sulfamethoxazole + trimethoprim




Full Prescribing Info
Co-trimoxazole: Sulfamethoxazole, trimethoprim.
Each pediatric tablet contains trimethoprim 20 mg and sulfamethoxazole 400 mg.
Each adult tablet contains trimethoprim 80 mg, and sulfamethoxazole 400 mg.
Pharmacology: Apo-Sulfatrim is a 1:5 combination of the antibacterial agents trimethoprim and sulfamethoxazole, which act sequentially in two successive steps in the biosynthesis of nucleic acids.
Trimethoprim is a selective inhibitor of dihydrofolate reductase, the enzyme which reduces dihydrofolic acid to its tetrahydro form. This biochemical step is essential in the production of the folate coenzymes which are involved in the biosynthesis of thymine, purine, serine and methionine. Sulfamethoxazole exerts its antibacterial activity by competing with PABA (para-aminobenzoic acid).
Most pathogenic bacteria meet their need for dihydrofolic acid by synthesizing it from PABA, pteridine and glutamic acid. Animals, in contrast, depend on exogenous sources for their folic acid need and do not rely upon intracellular synthesis.
Under usual circumstances, sulfamethoxazole or trimethoprim acting alone does not pro­duce a complete block in this biosynthesis of nucleic acids. Instead, they cause sufficient reduction in the synthesis of folate coenzymes to produce bacteriostasis. When the two agents act together, tha superimposition of their effects produces a virtually complete block in the synthesis, leading to the organism's death. This dual action is synergistic and reduces the minimum inhibitory concentrations (MIC) of each agent, thus converting a bacteriostatic action to a bactericidal action. The susceptibility of sulfonamide-resistant strains to sulfamethoxazole may be enhanced by trimethoprim.
Since sulfamathoxazole affects only the de novo synthesis of dihydrofolic acid by bacterial, it does not affect folate metabolism of animals. Since in animals, as in bacteria, the folates have to be recycled to the active form by dihydrofolate reductase, trimethoprim could be expected to affect mammalian folate metabolism. However, trimethoprim has a low toxicity for animals and a high toxicity for bacteria, since its affinity for the dihydrofolate reductase of bacteria is some 40,000 times greater than for the corresponding mammalian enzyme.
Both trimethoprim and sulfamethoxazole are rapidly absorbed following oral administration; detectable blood concentrations of both drugs are attained in about 5 minutes, and significant blood concentrations are reached within 1 hour. Peak blood concentrations for both components are usually attained in 2 to 4 hours.
The biological half-life of trimethoprim has been calculated to be 10 hours, this corresponds well with the half-life of sulfamethoxazole, which has been determined to be 9 to 11 hours.
Approximately 40 to 50% of orally ingested trimethoprim is excreted unchanged in the urine within 24 hours; very little appears in the feces. Approximately 10% of the excreted drug is in the form of metabolites with little or no antibacterial activity.
About 60% of orally ingested sulfamethoxazole is excreted in the urine within 48 hours. Approximately half of the excreted drug is the N4 acetylated derivative, a fifth is the N4 conjugate, a sixth is the unchanged compound, and about a tenth is another N4-free compound.
Detoxication sites: trimethoprim (liver); sulfamethoxazole (liver, kidney).
Gram-negative organisms generally responsive to Apo-Sulfatrim therapy include: H. lnfluenzae, N. gonorrhoeae, E.coli, Klebsiella species, Enterobacter (Aerobacter) aerogenes, P. mirabilis, P. vulgaris, S. typhi, S. paratyphi, S. typhimurium, S. enteritidis and Shigella species.
Gram-positive organisms generally responsive to Apo-Sulfatrim therapy include: Strep. pyogenes, Strep. viridans, Staph. albus, Staph. aureus and D. pneumoniae.
Perform sensitivity tests wherever possible to determine choice of therapy. Repeat these tests if there is failure to respond, relapse, or early recurrence.
The treatment of: chronic urinary tract infections due to susceptible organisms; typhoid fever resistant to both chloramphenicol and ampicillin; acute exacerbations of chronic lower respiratory tract infection unresponsive to ampicillin or tetracycline; infants and children with a diagnosis of Pneumocystitis carnii pneumonitis, especially if they are immunosuppressed.
There is evidence that Apo-Sulfatrim may also be useful in the following infections caused by susceptible strains of the organisms listed in previous text (see Pharmacology under Actions): acute, recurrent urinary tract infections; genital tract infections, uncomplicated gonococcal urethritis; upper and lower respiratory tract infections, particularly chronic bronchitis, and including otitis media; gastrointestinal infections; skin and soft tissue infections.
Apo-Sulfatrim is not indicated in infections associated with Pseudomonas, Mycoplasma or viruses. It has not yet been fully evaluated in streptococcal infections.
Dosage/Direction for Use
Adults and children over 12 years of age: Standard dosage: 2 adult tablets tablet twice daily (morning and evening).
Minimum dosage and dosage for long term treatment: 1 adult tablet twice daily.
Maximum dosage (overwhelming infections): 3 adult tablets twice daily.
Gonorrhea (uncomplicated): 2 adult tablets tablet 4 times daily for 2 days.
Children 6 to 12 years: 1 adult tablet or 2 to 4 pediatric tablets twice daily.
Children 2 to 5 years: 1 to 2 pediatric tablets twice daily.
In children, this corresponds to an approximate dose of 8 mg trimethoprim/kg body weight/day, plus 30 mg sulfamethoxazole/kg body weight/day, divided into 2 equal doses.
Continue therapy for at least 5 days in acute infections or until the patient is asymptomatic for at least 48 hours. If the drug has to be given for protracted periods, consider a dosage reduction.
