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Co-trimoxazole [Bactrim 400+80mg, 800+160mg] Tablets

Co-trimoxazole is a synergistic fixed combination of sulfamethoxazole (an intermediate-acting antibacterial sulfonamide), and trimethoprim; both sulfamethoxazole and trimethoprim are synthetic folate-antagonist anti-infectives.

Cautions

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The most frequent adverse effects of co-trimoxazole are adverse GI effects (nausea, vomiting, anorexia) and sensitivity skin reactions (e.g., rash, urticaria), each reportedly occurring in about 3.5% of patients. The incidence and severity of these adverse reactions are generally dose related, and adverse reactions may occasionally be obviated by a reduction in dosage. Hypersensitivity and hematologic reactions are the most serious adverse effects of co-trimoxazole, reportedly occurring in less than 0.5% of patients.

Fatal hypersensitivity reactions, including Stevens-Johnson syndrome and erythema multiforme, have occurred in several children who received co-trimoxazole. Deaths associated with hypersensitivity reactions, fulminant hepatocellular necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias have occurred with the administration of sulfonamides.

The frequency of some co-trimoxazole-induced adverse effects, including rash (usually diffuse, erythematous, and maculopapular), fever, leukopenia (neutropenia), thrombocytopenia, hyperkalemia, hyponatremia, and increased serum aminotransferase concentrations, is substantially higher in patients with acquired immunodeficiency syndrome (AIDS) than in other patients.Such adverse effects have occurred in up to 80% of AIDS patients receiving the drug, usually during the second week of therapy, but generally have been reversible following discontinuance of co-trimoxazole therapy. The exact mechanism(s) of this increased risk of co-trimoxazole toxicity has not been determined, but may be immunologically based.

While it has been suggested that glutathione deficiency in HIV-infected patients and resultant accumulation of reactive hydroxylamine metabolites of sulfamethoxazole may be involved in this increased risk, this hypothesis requires confirmation. These adverse effects usually recur following rechallenge with the drug, although cautious desensitization has been performed successfully in some patients in whom continued co-trimoxazole therapy was considered necessary. Limited evidence suggests that white AIDS patients may be at greater risk of these adverse effects than black AIDS patients, indicating that genetic factors may also be important. Some evidence also indicates that co-trimoxazole may be better tolerated in HIV-infected children than adults.

Adverse effects usually are less severe in patients receiving the drug for prophylaxis of Pneumocystis jiroveci (formerly Pneumocystis carinii) pneumonia compared with those receiving co-trimoxazole for treatment of the disease.

Sensitivity Reactions

Epidermal necrolysis, exfoliative dermatitis, Stevens-Johnson syndrome, serum sickness, and allergic myocarditis are the most severe allergic reactions reported with sulfonamides alone or co-trimoxazole. Other reported allergic and anaphylactoid reactions include anaphylaxis, arthralgia, erythema multiforme, Schonlein-Henoch purpura, pruritus, urticaria, periorbital edema, corneal ring infiltrates, conjunctival and scleral injection, and photosensitivity. Mild to moderate rashes, when they occur, usually appear within 7-14 days after initiation of co-trimoxazole. Rashes are generally erythematous, maculopapular, morbilliform, and/or pruritic. Generalized pustular dermatosis and fixed drug eruption also have been reported. Patients with AIDS appear to be at particular risk of developing rash (usually diffuse, erythematous, and maculopapular) during co-trimoxazole therapy.

Hematologic Effects

Co-trimoxazole-induced hematologic toxicity has resulted rarely in aplastic anemia, agranulocytosis, leukopenia, neutropenia, thrombocytopenia, eosinophilia, megaloblastic and/or hemolytic anemia, methemoglobinemia, pancytopenia, hypoprothrombinemia, and/or purpura. Hematologic toxicity may occur with increased frequency in folate-depleted patients including geriatric, malnourished, alcoholic, pregnant, or debilitated patients; in patients receiving folate antimetabolites (e.g., phenytoin) or diuretics; in patients with hemolysis or impaired renal function; and in patients receiving co-trimoxazole in high dosages and/or for prolonged periods (e.g., longer than 6 months). In geriatric patients receiving some diuretics (principally thiazides) and co-trimoxazole concomitantly, an increased incidence of thrombocytopenia with purpura has been reported. The risk of leukopenia, neutropenia, and thrombocytopenia also appear to be increased in patients with AIDS.

