ORIPRIM® (Co-Trimoxazole BP)
Sulfamethoxazole and Trimethoprim is a synthetic antibacterial combination product available in DS (double strength) tablets, each containing 800mg sulfamethoxazole and 160 mg trimethoprim. Sulfamethoxazole is N-(5-methyl-3-isioxazoly) sulfanilamide; the molecular formula is C10H11N3O3S. It is an almost white, odorless, tasteless compound with a molecular weight of 253.28. Trimethoprim is 2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine; the molecular formula is C14H16N4O3.
Co-Trimoxazole is rapidly absorbed following oral administration. Both sulfamethoxazole and trimethoprim exist in the blood as unbound, protein-bound, and metabolized forms; sulfamethoxazole also exists as the conjugated form. Sulfamethoxazole is metabolized in humans to at least 5 metabolites: the N4-acetyl-, N4-hydroxy-, 5-methylhydroxy-, N4-acetyl-5methylhydroxy- sulfamethoxazole metabolites, and an N-glucuronide conjugate. The formation of N4-hydroxy metabolite is mediated via CYP2C9.
Trimethoprim is metabolized in vitro to 11 different metabolites, of which, five are glutathione adducts and six are oxidative metabolites, including the major metabolites, 1- and-3-oxides and the 3- and 4-hydroxy derivatives.
The free forms of sulfamethoxazole and trimethoprim are considered to be the therapeutically active forms. In vitro studies suggest that trimethoprim is a substrate of P-glycoprotein, OCT1 and OCT2, and that sulfamethoxazole is not a substrate of P-glycoprotein.
Approximately 44% of trimethoprim and 70% of sulfamethoxazole are bound to plasma proteins. The presence of 10 mg percent sulfamethoxazole in plasma decreases the protein binding of trimethoprim by an insignificant degree; trimethoprim does not influence the protein binding of suflamethoxazole.
Peak blood levels for the individual components occur 1 to 4 hours after oral administration. The mean serum half-lives of sulfamethoxazole and trimethoprim are 10 and 8 to 10 hours, respectively. However patients with severely impaired renal function exhibit an increase in the half-lives of both components, requiring dosage regimen adjustment.
Detectable amounts of trimethoprim and sulfamethoxazole are present in the blood 24 hours after drug administration. During administration of 160 mg trimethoprim and 800 mg sulfamethoxazole b.i.d., the mean steady-state plasma concentration of trimethoprim was 1.72 mcg/mL. The steady-state minimal plasma levels of free and total sulfamethoxazole were 57.4 mcg/mL and 68.0 mcg/mL, respectively. These steady-state levels were achieved after 3 days of drug administration.
Excretion of sulfamethoxazole and trimethoprim is primarily by the kidneys through both glomerular filtration and tubular secretion. Urine concentrations of both sulfamethoxazole and trimethoprim are considerably higher than the concentrations in the blood. The average percentage of the dose recovered in urine from 0 to 72 hours after a single oral dose is 84.5% for total sulfonamides and 68.8% for free trimethoprim.
Thirty percent of the total sulfonamides is excreted as free sulfamethoxazole, with the remaining as N4-acetylated metabolite. When administered together as Co-Trimoxazole, neither sulfamethoxazole nor trimethoprim affects the urinary excretion pattern of the other.
Both trimethoprim and sulfamethoxazole distribute to sputum, vaginal fluid and middle ear fluid; trimethoprim also distributes to bronchial secretions and both pass the placenta barrier and are excreted in human milk.
Mechanism of action
Sulfamethoxazole inhibits bacterial synthesis of dihydrofolic acid by competing with para-aminobenzoic acid (PABA). Trimethoprim blocks the production of tetrahydrofolic acid from dihydrofolic acid by binding to and reversibly inhibiting the required enzyme, dihydrofolate reductase. Thus, Co-Trimoxazole blocks two consecutive steps in the biosynthesis of nucleic acids and proteins essential to many bacteria.
