t rather than the combination. acute otitis media: for the treatment of acute otitis media in pediatric patients due to susceptible strains of pneumoniae or haemophilus influenzae when in the judgment of the physician sulfamethoxazole and trimethoprim offers some advantage over the use of other antimicrobial agents. to date, there are limited data on the safety of repeated use of sulfamethoxazole and trimethoprim in pediatric patients under two years of age. sulfamethoxazole and trimethoprim is not indicated for prophylactic or prolonged administration in otitis media at any age. acute exacerbations of chronic bronchitis in adults: for the treatment of acute exacerbations of chronic bronchitis due to susceptible strains of streptococcus pneumoniae or haemophilus influenzae when in the judgment of the physician sulfamethoxazole and trimethoprim offers some advantage over the use of a single antimicrobial agent. shigellosis: for the treatment of enteritis caused by susceptible strains of shigella flexneri and shigella sonnei when antibacterial therapy is indicated. pneumocystis carinii pneumonia: for the treatment of documented pneumocystis carinii pneumonia and for prophylaxis against pneumocystis carinii pneumonia in individuals who are immunosuppressed and considered to be at an increased risk of developing pneumocystis carinii pneumonia. traveler’s diarrhea in adults: for the treatment of traveler’s diarrhea due to susceptible strains of enterotoxigenic e. coli.

should not be used for the treatment of group a - b hemolytic streptococcal infections. in an established infection, they will not eradicate the streptococcus and, therefore, will not prevent sequelae such as rheumatic fever. clostridium difficile associated diarrhea (cdad) has been reported with use of nearly all antibacterial agents, including sulfamethoxazole and trimethoprim tablets, and may range in severity from mild diarrhea to fatal colitis. treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of c. difficile a . c. difficile produces toxins a and b which contribute to the development of cdad. hypertoxin producing strains of c. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. cdad must be considered in all patients who present with diarrhea following antibiotic use. careful medical history is necessary since cdad has been reported to occur over two months after the administration of antibacterial agents a . if cdad is suspected or confirmed, ongoing antibiotic use not directed against c. difficile may need to be discontinued. appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of c. difficile, and surgical evaluation should be instituted as clinically indicated a .

2 or 1 double strength tablet for patients with impaired renal function: when renal function is impaired, a reduced dosage should be employed using the following table: creatinine recommended clearance (ml/min) dosage regimen above 30 usual standard regimen 15-30 1/2 the usual regimen below 15 use not recommended acute exacerbations of chronic bronchitis in adults: the usual adult dosage in the treatment of acute exacerbations of chronic bronchitis is 1 sulfamethoxazole and trimethoprim double strength tablet or 2 sulfamethoxazole and trimethoprim tablets every 12 hours for 14 days. pneumocystis carinii pneumonia: treatment: adults and children r : the recommended dosage for patients with documented pneumocystis carinii pneumonia is 75 to 100 mg/kg sulfamethoxazole and 15 to 20 mg/kg trimethoprim per 24 hours given in equally divided doses every 6 hours for 14 to 21 days11. the following table is a guideline for the upper limit of this dosage. weight dose – every 6 hours lb kg tablets 18 8 - 35 16 1 53 24 1 ½ 70 32 2 or 1 double strength tablet 88 40 2 ½ 106 48 3 or 1 ½ double strength tablets 141 64 4 or 2 double strength tablets 176 80 5 or 2 ½ double strength tablets for the lower limit dose (75 mg/kg sulfamethoxazole and 15 mg/kg trimethoprim per 24 hours) administer 75% of the dose in the above table. prophylaxis: adults: the recommended dosage for prophylaxis in adults is 1 sulfamethoxazole and trimethoprim double strength tablet daily 12r children r : for children r , the recommended dose is 750 mg/m 2 /day sulfamethoxazole with 150 mg/m 2 /day trimethoprim given orally in equally divided doses twice a day, on 3 consecutive days per week. the total daily dose should not exceed 1600 mg sulfamethoxazole and 320 mg trimethoprim 13r the following table is a guideline for the attainment of this dosage in children r : body surface area dose – every 12 hours (m 2 ) tablets 0.26 - 0.53 ½ 1.06 1 traveler’s diarrhea in adults: for the treatment of traveler’s diarrhea, the usual adult dosage is 1 sulfamethoxazole and trimethoprim double strength tablet or 2 sulfamethoxazole and trimethoprim tablets every 12 hours for 5 days.

