Vademecum

Vademecum

TRIMETOPRIM

Description: Trimethoprim is a synthetic antiinfective agent. It has activity against both gram-positive and gram-negative bacteria. It is commonly used systemically for the treatment and prophylaxis of uncomplicated urinary tract infections, for traveler's diarrhea, and, when combined with either sulfamethoxazole or dapsone, for prophylaxis and treatment of Pneumocystis carinii infections. Trimethoprim was originally available in combination with sulfamethoxazole in 1973, then was approved by the FDA for use as a single agent in 1980. It is also available in an ophthalmic solution in combination with polymyxin B. Mechanism of Action: Trimethoprim interferes with folate synthesis in susceptible bacteria. It binds tightly to bacterial dihydrofolate reductase, thousands of times (about 50,000 times) more readily than to the same human enzyme. This action interferes with the uptake of p-aminobenzoic acid (PABA) into folic acid, an essential component of bacterial development. Folic acid is a coenzyme responsible for the transport of one-carbon fragments from one molecule to another and is crucial during the synthesis of thymidine, purines, and certain amino acids. Tetrahydrofolic acid, or THF, is the metabolically active form of folic acid. Other dihydrofolate reductase inhibitors include pyrimethamine, methotrexate, and trimetrexate, all of which are more potent than trimethoprim. Sulfonamides inhibit bacterial dihydrofolate synthetase, the enzyme immediately preceding dihydrofolate reductase. Thus, the combination of trimethoprim with a sulfonamide can produce a synergistic effect. Trimethoprim is used to treat bacterial urinary tract infections caused by Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Enterobacter sp., and coagulase negative Staphylococcus species including S. saprophyticus. It also is effective against Pneumocystis carinii and most strains of Haemophilus influenzae. Trimethoprim is not effective in treating Pseudomonas aeruginosa, and it is generally inactive against anaerobic bacteria. There are some resistant strains of gram-positive and gram-negative bacteria, notably some enterococci. Moraxella catarrhalis isolates were found to be consistently resistant to trimethoprim in vitro. Resistance to trimethoprim occurs through several mechanisms. Pseudomonas aeruginosa is intrinsically resistant to trimethoprm due to the drug's inability to penetrate the bacteria's cell wall. In other bacteria, resistance to trimethoprim may occur secondary to an increase in dihydrofolate reductase (DHFR) levels or activity or via an increase in the synthesis of DHFR, which reduces the susceptibility to trimethoprim. Pharmacokinetics: Trimethoprim is administered orally. Following oral administration, trimethoprim is rapidly absorbed from the GI tract and reaches peak serum concentrations within 1—4 hours, depending on dose. Repeated dosing results in serum concentrations that are greater (50%) than those observed with single-dose administration. Trimethoprim distributes extensively into body tissues and fluids including the CSF and middle ear fluid. In children, following the administation of a single 4 mg/kg dose of trimpethoprim, the mean middle ear fluid concentration was 2 µg/ml. Trimethoprim crosses the placenta, and it is distributed into breast milk, prostatic fluid, and vaginal secretions at higher concentrations than those found in serum. The drug is about 45% bound to plasma protein. Although there is some hepatic metabolism (10—20%) to inactive metabolites, most of the drug is renally excreted unchanged (60-80%) within 24 hours via glomerular filtration and tubular secretion. Serum half-life is greatly extended in patients with renal dysfunction, from a normal of 8—10 hours to 20—30 hours. Acid urine increases and alkaline urine decreases excretion. Small amounts of the drug are excreted in the feces. Trimethoprim half-life, clearance, and volume of distribution vary with age. Excluding newborns, an apparent trend of increasing half-life and volume of distribution, and decreasing clearance is observed with increasing age until adulthood. Hemodialysis removes a significant amount of trimethoprim, so a full maintenance dose is required after dialysis. Peritoneal dialysis does not remove any significant amount of trimethoprim from the blood.