Dosage and administration
Co-trimoxazole is contraindicated in pediatric patients less than 2 months of age.
Urinary tract infections and Shigellosis in adults and paediatric patients and acute otitis media in paediatric patients: The usual dosage in the treatment of urinary tract infections is one Co-Trimoxazole tablet every 12 hours for 10 to 14 days. An identical daily dosage is used for 5 days in the treatment of Shigellosis
For patients with impaired renal function: When renal function is impaired, a reduced dosage should be employed.
Acute exacerbation of chronic bronchitis in adults: The usual adult dosage in the treatment of acute exacerbation of chronic bronchitis is one Co-Trimoxazole tablet every 12 hours for 14 days
Traveler’s diarrhea in adults: For the treatment of traveler’s diarrhea, the usual adults dosage is on Co-Trimoxazole tablet every 12 hours for 5 days
Pneumocystis jiroveci pneumonia: The recommended dosage for treatment of patients with documented P jiroveci pneumonia is 15 to 20 mg/kg trimethoprim and 75 to 100 mg/kg sulfamethoxazole per 24 hours given in equally divided doses every 6 hours for 14 to 21 days.
Mechanism of resistance
In Vitro studies have shown that bacterial resistance develops more slowly with Trimethoxazole than with either trimethoprim or sulfamethoxazole alone.
Co-Trimoxazole have been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections
Aerobic gram-positive microorganisms: Streptococcus pneumoniae
Aerobic gram-negative microorganisms:
- Escherichia coli
- Klebsiella species
- Enterobacter species
- Haemophilus influenzae
- Morganella morganii
- Proteus mirabilis
- Proteus vulgaris
- Shigella flexneri
- Shigella sonnei
Other organisms: Pneumocystis jiroveci
To reduce the development of drug resistance bacteria and maintain the effectiveness of Co-Trimoxazole and other antibacterial drugs, Co-Trimoxazole should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
Urinary tract infections
For the treatment of urinary tract infections due to susceptible strains of the following organisms: Escherichia coli, Klebsiella species, Enterobacter species, Morganella morganii, Proteus mirabilis and Proteus vulgaris. It is recommended that initial episodes of uncomplicated urinary tract infections be treated with s single effective antibacterial agent rather than the combination.
Acute otitis media
For the treatment of acute otitis media in pediatric patients due to susceptible strains of Streptococcus pneumoniae or Haemophilus influenzae when, in the judgment of the physician, Co-Trimoxazole offers some advantage over the use of other antimicrobial agents. To date, there is limited data on the safety of repeated Co-Trimoxazole in pediatric patients under two years of age. Co-trimoxazole is not indicated for prophylactic or prolonged administration in otitis media at any age.
Acute exacerbation of chronic bronchitis in adults
for the treatment of acute exacerbation of chronic bronchitis due to susceptible strains of Streptococcus pneumoniae or Hemophilus influenzae when, a physician deems that, Co-Trimoxazole could offer some advantage over the use of a single antimicrobial agent.
Traveler’s diarrhea in adults
For the treatment of traveler’s diarrhea due to susceptible strains ofenterotoxigenic E.coli
For the treatment of enteritis caused by susceptible strains of Shigella flexneri and Shigella sonnei when antibacterial therapy is indicated.
Pneumocystis jiroveci Pneumonia
For the treatment of documented Pneumocystis jiroveci pneumonia. For prophylaxis against Pneumocystis jiroveci pneumonia in individuals who are immunosuppressed and considered to be at an increased risk of developing Pneumocystis jiroveci pneumonia.