tion, pruritus, urticaria and rash. in addition, periarteritis nodosa and systemic lupus erythematosus have been reported. gastrointestinal: hepatitis (including cholestatic jaundice and hepatic necrosis), elevation of serum transaminase and bilirubin, pseudomembranous enterocolitis, pancreatitis, stomatitis, glossitis, nausea, emesis, abdominal pain, diarrhea, anorexia. genitourinary: renal failure, interstitial nephritis, bun and serum creatinine elevation, toxic nephrosis with oliguria and anuria, crystalluria and nephrotoxicity in association with cyclosporine. metabolic and nutritional: hyperkalemia (see precautions: use in the treatment of and prophylaxis for pneumocystis carinii pneumonia in patients with acquired immunodeficiency syndrome (aids). neurologic: aseptic meningitis, convulsions, peripheral neuritis, ataxia, vertigo, tinnitus, headache. psychiatric: hallucinations, depression, apathy, nervousness. endocrine: the sulfonamides bear certain chemical similarities to some goitrogens, diuretics (acetazolamide and the thiazides) and oral hypoglycemic agents. cross-sensitivity may exist with these agents. diuresis and hypoglycemia have occurred rarely in patients receiving sulfonamides. musculoskeletal: arthralgia and myalgia. isolated cases of rhabdomyolysis have been reported with sulfamethoxazole and trimethoprim, mainly in aids patients. respiratory: cough, shortness of breath and r pulmonary infiltrates (see warnings). miscellaneous : weakness, fatigue, insomnia.

the mean serum half-lives of sulfamethoxazole and trimethoprim are 10 and 8 to 10 hours, respectively. however, patients with severely impaired renal function exhibit an increase in the half-lives of both components, requiring dosage regimen adjustments (see dosage and administration section). detectable amounts of sulfamethoxazole and trimethoprim are present in the blood 24 hours after drug administration. during administration of 800 mg sulfamethoxazole and 160 mg trimethoprim bid, the mean steady-state plasma concentration of trimethoprim was 1.72 µg/ml. the steady-state mean plasma levels for free and total sulfamethoxazole were 57.4 µg/ml and 68.0 µg/ml, respectively. these steady-state levels were achieved after three days of drug administration 1 . excretion of sulfamethoxazole and trimethoprim is primarily by the kidneys through both glomerular filtration and tubular secretion. urine concentrations of both sulfamethoxazole and trimethoprim are considerably higher than the concentrations in the blood. the average percentage of the dose recovered in urine from 0 to 72 hours after a single oral dose of sulfamethoxazole and trimethoprim is 84.5% for total sulfonamide and 66.8% for free trimethoprim. thirty percent of the total sulfonamide is excreted as free sulfamethoxazole with the remaining as n 4 -acetylated metabolite. 2 when administered together as sulfamethoxazole and trimethoprim, neither sulfamethoxazole nor trimethoprim affects the urinary excretion pattern of the other. both sulfamethoxazole and trimethoprim distribute to sputum, vaginal fluid and middle ear fluid, trimethoprim also distributes to bronchial secretion, and both pass the palcental barrier and are excreted in human milk. geriatric pharmacokinetics: the pharmacokinetics of sulfamethoxazole 800 mg and trimethoprim 160 mg were studied in 6 geriatric subjects (mean age: 78.6 years) and 6 young healthy subjects (mean age: 29.3 years) using a non-us approved formulation. pharmacokinetic values for sulfamethoxazole in geriatric subjects were similar to those observed in young adult subjects. the mean renal clearance of trimethoprim was significantly lower in geriatric subjects compared with young adult subjects (19 ml/h/kg vs. 55 ml/h/kg). however, after normalizing by body weight, the apparent total body clearance of trimethoprim was on average 19% lower in geriatric subjects compared with young adult subjects. 3 microbiology: sulfamethoxazole inhibits bacterial synthesis of dihydrofolic acid by competing with para-aminobenzoic acid (paba). trimethoprim blocks the production of tetrahydrofolic acid from dihydrofolic acid by binding to and reversibly inhibiting the required enzyme, dihydrofolate reductase. thus, sulfamethoxazole and trimethoprim blocks two consecutive steps in the bio-synthesis of nucleic acids and proteins essential to many bacteria. in vitro studies have shown that bacterial resistance develops more slowly with both sulfamethoxazole and trimethoprim in combination than with either sulfamethoxazole or trimethoprim alone. sulfamethoxazole and trimethoprim have been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the indications and usage section. aerobic gram-positive microorganisms: streptococcus pneumoniae aerobic gram-negative microorganisms: escherichia coli (including susceptible enterotoxigenic strains implicated in traveler's diarrhea) klebsiella