Combiflox, 20 pcs., 500 mg+200 mg, film-coated tablets

Kombifloks®

Disability and potential irreversible serious adverse reactions associated with fluoroquinolones

The use of fluoroquinolones, including ofloxacin, has been associated with disability and the development of irreversible serious adverse reactions from various body systems that can occur simultaneously in the same patient.

Adverse reactions caused by fluoroquinolones include tendonitis, tendon rupture, arthralgia, myalgia, peripheral neuropathy, and nervous system side effects (hallucinations, anxiety, depression, insomnia, headaches, and confusion). These reactions may develop from several hours to several weeks after the start of ofloxacin therapy.

The development of these adverse reactions was observed in patients of any age or without the presence of previous risk factors. If the first signs or symptoms of any serious adverse reaction occur, ofloxacin should be discontinued immediately. Fluoroquinolones, including ofloxacin, should be avoided in patients who have experienced any of these adverse reactions.

Kidney, liver failure

In patients with renal failure, dose adjustment of the drug is necessary (see sections “With caution”, “Dosage and administration”).

In patients with impaired liver or kidney function, monitoring of plasma concentrations of ofloxacin is necessary.

Prevention of photosensitivity

During treatment, due to the risk of photosensitivity, exposure to bright sunlight and ultraviolet rays should be avoided.

Secondary infection

As with the use of other antimicrobial drugs, when taking the drug, the development of a secondary infection associated with the growth of drug-resistant microorganisms is possible, to exclude and confirm which the patient’s condition should be re-evaluated. If a secondary infection develops during therapy, the necessary measures should be taken to treat it.

Peripheral neuropathy

Sensory and sensorimotor neuropathy, which may have a rapid onset, has been reported in patients receiving fluoroquinolones, including ofloxacin, ornidazole.

Patients should be informed to report any symptoms of neuropathy to their healthcare provider. Fluoroquinolones should not be prescribed to patients with a history of peripheral neuropathy.

If patients develop symptoms of neuropathy, treatment should be discontinued to help minimize the possible risk of developing irreversible conditions (see Precautions).

Patients with glucose-6-phosphate dehydrogenase deficiency

Patients diagnosed with glucose-6-phosphate dehydrogenase deficiency may be predisposed to hemolytic reactions when treated with quinolones. Therefore, caution should be exercised when using the drug in such patients (see section "With caution").

Pseudomembranous colitis caused by Clostridium difficile

The appearance of diarrhea, especially severe, persistent and/or bloody, during or after treatment with the drug may be a manifestation of pseudomembranous colitis. If pseudomembranous colitis is suspected, treatment should be stopped immediately and appropriate specific antibacterial therapy (oral vancomycin, oral teicoplanin, or oral metronidazole) should be immediately prescribed. If this clinical situation occurs, drugs that suppress intestinal motility are contraindicated.

Patients predisposed to developing seizures

Like other quinolones, ofloxacin should be used with caution in patients predisposed to the development of seizures (patients with a history of central nervous system lesions, patients concomitantly receiving drugs that lower the seizure threshold of the brain (theophylline, fenbufen [and other similar non-steroidal anti-inflammatory drugs] ), (see section "With caution") If seizures develop, treatment with the drug should be discontinued.

Tendinitis and tendon rupture

Tendinitis, which rarely occurs with quinolone use, can sometimes lead to rupture of tendons, including the Achilles tendon, and can be bilateral. This undesirable effect may develop within 48 hours of starting treatment or several months after completion of fluoroquinolone therapy.

Elderly patients are more likely to develop tendinitis; In patients taking fluoroquinolones, the risk of tendon rupture may be increased with concomitant use of corticosteroids. In addition, post-transplant patients have an increased risk of developing tendinitis, so it is recommended to be careful when prescribing fluoroquinolones in this category of patients.

In patients with impaired renal function, the daily dose should be adjusted based on creatinine clearance. Patients should be advised to remain quiet at the first sign of tendonitis or tendon ruptures and to contact their healthcare provider.

If you suspect the development of tendinitis or tendon rupture, you should immediately stop treatment with the drug and begin appropriate treatment of the affected tendon, for example, providing it with sufficient immobilization (see sections “Contraindications” and “Side Effects”).