Folic acid may be administered during co-trimoxazole therapy and will not interfere with the drug's antibacterial effect. Megaloblastic anemia and occasionally neutropenia and thrombocytopenia can be reversed by administration of leucovorin (folinic acid). If signs of bone marrow suppression occur in patients receiving co-trimoxazole, leucovorin should be administered; some clinicians recommend a leucovorin dosage of 5-15 mg daily until normal hematopoiesis is restored.

GI Effects

Nausea, vomiting, and anorexia are the most frequent GI reactions to co-trimoxazole, but glossitis, stomatitis, abdominal pain, pancreatitis (sometimes fatal), pseudomembranous enterocolitis, and diarrhea also have been reported.

Local Effects

Pain, local irritation, inflammation, and rarely thrombophlebitis may occur with IV co-trimoxazole, especially if extravascular infiltration of the drug occurs.

Nervous System Effects

Adverse nervous system effects of co-trimoxazole include headache, insomnia, fatigue, apathy, nervousness, muscle weakness, ataxia, vertigo, tinnitus, peripheral neuritis, mental depression, aseptic meningitis, seizures, and hallucinations. Tremor and other neurologic manifestations (e.g., ataxia, ankle clonus, apathy) developed during co-trimoxazole therapy in several patients with AIDS; although such manifestations also have been associated with the underlying disease process, they resolved in these patients within 2-3 days after discontinuing the drug.

Other Adverse Effects

Other adverse effects reported with co-trimoxazole therapy include drug fever, chills, myalgia, hepatitis (including cholestatic jaundice and hepatic necrosis), increased serum aminotransferase and bilirubin concentrations, renal failure, interstitial nephritis, increased BUN and serum creatinine concentrations, crystalluria and stone formation, toxic nephrosis with oliguria and anuria, pulmonary infiltrates, cough, shortness of breath, hypotension, periarteritis nodosa, and a positive lupus erythematosus phenomenon. Rhabdomyolysis has been reported rarely in patients receiving co-trimoxazole, mainly in HIV-infected patients. Sulfonamides chemically resemble some goitrogens, diuretics (acetazolamide, thiazides), and oral hypoglycemic agents, and cross-sensitivity may exist with these agents. Diuresis and hypoglycemia have been reported rarely in patients receiving sulfonamides.

Precautions and Contraindications

Co-trimoxazole [Bactrim 400+80mg, 800+160mg] Tablets shares the toxic potentials of sulfonamides and trimethoprim, and the usual precautions associated with therapy with these drugs should be observed. (See Cautions in the Sulfonamides General Statement 8:12. and in Trimethoprim 8:36.) Fatalities, although rare, have occurred in patients receiving sulfonamides, secondary to severe reactions induced by the drugs, including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias.

Such fatal reactions also have been reported when sulfonamides were used in fixed combination with other drugs (e.g., with trimethoprim or erythromycin). Although probably rare, the precise incidence of severe dermatologic, hematologic, and hepatic effects with these combinations, including co-trimoxazole, is not known. Patients receiving co-trimoxazole should be monitored appropriately for the possible occurrence of such potentially severe reactions, and the drug should be discontinued at the first sign of such a reaction. The development of rash, sore throat, fever, pallor, arthralgia, cough, shortness of breath, purpura, or jaundice may be an early sign of a serious adverse reaction.

Co-trimoxazole should be used with caution in patients with impaired renal or hepatic function, possible folate deficiency (e.g., geriatric individuals, chronic alcoholics, patients receiving anticonvulsants, malnourished patients, those with malabsorption syndrome), with severe allergy or bronchial asthma, or with possible folate or glucose-6-phosphate-dehydrogenase (G-6-PD) deficiency.

Patients should be warned to report any early signs and symptoms of a serious hematologic disorder, including fever, sore throat, pallor, jaundice, or purpura. The manufacturers recommend that a complete blood count be obtained frequently in patients receiving co-trimoxazole, especially if signs and symptoms of blood disorders occur. The drug should be discontinued at the first appearance of rash or if any reduction in formed blood elements occurs.

Leucovorin (folinic acid) should be administered if bone marrow depression occurs, especially if megaloblastic anemia, neutropenia, or thrombocytopenia occurs. Patients with acquired immunodeficiency syndrome (AIDS) who receive co-trimoxazole should be carefully monitored, since they appear to have a particularly high incidence of adverse reactions to the drug (especially fever and adverse dermatologic and hematologic reactions).

