Tinidazole, Ciprofloxacin

Pharmacological properties

The drug is a combination of two known antibacterial agents - ciprofloxacin and tinidazole.

Pharmacodynamics Ciprofloxacin suppresses the DNA gyrase enzyme, which plays an important role in the process of segment despiralization and spiralization of the chromosome during the bacterial reproduction phase and prevents the chromosomal transcription of information necessary for normal bacterial cell metabolism, which inhibits the ability of the pathogen to multiply. The drug has a quick and pronounced bactericidal effect on microorganisms that are both in the breeding phase and in the resting phase. It is highly effective against almost all gram-negative and gram-positive pathogens. Escherichia coli, Shigella spp., Salmonella spp., Citrobacter spp., Klebsiella spp., Enterobacter spp., Serratia spp., Hafnia spp., Edwardsiella spp., Proteus (both indole-positive and indole-negative strains) are sensitive to ciprofloxacin spp., Providencia spp., Yersinia, Vibrio spp., Aeromonas spp., Plesiomonas Pasteurela, Haemophillus, Campylobacter spp., Pseudomonas spp. (including Pseudomonas aeruginosa), Legionella, Moraxella spp., Branhamella spp., Acinetobacter spp., Brucella spp., Staphylococcus spp., Listeria spp., Corinebacterium, Chlamidia, as well as plasmid forms of bacteria.

According to in vitro studies, as well as the results of the use of a surrogate marker, ciprofloxacin is active against Bacillus antracis.

Different sensitivity is exhibited by Neisseria spp., Gardnerella spp., Flavobacterium spp., Alcaligenes spp., Streptococcus agalactiae, Enterococcus faecalis, Streptococcus pyogenes, Streptococcus pneumoniae, Streptococcus viridans, Mycoplasma hominobium tuberculosis, Mycoplasma hominobium tuberculosis.

Anaerobic cocci (Peptococcus, Peptostreptococcus) are moderately sensitive to ciprofloxacin, and Bacteroides is resistant. Cifran ST is effective against bacteria that produce β-lactamases. The drug is also active against microorganisms that are resistant to almost all antibiotics, sulfonamide and nitrofuran drugs. In some cases, Cifran ST is active against strains of microorganisms that are resistant to other drugs of the fluoroquinolone group. However, it should be borne in mind that cross-resistance exists between different fluoroquinolones. As a rule, they are resistant to Enterococcus faecium, Ureaplasma urealiticum, Nocardia asteroides, Treponema pallidum. Resistance to ciprofloxacin develops slowly and gradually (multistage type).

The prevalence of resistant strains may vary by geographic region and may change over time. It is advisable to use local information on the sensitivity of microorganisms to ciprofloxacin, especially in the treatment of severe infections. This information allows you to get only approximate indicators of the sensitivity and resistance of certain microorganisms to ciprofloxacin.

Tinidazole is a 5-nitroimidazole derivative with an imidazole-substituted component that can act against anaerobic bacteria and protozoa. The mechanism of action of tinidazole on anaerobic bacteria and protozoa is associated with the penetration of the drug into the cells of microorganisms and DNA damage or inhibition of its synthesis.

Tinidazole is active against both simple and obligate anaerobic bacteria.

The simplest microorganisms sensitive to tinidazole are Trichomonas vaginalis, Entamoeba histolytica, and Giardia lamblia.

Tinidazole is active against Gardnerella vaginalis and most anaerobic bacteria, including Bacteroides fragilis, Bacteroides melaninogenicus, Bacteroides spp., Clostridium spp., Eubacterium spp., Fusobacterium spp., Peptococcus spp., Peptostpppppt.

Pharmacokinetics After oral administration, ciprofloxacin is rapidly and well absorbed, mainly from the duodenum and upper small intestine.

