Бактрим® forte

General characteristics. Structure:

Active agents: co-trimoxazole of 960 mg (there correspond 800 mg of sulfamethoxazole and 160 mg of Trimethoprimum);

Excipients: povidone, sodium starch glikolit (sodium carboxymethylstarch), magnesium stearate, sodium docusate;

Cover: gidroksipropilmetiltsellyuloz (gipromelloz), talc, titanium dioxide, polyethyleneglycol 6000 (macrogoal).

Pharmacological properties:

Pharmacodynamics. The combined bactericidal chemotherapeutic means
Bactrimum contains two active agents which have synergy effect, blocking two enzymes catalyzing consecutive stages of biosynthesis of folinovy acid in microorganisms. Thanks to this mechanism, bactericidal action of in vitro is reached at such concentration in which separate components of drug render only bacteriostatic effect. In addition, Bactrimum is often effective concerning the activators steady against one of its components.
In vitro antibacterial action of Bactrimum covers a wide range of gram-positive and gram-negative pathogenic microorganisms though sensitivity can depend on the geographic location.
Usually sensitive activators (MPK <80 mg/l on sulfamethoxazole)
Cocci: Branhamella catarrhalis.

Gram-negative microorganisms: Haemophilus influenzae (b-lactamazoforming and b-laktamazoneobrazuyushchiye strains), Haemophilus parainfluenzae, E. coli, Citrobacter freundii, other types of Citrobacter, Klebsiella pneumoniae, Klebsiella oxytoca, other types of Klebsiella, Enterobacter cloaceae, Enterobacter aerogenes, Hafnia alvei, Serratia marcescens, Serratis liquefaciens, other types of Serratia, Proteus mirabilis, Proteus vulgaris, Morganella morganii, Shigella spp., Yersinia enterocolitica, other types of Yersinia, Vibrio cholerae.
Various gram-negative microorganisms: Edwardsiella tarda, Alcaligenes faecalis, 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 = 80-160 mg/l on sulfamethoxazole)
Cocci: Staphylococcus aureus (metitsillinochuvstvitelny and metitsillinoustoychivy strains), Staphylococcus spp. (koagulazootritsatelny), Streptococcus pneumoniae (penitsillinochuvstvitelny and resistant to penicillin strains).
Gram-negative sticks: Haemophilus ducreyi, Providentia rettgeri, other types of Providentia, Salmonella typhi, Salmonella enteritidis, Stenotrophomonas maltophilia (earlier being called Xanthomonas maltophilia).

Various gram-negative microorganisms: Acinetobacter lwoffi, Acinetobacter anitratus (mainly, A. baumanii), Aeromonas hydrophilia.
Steady activators (MPK> of 160 mg/l on sulfamethoxazole)
Mycoplasma spp., Mycobacterium tuberculosis, Treponema pallidum.
If Bactrimum is appointed empirically, it is necessary to consider local features of resistance to Bactrimum of possible causative agents of a specific infectious disease.
At infections which can be caused by partially sensitive microorganisms it is recommended to carry out a sensitivity test to exclude resistance of the activator.
Sensitivity to Bactrimum can be determined by standard methods, for example, by the method of disks or a dilution method recommended by National Committee on Clinical Laboratory Standards (NKKLS).

NKKLS recommends the following criteria of sensitivity:

	Method of disks *, diameter of halo of inhibition of growth (mm)	Dilution method **, MPK (mkg/ml)
		Trimethoprimum	sulfamethoxazole
Sensitive Partially sensitive Steady	≥ 16 11-15 ≤ 10	≤ 2 4 ≥ 8	≤ 38 76 ≥ 152

Pharmacokinetics. Absorption.
After oral administration Trimethoprimum and sulfamethoxazole quickly and almost are completely soaked up in an upper part of digestive tract. In 1-4 h after a single dose of 160 mg of Trimethoprimum + 800 mg of sulfamethoxazole the maximum concentration of Trimethoprimum in plasma make 1.5-3 mkg/ml, and sulfamethoxazole - 40-80 mkg/ml. At multiple dose with an interval of 12 hours the minimum equilibrium concentration in 2-3 days are stabilized within 1.3-2.8 mkg/ml for Trimethoprimum and 32-63 mkg/ml for sulfamethoxazole.