Co-trimoxazole is contraindicated in patients with a known hypersensitivity to trimethoprim or sulfonamides, in patients with a history of drug-induced immune thrombocytopenia with use of trimethoprim and/or sulfonamides and in patients with documented megaloblastic anaemia due to folate deficiency. Co-trimoxazole is contraindicated in pediatric patients less than 2 months of age. Co-trimoxazole is also contraindicated in patients with marked hepatic damage or with severe renal insufficiency when renal function status cannot be monitored.
some epidemiologic studies suggest that exposure sulfamethoxazole/trimethoprim during pregnancy may be associated with an increased risk of congenital malformations, particularly neural tube defects, cardiovascular malformations, urinary tract defects, oral clefts, and club foot. If sulfamethoxazole/ trimethoprim is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be advised of the potential hazards to the fetus.
Sulfamethoxazole/ trimethoprim-induced thrombocytopenia may be an immune mediated disorder. Severe cases of thrombocytopenia that are fetal or life threatening have been reported. Thrombocytopenia usually resolves within a week upon discontinuation of sulfamethoxazole/ trimethoprim.
Streptococcal infections and Rheumatic fever
The sulfonamides should not be used for the treatment of group A beta-hemolytic streptococcal infections. In an established infection, they will not eradicated the streptococcus and, therefore, will not prevent sequelae such as rheumatic fever.
Clostridium difficile associated diarrhea
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Co-Trimoxazole, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C.difficile.
C.difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C.difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use.
Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
Development of drug resistance bacteria
Prescribing Co-trimoxazole in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistance bacteria.
Co-trimoxazole should be given with caution to patients with impaired renal or hepatic function, to those with possible folate deficiency (e.g., the elderly, chronic alcoholics, patients receiving anticonvulsant therapy, patients with malabsorption syndrome and patients in malnutrition states), and to those with severe allergy or bronchial asthma.
In glucose-6-phosphate dehydrogenase deficient individuals, hemolysis may occur. This reaction is frequently dose-related.
Cases of hypoglycemia in non-diabetic patients treated with sulfamethoxazole/trimethoprim have been reported, usually occurring after a few days of therapy. Patients with renal dysfunction, liver disease, malnutrition or those receiving high doses of Co-trimoxazole are particularly at risk.
Trimethoprim has been noted to impair phenylalanine metabolism, but is of no significance in phenylketonuric patients on appropriate dietary restriction.
Prophyria and Hypothyroidism
As with all drugs containing sulfonamides, caution is advisable in patients with prophyria or thyroid dysfunction.
Trimethoprim is an inhibitor of CYP2C8 as well as OCT2 transporter. Sulfamethoxazole is an inhibitor of CYP2C9. Caution is recommended when Co-Trimoxazole is co-administered with drugs that are substrates of CYP2C8 and CYP2C9 or OCT2.
In elderly patients concurrently receiving certain diuretics; primarily thiazides, an increased incidence of thrombocytopenia with purpura has been reported. In the literature, two cases of hyperkalemia in elderly patients have been reported after concomitant intake of trimethoprim/sulfamethoxazole and an angiotensin converting enzyme inhibitor.
It has been reported that Co-trimoxazole may prolong the prothrombin time in patients who are receiving the anticoagulant warfarin (a CYP2C9 substrate).
Co-trimoxazole may inhibit the hepatic metabolism of phenytoin (a CYP2C9 substrate). Co-trimoxazole, given at a common clinical dosage, increased the phenytoin half-life by 39% and decreased the phenytoin metabolic clearance rate by 27%.
Drug/laboratory test interactions
Co-trimoxazole specifically the trimethoprim component, can interfere with a serum methotrexate assay as determined by the competitive binding protein technique (CBPA) when a bacterial dihydrofolate reductase is used as the binding protein. No interference occurs, however, if methotrexate is measured by a radioimmunoassay (RIA). The presence of trimethoprim and sulfamethoxazole may also interfere with the Jaffe’ alkaline picrate reaction assay for creatinine, resulting in over estimations of about 10% in the range of normal values.
The most common adverse effects are gastrointestinal disturbance (nausea, vomiting and anorexia) and allergic skin reactions (such as rash and urticaria). Fatalities associated with the administration of sulfonamides, although rare, have occurred due to severe reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, other blood dyscrasias and hypersensitivity of the respiratory tract