C_max in blood plasma is reached after 60-120 minutes. Bioavailability is about 70–80%. The volume of distribution in a state of stable equilibrium is 2-3 l / kg. Since the binding of ciprofloxacin with proteins is insignificant (20–30%), and the substance is in the blood plasma mainly in non-ionized form, almost the entire amount of the drug administered can freely diffuse into the extravasal space. In this regard, the concentration of ciprofloxacin in some body fluids and tissues can be many times higher than the level of the drug in blood plasma (in particular, a high concentration in bile is noted). Ciprofloxacin is secreted mainly by the kidneys (≈45% unchanged, ≈11% in the form of metabolites).The remainder of the dose is released through the intestines (≈20% - unchanged, ≈5–6% - in the form of metabolites). The renal clearance is 3-5 ml / min / kg, the total clearance is 8-10 ml / min / kg. T_½ is 3-5 hours. Due to the fact that the drug is excreted in different ways, an increase in T_½ they are noted only with significant impairment of renal function (an increase of this indicator to 12 hours is possible).

Tinidazole is rapidly and completely absorbed by ingestion.

In studies of healthy volunteers who took tinidazole at a dose of 2 g orally, the plasma concentration reached a peak of 40–51 μg / ml within 2 hours and decreased to 11–19 μg / ml after 24 hours.

Plasma levels decreased slowly; tinidazole was detected in blood plasma (at a concentration of up to 1 μg / ml) 72 hours after ingestion. T_½ tinidazole from blood plasma is 12-14 hours.

Tinidazole is actively distributed throughout all body tissues and crosses the BBB. It appears in all tissues in therapeutically effective concentrations. The volume of distribution is ≈50 l. Almost 12% of tinidazole in plasma is associated with proteins.

Tinidazole is secreted by the liver and kidneys. Studies of healthy volunteers showed that within 5 days 60–65% of the administered dose is excreted by the kidneys, with 20–25% unchanged. About 5% of the dose is excreted in the feces.

Studies of patients with renal failure (creatinine clearance of 22 ml / min) indicate that the pharmacokinetics of tinidazole in these patients does not significantly change.

The combination of ciprofloxacin with tinidazole does not affect the pharmacokinetics of these active substances.

The combination of ciprofloxacin and tinidazole enhances the antibacterial effect of the drug and significantly expands the spectrum of action on microorganisms sensitive to it. Cifran ST is effective against aerobic-anaerobic infections, as well as mixed protozoal-bacterial infections.

Indications

Therapy for mixed infections caused by aerobic and anaerobic microorganisms sensitive to the drug: chronic sinusitis, lung abscess, empyema, intraperitoneal infections, inflammatory gynecological diseases, postoperative infections with the possible presence of aerobic and anaerobic bacteria, chronic osteomyelitis, skin and soft tissue infections, “Diabetic foot”, pressure sores, infections of the oral cavity (including periodontitis and periostitis).

Treatment of diarrhea or dysentery of amoebic or mixed (amoebic and bacterial) etiology.

Application

Cifran St is taken orally with a sufficient amount of water. The dosage regimen and duration of treatment are determined by the doctor individually, depending on the location, the severity of the pathological process, as well as the sensitivity of the pathogens.

Adults are recommended the following dosage: 1 tablet 2 times a day.

The maximum daily dose is 2 tablets of the drug Cifran ST.

Patients with creatinine clearance ≤30 ml / min, elderly people and patients with low body weight are prescribed ½ average dose.

The duration of treatment depends on the severity of the disease, clinical course and bacteriological profile.

The course of treatment for acute uncomplicated infections is 1–7 days, for the treatment of complicated and chronic recurrent infections - 10–14 days. For infections caused by streptococci, treatment should be continued for at least 10 days in order to avoid the risk of complications in the long term. For infections caused by Chlamydia, treatment should also be continued for at least 10 days. With osteomyelitis, the course of treatment can be up to 2 months. In patients with reduced immunity, treatment should be carried out during the entire period of neutropenia. Reception of Cifran ST should be continued within 2 days after the disappearance of the symptoms of the disease.

Contraindications

The drug is not prescribed for patients with hypersensitivity to ciprofloxacin or other fluoroquinolones, tinidazole or other nitroimidazole derivatives, as well as to any component of the drug in history.