QT prolongation

Some caution is warranted when taking fluoroquinolones, including ofloxacin, in patients with known risk factors for QT prolongation, such as:

• elderly age;
• uncorrected electrolyte imbalance (eg, hypokalemia, hypomagnesemia);
• congenital prolongation of the QT interval;
• diseases of the cardiovascular system (heart failure, myocardial infarction, bradycardia);
• simultaneous use of drugs that prolong the QT interval (classes IA and III antiarrhythmic drugs, tricyclic antidepressants, macrolides, antipsychotics).

Aneurysm and aortic dissection

Epidemiological studies have reported an increased risk of developing aortic aneurysm and/or aortic dissection after the use of fluoroquinolones, especially in elderly patients.

Therefore, fluoroquinolones should be used only after careful benefit/risk assessment and consideration of other treatment options in patients with a family history of aortic aneurysm or in patients with a known aortic aneurysm and/or aortic dissection or in the presence of other risk factors or conditions. predisposing to the development of aortic aneurysm and/or aortic dissection (for example, Marfan syndrome, vascular Ehlers-Danlos syndrome, Takayasu arteritis, giant cell arteritis, Behcet's disease, arterial hypertension, atherosclerosis).

If sudden pain in the abdomen, chest, or back occurs, patients should seek immediate medical attention at an emergency room.

Pseudoparalytic myasthenia gravis (myasthenia gravis)

Fluoroquinolones, including ofloxacin, have neuromuscular blocking activity and may increase muscle weakness in patients with myasthenia gravis.

In the post-marketing period, serious adverse reactions, including pulmonary failure requiring mechanical ventilation and death, have been observed with the use of fluoroquinolones in patients with myasthenia gravis. The use of the drug in a patient with an established diagnosis of pseudoparalytic myasthenia gravis is not recommended (see section “Side Effects”).

Severe skin reactions

Severe bullous reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported when taking ofloxacin. Patients should be informed that if skin reactions and/or lesions of the mucous membranes develop, they should immediately consult a doctor before continuing treatment with ofloxacin.

Hypersensitivity reactions and allergic reactions

When using fluoroquinolones, the development of hypersensitivity and allergic reactions has been reported after the first use (anaphylactic shock and anaphylactoid reactions, which can progress to a life-threatening condition). In these cases, you should stop using the drug and begin appropriate treatment.

Psychotic reactions

Psychotic reactions, including suicidal ideation/attempts, have been reported in patients taking fluoroquinolones, including ofloxacin, sometimes after a single dose. In case of development of any side effects from the central nervous system, including mental disorders, ofloxacin should be immediately discontinued and appropriate treatment should be initiated. In these cases, it is recommended to switch to therapy with an antibiotic other than a fluoroquinolone, if possible. Ofloxacin should be prescribed with caution to patients with psychotic disorders (including a history) (see section "Caution").

Liver dysfunction

The drug should be used with caution in patients with impaired liver function, as liver damage may occur (see section "Caution").

Cases of fulminant hepatitis leading to liver failure (including fatal cases) have been reported with the use of fluoroquinolones. Patients should be advised to stop treatment and consult a doctor if symptoms and signs of liver disease are observed, such as anorexia, jaundice, dark urine, itching, abdominal pain.

Dysglycemia (hypo- and hyperglycemia)

As with other fluoroquinolones, changes in blood glucose concentrations, including hypo- and hyperglycemia, were observed when using ofloxacin. During therapy with ofloxacin, dysglycemia occurred more often in elderly patients and patients with diabetes mellitus receiving concomitant therapy with oral hypoglycemic drugs (for example, sulfonylureas) or insulin.

When using ofloxacin in such patients, the risk of developing hypoglycemia, including hypoglycemic coma, increases. It is necessary to inform patients about the symptoms of hypoglycemia (confusion, dizziness, ravenous appetite, headache, nervousness, palpitations or increased heart rate, pale skin, perspiration, trembling, weakness).

If the patient develops hypoglycemia, treatment with ofloxacin should be discontinued immediately and appropriate therapy should be initiated. In these cases, it is recommended to switch to therapy with an antibiotic other than a fluoroquinolone, if possible. When treating with ofloxacin in elderly patients and patients with diabetes mellitus, careful monitoring of blood glucose concentrations is recommended.