species enterobacter species haemophilus influenzae morganella morganii proteus mirabilis proteus vulgaris shigella flexneri shigella sonnei other organisms: pneumocystis carinii susceptibility testing methods: dilution techniques: quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (mics). these mics provide estimates of the susceptibility of bacteria to antimicrobial compounds. the mics should be determined using a standardized procedure. standardized procedures are based on a dilution method 4 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of sulfamethoxazole/trimethoprim powder. the mic values should be interpreted according to the following criteria: for testing enterobacteriaceae mic (µg/ml) interpretation ≤2/38 susceptible (s) ≥4/76 resistant (r) when testing either haemophilus influenzae these interpretive standards are applicable only to broth microdilution susceptibility tests with haemophilus influenzae using haemophilus test medium (htm) 4 streptococcus pneumoniae the interpretive standards are applicable only to broth microdilution susceptibility tests using cation-adjusted mueller-hinton broth with 2% to 5% lysed horse blood 4 mic (µg/ml) interpretation ≤0.5/9.5 susceptible (s) 1/19 – 2/38 intermediate (i) ≥4/76 resistant (r) a report of “susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. a report of “intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. this category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. this category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. a report of “resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable, other therapy should be selected. quality control: standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. standard sulfamethoxazole/trimethoprim powder should provide the following range of values: microorganism mic (μg/ml) escherichia coli atcc 25922 ≤0.5/9.5 haemophilus influenzae this quality control range is applicable only to haemophilus influenzae atcc 49247 tested by broth microdilution procedure using haemophilus test medium (htm) 4 . atcc 49247 0.03/0.59 – 0.25/4.75 streptococcus pneumoniae this quality control range is applicable to tests performed by the broth microdilution method only using cation-adjusted mueller- hinton broth with 2% to 5% lysed horse blood 4 . atcc 49619 0.12/2.4 – 1/19 diffusion techniques: quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. one such standardized procedure 5 requires the use of standardized inoculum concentrations. this procedure uses paper disks impregnated with 1.25/23.75 μg of sulfamethoxazole/trimethoprim to test the susceptibility of microorganisms to sulfamethoxazole/trimethoprim. reports from the laboratory providing results of the standard single-disk susceptibility test with a 1.25/23.75 μg of sulfamethoxazole/trimethoprim disk should be interpreted according to the following criteria: for testing either enterobacteriaceae or haemophilus influenzae these zone diameter standards are applicable only for disk diffusion testing with haemophilus influenzae and haemophilus test medium (htm) 5 . zone diameter (mm) interpretation ≥16 susceptible (s) 11-15 intermediate (i) ≤10 resistant (r) when testing streptococcus pneumoniae these zone diameter interpretive standards are applicable only to tests performed using mueller-hinton agar supplemented with 5% defibrinated sheep blood when incubated at 5% co 2 5 . zone diameter (mm) interpretation ≥19 susceptible (s) 16-18 intermediate (i) ≤15 resistant (r) interpretation should be as stated above for results using dilution techniques. interpretation involves correlation of the diameter obtained in the disk test with the mic for sulfamethoxazole/trimethoprim. quality control: as with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. for the diffusion technique, the 1.25/23.75 μg sulfamethoxazole/trimethoprim disk* should provide the following zone diameters in these laboratory test quality control strains: microorganism zone diameter ranges(mm) escherichia coli atcc 25922 24-32 haemophilus influenzae this quality control range is applicable only to haemophilus influenzae atcc 49247 tested by disk diffusion procedure using haemophilus test medium (htm) 5 . atcc 49247 24-32 streptococcus pneumoniae this quality control range is applicable only to tests performed by disk diffusion using mueller-hinton agar supplemented with 5% defibrinated sheep blood when incubated at 5% co 2 5 . atcc 49619 20-28 *mueller-hinton agar should be checked for excessive levels of thymidine or thymine. to determine whether mueller-hinton medium has sufficiently low levels of thymidine and thymine, an enterococcus faecalis (atcc 29212 or atcc 33186) may be tested with sulfamethoxazole/trimethoprim disks. a zone of inhibition = 20 mm that is essentially free of fine colonies indicates a sufficiently low level of thymidine and thymine.