The drug is contraindicated in the presence of organic lesions of the nervous system and blood diseases.

Concomitant use with tizanidine.

Side effects

Ciprofloxacin-induced. infections and infestations: rarely - candidiasis; rarely - antibiotic-associated colitis; very rarely - with a possible fatal outcome.

From the hematopoietic and lymphatic systems: sometimes - eosinophilia; rarely - leukopenia, anemia, neutropenia, leukocytosis, thrombocytopenia, thrombocytosis; very rarely - hemolytic anemia, agranulocytosis, pancytopenia (life-threatening), bone marrow depression (life-threatening).

From the immune system: rarely - allergic reactions, allergic / angioedema; very rarely - anaphylactoid reactions, anaphylactic shock (life-threatening) and reactions similar to serum sickness.

Mental disorders: rarely - psychomotor irritability / anxiety; rarely - confusion and disorientation, anxiety, increased drowsiness, depression, hallucinations; very rarely - psychoses.

From the side of the nervous system: rarely - headache, dizziness, sleep disturbances, taste disturbances; rarely - paresthesia, dysesthesia, hypesthesia, tremor, convulsions, vertigo; very rarely - migraine, impaired coordination, impaired sense of smell, hyperesthesia and intracranial hypertension; peripheral neuropathy and polyneuropathy.

From the side of the organ of vision: rarely - visual impairment; very rarely - a violation of the perception of colors.

From the sensory organs and labyrinth disorders: rarely - ringing in the ears, deafness; very rarely - hearing impairment.

From the cardiovascular system: rarely - tachycardia, vasodilation, decreased blood pressure, fainting; very rarely - vasculitis, prolongation of the Q – T interval, ventricular arrhythmia, bidirectional ventricular tachycardia.

From the respiratory system: rarely - dyspnea (including asthmatic conditions).

From the gastrointestinal tract: rarely - anorexia; sometimes hyperglycemia; often - nausea, diarrhea; rarely - vomiting, bitterness in the mouth, epigastric pain, dyspeptic disorders, flatulence; very rarely - pancreatitis.

On the part of the hepatobiliary system: sometimes - a transient increase in transaminases, hyperbilirubinemia; rarely - impaired liver function, jaundice, hepatitis (non-infectious); very rarely - liver necrosis (very rarely progresses to liver failure, life-threatening).

On the part of the skin and subcutaneous tissue: rarely - rash (petechial, macular, urticaria, etc.), itching, urticaria; rarely - photosensitization, the appearance of non-specific bubbles; very rarely - petechiae, erythema multiforme, erythema nodosum, Stevens-Johnson syndrome and toxic epidermal necrolysis.

From the musculoskeletal system and connective tissue: sometimes - arthralgia; rarely - myalgia, arthritis, increased muscle tone and cramps; very rarely - muscle weakness, tendonitis, tendon ruptures (mainly Achilles), exacerbation of symptoms of myasthenia gravis.

From the urinary system: sometimes - impaired renal function; rarely - tubulointerstitial nephritis, renal failure, hematuria, crystalluria.

On the part of the body as a whole: sometimes - non-specific pain syndrome, general malaise, weakness, fever; rarely - edema, increased sweating (hyperhidrosis); very rarely - gait disturbance.

Deviation of laboratory parameters: sometimes - an increase in the level of liver enzymes (AlAT, AsAT, alkaline phosphatase), impaired liver function, increased levels of creatinine and urea in blood plasma; rarely - changes in prothrombin; very rarely - increased levels of amylase and lipase.

Caused by tinidazole.Adverse effects were rare, they were mild and resolved on their own.

From the nervous system: ataxia, convulsions (rarely), dizziness, headache, hypesthesia, paresthesia, peripheral neuropathy, sensory disturbances, vertigo, hot flashes.

From the digestive system: abdominal pain, a feeling of bitterness in the mouth, a metallic taste in the mouth, anorexia, diarrhea, plaque on the tongue, glossitis, stomatitis, nausea, and vomiting.

On the part of the blood and blood system: transient leukopenia.

