It may be given to animals as an antimicrobial used as an aid in preventing outbreaks of coccidiosis.  The FDA revoked all approved sub therapeutic uses of sulfonamide drugs in animal feed in 1975.

Enrofloxacin (Baytril) is a fluoroquinolone antibiotic.  May cause cartilage abnormalities in dogs less than 8 months old.  In 2005, the FDA withdrew approval of its use in poultry, as this practice was noted to promote the evolution of fluoroquinolone-resistant strains of the bacterium Campylobacter, a human pathogen.

Tilmicosin is a macrolide antibiotic specifically developed for bovine respiratory disease.  It is a FDA approved antimicrobial drug for use in medicated feeds for the control of bovine respiratory disease in groups of beef and non-lactating dairy cattle, sheep, and swine for the prevention of pneumonia.

Trimethoprim is a potentiated sulfonamide antibiotic with broad spectrum of activity.  It is a FDA drug approved for use in horses, which are non-food animals.  The drug is not intended for use in food-producing animals.  Studies have shown that the incidence of patients receiving sulfonamides and trimethoprim is higher than for any other drug.  The FDA revoked all approved sub therapeutic uses of sulfonamide drugs in animal feed in 1975.

*The maximum residue limit or MRL is based on the type and amount of residue considered to be without any toxicological hazard from human health.

References:

United States Department of Agriculture, Foreign Agricultural Service, Veterinary Drug: Maximum Residue Limits Database MRLD

European Medicines Agency, Veterinary Medicines: Maximum Residue Limits Database Reports (EPMAR)

University of Minnesota, Veterinary Formulary

Food Animal Residue Avoidance Databank (FARAD)

Veterinary Drug Residues in Processed Meats — Potential Health Risk

Codex Alimentarius, International Food Standards: Veterinary Drug Residue in Foods Database

The United States Pharmacopeial Convention

Merck Manual Renal Transport Abnormalities: Introduction

Merck Manual: Renal Transport Abnormalities: Renal Tubular Acidosis

Veterinary Pharmacovigilance Adverse Reactions to Veterinary Medicinal Products

Merck Veterinary Manual Sulfonamides and Sulfonamide Combinations : Special Clinical Concerns