SMZ/TMP

543.6

543.19000284

618652

DTXSID0032233

colorless to faint yellow

J - Antiinfectives for systemic use

Co-trimoxazole concentrate for injection should be stored at 15-30 °C and should not be refrigerated. Oral suspensions of the drug should be stored in tight, light resistant containers at 15-25 or 15-30 °C, depending on the formulation (the manufacturer's recommendations should be followed), and the tablets should be stored in well-closed, light-resistant containers at 15-30 °C.

LD50 orally in mice: 5513 mg/kg (Yamamoto)

-20°C

3

Xi

26-36/37

UV8240000

36/37/38-43

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

TMP-SMZ causes a characteristic idiosyncratic liver injury that has features of drug-allergy or hypersensitivityand that resembles the injury attributable to the sulfonamides. The typical onset is sudden development of fever and rash followed by jaundice within a few days or weeks of starting the medication. Eosinophilia or atypical lymphocytosis are also common. The pattern of injury is typically cholestatic or mixed and can be complicated and prolonged. As with other sulfonamides, TMP-SMZ has been linked to cases of hepatocellular injury that can be severe and lead to acute liver failure. In most recent case series, TMP-SMZ has ranked within the top 5 to 10 causes of drug induced, idiosyncratic fulminant hepatic failure. However, most cases resolve rapidly, usually within 2 to 4 weeks unless cholestasis is severe. TMP-SMZ can also cause mild elevations in ALT levels that do not proceed to more severe liver injury or jaundice, and may be accompanied by hepatic granulomas.

Concomitant administration of trimethoprim or trimethoprim/sulfamethoxazole with methotrexate may increase bone marrow suppression, probably as an additive antifolate effect.|/Oral/ antidiabetic agents, 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. /Sulfonamides/|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. /Sulfonamides/|Concurrent long-term use of sulfonamides /and estrogen-containing oral contraceptives/ may result in reduced contraceptive reliability and increased incidence of breakthrough bleeding. /Sulfonamides/|For more Interactions (Complete) data for TRIMETHOPRIM/SULFAMETHOXAZOLE (21 total), please visit the HSDB record page.

LD50 Mouse oral 5513 mg/kg

Sulfonamides and trimethoporim are excreted in breast milk.

Sulfonamides and trimethoporim are excreted in breast milk.

Sulfamethoxazole with trimethoprim is a fixed antibiotic combination that is widely used for mild-to-moderate bacterial infections and as prophylaxis against opportunistic infections. Like other sulfonamide-containing medications, this combination has been linked to rare instances of clinically apparent acute liver injury.

Antiinfective Agents

Anti-Infective Agents; Anti-Infective Agents, Urinary; Antimalarials|Co-trimoxazole has been used in the treatment of gonorrhea caused by penicillinase-producing Neisseria gonorrhoeae. Although other anti-infective agents are generally recommended by the US Centers for Disease Control and many clinicians for the treatment of urogenital or anorectal infections caused by penicillinase-producing Neisseria gonorrhoeae, co-trimoxazole may be effective for the treatment of pharyngeal infections caused by penicillinase-producing Neisseria gonorrhoeae Although clinical experience is limited, oral co-trimoxazole may also be effective as an alternative to currently recommended regimens for the treatment of acute sexually transmitted epididymitis caused by penicillinase-producing Neisseria gonorrhoeae.|Trimethoprim/sulfamethoxazole is an alternative to tetracycline in cholera. This combination is recommended in isosporiasis (Isospora belli).|Trimethoprim/sulfamethoxazole may be useful in serious infections, including meningitis, osteomyelitis, bacteremia, and endocarditis, caused by susceptible gram-negative bacteria when other antibacterial agents are ineffective or not tolerated. Of particular note, gram-negative bacillary meningitis caused by organisms only moderately susceptible to third generation cephalosporins (eg, Enterobacter cloacae, Serratia marcescens) or resistant to these antibiotics (Acinetobacter, Pseudomonas cepacia) may be candidates for trimethoprim/sulfamethoxazole therapy if the organisms are susceptible. This combination may be an effective alternative to ampicillin (or penicillin G) with or without an aminoglycoside for the treatment of meningitis and bacteremia caused by Listeria monocytogenes. Trimethoprim/sulfamethoxazole may be useful for the treatment of infective endocarditis caused by Coxiella burnetii. In a double-blind, randomized, prospective study, intravenous trimethoprim/sulfamethoxazole (640 mg/3200 mg daily) was shown to be as effective as vancomycin in the treatment of serious methicillin-resistant Staphylococcus aureus infections, including bacteremias, endocarditis, septic arthritis, and osteomyelitis. The details of this study have not been published, however, and some consultants expressed concern about the use of trimethoprim/sulfamethoxazole in deep-seated staphylococcal infections (eg, endocarditis) because this combination may only be bacteriostatic against this organism. Currently, each of these indications is considered investigational.|For more Therapeutic Uses (Complete) data for TRIMETHOPRIM/SULFAMETHOXAZOLE (25 total), please visit the HSDB record page.