On the part of the skin and appendages: hypersensitivity reactions (sometimes severe) in the form of skin rashes (petechial, macular, urticarial), itching, hyperemia, urticaria and angioedema.

From the urinary system: staining of urine in a dark color.

General condition disorders associated with the use of the drug: fever, fatigue.

special instructions

Patients with a history of seizures, with a history of seizures, with vascular diseases and organic brain damage due to the risk of adverse reactions from the central nervous system should be prescribed only for health reasons. if severe or prolonged diarrhea occurs during or after treatment, the possibility of developing pseudomembranous colitis, which requires immediate withdrawal of the drug and the appointment of appropriate therapy, should be excluded.

Genital tract infections. If it is suspected or known that genital tract infections are caused by fluoroquinolone-resistant microorganisms, it is especially important to obtain information about the degree of resistance to ciprofloxacin and tinidazole and to confirm sensitivity to the drug based on laboratory results.

Violation of cardiac activity. Ciprofloxacin, which is part of Cifran ST, is associated with prolongation of the Q – T interval on the ECG. Elderly patients may be more sensitive to the effects of the drug on the Q – T interval. Ciprofloxacin should be used with caution with concomitant drugs that can cause Q – T interval prolongation (for example, class Ia or III antiarrhythmic drugs), and in patients with risk factors for these conditions (for example, a history of Q – T prolongation, uncorrected hypokalemia).

Gastrointestinal tract. The occurrence during and after treatment of severe and persistent diarrhea can be a manifestation of a severe gastrointestinal disease (for example, pseudomembranous colitis with a possible fatal outcome), which requires immediate treatment. In such cases, the drug should be discontinued and the use of appropriate therapy started. Drugs that inhibit peristalsis are contraindicated.

There may be a transient increase in the activity of transaminases, alkaline phosphatase, or transient cholestatic jaundice, especially in patients with a history of liver disease.

Nervous system. Patients with epilepsy and patients with a history of impaired central nervous system function (for example, a decrease in the seizure threshold, convulsions, decreased blood circulation in the vessels of the brain, organic brain damage, and stroke) can use the drug only if the expected benefit prevails over the possible risk. In some cases, adverse reactions from the central nervous system are noted after the first dose of the drug. In rare cases, depression or psychosis may progress. In such cases, the drug should be discontinued.

Tinidazole in the composition of Cifran ST sometimes caused various neurological disorders, such as dizziness, ataxia, peripheral neuropathies, and only occasionally - convulsions. In the event of any neurological disorders, the drug should be discontinued.

Hypersensitivity to the drug. In some cases, hypersensitivity and allergic reactions are noted after the first dose.In isolated cases, anaphylactic / anaphylactoid reactions can progress, up to a shock that threatens the patients life. In some cases, they are detected after the first dose of ciprofloxacin. In these cases, the drug should be stopped and drug treatment should be carried out immediately.

Musculoskeletal system. For any signs of tendonitis (for example, painful swelling), treatment with ciprofloxacin should be stopped immediately and physical activity avoided.

Tendon rupture (mainly Achilles) was noted mainly with the use of the drug in the elderly or in connection with previous treatment with corticosteroids.

Leather. Ciprofloxacin contributes to the occurrence of photosensitivity reactions. Patients taking the drug should avoid intense ultraviolet radiation. If photosensitivity reactions occur (for example, like sunburn), drug therapy should be discontinued.

Cytochrome P450. Ciprofloxacin is known to be a moderate inhibitor of cytochrome P450 1A2 enzymes. Caution should be exercised while using ciprofloxacin and drugs that are metabolized by these enzymes, such as theophylline, methylxanthine, caffeine, duloxetine, clozapine and others, because an increase in the concentration of these drugs in blood plasma can cause specific side effects. During treatment and for at least 72 hours after treatment with Cifran ST (due to the presence of tinidazole), alcohol should be avoided, taking into account the possibility of an antabuse-like reaction (hot flashes, colicky abdominal pain, tachycardia).