Urinalysis and careful microscopic examination of the urine should be performed in patients receiving co-trimoxazole, especially patients with impaired renal function. Patients receiving co-trimoxazole should be cautioned to maintain adequate fluid intake to prevent crystalluria and stone formation.

Co-trimoxazole should be used with caution in geriatric patients, particularly when complicating conditions (e.g., impaired renal and/or hepatic function, concomitant use of other drugs) are present, since these patients may have an increased risk of severe adverse reactions to the drug. Severe adverse dermatologic reactions, generalized bone marrow suppression, and a specific decrease in platelets (with or without purpura) are the most frequently reported severe adverse effects of the drug in geriatric patients. Co-trimoxazole also should be used with caution in patients with a history of hypersensitivity to sulfonamide-derivative drugs (e.g., acetazolamide, thiazides, tolbutamide), since cross-sensitivity may exist with these agents.

Commercially available formulations of co-trimoxazole for injection concentrate contain sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low; such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.

Co-trimoxazole [Bactrim 400+80mg, 800+160mg] Tablets is contraindicated in patients with known hypersensitivity to trimethoprim or sulfonamides, with marked hepatic damage or severe renal impairment when renal function status cannot be monitored, or with documented megaloblastic anemia secondary to folate deficiency. However, cautious desensitization has been performed in some hypersensitive patients in whom co-trimoxazole therapy was considered necessary. The manufacturers recommend that the drug not be used in patients with creatinine clearances less than 15 mL/minute.

Pediatric Precautions

The manufacturers of co-trimoxazole recommend that the drug not be used in infants younger than 2 months of age. Commercially available co-trimoxazole injections contain benzyl alcohol as a preservative. Although a causal relationship has not been established, administration of injections preserved with benzyl alcohol has been associated with toxicity in neonates. Toxicity appears to have resulted from administration of large amounts (i.e., about 100-400 mg/kg daily) of benzyl alcohol in these neonates. Safety and efficacy of repeated courses of co-trimoxazole therapy in children younger than 2 years of age, except those with documented P. carinii infections, have not been fully evaluated. Co-trimoxazole should be used with caution in children who have the fragile X chromosome associated with mental retardation, because folate depletion may worsen the psychomotor regression associated with the disorder.

Mutagenicity and Carcinogenicity

Bacterial mutagenic studies have not been performed with co-trimoxazole. Trimethoprim did not exhibit mutagenic activity in the Ames test. No chromosomal damage was observed in cultured Chinese hamster ovary cells at concentrations approximately 500 times human plasma concentrations, but a low level of chromosomal damage was observed in some studies at concentrations approximately 1000 times human plasma concentrations. No chromosomal abnormalities were observed in human leukocytes cultured in vitro at trimethoprim concentrations up to 20 times human steady-state plasma concentrations. In addition, no chromosomal abnormalities were found in peripheral lymphocytes of patients receiving 320 mg of trimethoprim in combination with up to 1600 mg of sulfamethoxazole daily for as long as 112 weeks.

Long-term studies in animals to evaluate the carcinogenic potential of co-trimoxazole have not been performed.

Pregnancy, Fertitlity and Lactation

Trimethoprim and sulfamethoxazole, alone and in combination, have produced teratogenic effects, manifested principally as cleft palate, in some (but not all) studies in rats receiving dosages exceeding the usual human dosages. In addition, in some rabbit studies, an overall increase in fetal loss was associated with trimethoprim doses 6 times the usual human dose.

Although there are no adequate and controlled studies to date in humans, studies in pregnant women suggest that the incidence of congenital abnormalities in those who received co-trimoxazole was similar to that in those who received a placebo; there were no abnormalities in 10 children whose mothers had received the drug during the first trimester. In one report, there were no congenital abnormalities in 35 children whose mothers had received co-trimoxazole at the time of conception or shortly thereafter. Because co-trimoxazole crosses the placenta and may interfere with folic acid metabolism, the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus. Because sulfonamides may cause kernicterus in neonates, the manufacturers state that use of co-trimoxazole in pregnant women is contraindicated.

The effect of co-trimoxazole on fertility in humans is not known. Reproduction studies in rats using oral trimethoprim (as co-trimoxazole) dosages up to 70 mg/kg daily have not revealed evidence of impaired fertility.

