Professional Information

Sulfonamides and Trimethoprim (Systemic)

This monograph includes information on the following:

1) Sulfadiazine and Trimethoprim ^*
2) Sulfamethoxazole and Trimethoprim

BAN:
^{04}Sulfadiazine—Sulphadiazine
Sulfamethoxazole—Sulphamethoxazole

JAN:
^{04}Sulfamethoxazole—Acetylsulfamethoxazole
Sulfamethoxazole—Sulfamethoxazole sodium

VA CLASSIFICATION
Primary: AM650

Commonly used brand name(s): Apo-Sulfatrim²; Apo-Sulfatrim DS²; Bactrim²; Bactrim DS²; Bactrim I.V.²; Bactrim Pediatric²; Cofatrim Forte²; Coptin¹; Coptin 1¹; Cotrim²; Cotrim DS²; Cotrim Pediatric²; Novo-Trimel²; Novo-Trimel D.S.²; Nu-Cotrimox²; Nu-Cotrimox DS²; Roubac²; Septra²; Septra DS²; Septra Grape Suspension²; Septra I.V.²; Septra Suspension²; Sulfatrim²; Sulfatrim Pediatric²; Sulfatrim S/S²; Sulfatrim Suspension²; Sulfatrim-DS².

Other commonly used names are

• Cotrimazine Sulfadiazine and Trimethoprim

• Cotrimoxazole Sulfamethoxazole and Trimethoprim

• SMZ-TMP Sulfamethoxazole and Trimethoprim
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

^*Not commercially available in the U.S.

Category:

Antibacterial (systemic)—Sulfadiazine and Trimethoprim; ^*Sulfamethoxazole and Trimethoprim;

Antiprotozoal—Sulfamethoxazole and Trimethoprim;

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

General considerations
Sulfonamides, such as sulfadiazine and sulfamethoxazole, used together with trimethoprim, produce synergistic antibacterial activity. ^{14}^{156} Sulfadiazine and sulfamethoxazole have equal antibacterial properties, covering the same spectrum of activity. ^{14}These sulfonamides, in combination with trimethoprim, are active in vitro against many gram-positive and gram-negative aerobic organisms. They have minimal activity against anaerobic bacteria. ^{104} Susceptible gram-positive organisms include many Staphylococcus aureus , including some methicillin-resistant strains, S. saprophyticus , some group A beta-hemolytic streptococci, Streptococcus agalactiae , and most but not all strains of S. pneumoniae . ^{104} Gram-negative organisms that are susceptible include Escherichia coli, many Klebsiella species, Citrobacter diversus and C. fruendii , Enterobacter species, Salmonella species, Shigella species, Haemophilus influenzae , including some ampicillin-resistant strains, H. ducreyi , Morganella morganii , Proteus vulgaris and P. mirabilis , and some Serratia species. ^{104} Sulfonamide and trimethoprim combinations also have activity against Acinetobacter species, Pneumocystis carinii, Providencia rettgeri , P. stuarti , Aeromonas , Brucella , and Yersinia species. ^{104} They are also usually active against Neisseria meningitidis , Branhamella (Moraxella) catarrhalis , and some, but not all, N. gonorrhoeae . ^{104} Pseudomonas aeruginosa is usually resistant, but P. cepacia and P. maltophilia may be sensitive. ^{104}

The major difference between sulfadiazine and sulfamethoxazole exists in their respective pharmacokinetics. The primary distinction is that sulfadiazine is metabolized to a much lesser extent than is sulfamethoxazole. ^{14} ^{152} ^{156} This allows for a higher urinary concentration of unchanged sulfadiazine ^{152} ^{156} ^{164}, as well as an increased risk of crystalluria when it is administered in high doses ^{152}; the antibacterial urinary concentration of sulfadiazine is maintained over a 24-hour interval, allowing for once-a-day dosing in adults. ^{150} ^{164} Also, sulfadiazine achieves higher concentrations in the bile and cerebrospinal fluid. ^{14} ^{151}

Accepted

Bronchitis (treatment)—Oral sulfamethoxazole and trimethoprim combination is indicated in adults in the treatment of acute exacerbations of chronic bronchitis caused by susceptible organisms. ^{03} ^{05} ^{18} ^{22} ^{38}^{168}^{170}

Enterocolitis, Shigella species (treatment) —Oral and parenteral sulfamethoxazole and trimethoprim combinations are indicated in the treatment of enterocolitis caused by susceptible strains of Shigella flexneri and S. sonnei. ^{01} ^{03} ^{05} ^{21} ^{38}^{168}^{169}^{170}^{171}

Otitis media, acute (treatment)—Oral sulfamethoxazole and trimethoprim combination is indicated in the treatment of acute otitis media caused by susceptible organisms in children. ^{03} ^{05} ^{21} ^{38}^{168}^{170}

Pneumonia, Pneumocystis carinii (prophylaxis)¹—Oral sulfamethoxazole and trimethoprim combination is indicated in the prophylaxis of Pneumocystis carinii pneumonia (PCP) in patients who are immunocompromised and considered to be at increased risk of developing PCP, including patients with acquired immunodeficiency syndrome (AIDS). ^{168}^{170} It is considered to be the treatment of choice for this indication. ^{94} Sulfamethoxazole and trimethoprim combination is indicated in both secondary prophylaxis (patients who have already had at least one episode of PCP), and primary prophylaxis (HIV-infected adults with a CD4 lymphocyte count less than or equal to 200 cells per cubic millimeter and/or less than 20% of total lymphocytes; all children born to HIV-infected mothers, beginning at 4 to 6 weeks of age, and subsequent prophylaxis given as determined on the basis of age-specific CD4 lymphocyte count^{94}) of PCP. ^{03} ^{05} ^{53} ^{54} ^{55} ^{56} ^{57} ^{60} ^{61} ^{113}

Pneumonia, Pneumocystis carinii (treatment) —Oral and parenteral sulfamethoxazole and trimethoprim combinations are indicated as primary agents in the treatment of Pneumocystis carinii pneumonia (PCP) in immunocompromised patients, including patients with acquired immunodeficiency syndrome (AIDS). ^{01}^{03}^{05}^{18}^{95}^{168}^{169}^{170}^{171}Pentamidine is considered an alternative agent for PCP.

Traveler's diarrhea (treatment)—Oral sulfamethoxazole and trimethoprim combination is indicated in the treatment of traveler's diarrhea caused by susceptible strains of enterotoxigenic Escherichia coli and Shigella species. ^{03} ^{18} ^{38} ^{138} ^{139}^{168}^{170}

Urinary tract infections, bacterial (treatment)— Sulfadiazine and trimethoprim combination ^{150} ^{157} ^{158} ^{159} ^{160} ^{161} ^{162} ^{163} ^{164} and oral and parenteral sulfamethoxazole and trimethoprim combinations ^{01}^{03}^{22}^{38}^{140}^{141}^{168}^{169}^{170}^{171} are indicated in the treatment of urinary tract infections caused by susceptible organisms.