Distribution. The volume of distribution of Trimethoprimum makes about 130 l, sulfamethoxazole - about 20 l. 45% of Trimethoprimum and 66% of sulfamethoxazole are connected with proteins of plasma.
Trimethoprimum is slightly better, than sulfamethoxazole gets into uninflammed tissue of a prostate gland, semen, a vagina secret, the saliva healthy and the inflamed tissue of lungs, bile while both components of drug get into cerebrospinal fluid and watery moisture of an eye equally.
Large numbers of Trimethoprimum and a little smaller amounts of sulfamethoxazole arrive from a blood-groove in intersticial and other ekstravazalny liquids of an organism, at the same time concentration of Trimethoprimum and sulfamethoxazole exceed the minimum overwhelming concentration for the majority of pathogenic microorganisms.
The person has Trimethoprimum and sulfamethoxazole umbilical cord blood, in amniotic waters and fabrics of a fruit (a liver, lungs) are found in a placenta, that indicates penetration of both substances through a placental barrier. As a rule, concentration of Trimethoprimum at a fruit are close to that at mother, and concentration of sulfamethoxazole at a fruit are lower, than at mother.
Both substances are emitted with breast milk. Concentration in breast milk are close (Trimethoprimum) or are lower (sulfamethoxazole) of those in mother's plasma.

Metabolism.
About 50-70% of a dose of Trimethoprimum and 10-30% of a dose of sulfamethoxazole are removed in not changed look. The main metabolites of Trimethoprimum are 1-both 3 oxides and 3 ’-and 4’ - hydroxyderivatives. Some metabolites have antimicrobic activity. Sulfamethoxazole is metabolized in a liver, is preferential by N4 acetylation and, to a lesser extent, conjugation with glucuronic acid.

Removal. Elimination half-lives of two components are very close to each other (on average, 10 hours for Trimethoprimum and 11 hours for sulfamethoxazole).
Both substances, and also their metabolites, are removed almost only through kidneys as by glomerular filtering, and canalicular secretion owing to what concentration of both active agents in urine are much higher, than in blood. A small part of active agents is removed with a stake.

Pharmacokinetics in special clinical cases.
At patients of senile age, and also with a heavy renal failure (clearance of creatinine of 15-30 ml/min.), elimination half-lives of both components of drug increase that demands dose adjustment.

Indications to use:

It is only necessary to appoint Bactrimum when, according to the doctor, advantage of such therapy exceeds possible risk; it is necessary to resolve an issue of whether it is impossible to manage use of one effective antibacterial agent.
As sensitivity of bacteria to antibiotics of in vitro changes in different geographical areas and in time, at the choice of drug it is necessary to consider local features of bacterial sensitivity.

Respiratory infection and ENT organs: an exacerbation of chronic bronchitis, average otitis at children if there are enough bases to prefer a combination of Trimethoprimum and sulfamethoxazole of monotherapy by an antibiotic. Treatment and prevention (primary and secondary) the pneumonia caused by Pneumocystis carinii at adults and children.

Infections of an urinogenital path: infections of urinary tract, venereal ulcer.

Digestive tract infections: the typhoid and a paratyphoid, shigelloses (caused by sensitive strains of Shigella flexneri and Shigella sonnei if antibacterial therapy is shown), the diarrhea of travelers caused by enterotoksichesky strains of Escherichia coli, cholera (in addition to completion of liquid and electrolytes).

Other bacterial infections: the infections caused by a number of microorganisms (the combination to other antibiotics is possible), for example: brucellosis, acute and chronic osteomyelitis, nocardiosis, actinomycosis, toxoplasmosis and South American zymonematosis.

Route of administration and doses:

Inside, after food with enough liquid.
Standard dosing
Adults and children are more senior than 12 years:

	Tablets, coated
	morning	evening
Standard dose	1	1
Minimum dose and dose for prolonged treatment (more than 14 days)	0.5	0.5
The raised dose (in especially hard cases)	1.5	1.5

Treatment duration
At acute infections it is necessary to appoint Bactrimum to term not less than 5 days or until symptoms at the patient are not absent within 2 days. If in 7 days of therapy of clinical improvement does not come, it is necessary to estimate repeatedly the patient's condition for possible correction of treatment.