Co-trimoxazole is distributed into milk. Because co-trimoxazole may interfere with folic acid metabolism, the drug should be used in nursing women only if the potential benefits justify the possible risks to the infant. Because sulfonamides may cause kernicterus in infants younger than 2 months of age, a decision should be made whether to discontinue nursing or co-trimoxazole or to use an alternative drug, taking into account the importance of co-trimoxazole to the woman.

Drug Interactions

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Warfarin

Co-trimoxazole [Bactrim 400+80mg, 800+160mg] Tablets may prolong the prothrombin time (PT) of patients receiving concomitant warfarin by inhibiting metabolic clearance of warfarin. If co-trimoxazole is used with warfarin, dosage of warfarin and PT must be monitored carefully.

Other Drugs

Because co-trimoxazole possesses anti-folate properties, the drug could theoretically increase the incidence of folate deficiencies induced by other drugs such as phenytoin when used concomitantly. Co-trimoxazole inhibits the metabolism of phenytoin. Concomitant administration of usual dosages of co-trimoxazole and phenytoin can increase the half-life of phenytoin by 39% and decrease metabolic clearance rate of phenytoin by 27%. If the drugs are administered concomitantly, the possibility of an increase in effects associated with phenytoin should be considered.

Co-trimoxazole should be used with caution in patients receiving methotrexate, since sulfonamides can displace methotrexate from plasma protein-binding sites resulting in increased free methotrexate concentrations.

Marked but reversible nephrotoxicity has been reported in renal transplant recipients receiving co-trimoxazole together with cyclosporine.

Increases in serum digoxin concentrations can occur in patients receiving co-trimoxazole; this interaction is more likely to occur in geriatric patients. Serum digoxin concentrations should be monitored in patients receiving digoxin and co-trimoxazole.

Increased plasma sulfamethoxazole concentration may occur in patients receiving indomethacin.

Megaloblastic anemia has been reported in patients receiving co-trimoxazole and pyrimethamine dosages exceeding 25 mg weekly (for malaria prophylaxis).

Concomitant administration of tricyclic antidepressants and co-trimoxazole may decrease the efficacy of the antidepressant.

Like other sulfonamides, co-trimoxazole potentiates the effect of oral hypoglycemic agents.

Toxic delirium has been reported in one individual following administration of co-trimoxazole and amantadine.

Acute Toxcicity

Pathogenesis

Overdosage with co-trimoxazole may produce symptoms of nausea, vomiting, diarrhea, mental depression, confusion, facial swelling, headache, bone marrow depression, and slight elevations of serum aminotransferases (transaminases).

In acute overdosage with oral co-trimoxazole, the stomach should be emptied immediately by inducing emesis or by lavage. Supportive and symptomatic treatment should be initiated. Patients should be monitored with blood counts and other appropriate laboratory studies (e.g., serum electrolyte concentrations). Hemodialysis may remove only moderate amounts of the drug; peritoneal dialysis is not effective in enhancing the elimination of co-trimoxazole.

Mechanism of Action

Co-trimoxazole (Bactrim 400+80mg, 800+160mg) Tablets

Co-trimoxazole usually is bactericidal. Of its components, sulfamethoxazole is bacteriostatic and trimethoprim usually is bactericidal. Co-trimoxazole acts by sequentially inhibiting enzymes of the folic acid pathway; sulfamethoxazole inhibits the formation of dihydrofolic acid from p-aminobenzoic acid and, by inhibiting dihydrofolate reductase, trimethoprim inhibits the formation of tetrahydrofolic acid from dihydrofolic acid. By inhibiting synthesis of tetrahydrofolic acid, the metabolically active form of folic acid, co-trimoxazole inhibits bacterial thymidine synthesis.

Sequential inhibition by co-trimoxazole of two steps in the folic acid pathway appears to be responsible for the antibacterial synergism of the trimethoprim-sulfamethoxazole combination. For most organisms, optimum synergistic antibacterial action occurs in vitro at a trimethoprim:sulfamethoxazole ratio of about 1:20, which is also the approximate peak serum concentration ratio of the 2 drugs achieved following oral or IV administration of co-trimoxazole. Synergistic activity also has been observed in vitro at trimethoprim:sulfamethoxazole ratios of 1:1-1:40.

Susceptibility of organisms to trimethoprim usually is more critical to the efficacy of co-trimoxazole than is susceptibility to sulfamethoxazole. Many organisms that are resistant to sulfamethoxazole but susceptible or only moderately susceptible to trimethoprim will show synergistic antibacterial response to co-trimoxazole. However, for Neisseria gonorrhoeae, susceptibility to sulfamethoxazole is required for antibacterial response to co-trimoxazole.