Patients taking vitamin K antagonists

Due to the possible increase in prothrombin time/international normalized ratio and/or bleeding in patients taking concomitantly ofloxacin or ornidazole and vitamin K antagonists (for example, warfarin), close monitoring of blood clotting parameters is recommended.

Risk of developing resistance

The prevalence of acquired resistance may vary geographically and over time for individual species. Therefore, regional information on resistance is required. Microbiological diagnostics should be carried out with isolation of the pathogen and determination of its sensitivity, especially in severe infections or lack of response to treatment.

Escherichia coli infections

Escherichia coli resistance to fluoroquinolones

- the most common causative agent of urinary tract infections - varies in different geographic areas.
Clinicians are advised to consider regional resistance of Escherichia coli
to fluoroquinolones.

Infections caused by Neisseria gonorrhoeae

Due to increasing resistance of Neisseria gonorrhoeae,

ofloxacin should not be used as empirical treatment for suspected gonococcal urinary tract infection. Susceptibility testing of the pathogen to ofloxacin should be performed to guide targeted therapy.

Methicillin-resistant Staphylococcus aureus

There is a high likelihood that methicillin-resistant Staphylococcus aureus will be resistant to fluoroquinolones, including ofloxacin. Therefore, ofloxacin is not recommended for the treatment of known or suspected infections caused by methicillin-resistant Staphylococcus aureus unless laboratory tests have confirmed the organism's sensitivity to ofloxacin.

Effect on laboratory parameters and diagnostic tests

Ofloxacin may inhibit the growth of Mycobacterium tuberculosis

, leading to false negative results in the bacteriological diagnosis of tuberculosis.

When determining opiates and porphyrins in urine during treatment with ofloxacin, a false positive result is possible. It may be necessary to confirm positive results using more specific methods.

Other

During the treatment period, it is not recommended to consume ethanol.

In case of mixed infection caused, among other things, by Trichomonas vaginalis

, treatment of sexual partners should be carried out simultaneously.

In patients receiving lithium therapy, it is necessary to monitor the concentration of lithium, electrolytes and creatinine in the blood plasma.

Combiflox, 20 pcs., 500 mg+200 mg, film-coated tablets

Kidney, liver failure

In patients with renal failure, dose adjustment of the drug is necessary (see sections “With caution”, “Dosage and administration”).

In patients with impaired liver or kidney function, monitoring of plasma concentrations of ofloxacin is necessary.

Prevention of photosensitivity

During treatment, due to the risk of photosensitivity, exposure to bright sunlight and ultraviolet rays should be avoided.

Secondary infection

As with the use of other antimicrobial drugs, when taking the drug, the development of a secondary infection associated with the growth of drug-resistant microorganisms is possible, to exclude and confirm which the patient’s condition should be re-evaluated. If a secondary infection develops during therapy, the necessary measures should be taken to treat it.

Peripheral neuropathy

Sensory and sensorimotor neuropathy, which may have a rapid onset, has been reported in patients receiving fluoroquinolones, including ofloxacin, ornidazole. If patients develop symptoms of neuropathy, treatment should be discontinued to help minimize the possible risk of developing irreversible conditions (see Precautions).

Patients with glucose-6-phosphate dehydrogenase deficiency

Patients diagnosed with glucose-6-phosphate dehydrogenase deficiency may be predisposed to hemolytic reactions when treated with quinolones. Therefore, caution should be exercised when using the drug in such patients (see section "With caution").

Pseudomembranous colitis caused by Clostridium difficile

The appearance of diarrhea, especially severe, persistent and/or bloody, during or after treatment with the drug may be a manifestation of pseudomembranous colitis. If pseudomembranous colitis is suspected, treatment should be stopped immediately and appropriate specific antibacterial therapy (oral vancomycin, oral teicoplanin, or oral metronidazole) should be immediately prescribed. If this clinical situation occurs, drugs that suppress intestinal motility are contraindicated.

Patients predisposed to developing seizures

Like other quinolones, ofloxacin should be used with caution in patients predisposed to the development of seizures (patients with a history of central nervous system lesions, patients concomitantly receiving drugs that lower the seizure threshold of the brain (theophylline, fenbufen [and other similar non-steroidal anti-inflammatory drugs] ), (see section "With caution") If seizures develop, treatment with the drug should be discontinued.

