Lethal Weapons: Trimethoprim-sulfa Antibiotics

Trimethoprim-sulfa antibiotics are widely used because they’re inexpensive, effective against all kinds of bacteria, and considered very safe. Unfortunately, they aren’t without side-effects. Deerhounds have more than their share of serious consequences from these drugs.

by John Dillberger, DVM

Reprinted from the January/February 1998 Claymore

(Editor’s note: The list of sulpha antibiotics has changed since this article was first published; check with your vet when your dog is prescribed any antibiotic to make sure it is not T/S.)

Antibiotics are one of our greatest weapons in the war against human and animal diseases. These drugs have prevented untold suffering and death, and are rightly viewed as twentieth-century miracles. One of the most successful of these antibiotics is actually a combination of two separate bacteria-killers: trimethoprim and a sulfonamide (or sulfa drug for short).

Trimethoprim-sulfa antibiotics almost surely have saved Deerhound lives, but they’ve also taken the lives of more than one hound – most recently, one of Ms. Catherine Doyle’s. I spoke with Ms. Doyle several times during her dog’s illness, and was both baffled by what was happening to her dog and frustrated that I couldn’t help.

The death of Ms. Doyle’s Deerhound impelled me to review what I already knew about trimethoprim-sulfa antibiotics and dig deeply into the published scientific literature to see what more I could find. As it happens, I’m in a unique position to obtain further information on this drug, because it was “invented” and developed for human and veterinary use at Wellcome Laboratories, a predecessor of the company where I now work. Thus, I’ve been able to review unpublished reports of original research studies done in the 1950s and 1960s with trimethoprim alone and trimethoprim-sulfa combinations.

What I’ve found out disturbs me deeply. The perception that trimethoprim-sulfa antibiotics have a wide margin of safety in dogs rests on scanty published evidence, poorly interpreted. Unpublished research suggests just the opposite: that these drugs have a very narrow margin of safety. These unpublished studies caused Wellcome Laboratories and other manufacturers of trimethoprim-sulfa antibiotics to specify on their labels and package inserts that these antibiotics should be given at a dose no greater than 30 mg/kg/day and for no more than 14 days at a time.

Worse yet, published reports that trimethoprim-sulfa antibiotics have a wide margin of safety led veterinary dermatologists to recommend in journal articles and veterinary textbooks of the 1980s that these drugs be used at twice the recommended dose for up to 6 weeks at a time to treat stubborn skin infections. These widely publicized recommendations by perceived experts strengthened the popular feeling that trimethoprim-sulfa antibiotics were very safe in dogs.

Let me assure you that trimethoprim-sulfa antibiotics are potentially dangerous drugs in Deerhounds, and maybe in dogs of all breeds. These drugs have a narrow margin of safety in dogs in general, and their margin of safety varies greatly among individual dogs.

I’ve divided this article into three parts. Part I focuses on the problems that trimethoprim-sulfa antibiotics cause in Deerhounds and contains practical information, such as the names under which trimethoprim-sulfa antibiotics are sold in the United States, the nature of the risk these drugs pose to Deerhounds, and recommendations for how to treat affected hounds, including an experimental treatment to try if your dog gets into trouble with these drugs. Part II goes into more detail about the origins of trimethoprim-sulfa antibiotics and how they work. Part III reviews what we know about the safety of trimethoprim-sulfa antibiotics in dogs and explains why I think these drugs often cause life-threatening consequences in our breed. Parts II and III may interest those with a penchant for history and science.

For the rest of this article I’ll abbreviate trimethoprim-sulfa as T/S to make reading easier.

Part I

A Rose by Any Other Name…

T/S antibiotics are manufactured by half-a-dozen companies and sold under various brand names. I’ve listed the brand names currently sold in the United States in the table below.

Trimethoprim-Sulfa Antibiotics Sold in the United States
Veterinary Brands	Tribrissen® Di-Trim® UniprimÒ generic Sulfadiazine & Trimethoprim
Human Brands	Bactrim^TM Septra® SulfatrimÒ generic Sulfamethoxazole & Trimethoprim
Trimethoprim-only Human Brands	Proloprim® Trimpex® generic Trimethoprim

T/S antibiotics have been around long enough that generic forms are available, too, sold under the plain-and-simple names Sulfadiazine & Trimethoprim (for veterinary use) and Sulfamethoxazole & Trimethoprim (for human use).

