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Trimethoprim-Sulfamethoxazole
INFECTIONS AND ANTIBIOTICS
application on the intravenous catheter sites, the prevention of infections of myelomeningocele sacs, as an aerosolized polymyxin B for the prevention of the tracheobronchial colonization with gram-negative organisms of patients in intensive care units and as bladder irrigation with the use of neomycin and polymyxin B for the prevention of cystitis. There is in vitro synergy among trimethoprim, sulfamethoxazole and polymyxin B. This combination has been used for the treatment of multiple drugresistant Serratia. F. T.A. 92 references
Trimethoprim-Sulfamethoxazole
L. G.
SMITH AND J. SENSAKOVIC, Department of Infectious Diseases, St. Michael's Medical Center and New Jersey Medical School, Newark, New Jersey
Med. Clin. N. Amer., 66: 143-156 (Jan.) 1982 Trimethoprim-sulfamethoxazole is an antimicrobial combination drug of a fixed proportion of the diaminopyrimidine trimethoprim and the sulfonamide sulfamethoxazole. This combination was introduced in the United States in 1973 under the trade names of Bactrim and Septra. It is available in tablets containing 80 mg. trimethoprim and 400 mg. sulfamethoxazole, double strength tablets with 160 mg. trimethoprim and 800 mg. sulfamethoxazole, a pediatric suspension with 40 mg. trimethoprim and 200 mg. sulfamethoxazole per 5 ml. and an intravenous infusion with 80 mg. trimethoprim and 400 mg. sulfamethoxazole per 5 ml. In vitro studies showed that the trimethoprim and sulfamethoxazole combination is more active than either drug alone. Trimethoprim-sulfamethoxazole inhibits sequential steps in the synthesis of tetrahydrofolic acid, an essential metabolic cofactor in bacterial synthesis of purine and, subsequently, deoxyribonucleic acid. Trimethoprim and sulfamethoxazole are each bacteriostatic but sequential synergistic effect of the 2 drugs has been shown to exhibit bactericidal activity. Trimethoprim and sulfamethoxazole are extremely well absorbed from the upper intestinal tract. An oral dose of 160 mg. trimethoprim will give a peak serum level of 2 µg./ml. after 2 hours with a half-life of 13 hours. An oral dose of 1,200 mg. sulfamethoxazole will give a peak serum level of 60 µg./ml. after 2 hours with a half-life of about 12 hours. Approximately 44 per cent of trimethoprim and 70 per cent of sulfamethoxazole are protein-bound in the blood. Both drugs pass through the placenta and blood-brain barrier in the range of therapeutic effectiveness and are excreted in breast milk. About 50 per cent of trimethoprim and 30 per cent of sulfamethoxazole are excreted in the urine unchanged and the rest is excreted as acetylated or other metabolized forms. Because of the lipotrophic properties of trimethoprim its concentration in prostatic fluid is about 3 times greater than in serum. Also, aqueous humor, sputum, vaginal secretions, pleural fluid, bile and almost all tissues achieve a higher trimethoprim level than in the serum. Sulfamethoxazole levels in most tissues tend to be lower than the serum level. Renal excretions of trimethoprim and sulfamethoxazole occur by glomerular filtration and tubular secretion. In cases of renal failure dosage of trimethoprimsulfamethoxazole, more so for sulfamethoxazole, should be adjusted. Trimethoprim and sulfamethoxazole are not recommended for creatinine clearance <15 ml. per minute unless careful monitoring of the blood levels is available. Trimethoprim and sulfamethoxazole are removed effectively by dialysis. Trimethoprim and sulfamethoxazole are most active in vitro
875
and in vivo against the facultative gram-negative bacilli of the Enterobacteriaceae family. There is no cross-resistance between these 2 drugs. Trimethoprim and sulfamethoxazole are approved by the Food and Drug Administration for the treatment of chronic and recurrent urinary tract infections due to Escherichia coli, Klebsiella, Enterobacter, Proteus mirabilis and Proteus morgani. These drugs remove Enterobacteriaceae from the bowel without the selection of resistant flora, while achieving excellent antimicrobial concentrations in the kidney, urine, prostate and vagina. The development of resistant strains has not been a major problem even with prolonged use of trimethoprim-sulfamethoxazole. These drugs are effective even in cases of severe renal insufficiency but renal functions must be monitored constantly during prolonged therapy in patients with renal failure. One of the most effective means of preventing recurrent urinary tract infections, especially in sexually active women, is the use of half of a tablet (40 mg. trimethoprim and 200 mg. sulfamethoxazole) given every other night with the purpose of suppressing the vaginal flora before entering the urethra. Trimethoprim and sulfamethoxazole have not been approved for use in pregnancy. Many urologists prefer trimethoprim-sulfamethoxazole