Indications...Dosage The following organisms are generally considered susceptible to trimethoprim in vitro: Acinetobacter sp.†; Citrobacter sp.†; Enterobacter sp.; Escherichia coli; Haemophilus influenzae (beta-lactamase positive); Haemophilus influenzae (beta-lactamase negative); Klebsiella pneumoniae; Pneumocystis carinii†; Proteus mirabilis; Salmonella sp.†; Shigella sp.†; Staphylococcus epidermidis†; Staphylococcus saprophyticus†; Streptococcus pneumoniae; Streptococcus pyogenes (group A beta-hemolytic streptococci)†. For the treatment of acute otitis media due to susceptible strains of S. pneumoniae or H. influenzae: NOTE: Moraxella catarrhalis isolates were found consistently resistant to trimethoprim in vitro. Therefore, when infection with M. catarrhalis is suspected, the use of alternative agents is recommended. Oral dosage (Only Primsol™ FDA-approved): Children and infants >= 6 months of age: 5 mg/kg PO every 12 hours (total dose 10 mg/kg/day) for 10 days. Maximum dosage is 400 mg/day. Trimethoprim has been shown to be clinically equivalent to sulfamethoxazole-trimethoprim (SMX-TMP) in the treatment of acute otitis media, with a clinical success rate of 90% at 5 days post treatment. NOTE: Primsol™ is not indicated for prophylactic or prolonged treatment of otitis media. For treatment of acute, uncomplicated urinary tract infection (UTI) such as cystitis: Oral dosage: Adults and children >= 12 years of age: 100 mg PO every 12 hours, or 200 mg PO once daily. Dosage should be continued for 10—14 days. Children and infants† >= 2 months and < 12 years of age: Dosage has not been established, but 2—3 mg/kg PO twice daily (given every 12 hours) has been used. For urinary tract infection (UTI) prophylaxis†: Oral dosage: Adults and children >= 12 years of age: 100 mg PO once daily at bedtime for 6 weeks to 6 months. For the treatment of Pneumocystis carinii pneumonia† (PCP) in combination with either sulfamethoxazole or dapsone: Oral dosage: Adults: Trimethoprim 20 mg/kg/day PO given in 4 divided doses for 21 days combined with either sulfamethoxazole or dapsone has been studied in a double-blind trial. Dapsone-trimethoprim or sulfamethoxazole-trimethoprim were administered to 60 AIDS patients with a first episode of PCP. The study revealed that efficacy with each regimen was similar however serious adverse reactions were less frequent with the dapsone-trimethoprim regimen.[968] For traveler's diarrhea†: •For the treatment of traveler's diarrhea†: Oral dosage: Adults: 200 mg PO twice daily for 3—5 days.[510] •For traveler's diarrhea prophylaxis†: Oral dosage: Adults: 200 mg PO once daily, for up to 2 weeks of possible risk, beginning the day of travel and for 2 days after return.[510] Patients with renal impairment: CrCl > 30 ml/min: no dosage adjustment needed. CrCl 15—30 ml/min: reduce recommended dose by 50%. CrCl < 15 ml/min: use is not recommended. Intermittent hemodialysis: Supplemental dosing is required following completion of hemodialysis. †non-FDA-approved indication

Oral Administration •Take on an empty stomach (i.e., at least 1 hour prior to or 2 hours after a meal). If gastric irritation occurs, administer with food.