Tendinitis

Tendinitis, which rarely occurs with quinolones, can sometimes lead to rupture of tendons, including the Achilles tendon, especially in elderly patients and in patients concomitantly taking corticosteroids. This undesirable effect may develop within 48 hours after the start of treatment and be bilateral. If signs of tendinitis (inflammation of the tendon) appear, it is recommended to immediately stop treatment with the drug. Appropriate treatment (eg, immobilization) of the injured tendon may be required.

QT prolongation

Some caution is warranted when taking fluoroquinolones, including ofloxacin, in patients with known risk factors for QT prolongation, such as:

• elderly age;
• uncorrected electrolyte imbalance (eg, hypokalemia, hypomagnesemia);
• congenital prolongation of the QT interval;
• diseases of the cardiovascular system (heart failure, myocardial infarction, bradycardia);
• simultaneous use of drugs that prolong the QT interval (classes IA and III antiarrhythmic drugs, tricyclic antidepressants, macrolides, antipsychotics).

Pseudoparalytic myasthenia gravis (myasthenia gravis)

Fluoroquinolones, including ofloxacin, have neuromuscular blocking activity and may increase muscle weakness in patients with myasthenia gravis. In the post-marketing period, serious adverse reactions, including pulmonary failure requiring mechanical ventilation and death, have been observed with the use of fluoroquinolones in patients with myasthenia gravis. The use of the drug in a patient with an established diagnosis of pseudoparalytic myasthenia gravis is not recommended (see section “Side Effects”).

Severe skin reactions

Severe bullous reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported when taking ofloxacin. Patients should be informed that if skin reactions and/or lesions of the mucous membranes develop, they should immediately consult a doctor before continuing treatment with the drug.

Hypersensitivity reactions and allergic reactions

Hypersensitivity reactions and allergic reactions (anaphylactic shock and anaphylactoid reactions, which can progress to a life-threatening condition) have been reported with the use of ofloxacin and ornidazole. In these cases, you should stop using the drug and begin appropriate treatment.

Psychotic reactions

Psychotic reactions, including suicidal thoughts/attempts, have been reported in patients taking fluoroquinolones, including ofloxacin. If such reactions develop, the drug should be discontinued and appropriate treatment prescribed. The drug should be prescribed with caution to patients with psychotic disorders (including a history) (see section "With caution").

Liver dysfunction

The drug should be used with caution in patients with impaired liver function, as liver damage may occur (see section "Caution"). Cases of fulminant hepatitis leading to liver failure (including fatal cases) have been reported with the use of fluoroquinolones. Patients should be advised to stop treatment and consult a doctor if symptoms and signs of liver disease are observed, such as anorexia, jaundice, dark urine, itching, abdominal pain.

Dysglycemia (hypo- and hyperglycemia)

Both hypoglycemia and hyperglycemia have been reported with fluoroquinolones, including ofloxacin. Hypoglycemic coma has been reported in diabetic patients receiving concomitant oral hypoglycemic agents (eg, glibenclamide) or insulin. It is recommended to carefully monitor blood glucose concentrations in patients with diabetes mellitus.

Patients taking vitamin K antagonists

Due to the possible increase in prothrombin time/international normalized ratio and/or bleeding in patients taking concomitantly ofloxacin or ornidazole and vitamin K antagonists (for example, warfarin), close monitoring of blood clotting parameters is recommended.

Risk of developing resistance

The prevalence of acquired resistance may vary geographically and over time for individual species. Therefore, local information on resistance is required. Microbiological diagnostics should be carried out with isolation of the pathogen and determination of its sensitivity, especially in severe infections or lack of response to treatment.

Escherichia coli infections

Resistance to fluoroquinolones in Escherichia coli, the most common causative agent of urinary tract infections, varies across geographic areas. Physicians are advised to take into account the local resistance of Escherichia coli to fluoroquinolones.

Infections caused by Neisseria gonorrhoeae

Due to increasing resistance in Neisseria gonorrhoeae, ofloxacin should not be used as empirical treatment for suspected gonococcal urinary tract infection. Susceptibility testing of the pathogen to ofloxacin should be performed to guide targeted therapy.