[Biliary tract infections (treatment)]—Sulfamethoxazole and trimethoprim combination is used in the treatment of biliary tract infections caused by susceptible organisms. ^{38}

[Bone and joint infections (treatment)]—Sulfamethoxazole and trimethoprim combination is used in the treatment of bone and joint infections caused by susceptible organisms. ^{22} ^{38}

[Chancroid (treatment)]¹—Sulfamethoxazole and trimethoprim combination is used as an alternative agent in the treatment of chancroid. ^{38} ^{147} ^{148} ^{149}

[Chlamydial infections (treatment) ]¹—Sulfamethoxazole and trimethoprim combination is used as an alternative agent in the treatment of chlamydial infections. ^{37}

[Cyclospora infections (treatment) ]¹—Sulfamethoxazole and trimethoprim combination is used in the treatment of diarrhea caused by Cyclospora cayetanensis , but may not completely eradicate the organism. ^{106} ^{107} ^{108} ^{109}

[Endocarditis, bacterial (treatment) ]¹—Sulfamethoxazole and trimethoprim combination is used as an alternative agent in the treatment of bacterial endocarditis caused by susceptible organisms. ^{37} ^{38}

[Gonorrhea, endocervical and urethral, uncomplicated (treatment)]—Sulfamethoxazole and trimethoprim combination is used as an alternative agent in the treatment of gonorrhea caused by susceptible organisms. ^{22} ^{38} ^{146}

[Granuloma inguinale (treatment)]¹—Sulfamethoxazole and trimethoprim combination is used as an alternative agent in the treatment of granuloma inguinale. ^{37} ^{145}

[HIV-related infections in Africa (prophylaxis)]¹—Sulfamethoxazole and trimethoprim combination is used in the prophylaxis of HIV-related infections in Africa^{172}^{173}^{174}.
—Given the large number of patients with HIV-related infections throughout Africa and the high mortality they experience, sulfamethoxazole and trimethoprim combination prophylaxis if widely applicable and implemented could significantly affect care and survival (i.e., could significantly lower morbidity and mortality) among HIV-infected patients in Africa^{172}^{173}^{174}.

[Isosporiasis (prophylaxis and treatment) ]¹—Sulfamethoxazole and trimethoprim combination is used in the prophylaxis and treatment of isosporiasis caused by Isospora belli . ^{38} ^{39} ^{40} ^{104}

[Lymphogranuloma venereum (treatment) ]¹—Sulfamethoxazole and trimethoprim combination is used in the treatment of lymphogranuloma venereum. ^{38} ^{104}

[Meningitis (treatment)]—Sulfamethoxazole and trimethoprim combination is used as an alternative agent in the treatment of meningitis caused by susceptible organisms. ^{37} ^{38}

[Nocardiosis (treatment)]—Sulfamethoxazole and trimethoprim combination is used in the treatment of nocardiosis. ^{22} ^{38} ^{104} ^{137}

[Paracoccidioidomycosis (treatment) ]¹—Sulfamethoxazole and trimethoprim combination is used in the treatment of paracoccidioidomycosis. ^{38}

[Paratyphoid fever (treatment)] or
[Typhoid fever (treatment)]—Sulfamethoxazole and trimethoprim combination is used as an alternative agent in the treatment of paratyphoid and typhoid fevers caused by susceptible strains. ^{22} ^{38}

[Septicemia, bacterial (treatment)]—Sulfamethoxazole and trimethoprim combination is used as an alternative agent in the treatment of bacterial septicemia caused by susceptible organisms. ^{37} ^{38}

[Sinusitis (treatment)]¹—Sulfamethoxazole and trimethoprim combination is used in the treatment of sinusitis caused by susceptible organisms. ^{38} ^{103} ^{104}

[Skin and soft tissue infections (treatment)]—Sulfamethoxazole and trimethoprim combination is used in the treatment of skin and soft tissue infections, including burn wound infections caused by susceptible organisms. ^{22}

[Toxoplasmosis (prophylaxis)]¹—Sulfamethoxazole and trimethoprim combination is used in the primary prophylaxis of toxoplasmosis in patients with AIDS. ^{38} ^{94} ^{95} ^{100} ^{114} ^{115} ^{167}

[Urinary tract infections, bacterial (prophylaxis)]¹—Sulfamethoxazole and trimethoprim combination is used in the prophylaxis of bacterial urinary tract infections. ^{37} ^{102} ^{142}

[Whipple's disease (treatment)]¹—Sulfamethoxazole and trimethoprim combination is used in the treatment of Whipple's disease. ^{104} ^{105} ^{109} ^{110} ^{111} ^{112}

—Not all strains of a particular organism may be susceptible to sulfonamide and trimethoprim combinations.

Unaccepted
Sulfamethoxazole and trimethoprim combination is not indicated for prophylaxis or prolonged therapy in otitis media. ^{03}^{168}^{170} Sulfamethoxazole and trimethoprim combination is not effective in the treatment of syphilis^{37}^{38} andUreaplasm urealyticum ^{37}.

Sulfamethoxazole and trimethoprim combination should not be used in the treatment of group A beta-hemolytic streptococcal tonsillopharyngitis since it may not eradicate streptococci and therefore may not prevent sequelae such as rheumatic fever. ^{01} ^{05} ^{37}

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Sulfadiazine: 250.28 ^{04}
    Sulfamethoxazole: 253.28 ^{04}
    Trimethoprim: 290.32 ^{04}

Mechanism of action/Effect:

Sulfonamides:

Sulfonamides are broad-spectrum, bacteriostatic anti-infectives. ^{22} They are structural analogs of para-aminobenzoic acid (PABA) and competitively inhibit a bacterial enzyme, dihydropteroate synthetase, that is responsible for incorporation of PABA into dihydrofolic acid, the immediate precursor of folic acid. ^{23} This blocks the synthesis of dihydrofolic acid and decreases the amount of metabolically active tetrahydrofolic acid, a cofactor for the synthesis of purines, thymidine, and DNA. ^{37}

Susceptible bacteria are those that must synthesize folic acid. Mammalian cells require preformed folic acid and cannot synthesize it. ^{37} ^{38} The action of sulfonamides is antagonized by PABA and its derivatives (e.g., procaine and tetracaine) and by the presence of pus or tissue breakdown products, which provide the necessary components for bacterial growth. ^{23}

Trimethoprim:

Trimethoprim is a bacteriostatic lipophilic weak base structurally related to pyrimethamine. It binds to and reversibly inhibits the bacterial enzyme dihydrofolate reductase, selectively blocking conversion of dihydrofolic acid to its functional form, tetrahydrofolic acid. ^{03} ^{22} ^{37} This depletes folate, an essential cofactor in the biosynthesis of nucleic acids, resulting in interference with bacterial nucleic acid and protein production. ^{23} Bacterial dihydrofolate reductase is approximately 50,000 to 100,000 times more tightly bound by trimethoprim than is the corresponding mammalian enzyme. ^{37} ^{38}

Trimethoprim exerts its effect at a step in the folate biosynthesis immediately subsequent to the one at which sulfonamides exert their effect. When trimethoprim is administered concurrently with sulfonamides, synergism occurs, which is attributed to inhibition of tetrahydrofolate production at 2 sequential steps in its biosynthesis. ^{22} ^{23} ^{37}

Absorption:

Oral—Sulfonamides and trimethoprim are rapidly and well absorbed (70 to 100%). ^{22} ^{151} ^{152}

Distribution:

Sulfonamides:

Widely distributed throughout body tissues and fluids, including pleural ^{01} ^{23} ^{165}, peritoneal ^{01} ^{23} ^{165}, synovial ^{01} ^{23} ^{165}, middle ear ^{01} ^{23}, and ocular fluids ^{01} ^{23} ^{165}, as well as nasal secretions ^{154}, sputum ^{01} ^{23}, and prostate ^{152}, lymph ^{153}, and renal tissue ^{152}. Sulfadiazine is distributed throughout total body water ^{23} ^{37} and achieves higher concentrations in bile than does sulfamethoxazole ^{14}. Sulfonamides readily cross the placenta and are distributed into breast milk, also. ^{01} ^{23} ^{37} Sulfonamides penetrate into the cerebrospinal fluid (CSF) with CSF concentrations of sulfadiazine reaching 32 to 65% ^{151} and those of sulfamethoxazole reaching 14 to 30% of the corresponding blood concentrations. ^{23} ^{27} ^{37} ^{38} Sulfonamides may be detected in the urine in approximately 30 minutes. ^{23}