Dosing in special cases
Venereal ulcer
On 1 tablet two times a day. If in 7 days of healing of a skin element does not occur, it is possible to prolong therapy for 7 days. However it must be kept in mind that lack of effect can testify to resistance of the activator.

Acute uncomplicated infections of uric ways
One-time reception of 2-3 tablets is recommended to women with acute uncomplicated infections of uric ways. Whenever possible, they should be accepted in the evening after food or before withdrawal to a dream.

Patients on a hemodialysis
After reception of a usual load dose, the subsequent doses have to make a half or a third of standard and to be appointed each 24-48 hours.

The pneumonia caused by Pneumocystis carinii
To 20 mg of Trimethoprimum and to 100 mg of sulfamethoxazole on body weight kg the day divided into equal doses, each 6 hours for 14 days.
The upper limit of a dose is determined by the following table:

Body weight, kg	The doses accepted with an interval of 6 hours tablets, coated
32	1
40
48	1.5
64	2
80	2.5

For prevention of the pneumonia caused by Pneumocystis carinii, to adults and teenagers (12 years are more senior) about 1 tablet in days is recommended to appoint. At children for prevention of the pneumonia caused by Pneumocystis carinii it is necessary to use other dosage form of the drug Bactrimum – suspension for intake. Nocardiosis
The adult on 3-4 tablets within not less than 3 months. The dose should be adjusted depending on age, the body weight of the patient, function of kidneys and disease severity. Sometimes treatment is continued up to 18 months.

Patients with a renal failure
At clearance of creatinine> 30 ml/min. appoint a usual dose, at clearance of creatinine of 15-30 ml/min. - a half of a usual dose, and at clearance of creatinine <15 ml/min. are not recommended to apply Bactrimum.

Patients of senile age
At normal function of kidneys appoint a usual dose for adults.

Features of use:

At the first emergence of skin rash or any other heavy side reaction drug should be cancelled. Patients with tendency to allergic reactions and with bronchial asthma should appoint Bactrimum with care.
Treatment duration Bactrimum has to be shorter, especially at patients of advanced and senile age. At damage of kidneys the dose should be corrected as directed the section "Dosing in Special Cases".
At long purpose of Bactrimum it is necessary to define number of uniform elements of blood regularly. At considerable decrease in number of any blood cells Bactrimum should be cancelled. Patients with a serious hematologic illness can appoint Bactrimum only by way of exception.

Patients of advanced and senile age, and also at patients with already available deficit of folic acid or a renal failure, can have hematologic changes characteristic of a lack of folic acid. They disappear after purpose of folinovy acid.

The patient, it is long Bactrimum receiving treatment (especially at a renal failure), it is regularly necessary to do the general analysis of urine and to control function of kidneys. During treatment it is necessary to provide sufficient intake of liquid in an organism and an adequate diuresis for prevention of a crystalluria.

Because of a possibility of hemolysis it is possible to appoint Bactrimum the patient with deficit of a glyukozo-6-phosphate-dehydrogenase only according to absolute indications and in the minimum doses.
Trimethoprimum breaks phenylalanine exchange, however it does not influence patients with a fenilketonuriya on condition of observance of the corresponding diet.
As well as at purpose of any sulfonamides, it is necessary to be careful at patients with a porphyria or dysfunction of a thyroid gland.
Patients of whose metabolism "slow acetylation" is characteristic are more inclined to development of an idiosyncrasy to sulfonamides.

Side effects:

In the recommended doses Bactrimum usually well is transferred. The most frequent side effects are skin rash and gastrointestinal frustration.

Organism in general
Hypersensitivity reactions are described. As well as at treatment by any other drug, at patients with hypersensitivity to components of drug allergic reactions can develop: temperature increase, a Quincke's disease, anaphylactoid reactions, a serum disease, in rare instances - infiltrates in lungs as an eosinophilic or allergic alveolitis. They can clinically be shown by cough and short wind. At sudden appearance or increase of similar symptoms of the patient it is necessary to inspect and consider a question of the therapy termination by Bactrimum. In rare instances there was a nodular periarteritis and allergic myocarditis. Cases of fungal infections, such as candidiasis are described.