Spectrum

In Vitro Susceptibility Testing

For most organisms, inoculum size may influence the result of in vitro co-trimoxazole susceptibility tests. Accurate in vitro susceptibility testing requires that thymidine not be present in the growth medium or that the medium be supplemented with thymidine phosphorylase to inactivate any thymidine that might be present.

The National Committee for Clinical Laboratory Standards (NCCLS) states that, if results of in vitro susceptibility testing indicate that a clinical isolate is susceptible to co-trimoxazole, then an infection caused by this strain may be appropriately treated with the dosage of the drug recommended for that type of infection and infecting species, unless otherwise contraindicated. If results indicate that a clinical isolate has intermediate susceptibility to co-trimoxazole, then the strain has a minimum inhibitory concentration (MIC) that approaches usually attainable blood and tissue concentrations and response rates may be lower than for strains identified as susceptible.

Therefore, the intermediate category implies clinical applicability in body sites where the drug is physiologically concentrated or when a high dosage of the drug can be used. This intermediate category also includes a buffer zone which should prevent small, uncontrolled technical factors from causing major discrepancies in interpretation, especially for drugs with narrow pharmacotoxicity margins. If results of in vitro susceptibility testing indicate that a clinical isolate is resistant to co-trimoxazole, the strain is not inhibited by systemic concentrations of the drug achievable with normal dosage schedules and/or MICs fall in the range where specific microbial resistance mechanisms are likely and efficacy has not been reliable in clinical studies.

Disk Susceptibility Tests

When the disk-diffusion procedure is used for susceptibility testing, a 1.25-mcg trimethoprim/23.-mcg sulfamethoxazole disk should be used.

When the disk-diffusion susceptibility test is performed according to NCCLS standardized procedures, Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter, or Staphylococci with growth inhibition zones of 16 mm or greater are susceptible to co-trimoxazole, those with zones of 11-15 mm have intermediate susceptibility, and those with zones of 10 mm or less are resistant to the drug.

When disk-diffusion susceptibility testing is performed according to NCCLS standardized procedures using Haemophilus test medium (HTM), Haemophilus with growth inhibition zones of 16 mm or greater are susceptible to co-trimoxazole, those with zones of 11-15 mm have intermediate susceptibility, and those with zones of 10 mm or less are resistant to the drug.

When testing susceptibility of S. pneumoniae according to NCCLS standardized procedures using Mueller-Hinton agar (supplemented with 5% defibrinated sheep blood), S. pneumoniae with growth inhibition zones of 19 mm or greater are susceptible to co-trimoxazole, those with zones of 16-18 mm have intermediate susceptibility, and those with zones of 15 mm or less are resistant to the drug.

When the disk diffusion procedure is performed according to NCCLS standardized procedures, Vibrio cholerae with growth inhibition zones of 16 mm or greater are susceptible to co-trimoxazole, those with zones of 11-15 mm have intermediate susceptibility, and those with zones of 10 mm or less are resistant to the drug.

Dilution Susceptibility Tests

When dilution susceptibility testing (agar or broth dilution) is performed according to NCCLS standardized procedures, Enterobacteriaceae, Ps. aeruginosa, other non-Enterobacteriaceae gram-negative bacilli (e.g., Acinetobacter, Stenotrophomonas maltophilia, other Pseudomonas spp), or Staphylococcus with MICs equal to or less than 2 mcg/mL of trimethoprim and 38 mcg/mL of sulfamethoxazole are susceptible to co-trimoxazole and those with MICs equal to or greater than 4 mcg/mL of trimethoprim and 76 mcg/mL of sulfamethoxazole are resistant to the drug.

When dilution susceptibility testing for Haemophilus is performed according to NCCLS standardized procedures using HTM, Haemophilus with MICs equal to or less than 0.5 mcg/mL of trimethoprim and 9.5 mcg/mL of sulfamethoxazole are susceptible to co-trimoxazole and those with MICs equal to or greater than 4 mcg/mL of trimethoprim and 76 mcg/mL of sulfamethoxazole are resistant to the drug. Haemophilus with an MIC of 1-2 mcg/mL of trimethoprim and 19-38 mcg/mL of sulfamethoxazole have intermediate susceptibility to co-trimoxazole. These same interpretive criteria are used when dilution susceptibility testing for S. pneumoniae is performed according to NCCLS standardized procedures using cation-adjusted Mueller-Hinton broth (with 2-5% lysed horse blood).