as the treatment of choice in prostatitis even though it is not approved by the Food and Drug Administration because of good penetration of the prostate. This is owing to the lipid solubility and low protein binding of trimethoprim, which accumulates in the prostate at twice the serum concentration. Although trimethoprim-sulfamethoxazole cures most cases of acute prostatitis up to 60 per cent relapse occurs once the drug is stopped. This is attributable, in part, to the higher pH of spermatic fluid in cases of chronic prostatitis, which inactivates trimethoprim. Trimethoprim-sulfamethoxazole is extremely effective in the treatment of acute otitis media caused by Hemophilus influenzae or Staphylococcus pneumoniae and against Shigella flexneri and Shigella sonnei. They have been effective in acute cystitis in children, in treating and preventing infections caused by Pneumocystis carinii, as prophylactic treatment in acute leukemia, in transplant patients when cytomegalovirus is present, as a treatment of choice for nocardial infections and an excellent back-up drug in the treatment of salmonellosis. There are other uses of trimethoprimsulfamethoxazole, such as prophylaxis of infection in the neutropenic patient, venereal diseases, in the treatment of acute exacerbations and prophylaxis of chronic bronchitis, in isolated cases of brucellosis, plague, melioidosis, infections due to Serratia, Klebsiella and Pseudomonas cepacia, in Vibrio cholera, toxoplasmosis, malaria, mycetoma (Madura foot), South American blastomycosis and infections caused by Petriellidum boydii and Mycobacterium marinum. The most common toxic effects of trimethoprim-sulfamethoxazole are skin lesions and upper gastrointestinal symptoms but these are reversible. Other less common toxic effects are on the bone marrow, potentiates warfarin and oral hypoglycemic compounds, prolongs the life of diphenylhydantoin and produces thrombocytopenia, especially when combined with thiazide diuretics. Trimethoprim alone has an extremely high level in the urine sufficient to eliminate most Enterobacteriaceae. There is no statistical difference between the use of trimethoprim-sulfamethoxazole and trimethoprim alone in the treatment of urinary tract infections, except when there is a chronic infection with structural abnormalities. Another reason for using trimethoprim alone is the problem of sensitivity to sulfamethoxazole and toxic side effects, which are fewer with trimethoprim. F. T.A. 1 figure, 2 tables, 143 references
application on the intravenous catheter sites, the prevention of infections of myelomeningocele sacs, as an aerosolized polymyxin B for the prevention of the tracheobronchial colonization with gram-negative organisms of patients in intensive care units and as bladder irrigation with the use of neomycin and polymyxin B for the prevention of cystitis. There is in vitro synergy among trimethoprim, sulfamethoxazole and polymyxin B. This combination has been used for the treatment of multiple drugresistant Serratia. F. T.A. 92 references
Trimethoprim-Sulfamethoxazole
L. G.
SMITH AND J. SENSAKOVIC, Department of Infectious Diseases, St. Michael's Medical Center and New Jersey Medical School, Newark, New Jersey
Med. Clin. N. Amer., 66: 143-156 (Jan.) 1982 Trimethoprim-sulfamethoxazole is an antimicrobial combination drug of a fixed proportion of the diaminopyrimidine trimethoprim and the sulfonamide sulfamethoxazole. This combination was introduced in the United States in 1973 under the trade names of Bactrim and Septra. It is available in tablets containing 80 mg. trimethoprim and 400 mg. sulfamethoxazole, double strength tablets with 160 mg. trimethoprim and 800 mg. sulfamethoxazole, a pediatric suspension with 40 mg. trimethoprim and 200 mg. sulfamethoxazole per 5 ml. and an intravenous infusion with 80 mg. trimethoprim and 400 mg. sulfamethoxazole per 5 ml. In vitro studies showed that the trimethoprim and sulfamethoxazole combination is more active than either drug alone. Trimethoprim-sulfamethoxazole inhibits sequential steps in the synthesis of tetrahydrofolic acid, an essential metabolic cofactor in bacterial synthesis of purine and, subsequently, deoxyribonucleic acid. Trimethoprim and sulfamethoxazole are each bacteriostatic but sequential synergistic effect of the 2 drugs has been shown to exhibit bactericidal activity. Trimethoprim and sulfamethoxazole are extremely well absorbed from the upper intestinal tract. An oral dose of 160 mg. trimethoprim will give a peak serum level of 2 µg./ml. after 2 hours with a half-life of 13 hours. An oral dose of 1,200 mg. sulfamethoxazole will give a peak serum level of 60 µg./ml. after 2 hours with a half-life of about 12 hours. Approximately 44 per cent of trimethoprim and 70 per cent of sulfamethoxazole are protein-bound in the blood. Both drugs pass through the placenta and blood-brain barrier in the range of therapeutic