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Trimethoprim; Uses, Dosage, Side Effects, Interactions

Trimethoprim is a synthetic derivative of trimethoxybenzyl-pyrimidine with antibacterial and antiprotozoal properties. As a pyrimidine inhibitor of bacterial dihydrofolate reductase, trimethoprim binds tightly to the bacterial enzyme, blocking the production of tetrahydrofolic acid from dihydrofolic acid. The antibacterial activity of this agent is potentiated by sulfonamides

Trimethoprim (TMP) is an antibiotic used mainly in the treatment of bladder infections. Other uses include for middle ear infections and travelers’ diarrhea. A pyrimidine inhibitor of dihydrofolate reductase, it is an antibacterial related to pyrimethamine. The interference with folic acid metabolism may cause a depression of hematopoiesis. It is potentiated by sulfonamides and the trimethoprim-sulfamethoxazole combination is the form most often used. With sulfamethoxazole or dapsone, it may be used for Pneumocystis pneumonia in people with HIV/AIDS.

Mechanism of Action of Trimethoprim

Trimethoprim binds to dihydrofolate reductase and inhibits the reduction of dihydrofolic acid (DHF) to tetrahydrofolic acid(THF). THF is an essential precursor in the thymidine synthesis pathway and interference with this pathway inhibits bacterial DNA synthesis.Trimethoprim’s affinity for bacterial dihydrofolate reductase is several thousand times greater than its affinity for human dihydrofolate reductase. Sulfamethoxazole inhibits dihydropteroate synthase, an enzyme involved further upstream in the same pathway.Trimethoprim and sulfamethoxazole are commonly used in combination due to possible synergistic effects, and reduced development of resistance.This benefit has been questioned. Sulfamethoxazole inhibits dihydrofolate synthetase (aka dihydropteroate synthetase), an enzyme involved further upstream in the same pathway. Trimethoprim and sulfamethoxazole are commonly used in combination due to their synergistic effects. This drug combination also reduces the development of resistance that is seen when either drug is used alone.

To determine the incidence & severity of hyperkalemia during trimethoprim therapy, 30 consecutive patients with acquired immunodeficiency syndrome receiving high-dose (20 mg/kg/day) trimethoprim were studied; in addition, the mechanism of trimethoprim-induced hyperkalemia was investigated in rats. Trimethoprim increased serum potassium concn by 0.6 mmol/l despite normal adrenocortical function & glomerular filtration rate. Serum potassium levels >5 mmol/l were observed during trimethoprim treatment in 15 of 30 patients. In rats, iv trimethoprim inhibited renal potassium excretion by 40% & increased sodium excretion by 46%. It was concluded that trimethoprim blocks apical membrane sodium channels in the mammalian distal nephron. As a consequence, the transepithelial voltage is reduced & potassium secretion is inhibited. Decreased renal potassium excretion secondary to these direct effects on kidney tubules leads to hyperkalemia in a substantial number of patients being treated with trimethoprim-containing drugs.

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Indications of Trimethoprim

Acute otitis media
Pneumonia, Pneumocystis
Uncomplicated urinary tract infections
Urinary tract infections
Prevention of bladder infection
Bladder infection
Otitis media
Pneumocystis pneumonia
For the treatment of urinary tract infections, uncomplicated pyelonephritis (with sulfamethoxazole) and mild acute prostatitis. May be used as pericoital (with sulfamethoxazole) or continuous prophylaxis in females with recurrent cystitis. May be used as an alternative to treating asymptomatic bacteriuria during pregnancy (only before the last 6 weeks of pregnancy). Other uses include an alternative agent in respiratory tract infections (otitis, sinusitis, bronchitis, and pneumonia), treatment of Pneumocystis jirovecii pneumonia (acute or prophylaxis), Nocardia infections, and traveler’s diarrhea.