Contraindications Trimethoprim use is contraindicated in megaloblastic anemia due to its propensity to cause folic acid deficiency. Trimethoprim interferes with folate metabolism and should be used with caution in patients with folate deficiency. Patients should be aware of signs of hematologic disorders and, if necessary, have a complete blood count taken. If blood dyscrasias occur, the drug should be discontinued. Leucovorin has been recommended to offset the hematologic toxicity of trimethoprim without affecting its antibacterial effects.[188] Trimethoprim is contraindicated in patients with severe renal impairment or renal failure (creatinine clearance less than 15 ml/minute). Patients with less severe renal impairment (creatinine clearance 15—30 ml/min) should have their dose of trimethoprim adjusted to avoid drug accumulation and potential toxicity (see Dosage). Trimethoprim is distributed into breast milk in concentrations higher than those in maternal plasma. Because trimethoprim may interfere wth folate metabolism, caution should be excercised when trimethoprim is administered to a woman who is breast-feeding her infant. Trimethoprim is classified as FDA pregnancy risk category C. Teratogenic effects have been noted in animal studies with trimethoprim doses 40-times the human dose. Trimethoprim crosses the placenta. Because trimethoprim may interfere with folic acid metabolism, it should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Safety and effectiveness of trimethoprim in infants below the age of 2 months have not been established. The effectiveness of trimethoprim in the treatment of acute otitis media in infants < 6 months of age has not been established. Trimethoprim should be used with caution in patients with hepatic disease.

Interactions Mental status changes have been reported after sulfamethoxazole; trimethoprim, SMX-TMP was administered to a patient taking amantadine. Although it is not clear which drug in sulfamethoxazole; trimethoprim, SMX-TMP combination may be responsible, trimethoprim and amantadine both undergo renal tubular secretion. As a result, each drug can interfere with the renal clearance of the other. Trimethoprim should be used cautiously in patients receiving therapy with amantadine. Use of other folate antagonists should be avoided during therapy with trimethoprim. Hematologic toxicity can be increased by concurrent use of divalproex or valproic acid, methotrexate, pyrimethamine, triamterene, trimetrexate, or other bone marrow depressants. The half-life of phenytoin may be increased when trimethoprim or sulfamethoxazole; trimethoprim, SMX-TMP, but not by sulfamethoxazole alone, is given concurrently with phenytoin. It is thought that trimethoprim may interfere with phenytoin hepatic metabolism. Reduced phenytoin clearance can lead to toxicity. Phenytoin or fosphenytoin doses may need to be reduced during concomitant use of trimethoprim. Concurrent administration of dapsone with trimethoprim increases the plasma concentrations of both drugs. The efficacy of dapsone is increased, which may provide a therapeutic advantage in the treatment of Pneumocystis carinii pneumonia; however, an increase in the frequency and severity of dapsone toxicity (methemoglobinemia, hemolytic anemia) also has been noted. Trimethoprim can interfere with the renal tubular secretion of digoxin. The renal clearance of digoxin decreased significantly in elderly subjects receiving trimethoprim for 14 days, resulting in a 30% to 50% increase in digoxin concentrations. Similar changes were not noted in a single-dose study of young healthy volunteers. Patients, especially the elderly, receiving digoxin should be monitored carefully for digoxin toxicity if trimethoprim is added. Concurrent use of enalapril or quinapril and trimethoprim has been associated with hyperkalemia. Additive inhibition of potassium secretion is the probable mechanism of this interaction. Patients, especially those with renal dysfunction, should be carefully monitored for hyperkalemia during concomitant use of ACE inhibitors and trimethoprim. Use of leucovorin has been recommended to offset the hematologic toxicity of trimethoprim without affecting its antibacterial effects.[188] Trimethoprim and procainamide both undergo tubular secretion. As a result, each drug can interfere with the renal clearance of the other. Trimethoprim can also interfere with the renal clearance of the procainamide metabolite, NAPA. In a study of healthy volunteers, concurrent use of trimethoprim and procainamide resulted in significant increases in AUC for procainamide (63%) and NAPA (52%). In addition, a further increase in the QT interval was noted with concomitant therapy. Although it is not necessary to avoid concomitant use of these two drugs, lower doses of procainamide may be necessary during trimethoprim administration. Procainamide and NAPA concentrations should be monitored closely as the dose may need to be readjusted after trimethoprim is discontinued. Rifampin can increase the elimination of trimethoprim, reducing its effectiveness. Trimethoprim can inhibit the metabolism of warfarin, increasing anticoagulant activity and increasing the risk of developing hematological side effects. The concurrent use of dofetilide with trimethoprim alone or in combination with sulfamethoxazole is contraindicated. Trimethoprim is an inhibitor of renal cationic secretion and decreases the renal tubular secretion of dofetilide. The combination of trimethoprim 160 mg and 800 mg sulfamethoxazole co-administered twice daily with dofetilide (500 mcg BID) for 4 days has been shown to increase dofetilide AUC by 93% and Cmax by 103%. Trimethoprim has been shown to reduce the clearance of unbound tolbutamide and prolong tolbutamide half-life. The reductions in tolbutamide clearance are relatively small. While the risk of enhanced hypoglycemic effects appears low, closely monitor blood glucose during concomitant therapy. Trimethoprim, when used concomitantly with metformin, may increase the risk of lactic acidosis. Trimethoprim may decrease metformin elimination by competing for common renal tubular transport systems. Careful patient monitoring while on concurrent therapy with metformin is recommended.