The name of any drug should appear (legibly!) on the bottle or envelope in which the drug is dispensed to you. If it doesn’t, then ask. Also, I recommend that you don’t rely solely on the table I’ve provided or on your memory. Whenever a drug is prescribed for your hound, ask if it’s a T/S antibiotic.

Deerhounds and Cytopenia

Life-threatening T/S side-effects in Deerhounds are always variations on one theme: cytopenia. Cytopenia (from the Greek cyto = cell, and penia = poverty) is a general term that means too few cells in the bloodstream. If all types of blood cells are scarce, then the condition is termed pancytopenia. If only one type of blood cell is scarce, then other terms are used. Anemia (or erythropenia) means that red blood cells are scarce; leukopenia, that white blood cells are scarce; thrombocytopenia, that platelets (also called thrombocytes) are scarce.

Normal bone marrow constantly produces blood cells to replace those that get damaged, destroyed, or removed from the circulation. Blood cells take a real beating in the turbulent currents of the bloodstream, and they don’t last long. White blood cells live only a few hours; platelets, a few days; and red blood cells, a few months. Only intestinal lining cells turn over as rapidly as blood cells.

How T/S Drugs Cause Cytopenia

Drugs can cause cytopenia in two ways: they can cause blood cells to be destroyed faster than the bone marrow can produce them, or they can suppress or even stop the marrow from producing new blood cells.

Drugs can destroy blood cells by directly damaging them, or can cause cells to be destroyed by sticking to the cell surface, thereby tricking the immune system into mistaking the cell for a foreign invader and attacking it. Sulfa drugs can stick to cells and cause cytopenia by the second means, which is aptly called immune-mediated cytopenia.

Drugs also can cause cytopenia by interfering with blood cell production in bone marrow. Trimethoprim can do so; in fact, it can prevent bone marrow from producing blood cells in the same way that it prevents bacteria from producing new bacteria. Bone marrow that isn’t producing normal numbers of blood cells is described as either hypoplastic (suppressed) or aplastic (totally inactive).

T/S drugs, then, might cause cytopenia by either mechanism. How do you know which mechanism is responsible for cytopenia in a particular Deerhound? There are many ways, but the fastest and easiest is to look at a blood smear. Here’s why.

With immune-mediated cytopenia, the bone marrow will be churning out new blood cells as fast as it can, trying to replace the losses. One trick the marrow employs is to release cells early, before they’re mature. Blood smears from dogs with immune-mediated cytopenia contain lots of these immature blood cells.

On the other hand, with cytopenia due to marrow hypoplasia, the bone marrow’s inability to produce blood cells is the cause of the cytopenia in the first place. As the marrow isn’t making any blood cells at all (mature or immature), it has none to release. Blood smears from dogs with cytopenia due to marrow hypoplasia don’t contain immature blood cells.

Unless the cause is obvious from a blood smear or other tests (such as a bone marrow exam), cytopenia in a Deerhound that is taking or has recently finished taking a T/S drug should be presumed due to both mechanisms, and the dog should be treated accordingly.

Treating T/S-Caused Cytopenia

Immune-mediated cytopenia is treated by suppressing the immune system to stop it from destroying blood cells. The drugs most often used are corticosteroids, especially prednisone. Very large doses may be needed to slow blood cell destruction.

Cytopenia due to bone marrow hypoplasia often can’t be treated, but in researching this article, I came across a potential treatment for T/S-caused marrow hypoplasia. A human drug called leucovorin, developed as an antidote for bone marrow suppression caused by anti-leukemia drugs, might work as an antidote for T/S-caused marrow hypoplasia, too. Incidentally, leucovorin was “invented” and developed by Wellcome Laboratories.

In human patients, leucovorin is injected intravenously or intramuscularly at 10 mg/m² as soon as cytopenia is detected. The same dose is repeated every 6 hours until blood cell counts begin to return toward normal. Doses after the first one may be given orally instead of intravenously.