Trimethoprim:

Rapidly and widely distributed to various tissues and fluids, including kidneys, liver, spleen, bronchial secretions, saliva, sputum, middle ear, and prostatic tissue and fluid. ^{01} ^{23} ^{37} Trimethoprim is also distributed into bile, aqueous humor, bone, mucosa, and seminal fluid. ^{37} ^{38} It penetrates into the CSF with CSF concentrations reaching 20 to 40% of corresponding plasma concentrations. ^{37} ^{38} Trimethoprim crosses the placenta and is distributed into breast milk. ^{01} ^{37}

Urine solubility:

Sulfadiazine: Acetylated sulfadiazine has the least solubility, followed by sulfadiazine. ^{152}

Sulfamethoxazole: Acetylated sulfamethoxazole is more soluble than sulfadiazine, but less soluble than sulfamethoxazole. ^{152}

Vol _D:

Sulfadiazine: Approximately 33.7 liters. ^{165}

Sulfamethoxazole: Approximately 0.21 liters per kg of body weight (L/kg). ^{23} ^{37}

Trimethoprim: Approximately 1.8 L/kg. ^{23} ^{37}

Protein binding:

Sulfonamides:

Sulfonamides compete with bilirubin for binding to albumin. Kernicterus may develop in premature infants or neonates. ^{37} Binding is decreased in patients with severely impaired renal function. ^{38} Only free, unbound drug has antibacterial activity. ^{27}

Sulfadiazine: Moderate (38 to 56%). ^{151} ^{152}

Sulfamethoxazole: Moderate to high (60 to 70%). ^{01} ^{23} ^{38}

Trimethoprim:

Moderate (40 to 45%). ^{01} ^{23} ^{24} ^{37} Protein binding does not significantly decrease in patients with uremia. ^{38}

Biotransformation:

Sulfonamides—Hepatic; primarily by acetylation to inactive metabolites, which retain the toxicity of the parent compound. ^{23} Some hepatic glucuronide conjugation may occur. ^{37}

Trimethoprim—Hepatic; 10 to 20% metabolized to inactive metabolites by O-demethylation, ring N-oxidation, and alpha-hydroxylation; metabolites may be free or conjugated. ^{24}

Half-life:

Sulfadiazine:

Normal renal function: 9 to 13.7 hours. ^{152} ^{155} ^{156}

Renal failure: Approximately 34 hours. ^{23} ^{38}

Sulfamethoxazole:

Normal renal function: 10 to 12 hours. ^{01} ^{03} ^{22} ^{23} ^{37} ^{38}

Creatinine clearance less than 10 mL per minute (mL/min) (0.17 mL per second [mL/sec]): 18 to 50 hours. ^{38} ^{118}

Trimethoprim:

Normal renal function: 8 to 10 hours. ^{01} ^{03} ^{22} ^{23} ^{24} ^{37} ^{152} ^{156}

Creatinine clearance less than 10 mL/min (0.17 mL/sec): Approximately 24 hours. ^{38} ^{118}

Time to peak serum concentration

Oral:

Sulfadiazine: 2.7 to 4 hours. ^{152} ^{155} ^{156}

Sulfamethoxazole: 2 to 4 hours. ^{22} ^{23}

Trimethoprim: 1 to 4 hours. ^{03} ^{22} ^{23} ^{37} ^{38} ^{156}

Peak serum concentration:

Sulfadiazine:

Single 820-mg dose: 27.5 to 31.7 mcg/mL. ^{152} ^{155} ^{156}

Sulfamethoxazole:

Oral, 800 mg twice a day: Approximately 40 mcg/mL. ^{23} ^{38}

Intravenous, 800 mg three times a day: Approximately 106 mcg/mL. ^{37} ^{38}

Trimethoprim:

Oral, 160 mg twice a day: Approximately 2 to 2.4 mcg/mL. ^{23} ^{38} ^{156}

Intravenous, 160 mg three times a day: Approximately 9 mcg/mL. ^{37} ^{38}

Elimination:

Sulfonamides—
        Renal, by glomerular filtration, with some tubular secretion ^{01} and reabsorption of both active medication and metabolites. Excretion is increased in alkaline urine ^{37} ^{38}.

Percent of medication unchanged in the urine—
        Sulfadiazine: 43 to 58% in 24 hours. ^{151} ^{155} ^{156}
        Sulfamethoxazole: 20 to 40%. ^{23} ^{37}

        Small amounts are excreted in the feces, bile, and other body secretions. ^{38}

In dialysis—
        Sulfamethoxazole is removed from the blood by hemodialysis. ^{21} ^{37} However, peritoneal dialysis is not effective. ^{27} ^{118}

Trimethoprim—
        Renal, 40 to 60% excreted within 24 hours, primarily by glomerular filtration and tubular secretion ^{03} ^{22} ^{23} ^{37} ^{156}; of this amount, 80 to 90% is excreted unchanged and the remainder is excreted as inactive metabolites. ^{37} Excretion is increased in acid urine and decreased in alkaline urine. ^{38}
        Small amounts are excreted in the feces and bile. ^{22}

In dialysis—
        Significant amounts of trimethoprim are removed from the blood by hemodialysis ^{21}, requiring a full maintenance dose after dialysis. Peritoneal dialysis is not effective in removing trimethoprim from the blood. ^{118}

Precautions to Consider

Cross-sensitivity and/or related problems

Patients allergic to sulfonamides or trimethoprim may be allergic to sulfonamide and trimethoprim combinations. ^{01} ^{150}

Patients allergic to furosemide, thiazide diuretics, sulfonylureas, or carbonic anhydrase inhibitors may be allergic to sulfonamides also. ^{25} ^{26}

Patients sensitive to sulfites may have an allergic reaction to Bactrim I.V. since it contains sodium metabisulfite. ^{01}

Carcinogenicity

Sulfamethoxazole and trimethoprim—Long-term studies to evaluate the carcinogenic potential of sulfamethoxazole and trimethoprim combination have not been done. ^{01}

Mutagenicity

Sulfamethoxazole and trimethoprim—Bacterial mutagenicity studies with sulfamethoxazole and trimethoprim combination have not been done. Trimethoprim has not been shown to be mutagenic in the Ames assay. Studies in human leukocytes cultured in vitro with sulfamethoxazole and trimethoprim combination, using concentrations that exceeded therapeutic serum concentrations, have not shown that sulfamethoxazole and trimethoprim combination causes chromosomal damage. ^{01}

Pregnancy/Reproduction
Fertility—
Sulfamethoxazole and trimethoprim: Studies in rats, given oral doses as high as 70 mg of trimethoprim per kg of body weight (mg/kg) and 350 mg/kg of sulfamethoxazole daily, have not shown that sulfamethoxazole or trimethoprim causes any adverse effects on fertility or general reproductive performance. ^{01}

Pregnancy—
Sulfadiazine: FDA Pregnancy Category C. ^{151}

Sulfamethoxazole and trimethoprim: Sulfamethoxazole and trimethoprim cross the placenta. Adequate and well-controlled studies in humans have not been done. ^{01} However, prophylaxis for Pneumocystis carinii pneumonia (PCP) is recommended in HIV-infected pregnant women. ^{94} In one retrospective study in 186 women who received placebo or sulfamethoxazole and trimethoprim combination during pregnancy, the incidence of congenital abnormalities was lower (3.3% versus 4.5%) in the sulfamethoxazole and trimethoprim combination–treated group. No abnormalities were reported in the 10 children whose mothers received sulfamethoxazole and trimethoprim combination during the first trimester. In another study, no congenital abnormalities were reported in 35 children whose mothers received sulfamethoxazole and trimethoprim combination at the time of conception or shortly thereafter. However, sulfamethoxazole and trimethoprim may interfere with folic acid metabolism in the fetus. ^{01}