Adverse Reactions Adverse GI effects are commonly reported during therapy with trimethoprim. They include anorexia, nausea/vomiting, diarrhea, glossitis, abdominal pain, and abnormal taste (dysgeusia). If adverse gastric effects occur, trimethoprim may be taken with food. Hematologic effects of trimethoprim are likely to result in anemia because the drug interferes with folic acid metabolism. Most effects are mild and reversible. Following 1 month of daily dosing, adverse effects can include thrombocytopenia, leukopenia, neutropenia, methemoglobinemia, hemolytic anemia, and megaloblastic anemia. Patients who are folate-deficient, such as debilitated, malnourished, alcoholic, geriatric, or pregnant patients, may be at greater risk, as are those who are receiving long-term therapy. If signs and symptoms indicate onset of hematologic abnormality, patients should have a complete blood count taken. The drug should be withdrawn if blood dyscrasias are evident. Warning signs include bluish fingernails, unusual tiredness and weakness, sore throat, unusual bruising and bleeding, headache, and difficulty in breathing. Leucovorin may be administered to offset significant hematological side effects The most common dermatologic effects of trimethoprim are maculopapular rash and pruritus, which may occur 7—14 days after beginning therapy. At recommended doses, the incidence of rash (unspecified) is 2.9—6.7%. Higher doses of trimethoprim are associated with an increased incidence of rash. Patients should be monitored closely if they experience peeling or blistering skin, or unusual tiredness or weakness because these complications can precede more serious reactions such as exfoliative dermatitis, toxic epidermal necrolysis, or Stevens-Johnson syndrome. Some patients report photosensitivity reactions. Trimethoprim has been associated with hyperkalemia. Trimethoprim may inhibit sodium channels in the renal distal tubules resulting in decreased in urinary excretion of potassium. Trimethoprim may cause a significant, reversible increase in serum creatinine after 7 to 14 days of treatment. Tubular secretion of creatinine is inhibited by trimethoprim; however, other markers of renal function (e.g., glomerular filtration) are not affected. Creatinine clearance increases rapidly after trimethoprim is discontinued. In addition, trimethoprim has been associated with elevations in BUN (e.g., azotemia). Use of trimethoprim for the treatment of urinary tract infections in women has been associated with the development of vaginal candidiasis. Other adverse reactions that have been reported with use of trimethoprim include fever, elevated hepatic enzymes, hyperbilirubinemia, and hyponatremia.

 

188. Kinzie BJ, Taylor JW. Trimethoprim and folinic acid. Ann Intern Med 1984;101:565.

Trimethoprim Primsol™, Proloprim®, Trimpex® | Trimpex®, Proloprim® | Primsol™

968. Medina I, Mills J, Leoung G et al. Oral therapy for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. N Engl J Med 1990;323:776—82.

510. DuPont HL, Ericsson CD. Prevention and treatment of traveler's diarrhea. N Engl J Med 1993;328:1821—6.

188. Kinzie BJ, Taylor JW. Trimethoprim and folinic acid. Ann Intern Med 1984;101:565.