I know of no instance in which leucovorin has been used to treat T/S-caused marrow suppression and cytopenia in dogs, but if my hound were in danger, I’d sure try it. The dog dose of leucovorin equivalent to the human dose would be 0.5 mg/kg (about 0.2 mg/pound), so a 100‑pound Deerhound would receive a dose of 20 mg. Leucovorin is available in 100-mg injection vials and 5- or 25-mg tablets.

Besides treating the cause of cytopenia with corticosteroids and/or leucovorin, general supportive care is necessary to keep dogs alive long enough for these primary therapies to work. The type of supportive care will depend upon the type of cytopenia. With anemia, dogs don’t have enough red blood cells to carry oxygen to tissues, and they may benefit from supplemental oxygen or a blood transfusion. With leukopenia, dogs don’t have enough white blood cells to fight infection, and they should be given broad-spectrum antibiotics (other than T/S drugs!). With thrombocytopenia, dogs don’t have enough platelets to form blood clots, so they bleed easily and excessively. The only treatment for this is to transfuse the dog with whole blood or blood platelets.

Part II

The two drugs that make up T/S antibiotics were discovered and developed separately. Sulfa drugs were the first effective anti-bacterial agents ever used. Before penicillin was widely available, they were the mainstay for fighting bacterial infections. Trimethoprim was discovered and developed as an anti-malarial drug, but proved better at killing bacteria than malaria parasites. The common thread running through the discovery and development of sulfa drugs, trimethoprim, and T/S antibiotics is folic acid, so that’s where I’ll begin my narrative.

Folic Acid

Researchers discovered folic acid by first observing that corn-based diets caused a nutritional cytopenia in monkeys, and then observing that this deficiency disease could be cured by feeding yeast. Spinach leaves turned out to contain large amounts of the “yeast factor,” so it was named folic acid (from the Latin folium = leaf).

The folic acid originally purified from spinach leaves is only one of a whole family of chemically-related molecules known collectively as folates, which are present in all forms of life. To simplify things, I’ll use the term folic acid in this article to refer to folates as a group.

Folic acid is so wide-spread in nature because it plays a role in processes vital to the life of every cell, from single bacterial cells to the cells that make up spinach leaves, Deerhounds, and us. Cells need folic acid to make new DNA, the stuff of genes. Without folic acid, cells can’t copy their genes, and so can’t reproduce themselves. Without folic acid, cell production ceases.

Cells can get folic acid in two ways: make it themselves from simple building blocks, or absorb it from outside. Plants and bacteria make their own folic acid, but mammals (including Deerhounds) don’t; instead, they absorb folic acid that’s present in their food or that’s made by bacteria living in their own intestinal tract.

Why don’t bacteria just absorb folic acid from the environment around them, like mammalian cells do? They can’t – apparently, bacteria never developed the ability to absorb folic acid because they didn’t need to, being able to make their own folic acid from scratch.

To use folic acid, all cells must chemically convert it into a substance called THF (tetrahydrofolic acid). Cells make THF using an enzyme called DHF reductase (dihydrofolate reductase).

Dyes and Sulfa Drugs

The difference in how bacteria and mammalian cells get folic acid was exploited in the first half of the 20^th century to develop a whole class of antibiotics called sulfa drugs. Actually, sulfa drugs were a spin-off from the German dye industry, much as the microwave oven was a spin-off from the U.S. Space Program.

Sulfa drugs chemically mimic a compound called PABA (para-aminobenzoic acid), one of the building blocks that bacteria use to make folic acid. When bacteria try to make folic acid out of sulfa drug instead of PABA, they fail, and without folic acid, bacteria can’t grow or divide. This makes them easy prey for the body’s white blood cells, which gobble up the bacteria and eliminate the infection.

(As an aside, antibiotics like sulfa drugs, which stop bacteria from dividing but don’t kill them outright, are called bacteriostatic. Antibiotics that kill bacteria directly are called bacteriocidal. The distinction is important, because bacteriostatic antibiotics will eliminate infection only in animals that have adequate immune systems with plenty of properly functioning white blood cells to devour bacteria “paralyzed” by the antibiotic. Bacteriocidal antibiotics will eliminate infection even in animals with poorly working immune systems.)