Studies in rats given oral doses of 200 mg/kg of trimethoprim and 533 mg/kg of sulfamethoxazole have shown that sulfamethoxazole causes teratogenic effects (primarily cleft palates). However, doses of 192 mg/kg of trimethoprim and 512 mg/kg of sulfamethoxazole, when administered separately, did not cause cleft palates in rats. Doses of 88 mg/kg of trimethoprim and 355 mg/kg of sulfamethoxazole have been shown to cause cleft palates when administered concurrently. ^{01} Studies in rabbits given doses of trimethoprim 6 times the usual human therapeutic dose have shown that trimethoprim causes an increase in the number of dead, resorbed, and malformed fetuses. ^{01}

FDA Pregnancy Category C. ^{01}

Labor and delivery—

Sulfonamides are not recommended at term since they may cause jaundice, hemolytic anemia, and kernicterus in the newborn. ^{26} ^{38}

Breast-feeding

Sulfonamides—Sulfonamides are distributed into breast milk. ^{01} Use is not recommended in nursing women since sulfonamides may cause kernicterus in nursing infants. ^{01} ^{18} ^{150} Also, sulfonamides may cause hemolytic anemia in glucose-6-phosphate dehydrogenase (G6PD)–deficient infants. ^{26}

Trimethoprim—Trimethoprim is distributed into breast milk. ^{01} Trimethoprim may interfere with folic acid metabolism in nursing infants.

Pediatrics

Sulfonamides compete for bilirubin binding sites on plasma albumin, increasing the risk of kernicterus in the newborn. Also, because the acetyltransferase system is not fully developed in the newborn, increased blood concentrations of the free sulfonamide can further increase the risk of kernicterus. ^{26} ^{38}

Sulfadiazine and trimethoprim:

Sulfadiazine and trimethoprim combination is not recommended in premature infants and neonates up to 12 weeks of age. ^{150}

Sulfamethoxazole and trimethoprim:

Although sulfamethoxazole and trimethoprim combination is indicated in the treatment of acute otitis media in children, it is not indicated for prophylaxis or prolonged therapy. ^{03}

Except as concurrent adjunctive therapy with pyrimethamine in the treatment of congenital toxoplasmosis or for the prophylaxis of Pneumocystis carinii pneumonia (PCP) in infants 4 weeks of age or over, the use of sulfamethoxazole and trimethoprim combination is contraindicated in infants up to 2 months of age since sulfonamides may cause kernicterus in neonates. ^{18} ^{56}

Geriatrics

Elderly patients may be at increased risk of severe side/adverse effects. Severe skin reactions, generalized bone marrow depression, and decreased platelet count (with or without purpura) are the most frequently reported severe side/adverse effects in the elderly. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients who are receiving diuretics, primarily thiazides, concurrently with sulfonamide and trimethoprim combinations. ^{01} ^{18} ^{27} ^{150}

Pharmacogenetics
Sulfonamides are metabolized primarily by acetylation. ^{41} Patients can be divided into 2 groups, slow and fast acetylators. Slow acetylators have a higher incidence of severe sulfonamide reactions, although a slow acetylator phenotype is not thought to be the sole reason for sulfonamide toxicity. ^{41} ^{42} ^{43} ^{44} ^{83} The incidence of the slow acetylator phenotype is approximately 50% in North American blacks and whites. ^{41} ^{42} ^{45} ^{83} Approximately 30% of the Hispanic population ^{43} and 10% of the Asian population ^{42} are slow acetylators. Also, acquired immunodeficiency syndrome (AIDS) patients with acute illness, but not AIDS patients who are stable or human immunodeficiency virus (HIV)-infected patients without AIDS, have an increased incidence of slow acetylation. ^{43}

Dental

The leukopenic and thrombocytopenic effects of sulfonamides may result in an increased incidence of certain microbial infections, delayed healing, and gingival bleeding. If leukopenia or thrombocytopenia occurs, dental work should be deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene, including caution in use of regular toothbrushes, dental floss, and toothpicks.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Anticoagulants, coumarin- or indandione-derivative or ^{01} ^{47} ^{124} ^{125} ^{150}^{168}^{169}^{170}^{171}
» Anticonvulsants, hydantoin or ^{01} ^{47} ^{122} ^{150}^{168}^{169}^{170}^{171}
» Antidiabetic agents, oral ^{47} ^{120} ^{121} ^{150}^{168}^{170}^{171}    (these medications may be displaced from protein binding sites and/or their metabolism may be inhibited by some sulfonamides, resulting in increased or prolonged effects and/or toxicity; dosage adjustments may be necessary during and after sulfonamide therapy)

Atovaquone ^{149}    (concurrent administration of sulfamethoxazole and trimethoprim combination with atovaquone suspension resulted in an 8 and 17% decrease in the steady-state serum concentration of sulfamethoxazole and trimethoprim, respectively; this effect is thought to be minor and is not expected to produce clinically significant events)

Bone marrow depressants (See Appendix II )    (concurrent use of bone marrow depressants with sulfonamides may increase the leukopenic and/or thrombocytopenic effects; if concurrent use is required, close observation for myelotoxic effects should be considered)

Contraceptives, estrogen-containing, oral ^{29}    (concurrent long-term use of sulfonamides may result in reduced contraceptive reliability and increased incidence of breakthrough bleeding)

Cyclosporine ^{47} ^{48} ^{49} ^{50}^{168}    (concurrent use with sulfonamides may increase the metabolism of cyclosporine, resulting in decreased plasma concentrations and potential transplant rejection; there may also be additive nephrotoxicity; plasma cyclosporine concentrations and renal function should be monitored)

Dapsone ^{35}    (concurrent use with trimethoprim will usually increase the plasma concentrations of both dapsone and trimethoprim, possibly due to an inhibition in dapsone metabolism, and/or competition for renal secretion between the 2 medications; increased serum dapsone concentrations may increase the number and severity of side effects, especially methemoglobinemia)

» Digoxin ^{168}    (concurrent use with trimethoprim and sulfamethoxazole may increase the serum concentration of digoxin; serum digoxin levels should be monitored)

Folate antagonists, other (See Appendix II ) ^{150}    (concurrent use with trimethoprim or use of trimethoprim between courses of other folic acid antagonists is not recommended because of the possibility of megaloblastic anemia)

» Hemolytics, other (See Appendix II )    (concurrent use with sulfonamides may increase the potential for toxic side effects)

» Hepatotoxic medications, other (See Appendix II )    (concurrent use with sulfonamides may result in an increased incidence of hepatotoxicity; patients, especially those on prolonged administration or those with a history of liver disease, should be carefully monitored)

Lamivudine (3TC)    (in one small study, sulfamethoxazole and trimethoprim combination was found to decrease significantly the clearance, steady-state volume of distribution, and elimination half-life of lamivudine ^{36}; trimethoprim was also found to decrease the renal clearance of lamivudine by approximately 59% in an isolated perfused rat kidney ^{67})

» Methenamine ^{37} ^{38}    (in acid urine, methenamine breaks down into formaldehyde, which may form an insoluble precipitate with certain sulfonamides and may also increase the danger of crystalluria; concurrent use is not recommended)