Trimethoprim-sulfamethoxazole should not be used to treat streptococcal pharyngitis, since it does not eradicate the microorganism.|Since serious reactions such as the Stevens-Johnson syndrome have occurred in some individuals, therapy should be discontinued at the first appearance of skin rash or other adverse effects.|May increase the action of warfarin and phenytoin.|Should not be used in pregnancy at term or during the nursing period.|For more Drug Warnings (Complete) data for TRIMETHOPRIM/SULFAMETHOXAZOLE (13 total), please visit the HSDB record page.

The frequency of development of bacterial resistance to trimethoprim- sulfamethoxazole is lower than it is to either of the agents alone. This is logical, since a microoganism that has acquired resistance to one of the components may still be killed by the other. Trimethoprim-resistant microorganisms may arise by mutation. Resistance in gram-negative bacteria is often associated with the acquisiton of a plasmid that codes for an altered dihydrofolate reductase. Resistance to trimethoprim in Staphylococcus aureus appears to be determined by a chromosomal gene rather than by a plasmid. The development of resistance to the combination also occurs in vivo. Resistance of Staphylococcus aureus increased from 0.4% to 12.6% during one 5-year period of use. In New York, 10 to 20% of gram-negative microorganisms were found to be resistant.

Substances capable of killing agents causing urinary tract infections or of preventing them from spreading. (See all compounds classified as Anti-Infective Agents, Urinary.)|Substances that inhibit the growth or reproduction of BACTERIA. (See all compounds classified as Anti-Bacterial Agents.)|Agents used in the treatment of malaria. They are usually classified on the basis of their action against plasmodia at different stages in their life cycle in the human. (From AMA, Drug Evaluations Annual, 1992, p1585) (See all compounds classified as Antimalarials.)

Co-trimoxazole is widely distributed into body tissues and fluids, including sputum, aqueous humor, middle ear fluid, prostatic fluid, vaginal fluid, bile, and cerebrospinal fluid; trimethoprim also distributes into bronchial secretions. Trimethoprim has a larger volume of distribution than does sulfamethoxazole. In adults, apparent volume of distribution of 100-120 and 12-18 l have been reported for trimethoprim and sulfamethoxazole, respectively. In patients with uninflamed meninges, trimethoprim and sulfamethoxazole concentrations in cerebrospinal fluid are about 50 and 40%, respectively, of concurrent serum concentrations of the drugs. Trimethoprim and sulfamethoxazole concentrations in middle ear fluid are approximately 75 and 20%, respectively, and in prostatic fluid are approximately 200 and 35%, respectively, of concurrent serum concentrations of the drugs.|After a single oral dose of the combined preparation, trimethoprim is absorbed more rapidly than sulfamethoxazole. The concurrent administration of the drugs appears to slow the absorption of sulfamethoxazole. Peak blood concentrations of trimethoprim ususally occur by 2 hours in most patients, while peak concentrations of sulfamethoxazole occur by 4 hours after a single oral dose.|Trimethoprim is rapidly distributed and concentrated in tissues, and about 40% is bound to plasma protein in the presence of sulfamethoxazole. The volume of distribution of trimethoprim is almost nine times that of sulfamethoxazole. The drug readily enters cerebrospinal fluid and sputum. High concentrations of each component of the mixture are also found in bile.|The pharmacokinetics of trimethoprim-sulfamethoxazole were studied in 12 healthy adult subjects receiving trimethoprim at 20 mg/kg of body weight per day and sulfamethoxazole at 100 mg/kg/day, which is the conventional dose for treating Pneumocystis carinii pneumonia. Daily doses were evenly divided and orally administered every 6 h for 3 days. Trimethoprim, sulfamethoxazole, and N4-acetylsulfamethoxazole concn in serum and urine were measured by HPLC. Five subjects withdrew from the study because of intolerable GI and CNS toxicities. In the seven subjects that completed the study, the mean maximum serum drug concn after the last dose were 13.6 + or - 2.0, 372 + or - 64, and 50.1 + or - 10.9 ug/ml for trimethoprim, sulfamethoxazole, and N4-acetylsulfamethoxazole, respectively. The mean half-lives were 13.6 + or - 3.5, 14.0 + or - 2.3, and 18.6 + or - 4.3 hr, respectively. Changes in absolute neutrophil count were significantly correlated with the minimum concn of trimethoprim and sulfamethoxazole in serum and trimethoprim area under the concn-time curve (for all three parameters, r2 = 0.6 and p < 0.05). These findings add to the evidence that serum drug concn in adults following the conventional dose of trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia are excessive and contribute to certain adverse reactions.|This article reviews the pharmacokinetics, clinical use, and adverse effects of trimethoprim/sulfamethoxazole in renally impaired patients. Renal dysfunction changes the pharmacokinetics of both component drugs. Trimethoprim and sulfamethoxazole disposition are not significantly altered until creatinine clearance is less than 30 ml/min, when sulfamethoxazole metabolites and trimethoprim accumulate and may lead to toxicity. Renal dysfunction, however, does not preclude the use of trimethoprim/sulfamethoxazole to treat susceptible infections, even when creatinine clearance is less than 15 ml/min. Adverse effects may occur more frequently in renally impaired patients but are not clearly related to increased serum concentrations of either drug. Guidelines for appropriate dosing and monitoring of trimethoprim/sulfamethoxazole therapy in these patients are presented.