When dilution susceptibility testing is performed according to NCCLS standardized procedures, V. cholerae with MICs equal to or less than 2 mcg/mL of trimethoprim and 38 mcg/mL of sulfamethoxazole are susceptible to co-trimoxazole and those with MICs of 4 mcg/mL or greater of trimethoprim and 76 mcg/mL or greater are resistant to the drug.

Gram-positive Aerobic Bacteria

In vitro, when the optimum 1:20 synergistic ratio of trimethoprim: sulfamethoxazole is used, trimethoprim concentrations of 0.05-0.15 mcg/mL and sulfamethoxazole concentrations of 0.95-2.85 mcg/mL inhibit most strains of Streptococcus pneumoniae. Many strains of Staphylococcus aureus, group A b-hemolytic streptococci (Streptococcus pyogenes), and Nocardia also are susceptible to co-trimoxazole. Some strains of enterococci, including some E. faecalis (formerly Streptococcus faecalis), are not susceptible to the drug; to accurately determine susceptibility of enterococci to co-trimoxazole, the growth medium must be free of thymidine and other sources of exogenous folate. Some group A b-hemolytic streptococci may not respond to co-trimoxazole in tonsillopharyngeal infections, possibly because of inadequate concentrations of the drug in this area.

Bacillus anthracis strains with in vitro resistance to sulfamethoxazole or trimethoprim have been reported, and these anti-infectives should not be used in the treatment of B. anthracis infections (i.e., anthrax).

Gram-negative Aerobic Bacteria

Co-trimoxazole is active in vitro against common gram-negative bacteria associated with urinary tract infections, including most Enterobacteriaceae. The drug is not active against Pseudomonas aeruginosa.

Generally, co-trimoxazole is active in vitro against most of the following Enterobacteriaceae: Acinetobacter, Enterobacter, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Salmonella, and Shigella. When the optimum 1:20 synergistic ratio of trimethoprim:sulfamethoxazole is used in vitro, the MIC for most of these organisms is 1.5 mcg/mL or less of trimethoprim; for sulfamethoxazole, MICs for P. mirabilis, Shigella, and Salmonella generally are 2.85 mcg/mL or less, for E. coli are 9.5 mcg/mL or less, and for Klebsiella and Enterobacter are 28. mcg/mL or less. Co-trimoxazole also is active in vitro against Haemophilus influenzae (including ampicillin-resistant strains), H. ducreyi, and Neisseria gonorrhoeae.Approximately 70% of indole-positive Proteus and 50% of Providencia and Serratia strains are susceptible to Co-trimoxazole [Bactrim 400+80mg, 800+160mg] Tablets.

Anaerobic Bacteria

Co-trimoxazole generally is considered inactive against most strains of Bacteroides, and appears to have no activity against strict anaerobes (e.g., Clostridium).

Protozoa

Co-trimoxazole is active in vitro and in vivo against Pneumocystis carinii.

Resistance

In vitro, resistance develops more slowly to co-trimoxazole than to trimethoprim or sulfamethoxazole alone.

Use of sulfamethoxazole alone results in rapid selection of sulfonamide-resistant fecal coliforms. As many as 50% of hospital-isolated and 20% of community-isolated Escherichia coli are resistant to sulfonamides, including sulfamethoxazole.

Resistance to sulfamethoxazole in gram-negative bacteria is usually plasmid mediated. In many organisms (e.g., E. coli, Neisseria meningitis, Streptococcus pneumoniae, Plasmodium falciparum), point mutations in conserved regions of dihydropteroate synthase (DHPS), an essential enzyme for folate biosynthesis, confer sulfonamide resistance.

Mutations in DHPS also have been identified in Pneumocystis carinii isolates obtained from HIV-infected patients, including some patients who had not previously received a sulfonamide, and these mutations are being reported with increasing frequency in this organism. It is unclear whether DHPS mutations in P. carinii are associated with resistance to co-trimoxazole since P. carinii pneumonia has been effectively treated with co-trimoxazole in some patients despite the presence of DHPS mutants. However, there is some evidence from a study in HIV-infected patients with P. carinii pneumonia that presence of strains with DHPS mutations may be associated with decreased survival.