» Methotrexate or ^{01} ^{38} ^{51} ^{123} ^{150}^{168}^{169}^{170}^{171}
Phenylbutazone or ^{37} ^{38} ^{150}
Sulfinpyrazone ^{18} ^{38} ^{150}    (the effect of methotrexate may be potentiated during concurrent use with sulfonamides because of displacement from plasma protein binding sites; phenylbutazone and sulfinpyrazone may displace sulfonamides from plasma protein-binding sites, increasing sulfonamide concentrations)

Procainamide ^{31} ^{32}    (concurrent use with trimethoprim may increase the plasma concentration of both procainamide and its metabolite, N-acetylprocainamide [NAPA], by decreasing their renal clearance)

Rifampin ^{30} ^{38}    (concurrent use may significantly increase the elimination and shorten the elimination half-life of trimethoprim)

Thiazide diuretics ^{01}    (there has been an increased incidence of thrombocytopenia with purpura in elderly patients who received sulfamethoxazole and trimethoprim combination with thiazide diuretics)

Tricyclic antidepressants    (efficacy of tricyclic antidepressants may be decreased)

Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Benedict"s test ^{37} ^{52}    (sulfonamides may produce a false-positive Benedict"s test for urine glucose )

Creatinine determinations ^{01} ^{18}^{168}    (trimethoprim may interfere with the Jaffé alkaline picrate assay for creatinine, resulting in creatinine values that are approximately 10% higher than actual values)

Methotrexate assays, serum ^{01} ^{18}^{168}^{169}    (trimethoprim may interfere with serum methotrexate assays if methotrexate is measured by the competitive binding protein technique [CBPA] using a bacterial dihydrofolate reductase as the binding protein; no interference occurs if methotrexate is measured by radioimmunoassay [RIA])

Sulfosalicylic acid test ^{37} ^{52}    (sulfonamides may produce a false-positive sulfosalicylic acid test for urine protein)

Urine urobilinogen test strip (e.g., Urobilistix) ^{37} ^{52}    (sulfonamides may interfere with the Urobilistix test for urinary urobilinogen )

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]) values, serum and
Aspartate aminotransferase (AST [SGOT]) values, serum and
Bilirubin, serum    (concentrations may be increased ^{01} ^{18} ^{66} ^{150})

Blood urea nitrogen (BUN) and
Creatinine, serum    (concentrations may be increased ^{01} ^{37} ^{49} ^{66})

Glucose, blood    (concentrations may be decreased, resulting in hypoglycemia on rare occasions ^{65})

Potassium, serum    (concentrations may be increased; this usually occurs with higher doses, such as for the treatment of Pneumocystis carinii pneumonia, but may also occur at regular doses ^{76} ^{77} ^{78} ^{79} ^{80} ^{81})

Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).

Except under special circumstances, this medication should not be used when the following medical problem exists:
» Allergy to sulfonamides, furosemide, thiazide diuretics, sulfonylureas, carbonic anhydrase inhibitors, sulfites, or trimethoprim ^{01} ^{18}
Risk-benefit should be considered when the following medical problems exist
» Blood dyscrasias or
» Megaloblastic anemia due to folate deficiency ^{01} ^{24} ^{27}^{168}^{169}^{170}^{171}    (trimethoprim may cause folic acid deficiency; sulfonamides and trimethoprim may cause blood dyscrasias)

» Glucose-6-phosphate dehydrogenase (G6PD) deficiency ^{01} ^{37} ^{116} ^{117} ^{150}^{168}^{169}^{170}^{171}    (hemolysis may rarely occur; frequency may be dose-related)

» Hepatic function impairment ^{01} ^{21} ^{150}^{168}^{169}^{170}^{171}    (sulfonamides and trimethoprim are metabolized in the liver; delayed metabolism may increase the risk of toxicity; also, sulfonamides may cause fulminant hepatic necrosis)

» Porphyria ^{26} ^{28}    (sulfonamides may precipitate an acute attack of porphyria)

» Renal function impairment ^{01} ^{21} ^{27} ^{150}^{168}^{169}^{170}^{171}    (sulfonamides and trimethoprim are renally excreted; delayed elimination may increase the risk of toxicity; sulfonamides may cause tubular necrosis or interstitial nephritis)

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Complete blood counts (CBCs) ^{01} ^{27} ^{150}^{168}^{169}^{170}^{171}    (may be required prior to and monthly during treatment to detect blood dyscrasias in patients on prolonged therapy; therapy should be discontinued if a significant decrease in the count of any formed blood elements occurs)

Urinalyses ^{01} ^{27} ^{150}^{168}^{169}^{170}^{171}    (may be required prior to and periodically during treatment to detect crystalluria and/or urinary calculi formation in patients on long-term or high-dose therapy and in patients with impaired renal function)

Side/Adverse Effects

Note: Fatalities have occurred, although rarely, due to severe reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. Therapy should be discontinued at the first appearance of skin rash or any serious side/adverse effects or if signs of folic acid deficiency occur. ^{01} ^{18}^{168}^{169}^{170}^{171}
Patients infected with human immunodeficiency virus (HIV) have a greater incidence of side/adverse effects, especially rash, fever, and leukopenia, than do non-HIV–infected patients. ^{01} ^{85} ^{86}^{168}^{169}^{170}^{171} On rare occasions, adverse reactions may become very severe or life-threatening. ^{85} ^{86} ^{87} ^{88} Adverse effects may occur in up to 65% of acquired immunodeficiency syndrome (AIDS) patients ^{66} ^{84}, with 24 to 57% having such severe toxicity that therapy has to be discontinued. ^{66} Sulfamethoxazole and trimethoprim combination desensitization in HIV-infected patients has been successful in some patients, who have then been able to tolerate regular dosing for the prophylaxis of Pneumocystis carinii pneumonia (see Selected Bibliography). ^{89} ^{90} ^{91} ^{92} ^{93} ^{166}
The multiorgan toxicity of sulfonamides is thought to be the result of the way sulfonamides are metabolized in certain patients. It is probably due to the inability of the body to detoxify reactive metabolites. Sulfonamides are metabolized primarily by acetylation. ^{41} ^{83} ^{135} Patients can be divided into slow and fast acetylators. Slow acetylation of sulfonamides makes more of the medication available for metabolism by the oxidative pathways of the cytochrome P-450 system. ^{44} ^{45} ^{83} These pathways produce reactive toxic metabolites, such as hydroxylamine and nitroso compounds. ^{43} ^{44} ^{45} ^{135} The metabolites are normally detoxified by scavengers, such as glutathione. However, some populations, such as HIV-infected patients, have low concentrations of glutathione and these metabolites accumulate, producing toxicity. ^{43} ^{46} ^{83} ^{135} Patients who are slow acetylators have a higher incidence of sulfonamide hypersensitivity reactions ^{41} ^{42} ^{43} ^{44}, although severe toxicity has also been seen in fast acetylators. ^{41} Acetylation status alone cannot fully explain sulfonamide toxicity ^{45} ^{83} since approximately 50% of North American blacks and whites are slow acetylators and severe reactions occur in less than 1% of patients treated with sulfonamides. ^{45} However, decreased acetylation may increase the amount of sulfonamide metabolized to toxic metabolites. ^{45} ^{135}
Sulfonamides have been associated with crystalluria in the past; however, the risk is small with current sulfonamides and the doses used. Acetylated sulfadiazine has the least solubility, followed by sulfadiazine, acetylated sulfamethoxazole, and sulfamethoxazole. ^{152} Solubility also varies with pH and dose. The risk of crystalluria is high with sulfadiazine at a combined dose of 6 grams a day (4920 mg of sulfadiazine and 1080 mg of trimethoprim); however, this is 6 times the recommended daily dose. ^{152}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent

Hypersensitivity (fever; itching; skin rash)^{01}^{18}^{37}^{66}

photosensitivity (increased sensitivity of skin to sunlight)^{01}^{18}^{37}

Incidence less frequent

Blood dyscrasias (fever and sore throat; pale skin; unusual bleeding or bruising; unusual tiredness or weakness)^{01}^{18}^{23}^{59}^{66}^{133}^{134}^{150}^{168}^{169}^{170}^{171}

cholestatic hepatitis (yellow eyes or skin )^{01}^{68}^{69}^{70}^{71}^{129}^{130}^{150}^{168}^{169}^{170}^{171}

pancreatitis (back or stomach pain, severe; fast heart beat; fever; nausea or vomiting; swelling of the stomach)^{168}^{169}^{170}^{171}

Stevens-Johnson syndrome (aching joints and muscles; redness, blistering, peeling, or loosening of skin; unusual tiredness or weakness)^{01}^{18}^{23}^{37}^{150}^{168}^{169}^{170}^{171}

toxic epidermal necrolysis ( difficulty in swallowing; redness, blistering, peeling, or loosening of skin)^{01}^{18}^{23}^{37}^{150}^{168}^{169}^{170}^{171}

Incidence rare

Aseptic meningitis (confusion; drowsiness; general feeling of illness; severe headache; nausea; stiff neck and/or back)^{01}^{33}^{34}^{72}^{73}^{74}^{75}^{131}^{132}^{168}^{169}^{170}^{171}

central nervous system (CNS) toxicity (anxiety; hallucinations; mental depression; nervousness; seizures (convulsions))^{01}^{126}^{127}^{128}^{150}^{168}^{169}^{170}^{171}

Clostridium difficile colitis ( severe abdominal or stomach cramps and pain; abdominal tenderness ; watery and severe diarrhea, which may also be bloody; fever)—may occur up to several weeks after discontinuation of medication^{01}^{82}^{136}

crystalluria or hematuria (blood in urine ; lower back pain; pain or burning while urinating)^{01}^{152}

goiter or thyroid function disturbance ( swelling of front part of neck)^{01}^{37}

interstitial nephritis or tubular necrosis (greatly increased or decreased frequency of urination or amount of urine; increased thirst; loss of appetite ; nausea; vomiting)^{01}^{37}^{150}^{168}^{169}^{170}^{171}

methemoglobinemia (bluish fingernails, lips, or skin; difficult breathing; pale skin; sore throat and fever; unusual bleeding or bruising; unusual tiredness or weakness)^{01}^{37}^{168}^{169}^{170}^{171}

rhabdomyolysis ( fatigue; muscle pain; muscle weakness)—has been reported mainly in AIDS patients

thrombophlebitis (pain at site of injection)^{01}^{37}

Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent

CNS effects (dizziness; headache; ringing in the ears; tiredness)^{01}^{23}^{37}^{150}

gastrointestinal disturbances (abdominal pain ; diarrhea; loss of appetite; nausea or vomiting)^{01}^{18}^{23}^{37}^{66}^{150}

glossitis or stomatitis (mouth sores; swelling of the tongue)^{168}^{169}^{170}^{171}

Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Sulfonamides and Trimethoprim (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Allergy to sulfonamides, furosemide, thiazide diuretics, sulfonylureas, carbonic anhydrase inhibitors, sulfites, or trimethoprim

Pregnancy—Sulfonamides and trimethoprim cross the placenta; trimethoprim may interfere with folic acid metabolism; use is not recommended at term since sulfonamides may cause jaundice, hemolytic anemia, and kernicterus in neonates

Breast-feeding—Sulfonamides and trimethoprim are distributed into breast milk; sulfonamides may cause kernicterus in nursing infants; trimethoprim may interfere with folic acid metabolism

Use in children—Sulfadiazine and trimethoprim combination is contraindicated in infants up to 3 months of age and sulfamethoxazole and trimethoprim combination is contraindicated in infants up to 2 months of age for most indications since sulfonamides may cause kernicterus in neonates; however, sulfamethoxazole and trimethoprim combination is indicated in all infants born to human immunodeficiency virus (HIV)–infected mothers, starting at 4 to 6 weeks

Use in the elderly—Elderly patients, especially those also taking diuretics, may be at increased risk of severe side/adverse effects
Other medications, especially coumarin- or indandione-derivative anticoagulants, hydantoin anticonvulsants, oral antidiabetic agents, other hemolytics, other hepatotoxic medications, methenamine, or methotrexate
Other medical problems, especially blood dyscrasias, G6PD deficiency, hepatic function impairment, megaloblastic anemia due to folic acid deficiency, porphyria, and renal function impairment

Proper use of this medication
» Not giving sulfadiazine and trimethoprim combination to infants under 3 months of age, or sulfamethoxazole and trimethoprim combination to infants under 2 months of age, except under special circumstances

» Maintaining adequate fluid intake

Proper administration technique for oral liquids

» Compliance with full course of therapy

» Importance of not missing doses and taking at evenly spaced times

» Proper dosing
Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
» Regular visits to physician to check blood counts

Checking with physician if no improvement within a few days

Caution in use of regular toothbrushes, dental floss, and toothpicks; deferring dental work until blood counts have returned to normal; checking with physician or dentist concerning proper oral hygiene

» Possible skin photosensitivity

» Caution if dizziness occurs

Side/adverse effects
Severe skin problems and blood problems may be more likely to occur in elderly patients who are taking sulfamethoxazole and trimethoprim combination, especially if diuretics are being taken concurrently

Signs of potential side effects, especially hypersensitivity, photosensitivity, blood dyscrasias, cholestatic hepatitis, pancreatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, aseptic meningitis, central nervous system toxicity, Clostridium difficile colitis, crystalluria, hematuria, goiter, thyroid function disturbance, interstitial nephritis, tubular necrosis, methemoglobinemia, rhabdomyolysis and thrombophlebitis

General Dosing Information
Fluid intake should be sufficient to maintain urine output of at least 1200 mL per day in adults. ^{05} ^{18}

Adults with renal function impairment require a reduction in dose in sulfonamide and trimethoprim combinations as follows: ^{01} ^{150}

Creatinine Clearance (mL/min)/(mL/sec)	Dose
>30/0.50	See Usual adult and adolescent dose
15–30/0.25–0.50	1/2 the Usual adult and adolescent dose
<15/0.25	Use is not recommended

SULFADIAZINE AND TRIMETHOPRIM

Summary of Differences
Indications: Sulfadiazine and trimethoprim combination is recommended for use only in the treatment of urinary tract infections.

Pharmacology/pharmacokinetics: Compared to sulfamethoxazole, sulfadiazine achieves higher concentrations in the bile and cerebrospinal fluid, is metabolized to a lesser extent, and a higher percentage of active medication is eliminated in the urine. ^{14} ^{23} ^{37} ^{151} ^{152} ^{155} ^{156} ^{165}

Additional Dosing Information
The usual length of therapy when treating an uncomplicated lower urinary tract infection with sulfadiazine and trimethoprim combination is three ^{157} ^{159} ^{160} to five ^{158} days in women and seven to ten days in men ^{64}. Therapy should be continued for fourteen days or more in upper urinary tract infections. ^{64}

Oral Dosage Forms

SULFADIAZINE AND TRIMETHOPRIM ORAL SUSPENSION

Usual adult and adolescent dose
Antibacterial
Oral, 820 mg of sulfadiazine and 180 mg of trimethoprim once a day. ^{150}

Usual pediatric dose
Antibacterial
Infants up to 3 months of age: Use is not recommended. ^{150}

Children 3 months to 12 years of age: Oral, 7 mg of sulfadiazine and 1.5 mg of trimethoprim per kg of body weight every twelve hours. ^{150}

Children over 12 years of age: See Usual adult and adolescent dose. ^{150}

Strength(s) usually available
U.S.—
Not commercially available.

