Co-trimoxazole

General characteristics. Structure:

Active ingredient: 400 mg of sulfamethoxazole, 80 mg of Trimethoprimum in 1 tablet.

Excipients: potato starch, povidone, calcium stearate.

Pharmacological properties:

Pharmacodynamics. The combined antimicrobic medicine. The sulfamethoxazole similar on a structure to paraaminobenzoic acid (PABK), breaks synthesis of dihydrofolic acid in bacterial cells, interfering with inclusion of PABK in its molecule. Trimethoprimum strengthens effect of sulfamethoxazole, breaking recovery of dihydrofolic acid in tetrahydrofolic - the active form of folic acid responsible for protein metabolism and division of a microbic cell.

In vitro is bactericidal drug of a broad spectrum of activity, however sensitivity can depend on the geographic location.

Usually sensitive activators (MPK less than 80 mg/l on sulfamethoxazole): Moraxella (Branhamella) catarrhalis. Haemophilus influenzae (beta lactamazoforming and beta лактамазонеобразующие strains), Haemophilus parainfluenzae, Escherichia coli (including enterotoxigenic strains), Citrobacter spp. (including Citrobacter freundii), Klebsiella spp. (including Klebsiella pneumoniae, Klebsiella oxytoca), Enterobacter cloaceae, Enterobacter aerogenes, Hafnia alvei, Serratia spp. (including Serratia marcescens, Serratia liquefaciens), Proteus mirabilis, Proteus vulgaris, Morganella morganii, Shigella spp. (including Shigella flexneri, Shigella sonnei), Yersinia spp. (including Yersinia enterocolitica), Vibrio cholerae, Edwardsiella tarda, Alcaligenes faecalis, Burkholderia (Pseudomonas) cepacia, Burkholderia (Pseudomonas) pseudomallei.

Clinical experience shows that also Brucella spp can be sensitive., Listeria monocytogenes, Nocardia asteroides, Pneumocystis carinii, Cyclospora cayetanensis.

Partially sensitive activators (MPK of 80-160 mg/l on sulfamethoxazole): Streptococcus pneumoniae (penitsillinochuvstvitelny and resistant to penicillin strains), Haemophilus ducreyi, Providencia spp. (including Providencia rettgeri), Salmonella typhi, Salmonella enteritidis, Stenotrophomonas maltophilia (which was earlier called by Xanthomonas maltophilia), Acinetobacter lwoffii, Acinetobacter baumanii, Aeromonas hydrophila.

Steady activators (MPK more than 160 mg/l on sulfamethoxazole): Mycoplasma spp., Mycobacterium tuberculosis, Treponema pallidum, Pseudomonas aeruginosa.

If drug is appointed empirically, it is necessary to consider local features of stability to drug of possible causative agents of a specific infectious disease.

Pharmacokinetics. At oral administration absorption bystry and almost full – 90%. After a single dose of 160 mg of Trimethoprimum + 800 mg of Cmax sulfamethoxazole of Trimethoprimum – 1,5-3 mkg/ml, and sulfamethoxazole – 40-80 mkg/ml. TCmax is 1-4 h, therapeutic concentration remains 7 h after a single dose.

The volume of distribution of Trimethoprimum makes about 130 l, sulfamethoxazole - about 20 l. Gets through a blood-brain barrier, a placental barrier and into breast milk. In lungs and urine creates the concentration exceeding the content in plasma. Gets into uninflammed tissue of a prostate gland, semen, a vagina secret, the saliva healthy and the inflamed tissue of lungs, bile.

Communication with proteins of plasma – 66% at sulfamethoxazole, at Trimethoprimum – 45%.

It is metabolized in a liver preferential by N4 acetylation and, to a lesser extent, by conjugation with glucuronic acid. Some metabolites have antimicrobic activity.

It is removed by kidneys in the form of metabolites (80% during 72 h) and in not changed look (20% of sulfamethoxazole, 50% of Trimethoprimum) concentration of both active agents in urine are much higher, than in blood; insignificant quantity - through intestines.