Co-trimoxazole is metabolized in the liver. Trimethoprim is metabolized to oxide and hydroxylated metabolites and sulfamethoxazole is principally N-acetylated and also conjugated with glucuronic acid. Both drugs are rapidly excreted in urine via glomerular filtration and tubular secretion. In adults with normal renal function, approximately 50-60% of a trimethoprim and 45-70% of a sulfamethoxazole oral dose are excreted in urine within 24 hours. Approximately 80% of the amount of trimethoprim and 20% of the amount of sulfamethoxazole recovered in urine are unchanged drug. In adults with normal renal function, urinary concentrations of active trimethoprim are approximately equal to those of active sulfamethoxazole. Urinary concentrations of both active drugs are decreased in patients with impaired renal function.

The half-lives of trimethoprim and sulfamethoxazole are approximately 11 and 10 hours, respectively.

Trimethoprim/sulfamethoxazole ... inhibits sequential steps in the synthesis of tetrahydrofolic acid, an essential metabolic cofactor in the bacterial synthesis of purines, thymidine, glycine, and methionine. Sulfonamides, including sulfamethoxazole, are structural analogues of para-aminobenzoic acid and block the synthesis of dihydropteroic acid, the immediate precursor of dihydrofolic acid, from para-aminobenzoic acid and peridine. Trimethoprim subsequently acts to inhibit the reduction of dihydrofolic acid to the metabolically active tetrahydrofolic acid by the enzyme, dihydrofolate reductase. The most important consequence of this sequential enzymatic inhibition appears to be the interruption of thymidine synthesis.|The synergistic interaction between sulfonamide and trimethoprim is thus predictable from their respective mechanisms. There is an optimal ratio of the concentrations of the two agents for synergism, and this is equal to the ratio of the minimal inhibitory concentrations of the drugs acting independently. While this ratio varies for different bacteria, the most effective ratio for the greatest number of microorganisms is 20 parts of sulfamethoxazole to one part of trimethoprim. The combination is formulated to achieve a sulfamethoxazole concentration in vivo 20 times greater than that of trimethoprim. ... The pharmacokinetic properties of the sulfonamide chosen to be in combination with trimethoprim are important, since relative constancy of the concentrations of the two compounds in the body is desired.|Trimethoprim/sulfamethoxazole is active in vitro against a variety of gram-negative and gram-postive bacteria. Among aerobic gram-negative enteric bacteria, Escherichia coli, Proteus mirabilis, Salmonella (including Salmonella typhi), Shigella, and Citrobacter are very susceptible. Indole-positive Proteus, Serratia marcescens, Klebsiella pneumoniae, Enterobacter, Providencia stuartii are moderately susceptible.|An immunoassay was developed for the detection of sulfamethoxazole reactive IgE antibodies in the sera of patients who experienced life threatening anaphylactic reactions following the ingestion of co-trimoxazole (trimethoprim and sulfamethoxazole). Patients who had significant levels of sulfamethoxazole reactive IgE antibodies in their sera did not have IgE antibodies that reacted with trimethoprim-Sepharose. Inhibition experiments with a number of sulfonamides to determine the fine structural specificities of the sulfamethoxazole reactive IgE antibodies in three patients revealed that sulfamethoxazole and, depending on the serum, sulfamerazine and sulfamethizole, were the most potent inhibitors of IgE binding, whereas the parent sulfonamide, sulfanilamide, was a very poor inhibitor. From a detailed examination of structure-activity relationships, we concluded that the 5-methyl-3-isoxazolyl group on the sulfamethoxazole molecule was the allergenic determinant for all three patients with the 5-methyl group being particularly important for IgE antibody recognition. The assays for the detection of IgE antibodies to sulfamethoxazole and trimethoprim should prove useful for the diagnosis of immediate hypersensitivity to co-trimoxazole and perhaps for monitoring drug therapy in AIDS patients where a high incidence of adverse reactions to co-trimoxazole has been reported.