Canada—

205 mg of sulfadiazine and 45 mg of trimethoprim per 5 mL (Rx) [Coptin]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Shake well.
   • Take with a full glass of water.
   • May cause dizziness.
   • Avoid too much sun or use of sunlamp.
   • Continue medicine for full time of treatment.

Note: When dispensing, include a calibrated liquid-measuring device.

SULFADIAZINE AND TRIMETHOPRIM TABLETS

Usual adult and adolescent dose
See Sulfadiazine and Trimethoprim Oral Suspension . ^{150}

Usual pediatric dose
See Sulfadiazine and Trimethoprim Oral Suspension . ^{150}

Strength(s) usually available
U.S.—
Not commercially available.

Canada—

410 mg of sulfadiazine and 90 mg of trimethoprim (Rx) [Coptin]

820 mg of sulfadiazine and 180 mg of trimethoprim (Rx) [Coptin 1]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Take with a full glass of water.
   • May cause dizziness.
   • Avoid too much sun or use of sunlamp.
   • Continue medicine for full time of treatment.

SULFAMETHOXAZOLE AND TRIMETHOPRIM

Summary of Differences
Pharmacology/pharmacokinetics: Sulfamethoxazole is more soluble in urine than is sulfadiazine. ^{152}

Additional Dosing Information
Therapy should be continued for at least ten to fourteen days in acute exacerbations of chronic bronchitis ^{05}; as single-dose therapy or for three to five ^{119} days in urinary tract infections ^{101} ^{140} ^{141} ^{143} ^{144}; for five ^{05} to seven ^{119} days in shigellosis; for ten days in acute otitis media in children ^{05}; for five days in travelers diarrhea ^{05}; and for fourteen to twenty-one days in Pneumocystis carinii pneumonia ^{05}. Sulfamethoxazole and trimethoprim combination may also be given for one or two days or as single-dose therapy for lower urinary tract infections. Therapy should be continued for fourteen days or more in upper urinary tract infections. ^{64}

Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

SULFAMETHOXAZOLE AND TRIMETHOPRIM ORAL SUSPENSION USP

Usual adult and adolescent dose
Antibacterial (systemic)
Oral, 800 mg of sulfamethoxazole and 160 mg of trimethoprim every twelve hours. ^{03} ^{05}

Antiprotozoal

Pneumocystis carinii pneumonia ^{03}:

Treatment—
Oral, 18.75 to 25 mg of sulfamethoxazole and 3.75 to 5 mg of trimethoprim per kg of body weight every six hours for fourteen to twenty-one days ^{03} ^{05}^{168}^{169}^{170}^{171}.

Prophylaxis¹—
Oral, 800 mg of sulfamethoxazole and 160 mg of trimethoprim once a day. ^{05} ^{94} ^{97} ^{98} ^{99}^{168}^{170}

Acceptable alternative dosing schedules include—
Oral, 800 mg of sulfamethoxazole and 160 mg of trimethoprim three times a week (e.g., Monday, Wednesday, Friday) ^{55} ^{62} ^{63} ^{94}.

Oral, 400 mg of sulfamethoxazole and 80 mg of trimethoprim once a day ^{94} ^{96} ^{99}.

[Toxoplasmosis (prophylaxis)]¹:
Oral, 800 mg of sulfamethoxazole and 160 mg of trimethoprim once a day. ^{94}

Acceptable alternative dosing schedules include—
Oral, 800 mg of sulfamethoxazole and 160 mg of trimethoprim three times a week (e.g., Monday, Wednesday, Friday) ^{94}.

Oral, 400 mg of sulfamethoxazole and 80 mg of trimethoprim once a day. ^{94}

[ HIV-related infection in Africa (prophylaxis)]¹
Oral, 800 mg of sulfamethoxazole and 160 mg of trimethoprim once a day^{172} ^{173}^{174}.

Usual pediatric dose
Antibacterial (systemic)

Infants up to 2 months of age:
Use is not recommended since sulfonamides may cause kernicterus in neonates. ^{03}^{168}^{169}^{170}^{171}

Infants 2 months of age and over:
Infants and children up to 40 kg of body weight—Oral, 20^{168}^{170} to 30 mg of sulfamethoxazole and 4 ^{168}^{170}to 6 mg of trimethoprim per kg of body weight every twelve hours. ^{03} ^{58}

Children 40 kg of body weight and over—See Usual adult and adolescent dose.

Antiprotozoal

Pneumocystis carinii pneumonia (PCP):

Treatment—
Oral, 18.75 to 25 mg of sulfamethoxazole and 3.75 to 5 mg of trimethoprim per kg of body weight every six hours for fourteen to twenty-one days. ^{03}

Prophylaxis¹—

Children 4 weeks of age and over—
Oral, 375 mg of sulfamethoxazole per square meter and 75 mg of trimethoprim per square meter of body surface two times a day, three times a week on consecutive days (e.g., Monday, Tuesday, Wednesday). ^{03} ^{05} ^{56} ^{57} ^{94}

Acceptable alternative dosing schedules include ^{56} ^{94}—
Oral, 750 mg of sulfamethoxazole per square meter and 150 mg of trimethoprim per square meter of body surface as a single daily dose three times a week on consecutive days (e.g., Monday, Tuesday, Wednesday).

Oral, 375 mg of sulfamethoxazole per square meter and 75 mg of trimethoprim per square meter of body surface two times a day seven days a week.

Oral, 375 mg of sulfamethoxazole per square meter and 75 mg of trimethoprim per square meter of body surface two times a day, three times a week on alternate days (e.g., Monday, Wednesday, Friday).

Note: PCP prophylaxis is recommended for all infants born to HIV-infected mothers starting at 4 weeks of age, regardless of their CD4 lymphocyte counts. However, if the infant is receiving zidovudine during the first 6 weeks of life for the prevention of perinatal HIV transmission, sulfamethoxazole and trimethoprim combination prophylaxis should be delayed until zidovudine is discontinued at 6 weeks of age, to reduce the chance of anemia that may occur if these two medications are given concurrently. ^{56}

[Toxoplasmosis (prophylaxis)]¹:
Oral, 375 mg of sulfamethoxazole per square meter and 75 mg of trimethoprim per square meter of body surface two times a day, three times a week on consecutive days (e.g., Monday, Tuesday, Wednesday). ^{94}

Acceptable alternative dosing schedules include—
Oral, 750 mg of sulfamethoxazole per square meter and 150 mg of trimethoprim per square meter of body surface as a single daily dose three times a week on consecutive days (e.g., Monday, Tuesday, Wednesday). ^{94}

Oral, 375 mg of sulfamethoxazole per square meter and 75 mg of trimethoprim per square meter of body surface two times a day seven days a week. ^{94}

Oral, 375 mg of sulfamethoxazole per square meter and 75 mg of trimethoprim per square meter of body surface two times a day, three times a week on alternate days (e.g., Monday, Wednesday, Friday). ^{94}

[HIV-related infection in Africa (prophylaxis)]¹
Studies have not been performed in children^{172} ^{173}^{174}.