T ½ of sulfamethoxazole is 9-11 h, Trimethoprimum – 10-12 h; at children - significantly less also depends on age: till 1 year – 7-8 h, 1 - 10 years – 5 - 6 h. At elderly and patients and/or with a renal failure (KK of 15-20 ml/min.) T ½ increases that demands dose adjustment.

Indications to use:

Co-trimoxazole has to be applied only at treatment of the infections caused by microorganisms, highly sensitive to it.

- The uncomplicated infections of urinogenital bodies in early stages including caused by highly sensitive strains of Escherichia coli, Klebsiella spp., Enterobacter spp., Morganella morganii, Proteus mirabilis and Proteus vulgaris;

- respiratory infections: an exacerbation of the chronic bronchitis caused by susceptible Streptococcus pneumonia, Haemphilus influenza (in the absence of a possibility of alternative therapy); pneumocystic pneumonia (treatment and prevention) at adults and children from risk groups;

- infections of ENT organs: treatment of the average otitis caused by susceptible Streptococcus pneumonia, Haemphilus influenza (in the absence of a possibility of alternative therapy) at children is aged more senior than 2 years;

- digestive tract infections: the shigellosis (caused by sensitive strains of Shigella flexneri and Shigella sonnei); the diarrhea of travelers caused by enterotoksichny strains of Escherichia coli.

Route of administration and doses:

Inside after food with enough liquid. At treatment of infections of uric ways, shigelloses, average otitis at adults and children 12 years are more senior: on 960 mg (2 tablets) each 12 h within 10-14 days (at shigelloses – within 5 days). For children 12 years are aged younger: the recommended dose of 40 mg/kg on sulfamethoxazole and 8 mg/kg on Trimethoprimum divided into 2 receptions a day within 10 days that corresponds at the body weight of the child of 20-30 kg – 1 tablet 2 times a day, 30-40 kg – 1½ tablets 2 times a day, weighing over 40 kg – to 2 tablets 2 times a day.

At treatment of an exacerbation of chronic bronchitis on 2 tablets each 12 hours within 14 days.

At treatment of pneumocystic pneumonia appoint in a dose 75-100 mg/days on sulfamethoxazole and 15-20 mg/days on Trimethoprimum divided into 4 receptions a day within 14-21 days. When using the maximum mode of dosing the single dose corresponds at the body weight of 16-24 kg – 1½ to tablets, 24 - 32 kg – to 2 tablets, 32-40 kg – 2½ to tablets, 40-48 kg – to 3 tablets, 48-64 kg – to 4 tablets, 64-80 kg – to 5 tablets. In case of use of the minimum mode of dosing – these doses need to be reduced by 25%.

For prevention of pneumocystic pneumonia the recommended dose 2 tablets a day the adult; to children at the rate of 750 mg/sq.m/days of sulfamethoxazole and 150 mg/sq.m/days of Trimethoprimum divided into 2 receptions a day within 3 days a week. It corresponds to the following mode of dosing: at the surface area of a body of 0,26-0,53 sq.m – on ½ tablets, 0,53-1,06 sq.m – on 1 tablet.

At diarrhea of travelers - on 2 tablets each 12 h within 5 days.

At a chronic renal failure the dose depends on size KK: at KK more than 30 ml/min. - a standard dose; at 15-30 ml/min. - ½ standard doses. At KK less than 15 ml/min. - reception is not recommended.

Features of use:

AT RECEPTION OF STREPTOCIDES EXCEPTIONAL CASES OF SIDE REACTIONS MET THE LETHAL OUTCOME, INCLUDING STEPHENS-JOHNSON'S SYNDROME, THE TOXIC EPIDERMAL NECROLYSIS, FULMINANTNY HEPATITIS, THE AGRANULOCYTOSIS, APLAS-TICHESKUYU ANEMIA AND DISTURBANCES OF THE HEMOPOIESIS.