During the treatment period, changes in some laboratory parameters are possible: the appearance of sediment in the urine; a temporary increase in the concentration of urea, creatinine, bilirubin, hepatic transaminases in the blood plasma, in some cases - hyperglycemia, crystalluria or hematuria, a change in prothrombin. In patients with impaired liver and / or kidney function, it is recommended to control the concentration of ciprofloxacin in blood plasma.

Avoid concomitant use of tablets and dairy / calcium-fortified foods (e.g. yogurt, high calcium juices). Other calcium-containing products do not affect the absorption of ciprofloxacin.

The drug is indicated for the treatment of acute tonsillitis (tonsillar tonsillitis).

Influence on the ability to drive vehicles and work with dangerous machinery. Patients taking Cifran ST should refrain from activities requiring increased attention and speed of psychomotor reactions, as well as from driving vehicles.

Use during pregnancy and lactation. Cifran ST should not be prescribed to pregnant women and women who are breast-feeding. Given the data from animal tests, the likelihood of damage to the articular cartilage in newborns cannot be completely ruled out, while the possibility of teratogenic effects (malformations) has not been confirmed. Tinidazole passes into breast milk, where it is detected for more than 72 hours after use. Women should not breast-feed during the use of the drug and within 3 days after discontinuation of the drug.

Children. Do not use in children.

Interactions

Caution should be exercised while using Cifran st and antiarrhythmic drugs of class ia or iii, since ciprofloxacin can enhance the prolongation of the q – t interval.

The simultaneous use of ciprofloxacin preparations with iron preparations, phosphate-binding polymers (e.g. Sevelamer), sucralfate and antacids containing magnesium, aluminum, calcium, and drugs with a large buffer capacity (e.g. antiretroviral) reduces the absorption rate of ciprofloxacin.In this regard, Cifran ST should be prescribed 1-2 hours before or 4 hours after taking these drugs. The specified restriction does not apply to the class of blockers N₂receptors.

With the combined use of ciprofloxacin and omeprazole, a slight decrease in C may be noted_max plasma drug and decreased AUC.

The simultaneous use of Cifran ST and drugs containing theophylline can lead to an undesirable increase in theophylline concentration in blood plasma, which, in turn, can lead to the development of side effects. In rare cases, side effects can be life threatening / fatal. If the simultaneous use of these drugs cannot be avoided, the plasma concentration of theophylline should be monitored and its dose adequately reduced.

After the simultaneous use of Cifran ST and drugs containing caffeine or pentoxifylline (oxpentifillin), an increase in the concentration of these xanthines in the blood plasma was reported.

The combined use of quinolones in very high doses (gyrase inhibitors) and some NSAIDs (excluding acetylsalicylic acid) can provoke seizures.

With the simultaneous use of Cifran ST and cyclosporine in some cases, an increase in the concentration of creatinine in the blood plasma was noted, therefore, regular monitoring of this indicator (2 times a week) is necessary.

With the simultaneous use of Cifran ST and a vitamin K antagonist, the anticoagulant effect of ciprofloxacin may be enhanced. The risk may vary depending on the infection, age, general condition of the patient, so it is difficult to assess the exact effect of ciprofloxacin on increasing the value of the international normalized ratio (INR). Regular INR monitoring should be performed during and immediately after the combined use of Cyfran ST and a vitamin K antagonist (e.g. warfarin, acenocumarol, fenprocoumone or fluindione).

Due to the interaction of ciprofloxacin and glibenclamide, an increase in the severity of the action of the latter is possible, which is manifested by hypoglycemia.

The combined use of Cifran ST and probenecid is accompanied by an increase in the concentration of ciprofloxacin in the blood plasma.

With simultaneous use with ciprofloxacin, a slowdown in the tubular transport (renal metabolism) of methotrexate is possible, which may be accompanied by an increase in the concentration of methotrexate in blood plasma. In this case, the likelihood of side effects caused by methotrexate may increase. In this regard, patients receiving combination therapy with methotrexate and ciprofloxacin should be carefully monitored.