Because mammals don’t make their own folic acid, sulfa drugs don’t interfere with the activity of their cells. Put another way, sulfa drugs selectively poison bacteria but not mammals, because they interfere with a chemical reaction that occurs in bacteria but not mammals. All drugs designed to destroy unwanted cells (antibiotics, anti-parasitic drugs, anti-cancer drugs, etc.) must be selective in some way, or they will destroy normal cells along with their intended target.

The sulfa drug story would end here happily, were bacteria not masters at adapting to changed environments. When veterinarians and physicians began using sulfa drugs to treat infections, bacteria adapted fast. They developed ways to keep the sulfa drugs out of their cells, ways to get more PABA into their cells, ways to distinguish PABA from sulfa drugs, ways to make folic acid without PABA, and maybe even ways to absorb folic acid instead of make it. As a result, more and more infections turned up that were resistant to sulfa drugs.

Cancer, Malaria, and Trimethoprim

A Wellcome Laboratories scientist named Dr. George Hitchings theorized that if he could combine sulfa drugs (which stop bacteria from making folic acid) with another drug that would stop bacteria from converting folic acid to THF, then the combination would circumvent bacterial defenses and be effective against sulfa-resistant infections. Dr. Hitchings had a good idea where to start looking for a drug to block THF synthesis, because he and other researchers already had developed several drugs of this kind to kill the cancer cells of leukemia and the parasites that cause malaria.

Leukemia is a cancer of blood cells in which cell production goes berserk. The bone marrow drowns in leukemic blood cells and can’t produce enough normal blood cells. Leukemic cells spill over into the blood stream and flood all organs of the body.

Recall that diets deficient in folic acid caused cytopenia in monkeys because their bone marrow lacked enough folic acid to produce blood cells. Dr. Hitchings and other cancer researchers read about this nutritional cytopenia in monkeys and theorized that a drug that prevented leukemic blood cells from using folic acid would halt their proliferation, just as folic acid-deficient diets halted production of normal blood cells. Of course, unless such a drug selectively targeted leukemic blood cells and spared normal blood cells, it also would interfere with production of normal blood cells (and other sorts of normal cells).

Researchers created drugs that mimicked folic acid, such as aminopterin and methotrexate, and tested them against cancer cells in the laboratory. When the cancer cells tried to make THF out of these drugs instead of folic acid, they failed, and the cancer cells couldn’t reproduce themselves. When the drugs were tested in patients, they worked! – not every time or in every patient, but these drugs did produce the first remissions ever achieved in leukemia patients. They still are used today.

These anti-cancer drugs aren’t free of side-effects because they don’t completely spare normal cells. They interfere with production of normal blood cells in bone marrow and normal intestinal lining cells (which, like blood cells, are lost and replaced constantly). The results are cytopenia and diarrhea, which are serious but acceptable side-effects, given the nature of the disease being treated.

Unfortunately for Dr. Hitchings, who was looking to make a new antibiotic by combining sulfa drugs with a drug that blocked THF synthesis, these anti-cancer drugs didn’t seem to affect bacteria at all. We now know that’s because the drugs, like the folic acid that they closely resemble, aren’t absorbed by bacteria. However, at the same time that these anti-cancer drugs were being developed and tested, other drugs that blocked THF synthesis were being developed to treat malaria, and these held more promise for use against bacteria.

Malaria is caused by a protozoan parasite that reproduces at a fantastic rate in red blood cells, destroying the cells in the process. Malaria researchers theorized that interfering with the parasite’s use of folic acid might effectively treat the disease. Because malaria parasites, like bacteria, didn’t absorb drugs that mimicked folic acid, researchers created new drugs that could penetrate the parasites and block THF synthesis. Sure enough, these drugs proved successful. The best of these new drugs was pyrimethamine; another, which turned out to be only modestly good, was trimethoprim.