Resistance to trimethoprim has been shown to occur by several mechanisms, most often chromosomally mediated, but also rarely involving mutation of bacteria to thymidine-dependent strains or plasmid-mediated resistance involving altered production or sensitivity of bacterial dihydrofolate reductase. Plasmid-mediated resistance to trimethoprim has been shown to be transferable among some bacterial strains; plasmid-mediated resistance to trimethoprim usually results in concomitant coding for sulfonamide resistance. Thymidine-dependent strains account for less than 1% of trimethoprim resistance, and chromosomal- and plasmid-mediated resistance accounts for approximately 90% and 10% of reported resistant strains, respectively.

Resistant strains of Enterobacteriaceae, especially E. coli, Klebsiella, and Proteus, have occurred during therapy with co-trimoxazole. Strains of Klebsiella and Proteus that are only moderately susceptible to co-trimoxazole in vitro at the beginning of therapy appear to be especially likely to develop resistance during therapy. The incidence of trimethoprim resistance among Enterobacteriaceae in fecal flora and associated with urinary tract infections has been reported to range from 8-38% in some hospitals and to range from 30-100% among fecal Enterobacteriaceae following 2 weeks of co-trimoxazole therapy. In a study in Mexico, more than 95% of fecal E. coli resistant to trimethoprim also were resistant to sulfamethoxazole, but the resistant strains were not associated with clinical infection.Strains of Enterobacteriaceae and S. pneumoniae resistant to trimethoprim, but sensitive to sulfonamides and penicillin, respectively, have been reported.

Although co-trimoxazole previously was considered nearly uniformly active against H. influenzae, resistant strains have been reported rarely. In a national collaborative study of H. influenzae isolates from 1986, the incidence of co-trimoxazole resistance was about 1%, including several strains that also were resistant to ampicillin (b-lactamase mediated), chloramphenicol, and tetracycline.

Pharmacokinetics

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Absorption

Co-trimoxazole is rapidly and well absorbed from the GI tract. Peak serum concentrations of 1-2 mcg/mL of trimethoprim and 40-60 mcg/mL of unbound sulfamethoxazole are reached 1-4 hours after a single oral dose of co-trimoxazole containing 160 mg of trimethoprim and 800 mg of sulfamethoxazole. Following multiple-dose oral administration, steady-state peak serum concentrations of co-trimoxazole usually are 50% greater than those obtained after single-dose administration of the drug. Following oral administration of the fixed-ratio combination preparation, the trimethoprim:sulfamethoxazole ratio of mean steady-state serum concentrations usually is about 1:20.

Mean peak steady-state serum concentrations of approximately 9 and 105 mcg/mL of trimethoprim and sulfamethoxazole, respectively, are reached after IV infusion of 160 mg of trimethoprim and 800 mg of sulfamethoxazole every 8 hours in adults with normal renal function. Steady-state trough concentrations reached with this IV dose are approximately 6 mcg/mL of trimethoprim and 70 mcg/mL of sulfamethoxazole.

Distribution

Co-trimoxazole is widely distributed into body tissues and fluids, including sputum, aqueous humor, middle ear fluid, prostatic fluid, vaginal fluid, bile, and CSF; trimethoprim also distributes into bronchial secretions. Trimethoprim has a larger volume of distribution (Vd) than does sulfamethoxazole. In adults, apparent Vds 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 CSF 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.

Trimethoprim is approximately 44% and sulfamethoxazole is approximately 70% bound to plasma proteins.

Co-trimoxazole readily crosses the placenta. Amniotic fluid concentrations of trimethoprim and sulfamethoxazole are reported to be 80 and 50%, respectively, of concurrent maternal serum concentrations. Co-trimoxazole is distributed into milk. Trimethoprim and sulfamethoxazole concentrations in milk are approximately 125 and 10%, respectively, of concurrent maternal serum concentrations.

Elimination

Trimethoprim and sulfamethoxazole have serum half-lives of approximately 8-11 and 10-13 hours, respectively, in adults with normal renal function. In adults with creatinine clearances of 10-30 and 0-10 mL/minute, serum half-life of trimethoprim may increase to 15 and greater than 26 hours, respectively. In adults with chronic renal failure, sulfamethoxazole half-life may be 3 times that in patients with normal renal function. Trimethoprim serum half-lives of about 7.7 and 5.5 hours have been reported in children less than 1 year of age and between 1 and 10 years of age, respectively.

Co-trimoxazole [Bactrim 400+80mg, 800+160mg] Tablets 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.