Acute urinary tract infections: 2 adult tablets twice daily until urine is sterile. Patients with a history of chronic reinfection: 1 adult tablet twice daily for prophylaxis.
For chest infections, adequate dosage is important in order to maintain high sputum con­centrations. Satisfactory results in acute exacerbations of chronic bronchitis have been reported with 2 adult tablets tablet twice daily; but in patients with advanced disease, better results may be obtained with 3 adult tablet twice daily. Continue the drug for 2 days following eradication of purulent sputum. In chronic chest lnfections, 1 adult tablet twice daily may be adequate for prophylaxis, but in some patients 2 adult tablets tablet twice daily may be necessary.
Acute salmonellosis: 2 adult tablets tablet twice daily, continue for at least 7 days after defervescence.
Carriers: 1 adult tablet twice daily until repeated stool cultures are negative.
20 mg trimethoprim/kg body weight/day and 100 mg sulfamethoxazole/kg body weight /day in 4 divided doses continued for at least 14 days.
With respect to bioavailability and pharmacokinetics, no difference was noted following administration of 2 adult tablets tablet, this was further confirmed by statistical evaluation.
Treatment: Gastric lavage and/or emesis. Force fluids orally or parenterally if renal function is normal. In extreme overdosage in patients with impaired renal function, consider dialysis as a means of eliminating the compound from the blood and reducing the risk of uremia; both drugs are readily dialyzable. No known antidote for sulfonamide poisoning exists; however, calcium folinate (3 to 6 mg intramuscularly for 5 to 7 days) is an effective antidote for adverse effects in the hemopoietic system caused by trimethoprim.
Marked liver parenchymal damage, blood dyscrasia, known hypersensitivity to trimethoprim or sulfonamides.
Marked renal impairment where repeated serum assays cannot be carried out.
Premature or newborn babies during the first few weeks of life.
Pregnancy: If pregnancy cannot be excluded, weigh the possible risks of therapy against the expected effect.
Special Precautions
Make a critical appraisal of benefit versus risk in patients with liver damage, renal damage, urinary obstruction, blood dyscrasias, allergies or bronchial asthma.
In patients with renal impairment, administer a reduced or less frequent dosage to avoid accumulation of trimethoprim in the blood. Non-ionic diffusion is the main factor in the renal handling of trimethoprim, and as renal failure advances, trimethoprim excretion decreases.
Do not use Apo-Sulfatrim when the serum creatinine concentration exceeds 2 mg/100 ml.
There is an increased risk of adverse reactions in elderly patients, in particular blood disorders and adverse renal hepatic reactions.
Because of possible interference with folate metabolism, conduct regular blood counts in patients on long term therapy. In those predisposed to folate deficiency (i.e. the elderly, chronic alcoholics and rheumatoid arthritics). In malabsorption syndromes, malnutrition states, or during the treatment of epilepsy with anticonvulsant drugs (diphenylhydantoin, primidone or barbiturates). Changes indicative of folic acid impairment have, in certain specific situations, been reversed by folic acid therapy.
The possibility or superinfection with non-sensitive organism should be borne in mind.
Use In Pregnancy & Lactation
This drug is contraindicated during pregnancy, if pregnancy cannot be excluded, weigh the possible risks of therapy against the expected effect.
Adverse Reactions
Hematological changes have been observed in some patients, particularly the elderly. The great majority of these changes were mild, asymptomatic, and proved reversible on withrawal of the drug; in some instances, this was necessary before therapy could be completed. The reported changes consist primarily of neutropenia and thrombocytopenia. Observed less frequently: leukopenia, aplastic and hemolytic anemia, purpura, agranulocytosis and bone marrow depression.
Other adverse effects which have been observed most frequently to date include: nausea, vomiting, gastric intolerance and skin rash. Those of less frequent occurence include: diarrhoea, constipation, flatulence, anorexia, pyrosis, gastritis, gastroenteritis, urticaria, headache and liver changes (as indicated by abnormal elevations in alkaline phosphatase and serum transaminase concentrations). There has also been an occasional report of the following adverse effects: erythema, edema, pruritus, toxicoderma, photosensitivity, glossitis, stomatitis, dyspepsia, dry mouth, dysuria, oliguria, anuria, hematuria, urgency, dyspnea, tremor, vertigo, tiredness, jaundice, vision troubles, drug fever, alopecia, epistaxis, kidney changes (as indicated by abnormal elevations in BUN, blood NPN, serum creatinine and urine protein concentrations) and anaphylactoid reactions (sweating and collapse).
Drug Interactions
Sulfonylurea oral hypoglycemics and methotrexate may increase the antibacterial activity of sulfamethoxazole. PABA or its derivatives antagonize sulfamethoxazole. Increased sulfamethoxazole blood concentrations may occur in patients who are also recieving urinary acidifiers, oral anticoagulants, phenylbutazone, oxyphenbutazonone, indomethacin, sulfinpyrazone or salicylates. With regard to plasma folate, it is theoretically possible that folate administration could result in impairment of Apo-Sulfatrim antibacterial activity.
Urinary, hepatic and hematopoietic laboratory tests may be interfered with.
Caution For Usage
Incompatibilities: None known.
Store in a cool dry place. Protect from light.
ATC Classification
J01EE01 - sulfamethoxazole and trimethoprim ; Belongs to the class of combinations of sulfonamides and trimethoprim, including derivatives. Used in the systemic treatment of infections.
Pediatric tab 100/20 mg (white, cylindrical, biplane, single-scored on one side) x 100's. Tab 400 mg/80 (round biconvex, white, plain on on one side with score on the other) x 1,000's.
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