Strength(s) usually available
U.S.—

200 mg of sulfamethoxazole and 40 mg of trimethoprim per 5 mL (Rx) [Bactrim Pediatric ( edetate disodium) (glycerin) ( microcrystalline cellulose) (polysorbate 80) (saccharin) (simethicone) (sorbitol) (FD&C Yellow No. 6) (FD&C Red No. 40) (flavors)] [Cotrim Pediatric] [Septra Suspension (sodium benzoate 0.1%) (carboxymethylcellulose sodium) (citric acid) (FD&C Red No. 40) ( FD&C Yellow No. 6) (flavor) ( glycerin) (microcrystalline cellulose) (polysorbate 80) (saccharin) (sorbitol)] [Septra Grape Suspension (sodium benzoate 0.1%) (carboxymethylcellulose sodium) (citric acid) (FD&C Red No. 40) ( FD&C Blue No. 1) (flavor) ( glycerin) (microcrystalline cellulose) (polysorbate 80) (saccharin) (sorbitol)] [Sulfatrim Pediatric] [Sulfatrim Suspension]

Canada—

200 mg of sulfamethoxazole and 40 mg of trimethoprim per 5 mL (Rx) [Apo-Sulfatrim] [Bactrim] [Novo-Trimel] [Nu-Cotrimox] [Septra]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container. ^{03}

Auxiliary labeling:
   • Shake well.
   • Take with a full glass of water.
   • May cause dizziness.
   • Avoid too much sun or use of sunlamp.
   • Continue medicine for full time of treatment.

Note: When dispensing, include a calibrated liquid-measuring device.

SULFAMETHOXAZOLE AND TRIMETHOPRIM TABLETS USP

Usual adult and adolescent dose
See Sulfamethoxazole and Trimethoprim Oral Suspension USP .

Usual adult prescribing limits
See Sulfamethoxazole and Trimethoprim Oral Suspension USP .

Usual pediatric dose
See Sulfamethoxazole and Trimethoprim Oral Suspension USP .

Strength(s) usually available
U.S.—

400 mg of sulfamethoxazole and 80 mg of trimethoprim (Rx) [Bactrim (magnesium stearate) (pregelatinized starch) (sodium starch glycolate) (FD&C Blue No. 1 lake) (FD&C Yellow No. 6 lake) (FD&C Yellow No. 10 lake )] [Cotrim] [Septra (docusate sodium 0.4 mg) ( FD&C Red No. 40) (magnesium stearate) (povidone) (sodium starch glycolate )] [Sulfatrim] [Sulfatrim S/S]

800 mg of sulfamethoxazole and 160 mg of trimethoprim (Rx) [Bactrim DS (magnesium stearate) (pregelatinized starch) (sodium starch glycolate)] [Cofatrim Forte] [Cotrim DS] [Septra DS ( docusate sodium 0.8 mg) (FD&C Red No. 40) (magnesium stearate) (povidone) (sodium starch glycolate)] [Sulfatrim-DS]

Canada—

100 mg of sulfamethoxazole and 20 mg of trimethoprim (Rx) [Apo-Sulfatrim]

400 mg of sulfamethoxazole and 80 mg of trimethoprim (Rx) [Apo-Sulfatrim (scored)] [Bactrim] [Novo-Trimel (scored)] [Nu-Cotrimox] [Septra]

800 mg of sulfamethoxazole and 160 mg of trimethoprim (Rx) [Apo-Sulfatrim DS] [Bactrim DS ( scored)] [Novo-Trimel D.S. (scored)] [Nu-Cotrimox DS] [Roubac] [Septra DS]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed, light-resistant container. ^{03}

Auxiliary labeling:
   • Take with a full glass of water.
   • May cause dizziness.
   • Avoid too much sun or use of sunlamp.
   • Continue medicine for full time of treatment.

Parenteral Dosage Forms

SULFAMETHOXAZOLE AND TRIMETHOPRIM FOR INJECTION CONCENTRATE USP

Usual adult and adolescent dose
Antibacterial (systemic)
Intravenous infusion, 10 to 12.5 mg of sulfamethoxazole and 2 to 2.5 mg of trimethoprim per kg of body weight every six hours; 13.3 to 16.7 mg of sulfamethoxazole and 2.7 to 3.3 mg of trimethoprim per kg of body weight every eight hours; or 20 to 25 mg of sulfamethoxazole and 4 to 5 mg of trimethoprim per kg of body weight every twelve hours. ^{01}^{169}^{171}

Antiprotozoal
Pneumocystis carinii pneumonia: Intravenous infusion, 18.75 to 25 mg of sulfamethoxazole and 3.75 to 5 mg of trimethoprim per kg of body weight every six hours; or 25 to 33.3 mg of sulfamethoxazole and 5.0 to 6.7 mg of trimethoprim per kg of body weight every eight hours for fourteen days. ^{01}^{169}^{171}

Usual pediatric dose
Infants up to 2 months of age—Use is not recommended since sulfonamides may cause kernicterus in neonates. ^{01}^{169}^{171}

Infants 2 months of age and over—See Usual adult and adolescent dose. ^{01}^{169}^{171}

Strength(s) usually available
U.S.—

400 mg of sulfamethoxazole and 80 mg of trimethoprim per 5 mL (Rx) [Bactrim I.V. (diethanolamine 0.3%) (sodium hydroxide)] [Septra I.V. (diethanolamine 0.3%) ( sodium hydroxide)]

Canada—

400 mg of sulfamethoxazole and 80 mg of trimethoprim per 5 mL (Rx) [Septra]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a light-resistant container. Do not refrigerate. ^{01}

Preparation of dosage form:
The contents of each vial (5 mL) must be diluted. Each 5 mL of solution should be added to 75 to 125 mL of 5% dextrose injection prior to administration by intravenous infusion. The resulting solution should be administered by intravenous infusion over a 60- to 90-minute period. ^{01}^{169}^{171}

Caution: Use of products containing benzyl alcohol is not recommended for use in neonates. A fatal toxic syndrome consisting of metabolic acidosis, CNS depression, respiratory problems, renal failure, hypotension, and possibly seizures and intracranial hemorrhages has been associated with this use.

Stability:
After initial dilution with 75 or 125 mL of 5% dextrose injection, infusion should be administered within 2 or 6 hours, respectively. ^{01}^{169}^{171}

Do not use if solution is cloudy or contains a precipitate. Do not mix with other medications or solutions. ^{01}^{169}^{171}

After initial entry of a needle into the vial, the remaining contents should be used within 48 hours. ^{01}^{169}^{171}

Sulfamethoxazole and trimethoprim combination is very unstable when mixed with other medications and diluents other than 5% dextrose injection. ^{02}^{169}^{171}

Note: Do not administer rapidly or by bolus injection. ^{01}^{169}^{171}
Do not administer intramuscularly. ^{01}^{169}^{171}

Revised: 08/08/2000

References

Sulfamethoxazole and trimethoprim (Bactrim I.V., Roche). In: PDR Physicians" desk reference. 49th ed. 1995. Montvale, NJ: Medical Economics Data Production Company, 1995: 2026-8.

Kaufman MB, Scavone JM, Foley JJ. Stability of undiluted trimethoprim-sulfamethoxazole for injection in plastic syringes. Am J Hosp Pharm 1992; 49: 2782-3.

Sulfamethoxazole and trimethoprim package insert (Bactrim, Bacatrim DS, and Bactrim Pediatric; Roche—US), Rev 1/94, Rec 7/94.

Fleeger CA, editor. USP dictionary of USAN and international drug names 1996. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1995: 660, 661, 725.

Sulfamethoxazole and trimethoprim package insert (Septra, Septra DS; Glaxo Wellcome—US). Rev 8/94, Rec 3/95.

Sulfamethoxazole and trimethoprim (Cofatrim Forte, Ampharco). Red book 1995. Montvale, NJ: Medical Economics Data, 1995: 186.

Sulfamethoxazole and trimethoprim (Sulfatrim, Sulfatrim Pediatric; Barre). Red book 1995. Montvale, NJ: Medical Economics Data, 1995: 426-7.

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