While trimethoprim had only lackluster activity against malaria, it had superb activity against bacteria. Bacteria readily took in trimethoprim, and even tiny concentrations of the drug completely blocked THF synthesis in bacteria. Thus, when Dr. Hitchings looked around for a drug to combine with sulfa drugs to treat bacterial infections, he settled upon trimethoprim.

T/S Antibiotics

The trimethoprim-sulfa combination proved even more effective against bacteria than hoped. It stopped the growth of a wide range of bacteria in the laboratory and cured infections in patients. Better yet, bacteria didn’t become resistant to the drug combination. As Dr. Hitchings had predicted, bacteria seemed unable to circumvent the double blockade of folic acid synthesis and THF synthesis.

But wait! – when patients took T/S drugs, why didn’t trimethoprim also enter their own cells and block THF synthesis, causing the same side-effects as the anti-cancer drugs did? The answer is that trimethoprim does enter mammalian cells, but it isn’t nearly as good at blocking THF synthesis in mammalian cells as in bacterial cells. That’s because the enzyme responsible for making THF differs among species, and trimethoprim works better against some forms of the enzyme than against others. For example, it takes 50,000 times more trimethoprim to block rat DHF reductase (the THF-making enzyme) than to block bacterial DHF reductase.

Part III

Since they first became available, T/S antibiotics have been widely used by physicians and veterinarians alike. Veterinarians are especially likely to prescribe T/S antibiotics to treat infections in large dogs like Deerhounds. There are good reasons for this.

First, these antibiotics are relatively inexpensive, making them a practical choice for large dogs. Second, T/S antibiotics can be given only once or twice a day, which fits into owner schedules. Third, these drugs have a broad spectrum of activity, meaning that they kill many different kinds of bacteria. Fourth, bacteria rarely become resistant to T/S drugs. Fifth, these drugs are considered safe because side-effects are rare and resolve quickly if the drug is withdrawn.

Why T/S Drugs Are Considered “Safe”

The widespread perception that T/S antibiotics are safe in dogs rests on two studies published in 1976 and 1978. To put these studies in perspective, keep in mind that the recommended dose for treating bacterial infections with T/S antibiotics is 30 mg/kg/day for 2 weeks.

The first study, authored by two Wellcome scientists, concluded that T/S antibiotics “demonstrated a high margin of safety in dogs” because 12 beagles tolerated 300 mg/kg/day (10 times the recommended dose) for three weeks without problems. The second study, authored by a pair of Canadian veterinarians, also reported that T/S antibiotics “afford[ed] a wide margin of safety,” despite the fact that one of four mixed-breed dogs given daily doses of 90 mg/kg (three times the recommended dose) for 8 weeks developed cytopenia due to marrow hypoplasia after only 4 weeks of treatment.

Despite the dog that developed cytopenia in the Canadian study, T/S antibiotics were considered safe in dogs. Despite subsequent reports in recent years of T/S-caused cytopenia (aplastic anemia in a one dog in 1987 and in two more dogs in 1993, and thrombocytopenia in a dog in 1992), T/S antibiotics still are perceived as very safe in dogs.

The perceived safety of T/S drugs is reinforced by the package inserts. Although inserts from the veterinary products Tribrissen® and Di-Trim® caution veterinarians not to extend therapy “for more than 14 consecutive days,” they also contain the following sentence:

“During long-term treatment of dogs, periodic platelet counts and white and red blood cell counts are advisable.”

This implies that long-term treatment can be done safely, as do the following sentences about side-effects, which appear in both inserts:

“Toxicity is low. …Dogs can tolerate up to ten times the recommended therapeutic dose without exhibiting ill effects. Dogs dosed at 300 mg/kg/day for a period of 20 days revealed only slight changes in hematologic values.”

The source of the assurance in the paragraph above is, of course, the 1976 study that used 12 beagles, conducted by Wellcome scientists.

Why T/S Drugs Are Less “Safe” Than Believed

The common perception notwithstanding, I now know that T/S antibiotics have a pretty low margin-of-safety in dogs. I know this because I’ve read unpublished reports of two research studies conducted at Wellcome Laboratories with trimethoprim alone and T/S antibiotics.