In decreasing order of frequency the following side effects can be observed.
Skin: side reactions are usually expressed poorly and quickly disappear after drug withdrawal. As well as in rare instances can lead other drugs containing sulfonamides, Bactrimum to a photosensitization, development of a multiformny erythema, Stephens-Johnson's syndrome, toxic epidermal necrolysis (Lyell's disease) and Shenleyn-Genokh's purpura.

Digestive tract: nausea (with vomiting or without), stomatitis, diarrhea, a liver necrosis, exceptional cases of hepatitis, a cholestasia, a glossitis, separate cases of a pseudomembranous coloenteritis, increase in activity of transaminases and concentration of bilirubin, separate cases of a syndrome of "a disappearing bilious channel". Cases of acute pancreatitis against the background of treatment are described by Bactrimum, however several such patients had a serious illness, including AIDS.

Hematologic changes: a leukopenia, a neutropenia, a granulocytopenia and thrombocytopenia (are most often expressed poorly or proceed asymptomatically and disappear after drug withdrawal); very seldom - an agranulocytosis, anemia (megaloblastny, hemolitic/autoimmune or aplastic), a methemoglobinemia, a pancytopenia or a purpura.

Urinary tract: in rare instances - a renal failure, intersticial nephrite, increase in an urea nitrogen of blood, serum creatinine, a crystalluria. Sulfonamides, including Bactrimum, can lead to increase in a diuresis, especially at patients with hypostases of a cordial origin.

Nervous system: neuropathy (including peripheral neuritis and paresthesias), hallucinations, uveitis, exceptional cases of aseptic meningitis or meningeal symptomatology, ataxy, spasms, rotatory and not rotatory vertigo.

System of a respiratory organs: separate cases of pulmonary infiltrates, similar subjects which arise at an eosinophilic or allergic alveolitis. They can be shown by such symptoms as cough or short wind. At sudden emergence or increase of this symptomatology it is necessary to inspect repeatedly the patient and to consider a question of the treatment termination by Bactrimum.

Musculoskeletal system: seldom - arthralgias and mialgiya, separate cases of a rabdomioliz are described.

Metabolism: the high doses of Trimethoprimum applied to treatment of pneumocystic pneumonia bring to progressing, but to reversible increase in content of potassium in serum at considerable number of patients. Can cause a hyperpotassemia

even reception of the recommended Trimethoprimum doses if it is appointed against the background of disturbances

potassium exchange, renal failure or concomitant use of the drugs provoking a hyperpotassemia. At these patients it is regularly necessary to control the content of potassium in serum. Hyponatremia cases are described. At the persons who are not suffering from a diabetes mellitus and receiving Trimethoprimum sulfamethoxazole hypoglycemia cases, usually in several days after an initiation of treatment are occasionally observed. The risk of a hypoglycemia is higher at patients with renal failures, liver diseases, a hyponutrient or receiving high doses of Trimethoprimum sulfamethoxazole.

Side reactions at patients with AIDS. Frequency of by-effects, especially rashes, fevers, a leukopenia and a superactivity of aminotransferases in serum at patients with AIDS, is much higher, than similar indicators at the persons who do not have AIDS.

Interaction with other medicines:

At the patients of advanced and senile age who were at the same time accepting some diuretics (generally tiazida), the increased thrombocytopenia frequency was observed.

Bactrimum can increase serumal concentration of digoxin, especially at elderly patients therefore monitoring of concentration of digoxin in serum is necessary.

Bactrimum can strengthen anticoagulative effect of warfarin. Patients who already receive anticoagulants should remember a possibility of such interaction at purpose of Bactrimum. In such cases it is necessary to define a blood clotting time again.

Bactrimum can oppress hepatic metabolism of Phenytoinum. After purpose of Bactrimum in usual clinical doses increase in an elimination half-life of Phenytoinum by 39% and reduction of speed of its metabolic clearance by 27% was observed. At co-administration of both drugs it is important to monitor toxic action of Phenytoinum.