Only small amounts of trimethoprim are excreted in feces via biliary elimination. Trimethoprim and active sulfamethoxazole are moderately removed by hemodialysis.

Chemistry and Stability

Chemistry

Co-trimoxazole is a fixed combination of sulfamethoxazole and trimethoprim. Sulfamethoxazole is an intermediate-acting antibacterial sulfonamide. Both sulfamethoxazole and trimethoprim are synthetic folate-antagonist anti-infectives. Co-trimoxazole contains a 5:1 ratio of sulfamethoxazole to trimethoprim. Potency of co-trimoxazole is expressed in terms of the trimethoprim content.

Trimethoprim occurs as white to cream-colored, bitter-tasting, odorless crystals or crystalline powder and sulfamethoxazole occurs as a white to off-white, practically odorless, crystalline powder. Sodium hydroxide is added during manufacture of co-trimoxazole for injection concentrate to adjust pH to 10. Co-trimoxazole oral suspension has a pH of 5-6.5.

Stability

Co-trimoxazole for injection concentrate should be stored at 15-25°C or 15-30°C, depending on the formulation (the manufacturers' recommendations should be followed) 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 manufacturers' recommendations should be followed), and the tablets should be stored in well-closed, light-resistant containers at 15-30°C.

Co-trimoxazole for injection concentrate is physically and chemically compatible with IV solutions of 5% dextrose; admixed solutions of co-trimoxazole in 5% dextrose that are cloudy or contain a precipitate should be discarded. Because of the potential for incompatibility, the manufacturers state that co-trimoxazole IV solutions should not be admixed with other drugs or solutions other than 5% dextrose. Specialized references should be consulted for specific compatibility information.

Co-trimoxazole solutions containing 0.64 mg of trimethoprim and 3.2 mg of sulfamethoxazole per mL of 5% dextrose (1:25 dilution) are stable for 6 hours at room temperature. Co-trimoxazole solutions containing 0.64-0.8 mg of trimethoprim and 3.2-4 mg of sulfamethoxazole per mL of 5% dextrose (1:20 dilution) are stable for 4 hours at room temperature. Co-trimoxazole solutions containing 0.8-1.1 mg of trimethoprim and 4-5.3 mg of sulfamethoxazole per mL of 5% dextrose (1:15 dilution) are stable for 2 hours at room temperature. When mixed as directed in 5% dextrose injection, solutions prepared from ADD-Vantage® vials of the drug are stable for 6 hours at room temperature. Co-trimoxazole solutions in 5% dextrose should not be refrigerated. Prior to infusion, solutions of the drug should be inspected visually and discarded if there is evidence of crystallization or cloudiness.

Following initial entry into a multiple-dose vial of co-trimoxazole for injection concentrate, the manufacturers recommend that the contents be used within 48 hours.

Preparations

Before purchase Co-trimoxazole, you must read how to store

Co-trimoxazole

Oral Suspension Trimethoprim 40 mg/5 mL and Septra® Suspension, (with Sulfamethoxazole 200 mg/5 mL 0.26% alcohol, 0.1% methylparaben, and 0.1% sodium benzoate)

Monarch Septra® Grape Suspension, (with 0.26% alcohol, 0.1% methylparaben, and 0.1% sodium benzoate)

Monarch Sulfatrim® Pediatric Suspension, Alpharma Sulfatrim® Suspension, Alpharma United Research

Tablets Trimethoprim 80 mg and Bactrim®, (scored) Women First Sulfamethoxazole 400 mg HealthCare Septra®, (with povidone; scored) Monarch

Sulfamethoxazole and Trimethoprim Tablets, Teva United Research

Trimethoprim 160 mg and Bactrim® DS, Women First Sulfamethoxazole 800 mg HealthCare Septra® DS, (with povidone; scored) Monarch

Parenteral

For injection Trimethoprim 16 mg/mL and Septra® I.V. Infusion, (with concentrate, for Sulfamethoxazole 80 mg/mL alcohol 10%, benzyl alcohol 1% IV infusion , diethanolamine 0.3%, propylene glycol 40%, and sodium metabisulfite 0.1%)

Monarch Sulfamethoxazole and Trimethoprim Concentrate for Injection, (with alcohol 10%, benzyl alcohol 1%, diethanolamine 0.3%, propylene glycol 40%, and sodium metabisulfite 0.1%) Elkins-Sinn GensiaSicor

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