In the first study, reported in 1960, groups of six beagles were given trimethoprim alone or a T/S combination at doses of 45 or 135 mg/kg/day, six days a week, for 3 months. Beagles tolerated 45 mg/kg/day without problems, but at 135 mg/kg/day, eight dogs didn’t last out the study: one dog given the T/S combination died on day 24, and three more dogs given T/S and four dogs given trimethoprim alone became so ill that they were taken off study after one month. The problem? – cytopenia due to bone marrow suppression and, in two dogs given trimethoprim alone, severe pneumonia. Pneumonia is a common secondary complication from cytopenia, when there are two few white blood cells to effectively fight infection.

In the second study, reported in 1982, groups of four beagles were given trimethoprim at doses of 25 or 125 mg/kg/day for 3 weeks. At 25 mg/kg/day, one beagle developed thrombocytopenia after 3 weeks, but the other three were unaffected. At 125 mg/kg/day, all four beagles developed thrombocytopenia and leukopenia due to bone marrow suppression, and one beagle also became anemic.

These two studies clearly show that trimethoprim alone or combined with a sulfa drug to make a T/S antibiotic has a margin-of-safety in Beagles of about 4. That is a low margin of safety! And the true margin of safety for T/S drugs in dogs may be as low as 2, because doses between 45 and 125 mg/kg/day weren’t tested. Recall that in the published Canadian study, one dog given 90 mg/kg/day developed cytopenia.

Why T/S Drugs May Be Even Less “Safe” in Specific Dog Breeds or Individuals

From word-of-mouth and the 1996 Deerhound Health Survey, it’s clear that T/S-caused cytopenia isn’t rare in Deerhounds. I’m not sure why that is, but I’ll share my suspicions.

A T/S drug’s margin of safety in a dog depends upon its selectivity; that is, the difference between its effect on bacterial cells and its effect on dog cells. The bases for T/S drug’s selective activity against bacteria but not dog cells are:

1) Sulfa drugs prevent bacteria from making folic acid, but don’t affect dog cells, which absorb folic acid rather than make it.
2) Small concentrations of trimethoprim prevent bacteria from converting folic acid to THF, but it takes larger concentrations to prevent dog cells from making THF from folic acid.

These two types of selectivity are different, and the difference is crucial. Sulfa drug selectivity is absolute, in that no matter how much sulfa drug a dog cell encounters, the dog cell will be unaffected by the drug. Not so with trimethoprim; its selectivity is relative, not absolute. At some concentration above that needed to block THF synthesis in bacteria, trimethoprim will block THF synthesis in dog cells, too.

You’ll recall that it takes 50,000 times more trimethoprim to block DHF reductase (the THF‑making enzyme) in rat cells than to block the bacterial version of this enzyme. This difference accounts for much of trimethoprim’s margin-of-safety in rats, which is huge. T/S antibiotics are very safe in rats. I suspect that it takes much less trimethoprim to block DHF reductase in dog cells, and that this accounts for the low margin of safety for T/S drugs in dogs.

So far I’ve been talking about dogs in general, but dogs aren’t uniform. The margin of safety for T/S drugs doesn’t just vary among species, but undoubtedly also varies among breeds within a species, and among individuals within a breed. To use a human example, consider antihistamines, which make some folks drowsy but leave others alert. In folks who get drowsy, antihistamines have a zero margin-of-safety; the same dose that relieves hay fever symptoms also causes drowsiness.

I suspect that the margin-of-safety for T/S drugs may be even lower in Deerhounds than in dogs in general, and that it might be as low as zero in some individual Deerhounds. I’ve got good reasons for supposing that this kind of variation exists within dog breeds, because I’ve already given you an example of it. In the unpublished 1960 Wellcome study, eight beagles given 135 mg/kg/day developed severe cytopenia within a month, but four other beagles took the same dose for 3 months with no problems.

What Accounts for Individual Variation?