At the patients receiving Trimethoprimum sulfamethoxazole and cyclosporine after renal transplantation the reversible deterioration in function of kidneys which is shown increase in level of creatinine can be observed. Possibly, this effect is caused by Trimethoprimum. At patients with normal function of kidneys reversible reduction of clearance of creatinine was observed that, perhaps, is caused by reversible oppression of canalicular secretion of creatinine.

Bactrimum can reduce efficiency of tricyclic antidepressants.

Sulfonamides, including sulfamethoxazole, can compete for linkng with proteins and renal transport of a methotrexate, increasing, thus, concentration of a free methotrexate and its system effect.

At the patients accepting Trimethoprimum and a methotrexate pancytopenia cases were described. Trimethoprimum has low affinity to a degidrofolatreduktaza of the person, however 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. For prevention of a miyelosupressiya such patients are recommended to appoint folic acid or фолинат calcium.

It is possible to assume that at co-administration of Bactrimum by the patient which receive Pyrimethaminum for prevention of malaria in doses more than 25 mg a week at them megaloblastichesky anemia can develop.

As well as effect of peroral glucose-lowering drugs can exponentiate other sulfonamides, Bactrimum.

Trimethoprimum, inhibiting transport system of kidneys, increases the area under a curve "concentration – time" AUC by 103% and the maximum concentration for 93% of a dofetilid. At increase in concentration дофетилид can cause serious ventricular arrhythmias with lengthening of an interval of QT, including arrhythmia of torsades de pointes. Co-administration of a dofetilid and Trimethoprimum is contraindicated.

At the patients accepting indometacin concentration of sulfamethoxazole in blood can increase.
One case of a toxic delirium after a concomitant use of Trimethoprimum sulfamethoxazole and an amantadin is described.

Laboratory researches
Bactrimum 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 also 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%.

Contraindications:

The expressed defeats of a parenchyma of a liver; a heavy renal failure (clearance of creatinine <15 ml/min.) if there is no opportunity regularly to define concentration of drug in plasma; blood diseases (aplastic anemia, B12-scarce anemia, agranulocytosis, leukopenia); hypersensitivity to drug components in the anamnesis; in a combination with dofetilidy; children's age up to 12 years; deficit glyukozo-6-fosfatdegidrogenazy.

With care
Porphyria, dysfunction of a thyroid gland, bronchial asthma, deficit of folic acid.

Pregnancy and period of feeding by a breast
Very high doses of Trimethoprimum and sulfamethoxazole caused the fruit malformations typical for insufficiency of folic acid in animals.
According to researches at pregnant women, literary reviews and separate messages on malformations reception of Bactrimum, apparently, is not accompanied by reliable risk of teratogenecity for the person.

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

Both Trimethoprimum, and sulfamethoxazole get into breast milk. In spite of the fact that with breast milk to the child the small quantity of Bactrimum gets, it is recommended to compare possible risk for the baby (a kernicterus, hypersensitivity) with the expected therapeutic effect for mother.

Overdose:

Symptoms of acute overdose: nausea, vomiting, diarrhea, a headache, dizziness, intellectual and visual frustration, in hard cases - a crystalluria, a hamaturia and an anury.

Symptoms of chronic overdose: hemopoiesis oppression (thrombocytopenia, a leukopenia), and also other pathological changes of a picture of blood owing to insufficiency of folinovy acid.

Treatment (depending on symptomatology): measures for prevention of further absorption of drug, strengthening of renal excretion by an artificial diuresis (alkalifying of urine promotes sulfamethoxazole removal), a hemodialysis (peritoneal dialysis is inefficient). It is necessary to control a pattern of blood and electrolytes. At the expressed pathological changes of a picture of blood or jaundice appoint specific treatment. For elimination of action of Trimethoprimum it is possible to appoint to a hemopoiesis фолинат calcium in a dose 3-6 mg in oil within 5-7 days.

Storage conditions:

At a temperature not above 30 °C, in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Tablets, coated, 960 mg
On 10 tablets in the blister from a film of PVC and aluminum foil.
On 1, 2 or 5 blisters together with the application instruction place in a cardboard pack.