RECEPTION OF STREPTOCIDES, INCLUDING RECEPTION OF KO-TRIMOK-SAZOLA, HAS TO BE IMMEDIATELY STOPPED AT EMERGENCE ON SKIN OF RASHES OR DEVELOPMENT OF ANY SIDE REACTION.

It is only necessary to appoint co-trimoxazole when advantage of such therapy before other drugs exceeds possible risk. At the choice of drug it is necessary to consider local features of bacterial sensitivity.

At long courses of treatment or reception of high doses regular blood tests are necessary. Trimethoprimum can increase toxicity of a methotrexate, especially in the presence of other risk factors, such as senile age, a hypoalbuminemia, a renal failure, oppression of marrow. Similar side reactions are more probable if the methotrexate is appointed in high doses. Hematologic changes can be reversible at purpose of folic acid (3-6 mg/days). Extra care has to be shown at treatment of elderly patients or patients with suspicion on initial shortage of folates. At considerable decrease in number of any blood cells drug should be cancelled.

It is inexpedient to use against the background of treatment the foodstuff containing paraaminobenzoic acid in large numbers - green parts of plants (a cauliflower, spinach, bean), carrots, tomatoes.

At long courses (especially at a renal failure), it is regularly necessary to do the general analysis of urine and to control function of kidneys.

The probability of toxic and allergic complications considerably increases at depression of function of kidneys. For prevention of a crystalluria it is recommended to support the sufficient volume of the emitted urine.

At sudden emergence or increase of cough or asthma it is necessary to inspect repeatedly the patient and to consider a question of the treatment termination by drug.

It is necessary to avoid excessive solar and UF-radiations.

The risk of side effects is much higher at patients with AIDS.

It is not recommended to apply at the diseases caused by a beta and hemolitic streptococcus of group A because of eurysynusic resistance of strains.

Trimethoprimum breaks phenylalanine exchange, however it does not influence patients with a fenilketonuriya on condition of observance of the corresponding diet.

Patients of whose metabolism "slow acetylation" is characteristic are more inclined to development of an idiosyncrasy to sulfonamides.

Duration of treatment has to be shorter, especially at patients of advanced and senile age.

Use at pregnancy and in the period of a lactation

Trimethoprimum and sulfamethoxazole get through a placental barrier and, thus, can influence exchange of folic acid, at pregnancy it is necessary to appoint drug only if the expected advantage of its use surpasses possible risk for a fruit. To the pregnant women receiving Co-trimoxazole about 5 mg of folic acid a day are recommended to appoint. On late durations of gestation it is necessary to avoid use of drug because of possible risk of a kernicterus at newborns.

Medicine is not appointed in the period of a lactation.

Influence on laboratory indicators

Co-trimoxazole and, in particular, Trimethoprimum which is its part can affect results of definition of concentration of the methotrexate in serum which is carried out by method of competitive linkng with proteins using a bacterial digidrofolatreduktaza as a ligand. However when determining a methotrexate by a radio immune method of an interference does not arise.

Trimethoprimum and sulfamethoxazole can influence results of reaction of Jaffe (definition of creatinine on reaction with picric acid in the alkaline environment), at the same time in the range of normal values results are overestimated approximately by 10%.

Influence on ability of driving and work with moving mechanisms

During treatment it is necessary to be careful during the driving of motor transport and occupation potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.

Side effects:

AT RECEPTION OF STREPTOCIDES EXCEPTIONAL CASES OF HEAVY SIDE REACTIONS MET THE LETHAL OUTCOME, INCLUDING STEPHENS-JOHNSON'S SYNDROME, THE TOXIC EPIDERMAL NECROLYSIS, THE AGRANULOCYTOSIS, APLASTIC ANEMIA AND DISTURBANCES OF THE HEMOPOIESIS.

From a nervous system: headache, dizziness; aseptic meningitis, peripheral neuritis, spasms, an ataxy, a ring in ears, a depression, hallucinations, apathy, nervousness.

From respiratory system: pulmonary infiltrates: eosinophilic infiltrate, allergic alveolitis (cough, short wind).