At least two factors could account for individual variation like that seen among the Wellcome beagles, and I want to elaborate on the factors because they may be relevant for Deerhounds. First, trimethoprim blocks THF synthesis by interacting with DHF reductase, the enzyme that grabs folic acid and converts it to THF. This enzyme may come in several forms, which differ in their sensitivity to trimethoprim blockade. Which form of DHF reductase a dog has could determine how susceptible it is to T/S-caused marrow hypoplasia and cytopenia.

Second, trimethoprim competes with folic acid for a seat on DHF reductase, and the outcome of this competition depends upon the ratio between trimethoprim and folic acid within a cell. If the cell contains more trimethoprim than folic acid, DHF reductase is more likely to grab the wrong molecule when it tries to make THF. A cell’s folic acid content depends in turn upon how much folic acid it can find to take in. Several factors influence folic acid availability:

How much folic acid is available in a dog’s intestine from diet and other sources
How well a dog absorbs folic acid from its intestine
How much folic acid a dog stores in its body
How efficiently a dog mobilizes stored folic acid and transports it to cells that need it.

Dog Food and Folic Acid

Dogs get their folic acid from two sources: folic acid that’s in their food, and folic acid made by their own intestinal bacteria. As soon as a dog begins taking a T/S antibiotic, its only source of folic acid is its food. Why? – because the sulfa portion of the antibiotic prevents intestinal bacteria from making folic acid, which after all, is the drug’s purpose.

Folic acid is destroyed by the heat used to process dog foods. Folic acid also is water soluble, so much of it is extracted when processing fluid is removed during the making of dry dog foods. That’s why synthetic folic acid is added to commercial dog foods after processing to ensure that they contain adequate amounts of folic acid when you buy them.

However, folic acid also is readily destroyed by exposure to light and oxygen, so foods that contain adequate folic acid when sealed in the bag may not have much folic acid left once the bag has been open for a while. I can find no data on how quickly folic acid disappears from dog food exposed to light and air.

Any dog taking a T/S antibiotic should be getting a diet that contains plenty of folic acid, and you shouldn’t assume that dog food alone will provide enough. Good sources of folic acid are liver (most animals store the bulk of their folic acid in the liver), other organ meats, soybeans, wheat germ or bran, yeast, and (of course) multiple vitamin supplements (provided they’re kept in a closed, opaque container).

To Sum It All Up

Let me summarize why I think Deerhounds so often have serious side-effects from T/S antibiotics:

1) Despite perceptions to the contrary, T/S antibiotics have a low margin-of-safety in dogs, meaning that even a slight overdose can cause problems. I suspect that the T/S drug margin-of-safety may be lower still in Deerhounds.
2) Individual dogs within a breed vary in their sensitivity to T/S side-effects, so that these drugs may have almost no margin-of-safety in some dogs. I suspect some Deerhounds fall into this category.
3) T/S-caused cytopenia is more likely if folic acid is in short supply. I suspect some Deerhounds may be borderline deficient in folic acid, either because they don’t absorb it well from their intestine or don’t store it adequately in their body.
4) T/S antibiotics stop intestinal bacteria from making folic acid, so dogs taking these drugs get all their folic acid from food.
5) Commercial dog foods contain adequate folic acid when sold, but might not have much left after they have been open for a while. I suspect this means that some dogs eating commercial foods might be getting most of their folic acid from intestinal bacteria, and that these dogs become folic acid-deficient when taking T/S antibiotics.

Conclusion

The easiest way to avoid T/S-caused cytopenia is not to give your Deerhound T/S antibiotics. You can use the table in this article to recognize and avoid them if you want to, but realize that avoiding T/S antibiotics means that you might have to use a more expensive drug and give it four times a day instead of once a day.

If you choose to give your hound a T/S antibiotic, you should make sure he gets plenty of folic acid in his food or takes a multiple vitamin supplement during antibiotic treatment and for several weeks thereafter (read Part III if you want to know why). Also, be alert for signs of trouble: pale gums, bleeding of any sort, a sudden turn for the worse, or the sudden appearance of a new symptom. If you plan to use these antibiotics for longer than one week, I’d suggest having your veterinarian draw a blood sample and do a complete blood count at least weekly; in this case, a few dollars of prevention may be worth a few hundred dollars of cure.