Metoclopramide accelerates the absorption of ciprofloxacin, resulting in a shorter time to reach C_max ciprofloxacin in plasma (this does not affect the bioavailability of the latter).

As a result of a clinical study involving healthy volunteers with the simultaneous use of ciprofloxacin and tizanidine, an increase in the concentration of tizanidine in blood plasma was revealed (C_max - 7 times, range - 4-21 times; increase in AUC - 10 times, range - 6-24 times). With an increase in the concentration of tizanidine in blood plasma, hypotensive and sedative side effects are associated. Thus, the simultaneous use of ciprofloxacin and tizanidine is contraindicated.

In clinical studies, it was found that the simultaneous use of duloxetine and potent inhibitors of the isoenzyme CYP 1A2 (such as fluvoxamine) can lead to an increase in AUC and C_max duloxetine. Despite the lack of clinical data on the interaction with ciprofloxacin, it is possible to envisage the possibility of interaction with the simultaneous use of ciprofloxacin and duloxetine.

Ciprofloxacin can be used in combination with azlocillin and ceftazidine for infections caused by Pseudomonas; with meslocillin, azlocillin and other effective β-lactam antibiotics - for streptococcal infections; with isoxazolepenicillins, vancomycin - with staphylococcal infections, with metronidazole, clindamycin - with anaerobic infections.

Uricosuric drugs (allopurinol) help to slow down the elimination of ciprofloxacin by 50% and increase its concentration in blood plasma.

The simultaneous use of ropinirole with ciprofloxacin, a moderate inhibitor of the isoenzyme CYP 1A2, leads to an increase in AUC and C_max ropinirole at 60 and 84%, respectively.

Monitoring of side effects of ropinirole and appropriate dose adjustment is recommended during and immediately after simultaneous administration with ciprofloxacin.

The simultaneous use of drugs containing lidocaine and ciprofloxacin hydrochloride, a moderate inhibitor of the isoenzyme CYP 1A2, reduces the clearance of lidocaine administered iv by 22%. Although treatment with lidocaine was well tolerated, after simultaneous use with ciprofloxacin, a certain interaction may be noted, which may be accompanied by adverse reactions.

After the simultaneous use of 250 mg of ciprofloxacin with clozapine for 7 days, the plasma concentrations of clozapine and N-desmethylclozapine were increased by 29 and 31%, respectively. Clinical surveillance and appropriate dose adjustment of clozapine is recommended during and immediately after co-administration with ciprofloxacin (see SPECIAL INSTRUCTIONS).

Studies with healthy volunteers showed an increase in C_max and AUC of sildenafil about 2 times after oral administration of 50 mg simultaneously with 500 mg of ciprofloxacin. Therefore, ciprofloxacin with sildenafil should be prescribed with caution, carefully assessing the risk and benefit.

The simultaneous use of alcohol and the use of Cyfran ST (due to the presence of tinidazole) can cause an antabuse-like reaction, so it must be excluded.

Anticoagulants: drugs of a similar chemical structure can enhance the effect of oral anticoagulants. It is necessary to constantly monitor the indicators of prothrombin time and take into account the possibility of dose adjustment of the anticoagulant.

Overdose

Due to an overdose of oral administration of ciprofloxacin, in some cases, a reversible toxic effect on the renal parenchyma was noted. therefore, in case of an overdose, in addition to the usual measures (gastric lavage, the use of vomiting agents, the introduction of a large amount of liquid, the creation of an acidic urine reaction), it is also recommended to monitor the state of renal function and take antacids containing magnesium and calcium, which reduce the absorption of ciprofloxacin. hemodialysis removes only a small amount of ciprofloxacin (10%).

The specific antidote is unknown.

Non-serious cases of overdose have been reported in patients receiving tinidazole, but they do not provide a complete picture of the symptoms of overdose.

There is no specific antidote for the treatment of tinidazole overdose. Treatment should be symptomatic and supportive. Gastric lavage may be helpful. Tinidazole is easily eliminated by hemodialysis.

Storage conditions

In a dry place at a temperature not exceeding 25 ° C.