From the alimentary system: nausea, vomiting, loss of appetite, diarrhea, gastritis, abdominal pain, glossitis, stomatitis, cholestasia, increase in activity of "hepatic" transaminases, hepatitis including cholestatic, гепатонекроз, syndrome of "a disappearing bilious channel" (duktopeniye), hyperbilirubinemia, pseudomembranous colitis, acute pancreatitis.

From bodies of a hemopoiesis: leukopenia, neutropenia, thrombocytopenia, prothrombinopenia, methemoglobinemia, eosinophilia.

From an urinary system: intersticial nephrite, a renal failure, a hamaturia, increase in maintenance of an urea nitrogen of blood, a giperkreatininemiya, a toxic nephropathy with an oliguria and an anury, a crystalluria.

From a musculoskeletal system: an arthralgia, a mialgiya, рабдомиолиз (mainly at patients with AIDS).

Allergic reactions: fervescence, Quincke's disease, itch, photosensitization, skin rash, small tortoiseshell, exfoliative dermatitis, allergic myocarditis, hyperemia of a conjunctiva, scleras; anaphylactic/anaphylactoid reactions, serum disease, hemorrhagic vasculitis (Shenleyn-Genokh's purpura), nodular periarteritis, volchanochnopodobny syndrome.

Others: a hyperpotassemia (mainly at patients with AIDS at therapy of pneumocystic pneumonia), a hyponatremia, a hypoglycemia, weakness, fatigue, sleeplessness, candidiasis.

Interaction with other medicines:

Increases activity of warfarin (dose adjustment is required), a methotrexate, peroral hypoglycemic HP. Increases serumal concentration of digoxin, control of concentration of digoxin in serum is necessary.

Reduces intensity of hepatic metabolism of Phenytoinum (extends it with T ½ for 39%), strengthening its effect and toxic action.

Pyrimethaminum in the doses exceeding 25 mg/week increases risk of development of megaloblastny anemia.

Diuretics (is more often thiazide and at elderly patients) increase risk of development of thrombocytopenia. The HP oppressing a marrowy hemopoiesis increase risk of a miyelosupressiya.

Reduces efficiency of tricyclic antidepressants.

At the patients accepting co-trimoxazole and cyclosporine after renal transplantation the reversible deterioration in function of kidneys which is shown a giperkreatininemiya can be observed.

At simultaneous use with indometacin increase in concentration of sulfamethoxazole in blood is possible.

The case of a toxic delirium at reception of co-trimoxazole and an amantadin is described.

At simultaneous use with APF inhibitors, especially at elderly patients, development of a hyperpotassemia is possible.

Simultaneous use of a dofetilid and Trimethoprimum is contraindicated.

Contraindications:

Hypersensitivity (including to streptocides), a liver and/or renal failure (KK less than 15 ml/min.), aplastic anemia, B12 - scarce anemia, an agranulocytosis, a leukopenia, deficit of a glyukozo-6-phosphate-dehydrogenase, the lactation period, children's age (for oral administration – up to 2 years), a concomitant use with dofetilidy.

With care. Dysfunction of a thyroid gland, heavy allergic reactions in the anamnesis, bronchial asthma, deficit of folic acid, a porphyria, pregnancy.

Overdose:

Symptoms: nausea, vomiting, intestinal colic, dizziness, headache, drowsiness, depression, unconscious states, confusion of consciousness, fever, hamaturia, crystalluria; at long overdose - thrombocytopenia, a leukopenia, megaloblastny anemia, jaundice.

Treatment: the gastric lavage (at intake), an artificial diuresis, acidulation of urine increases removal of Trimethoprimum, in oil - 5-15 mg/days of calcium of a folinat (eliminates action of Trimethoprimum on marrow), if necessary - a hemodialysis.

Storage conditions:

In the place protected from moisture and light, at a temperature not above 25 °C. To store in the place, unavailable to children. A period of validity - 3 years. Not to use after the termination of a period of validity.

Issue conditions:

According to the recipe

Packaging:

Tablets on 480 mg in a blister strip packaging No. 10 x 2.