Background

Ever since the development of penicillin, there has been a drive to make antibiotics better: better ability to penetrate into infected tissue, better efficacy against a more broad spectrum of bacterial organisms, less potential to harm host tissues. The combination of trimethoprim and sulfa antibiotics has created a very unique method to combat bacteria: the sequential blockade.

An essential nutrient used in the synthesis of many important biochemicals is folic acid. Folic acid is made from para-amino benzoic acid (PABA) through a step-by-step process involving two enzymes. The sulfa drug inhibits the first enzyme and trimethoprim inhibits the second enzyme. This double inhibition is called the sequential blockade and produces death of the bacterium whereas either antibiotic alone could only have inhibited bacterial reproduction. Mammal enzymes are far less sensitive to the blockade than bacterial enzymes but what really protects the infected host from the blockade is the simple fact that mammals do not have to manufacture their own folic acid; they can eat it in their diet.

How This Medication is Used

There are several special advantages to using trimethoprim sulfa. First, this medication has the special advantage of being able to penetrate into exudates and infected tissues that usually stop other antibiotics at their surface. This means trimethoprim sulfa can enter not only abscessed tissue but can penetrate the prostate gland, the blood brain barrier, and eye and treat infections in these locations.

Trimethoprim sulfa is a broad spectrum antibiotic with excellent activity against most gram-negative organisms and against Staphylococci in the skin. This makes trimethoprim sulfa a good choice for skin infections or as a general antibiotic when the actual identity of the infecting organism is not known. Trimethoprim sulfa is not generally effective against Pseudomonas aeruginosa.

Another advantage of trimethoprim sulfa is that it has minimal effect on the normal flora of the GI tract of the patient. This means less potential for antibiotic induced diarrheas and less resistant bacteria in the home.

Trimethoprim sulfa is given twice a day. It’s relatively low cost compared to other antibiotics, which makes it a popular choice.

Infections for which trimethoprim sulfa are especially helpful are:

• ïCoccidiosis
• ïKennel cough(Bordetella bronchiseptica)  
• ïPneumonia  
• ïStaph infections in the skin and ear  
• ïProstate infections

Side Effects 
Although side effects of trimethoprim sulfa are rare, they do have some potential for seriousness so it is a good idea to become familiar with what to look for. The following are syndromes that can occur in certain individuals taking trimethoprim sulfa. These syndromes represent idiosyncratic reactions which mean their occurrence has nothing to do with the amount of drug given but instead represent an unpredictable individual’s sensitivity to any dose:

Joint inflammation
A broad inflammatory syndrome has been observed in some individuals sensitive to trimethoprim sulfa. This includes arthritis, fever, muscle soreness, and even kidney inflammation, and even inflammation in the eye. This syndrome has been formally studied and has been found to occur almost exclusively after a previous uneventful exposure to trimethoprim sulfa and occurs 8 to 20 days after therapy has started. The Doberman pinscher seems to be over-represented and complete recovery can be expected within one week of discontinuing the medication.
 

Skin rashes
Drug related skin reactions do not have characteristic appearances; in fact, they can have any appearance. They do, however, begin around the start of treatment with the offending drug and vanish with cessation of administration of the offending drug. Any drug of any kind can produce a drug reaction in the skin; trimethoprim sulfa is somewhat over-represented in cases of skin related drug eruptions.

Inability to produce adequate tears
Sulfa drugs of any kind are capable of disrupting tear function. Classically, this occurs after long term therapy (i.e., weeks to months) of use but occasionally certain individuals suffer from dry eyes after only one dose of sulfa. In most cases, tear function resumes normally after the drug is discontinued but occasionally the effect is long term or permanent despite withdrawal of the drug.

Hepatitis
Liver failure can result when a sensitive individual receives this medication. Nausea, jaundice, and all the other complications that occur with liver failure of any origin may result. Discontinuing the medication should lead to recovery. If the liver is biopsied during its state of failure, changes associated with trimethoprim sulfa reaction are characteristic (i.e., it should be possible via biopsy to determine if a failing liver was caused by an idiosyncratic trimethoprim sulfa reaction.

Blood dyscrasias
Blood dyscrasias are abnormal blood cells or proportions of different blood cells. Blood dyscrasias might lead to immune dysfunction, bleeding tendency, or other problems depending on which blood cells are affected. With trimethoprim sulfa, loss of red blood cells, platelets, and white blood cells have been reported. This syndrome is typically part of the joint inflammation syndrome.

Sulfa bladder stones
Actual bladder stones made of the sulfa antibiotic can actually form. This has been reported in patients taking routine doses of sulfas for routine (as opposed to extended) periods of time.

In the September/October 2003 issue of the Journal of the American College of Veterinary Internal Medicine, a study by Trepanier et. al reviewed the histories of 40 dogs all with assorted sulfa drug reactions to determine what reactions were most common and most serious. They found:

• Samoyeds and Miniature Schnauzers were overrepresented in the group (suggesting these breeds are predisposed to sulfa reactions).
• The duration of sulfa exposure before symptoms showed up ranged from 5 days to 36 days (average of 12 days).
• The time it took to develop a reaction was not dependent on the type of sulfa drug used nor on the dose used.
• The most common reaction was fever (in 55% of reacting dogs).
• The next most common reaction was a drop in platelet count (in 54% of reacting dogs) and was associated with a 63% recovery rate.
• The third most common reaction was liver disease (in 28% of reacting dogs) and was associated with a 46% recovery rate.
• Reacting dogs that did not develop liver disease had an 89% recovery rate. Reacting dogs without platelet count drops had a 90% recovery rate.

Overall, of dogs that had sulfa reactions 77% recovered.

Interactions with other Drugs
Trimethoprim sulfa will interfere with thyroid function testing. It is not known precisely how long trimethoprim sulfa should be discontinued in order to get a valid thyroid reading.

The following drugs may be enhanced by trimethoprim sulfa use: phenylbutazone (an NSAID), thiazide diuretics, aspirin, and methotrexate (a cancer medication).

Antacids may interfere with the efficacy of trimethoprim sulfa.

Trimethoprim sulfa should not be used with cyclosporine (used for allergies, perianal fistulas, and immune suppression after organ transplant). This combination increases toxicity of the cyclosporine and reduces its beneficial effects.

Concerns and Cautions
Trimethoprim-sulfa should not be used by patients with a history of liver disease, blood dyscrasias, or known sulfa drug sensitivity.

This medication is best not used in pregnancy. Birth defects have been reported after this medication was given to pregnant rats.

It is important to become familiar with the above-described idiosyncratic reactions. These reactions are uncommon but it is important to be prepared.

Signs of overdose include nausea and diarrhea, confusion and depression, bone marrow disease, and facial swelling.

It is our policy not to give dosing information over the Internet.

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