A high incidence (up to 80%) of adverse reactions to trimethoprim/sulfamethoxazole occurs in AIDS patients receiving this combination for the treatment or prophylaxis of Pneumocystis carinii pneumonia. These adverse reactions have included nausea and vomiting, fever, cutaneous reactions (erythroderma, morbilliform rash, toxic epidermal necrolysis, Stevens-Johnson syndrome), peripheral cytopenias (neutropenia, thrombocytopenia, anemia), hepatitis, and azotemia. Some of these are believed to be hypersensitivity reactions because they recur with drug rechallenge. However, some of the serious toxic reactions associated with trimethoprim/sulfamethoxazole, such as myelosuppression, appear to be dose related. Concomitant zidovudine may exacerbate the myelosusppression.|Skin rashes are among the most common adverse effects caused by trimethoprim/sulfamethoxazole and are most often due to hypersensitivity to the sulfonamide component. These are usually mild, diffuse, maculopapular rashes that are reversible upon discontinuation of the drug. Serious skin reactions, including toxic epidermal necrolysis, erythema multitome, exfoliative dermatitis, and the Stevens-Johnson syndrome, have occurred rarely.|There is no evidence that trimethoprim-sulfamethoxazole, when given in the recommended doses, induces folate deficiency in normal persons. However, the margin between toxicity for bacteria and that for man may be relatively narrow when the cells of the patient are deficient in folate. In such cases, trimethoprim-sulfamethoxazole may cause or precipitate megaloblastosis, leukopenia, or thrombocytopenia. In routine use, the combination appears to exert little toxicity. About 75% of the untoward effects involve the skin. These are typical of those known to be produced by sulfonamides. However, trimethoprim-sulfamethoxazole has been reported to cause up to three times as many dermatological reactions as does sulfisoxazole when given alone.|Patients with AIDS frequently react adversely when trimethoprim-sulfamethoxazole is administered to treat infection due to Pneumocystis carinii. Fever, malaise, rash, and/or pancytopenia were noted in 8 of 18 patients in one series; the incidence was 90% in another. It may be possible to continue therapy if the dose of the combination is lowered and concentrations of trimethoprim in plasma are monitored. Renal allograft recipients may suffer from severe hematological toxicity.|For more Human Toxicity Excerpts (Complete) data for TRIMETHOPRIM/SULFAMETHOXAZOLE (13 total), please visit the HSDB record page.

Abactrim

A mixture of 5 parts of sulfamethoxazole and 1 part trimethoprim.

Sulfamethoxazole content of drug tablets, solutions, and ointments is determined by reverse phase LC using tenary aqueous mobile phase, UV detection at 254 nm, and sulfadimethoxine as internal standard.|HIGH PERFORMANCE LIQUID CHROMATOGRAPHIC DETERMINATION OF TRIMETHOPRIM & SULFONAMIDE COMBINATION IN PHARMACEUTICALS; SPECTROPHOTOMETRY AT 230 NM.

Trimethoprim and sulfamethoxazole concn in serum and urine are measured by HPLC.|A simple and rapid method is developed for the analysis of sulfamethoxazole in human plasma and urine by HPLC. It involves minimal sample preparation and single wavelength monitoring. The detection limit of the method is 0.1 ug/ml, and covers the entire concn range normally encountered therapeutically.

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