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Synopsis: Co-trimoxazole1 (trimethoprim-sulfamethoxazole) is a ‘broad spectrum’ antimicrobial which is active in vitro against a wide variety of micro-organisms. Clinical experience with this agent now spans a decade or more in many countries. While it is clearly established as the agent of first choice only in Pneumocystis carinii infections, it is effective in many other infectious diseases. Thus, it has been shown to be effective in acute and persistent or recurrent urinary tract infections (treatment and prophylaxis), ear, nose and throat infections (including β-lactamase producing H. influenzae), acute exacerbations of chronic bronchitis, enteric fever, gonorrhoea, prophylaxis in neutropenic patients, and in several other less well established areas of possible usefulness. Recent availability of a parenteral preparation has further expanded the potential clinical application of the drug.
Co-trimoxazole has made an important contribution to the treatment of infectious diseases, and will continue to do so for some time to come, as additional clinical experience and newer developments further clarify its optimum role in antimicrobial chemotherapy, with better definition of the role of the combination preparation versus its individual components.
Pharmacodynamic Properties: Co-trimoxazole is a ‘broad spectrum’ antimicrobial agent. In vitro it is active against a wide range of organisms including Gram-positive and -negative aerobic bacteria, chlamydia, Nocardia (actinomycetes), some mycobacteria and protozoa and many anaerobic bacteria. Organisms not susceptible to co-trimoxazole include Mycobacterium tuberculosis, Treponema pallidum, Pseudomonas aeruginosa and Mycoplasma species. Against most Gram-negative bacteria the activity of co-trimoxazole exceeds that of ampicillin and is comparable to that of chloramphenicol.
Synergy or a summation effect between the 2 components (trimethoprim and sulphamethoxazole in a 1: 5 ratio) has been demonstrated both in vitro and in animals in most studies investigating this consideration, although whether or not synergy occurs under clinical conditions is less clear. For most organisms the optimum ratio for maximum potentiation is about 1: 20 (trimethoprim: sulphamethoxazole), which is the approximate ratio present in plasma after administration of the standard formulation. However, some potentiation can be demonstrated in vitro over a wide range of ratios, analogous to the wide range found in various body fluids.
Co-trimoxazole exerts its antimicrobial effect by inhibiting synthesis of tetrahydrofolic acid, the metabolically active form of folic acid. Sulphamethoxazole acts primarily through inhibiting synthesis of dihydrofolic acid, while trimethoprim acts as a competitive inhibitor of dihydrofolate reductase, the final enzyme in the pathway to tetrahydrofolic acid. It appears that the major net effect of this action is inhibition of thymidine synthesis.
In vitro, resistance to trimethoprim alone can be produced by serial passage techniques. The clinical relevance of these findings is uncertain since the chromosomal resistance to trimethoprim seen in clinical strains is not usually due to the type of resistance selected in vitro by serial passage, but development of resistance in this manner by sulphonamidesensitive organisms is delayed or prevented with the addition of a sulphonamide to trimethoprim. Bacterial clinical isolates may display either intrinsic or acquired resistance to co-trimoxazole, and acquired resistance may be chromosomally mediated or involve R-factor plasmids.
Effects on faecal flora have usually included a major reduction or elimination of Enterobacteriaceae, but little effect on anaerobic flora. During chronic therapy such changes persist, but without overgrowth of Pseudomonas species or resistant Enterobacteriaceae; however, overgrowth by yeasts may occur.
Pharmacokinetic Properties: Both trimethoprim and sulphamethoxazole are well absorbed after oral administration. Peak blood concentrations after a single standard adult dose (trimethoprim 160mg, sulphamethoxazole 800mg) are about 1 to 2 gmg/ml for trimethoprim and 30 to 50 μg/ml for free sulphamethoxazole. Steady-state blood levels, achieved in adults in 2 to 3 days with a standard dose regimen, are about 50% higher. Trimethoprim is more widely distributed to body tissues than is sulphamethoxazole, producing a wide range of trimethoprim: sulphamethoxazole concentration ratios in various body tissues and fluids. The concentration of trimethoprim equals or exceeds the simultaneous plasma concentration in several tissues or fluids (saliva, intracellular fluid, breast milk, prostatic tissue, sputum, lung tissue, vaginal secretions and urine), while sulphamethoxazole tissue and fluid concentrations are considerably lower than plasma concentrations with the exception of urine concentrations which are higher. Both components of the drug are bound to plasma proteins to a similar extent (about 45 and 66% for trimethoprim and sulphamethoxazole respectively).