Contra-Indications of Trimethoprim

Inadequate folic acid
Anemia from inadequate folic acid
Decreased blood platelets
Decreased neutrophils a type of white blood cell
Liver problems
Kidney disease with a reduction in kidney function
Pregnancy

Dosage of Trimethoprim

Strengths: 100 mg; 200 mg; 50 mg/5 mL

Urinary Tract Infection

Recommended Dose

100 mg orally every 12 hours for 10 days or 200 mg orally every 24 hours for 10 days

Bacterial infections

Adults and children weighing 40 kilograms (kg) or more—800 milligrams (mg) of sulfamethoxazole and 160 mg of trimethoprim every 12 hours for 10 to 14 days. Your doctor may adjust this dose if needed.
Children 2 months of age and older, and weighing up to 40 kg—Dose is based on body weight and must be determined by your doctor. The usual dose is 40 milligrams (mg) per kilogram of body weight of sulfamethoxazole and 8 milligrams (mg) per kilogram of body weight of trimethoprim, given in two divided doses every 12 hours for 10 days.
Infants younger than 2 months of age—Use is not recommended.

Pneumocystis jiroveci pneumonia or Pneumocystis carinii pneumonia (PCP)

Adults and children 2 months of age and older—Dose is based on body weight and must be determined by your doctor. The usual dose is 75 to 100 milligrams (mg) per kilogram of body weight of sulfamethoxazole and 15 to 20 milligrams (mg) per kilogram of body weight of trimethoprim each day, given in equally divided doses every 6 hours for 14 to 21 days.
Children younger than 2 months of age—Use is not recommended.

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Pneumocystis jiroveci pneumonia or Pneumocystis carinii pneumonia (PCP)

Adults—800 milligrams (mg) of sulfamethoxazole and 160 mg of trimethoprim once a day.
Children 2 months of age and older—Dose is based on body size and must be determined by your doctor. The usual dose is 750 mg of sulfamethoxazole and 150 mg of trimethoprim per square meter (m[2]) of body surface each day. This is given in equally divided doses two times a day for 3 days a week on consecutive days (eg, Monday, Tuesday, Wednesday). However, the dose is usually not more than 1600 mg of sulfamethoxazole and 320 mg of trimethoprim per day.
Children younger than 2 months of age—Use is not recommended.

Traveler’s diarrhea

Adults—800 milligrams (mg) of sulfamethoxazole and 160 mg of trimethoprim every 12 hours for 5 days.
Children 2 months of age and older—Use and dose must be determined by your doctor.
Children younger than 2 months of age—Use is not recommended.

Side Effects of Trimethoprim

The most common

Common

fever, chills, body aches, flu symptoms, sores in your mouth and throat;
pale skin, easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin;
high potassium (slow heart rate, weak pulse, muscle weakness, tingly feeling); or
a severe headache with muscle cramps, confusion, weakness, loss of coordination, feeling unsteady, and weak or shallow breathing.
stomach pain, vomiting, diarrhea;
sore or swollen tongue; or
mild itching or skin rash.

Less common

Skin rash or itching
Black, tarry stools
blood in urine or stools
bluish fingernails, lips, or skin
changes in facial skin color
difficult breathing or shortness of breath
fever with or without chills
the general feeling of discomfort or illness
a headache
joint or muscle pain
nausea
neck stiffness
pale skin
pinpoint red spots on the skin
redness, blistering, burning, tenderness, peeling, or loosening of the skin or mucous membranes
redness, swelling, or soreness of tongue
red skin lesions, often with a purple center
a sore throat
swelling

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Drug Interactions of Trimethoprim

angiotensin-converting enzyme (ACE) inhibitors (e.g., ramipril, enalapril)
BCG vaccine
certain anti-HIV medications (e.g., delavirdine, efavirenz, lamivudine)
cyclosporine
dapsone
dofetilide
fluconazole
fluorouracil
gemfibrozil
ketamine
ketoconazole
methotrexate
nicardipine
paclitaxel
phenytoin
pioglitazone
procainamide
repaglinide
rosiglitazone
theophylline
tolbutamide
tretinoin
typhoid vaccine
zafirlukast

Pregnancy & Lactation of Trimethoprim

FDA Pregnancy Catagory D

Pregnancy

When trimethoprim is taken during pregnancy, it crosses the placenta and may affect the unborn baby. This medication should not be used during pregnancy unless the benefits outweigh the risks. If you become pregnant while taking this medication, contact your doctor immediately.

Lactation

This medication passes into breast milk. If you are a breastfeeding mother and are taking trimethoprim, it may affect your baby. Talk to your doctor about whether you should continue breastfeeding.