effectiveness and are excreted in breast milk. About 50 per cent of trimethoprim and 30 per cent of sulfamethoxazole are excreted in the urine unchanged and the rest is excreted as acetylated or other metabolized forms. Because of the lipotrophic properties of trimethoprim its concentration in prostatic fluid is about 3 times greater than in serum. Also, aqueous humor, sputum, vaginal secretions, pleural fluid, bile and almost all tissues achieve a higher trimethoprim level than in the serum. Sulfamethoxazole levels in most tissues tend to be lower than the serum level. Renal excretions of trimethoprim and sulfamethoxazole occur by glomerular filtration and tubular secretion. In cases of renal failure dosage of trimethoprimsulfamethoxazole, more so for sulfamethoxazole, should be adjusted. Trimethoprim and sulfamethoxazole are not recommended for creatinine clearance <15 ml. per minute unless careful monitoring of the blood levels is available. Trimethoprim and sulfamethoxazole are removed effectively by dialysis. Trimethoprim and sulfamethoxazole are most active in vitro
875
and in vivo against the facultative gram-negative bacilli of the Enterobacteriaceae family. There is no cross-resistance between these 2 drugs. Trimethoprim and sulfamethoxazole are approved by the Food and Drug Administration for the treatment of chronic and recurrent urinary tract infections due to Escherichia coli, Klebsiella, Enterobacter, Proteus mirabilis and Proteus morgani. These drugs remove Enterobacteriaceae from the bowel without the selection of resistant flora, while achieving excellent antimicrobial concentrations in the kidney, urine, prostate and vagina. The development of resistant strains has not been a major problem even with prolonged use of trimethoprim-sulfamethoxazole. These drugs are effective even in cases of severe renal insufficiency but renal functions must be monitored constantly during prolonged therapy in patients with renal failure. One of the most effective means of preventing recurrent urinary tract infections, especially in sexually active women, is the use of half of a tablet (40 mg. trimethoprim and 200 mg. sulfamethoxazole) given every other night with the purpose of suppressing the vaginal flora before entering the urethra. Trimethoprim and sulfamethoxazole have not been approved for use in pregnancy. Many urologists prefer trimethoprim-sulfamethoxazole as the treatment of choice in prostatitis even though it is not approved by the Food and Drug Administration because of good penetration of the prostate. This is owing to the lipid solubility and low protein binding of trimethoprim, which accumulates in the prostate at twice the serum concentration. Although trimethoprim-sulfamethoxazole cures most cases of acute prostatitis up to 60 per cent relapse occurs once the drug is stopped. This is attributable, in part, to the higher pH of spermatic fluid in cases of chronic prostatitis, which inactivates trimethoprim. Trimethoprim-sulfamethoxazole is extremely effective in the treatment of acute otitis media caused by Hemophilus influenzae or Staphylococcus pneumoniae and against Shigella flexneri and Shigella sonnei. They have been effective in acute cystitis in children, in treating and preventing infections caused by Pneumocystis carinii, as prophylactic treatment in acute leukemia, in transplant patients when cytomegalovirus is present, as a treatment of choice for nocardial infections and an excellent back-up drug in the treatment of salmonellosis. There are other uses of trimethoprimsulfamethoxazole, such as prophylaxis of infection in the neutropenic patient, venereal diseases, in the treatment of acute exacerbations and prophylaxis of chronic bronchitis, in isolated cases of brucellosis, plague, melioidosis, infections due to Serratia, Klebsiella and Pseudomonas cepacia, in Vibrio cholera, toxoplasmosis, malaria, mycetoma (Madura foot), South American blastomycosis and infections caused by Petriellidum boydii and Mycobacterium marinum. The most common toxic effects of trimethoprim-sulfamethoxazole are skin lesions and upper gastrointestinal symptoms but these are reversible. Other less common toxic effects are on the bone marrow, potentiates warfarin and oral hypoglycemic compounds, prolongs the life of diphenylhydantoin and produces thrombocytopenia, especially when combined with thiazide diuretics. Trimethoprim alone has an extremely high level in the urine sufficient to eliminate most Enterobacteriaceae. There is no statistical difference between the use of trimethoprim-sulfamethoxazole and trimethoprim alone in the treatment of urinary tract infections, except when there is a chronic infection with structural abnormalities. Another reason for using trimethoprim alone is the problem of sensitivity to sulfamethoxazole and toxic side effects, which are fewer with trimethoprim. F. T.A. 1 figure, 2 tables, 143 references