Trimethoprim is excreted in the urine primarily in unchanged form, while sulphamethoxazole is excreted primarily as inactive metabolites. The elimination half-life of trimethoprim is about 11 hours and that of sulphamethoxazole is about 9 hours. In the presence of severe renal failure sulphamethoxazole metabolites may accumulate, and dosage adjustments are required. In infants the elimination half-life of both drugs is longer than in the adult, but in children it may be shorter. There may be some reduction in clearance in the elderly, but important prolongation of half-life does not occur.
Therapeutic Use: Comparative studies have shown co-trimoxazole to be an effective treatment for both acute and persistent or recurrent urinary tract infections, even in patients with severe renal impairment. A single dose is often effective in uncomplicated bacterial cystitis. It is also effective in the prophylaxis of urinary tract infection. For these indications it is at least as effective as ampicillin, amoxycillin, cephalosporins or other commonly used agents such as nalidixic acid or nitrofurantoin. However, with the possible exception of chronic urinary tract infections, it appears that trimethoprim alone is as effective as the combination product in this area of use.
In ear, nose and throat infections co-trimoxazole is generally comparable in efficacy to ampicillin or amoxycillin, and importantly is highly effective against β-lactamase producing Haemophilus influenzae.
In the treatment or prevention of acute exacerbations of bronchitis co-trimoxazole is at least as effective as other frequently used drugs such as ampicillin, amoxycillin or various tetracyclines. It is also effective in Gram-negative pneumonias.
Co-trimoxazole is extremely effective in treating gonorrhoea when given for several days, but single dose or single day regimens may be unsatisfactory in the presence of relatively resistant strains of Neisseria gonorrhoeae. Variable results have been reported in non-gonococcal urethritis, and there are no studies comparing co-trimoxazole with tetracycline or erythromycin in this condition. The drug is not effective in treating syphilis.
Co-trimoxazole is effective in a number of enteric infections. It is a particularly useful alternative possibility (to chloramphenicol, parenteral ampicillin or oral amoxycillin) in Salmonella typhi infection, and a 5-day course is effective in acute shigellosis in adults or children.
In Pneumocystis carinii infections co-trimoxazole is the agent of first choice, with about two-thirds of patients responding. It also seems useful prophylactically in ‘lower’ doses in high risk patients to prevent Pneumocystis carinii infection.
In neutropenic patients co-trimoxazole (alone or in combination) may offer a useful alternative to non-absorbable oral antibiotics for prophylactic use in preventing or minimising infections. However, the possible effects of long term administration of co-trimoxazole (e.g. during bone marrow recovery following intensive cytotoxic therapy) needs further clarification.
Limited experience in some other areas of use, such as meningitis, nocardiosis, soft tissue or bone infections and acne have been encouraging, but such findings need further study before definitive statements of efficacy can be made.
Adverse Effects: The most common adverse reactions to co-trimoxazole are skin eruptions and mild gastrointestinal symptoms, each occurring in up to about 3% of patients. Haematological abnormalities, including thrombocytopenia, leucopenia or agranulocytosis, anaemia, eosinophilia or sulphaemoglobinaemia occur in less than 0.5% of adult patients. Haematological effects reported in children to date have not been clinically important. Patients with known folic acid or vitamin B12 deficiency are at increased risk of the antifolic acid effects of the drug. A predictable slight increase in serum creatinine and decrease in creatinine clearance occurs with co-trimoxazole administration, and rarely (usually in patients with underlying kidney disease) true renal dysfunction or renal failure may develop. Adverse hepatic effects (hepatitis, hepatic necrosis, intrahepatic cholestasis) have been reported in a few patients, as have serious cutaneous eruptions and other allergic reactions. As might be expected, trimethoprim used alone produces a lower overall incidence of side effects than co-trimoxazole.
Dosage and Administration: The usual recommended adult dosage is 2 standard tablets (trimethoprim 160mg, sulphamethoxazole 800mg) twice daily, but this can be increased in severe infections. In children the usual oral dose is trimethoprim 4 mg/kg, sulphamethoxazole 20 mg/kg given twice daily. The drug can also be given parenterally if necessary, by intramuscular injection (intramuscular preparation available in some countries) or intravenous infusion. In the presence of severe renal failure dosage should be reduced. (For detailed recommended dosage information on specific dosage forms the clinician should consult the product literature.)
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