Methicillin-resistant streptococcus aureus

There is a high likelihood that methicillin-resistant Staphylococcus aureus will be resistant to fluoroquinolones, including ofloxacin. Therefore, ofloxacin is not recommended for the treatment of known or suspected infections caused by methicillin-resistant Staphylococcus aureus unless laboratory tests have confirmed the organism's sensitivity to ofloxacin.

Effect on laboratory parameters and diagnostic tests

Ofloxacin may inhibit the growth of Mycobacterium tuberculosis, leading to false-negative results in the bacteriological diagnosis of tuberculosis.

When determining opiates and porphyrins in urine during treatment with ofloxacin, a false positive result is possible. It may be necessary to confirm positive results using more specific methods.

Other

During the treatment period, it is not recommended to consume ethanol.

In case of mixed infection, including those caused by Trichomonas vaginalis, treatment of sexual partners should be carried out simultaneously.

In patients receiving lithium therapy, it is necessary to monitor the concentration of lithium, electrolytes and creatinine in the blood plasma.

Impact on the ability to drive vehicles and machinery

During the treatment period, it is not recommended to drive vehicles or engage in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Combiflox

From the digestive system:

gastralgia, decreased appetite, nausea, vomiting, diarrhea, constipation, flatulence, abdominal pain, increased activity of liver transaminases, hyperbilirubinemia, cholestatic jaundice, pseudomembranous colitis, dry oral mucosa, colitis (including hemorrhagic), hepatitis.

From the nervous system:

headache, dizziness, insomnia, nervousness, uncertainty of movements, tremors, convulsions, numbness and paresthesia of the extremities, intense dreams, “nightmarish” dreams, anxiety, arousal, phobias, depression, confusion, hallucinations, increased intracranial pressure, insomnia, nervousness , drowsiness, epileptic seizures, extrapyramidal disorders, psychotic reactions with suicidal tendencies, sensory or sensorimotor peripheral neuropathy, impaired motor coordination, temporary loss of consciousness.

From the musculoskeletal system:

tendonitis, myalgia, arthralgia, tenosynovitis, tendon rupture, limb pain, muscle stiffness, rhabdomyolysis, muscle weakness.

From the senses:

impaired color vision, diplopia, taste disturbances, perversion of taste, disturbances of smell, hearing and balance.

From the cardiovascular system:

tachycardia, increase or decrease in blood pressure, collapse, prolongation of the QT interval, ventricular arrhythmia, incl. ventricular tachysystolic arrhythmia of the “pirouette” type.

Allergic reactions:

skin rash, itching, urticaria, allergic pneumonitis, allergic nephritis, eosinophilia, fever, angioedema, bronchospasm; exudative erythema multiforme (including Stevens-Johnson syndrome) and toxic epidermal necrolysis (Lyell's syndrome), photosensitivity, vasculitis, anaphylactic shock, itching of the external genitalia in women.

From the skin:

pinpoint hemorrhages (petechiae), bullous hemorrhagic dermatitis, papular rash with crust, indicating vascular damage (vasculitis).

From the hematopoietic organs:

leukopenia, agranulocytosis, anemia (including aplastic and hemolytic), thrombocytopenia, pancytopenia.

From the urinary system:

acute interstitial nephritis, renal dysfunction, hypercreatininemia, increased urea concentration, dysuria, urinary retention, acute renal failure.

Other:

intestinal dysbiosis, superinfection, hypoglycemia (in patients with diabetes), vaginitis, chest pain, fatigue, asthenia, general weakness, photosensitivity, vaginal discharge, nosebleeds, thirst, weight loss, pharyngitis, rhinitis, dry cough, acute attack porphyria (in patients with porphyria).

Bacterial infections are the most common human diseases throughout life. These infections also include the so-called urinary infections, which are widely encountered both in outpatient and hospital practice. Against the backdrop of an increase in the level of resistance of uropathogens to antibacterial drugs, the solution to this issue is currently one of the most pressing medical problems in most countries of the world. According to the recommendations of the European Association of Urology, urinary tract infections (UTIs) are divided into: uncomplicated lower urinary tract infection (acute uncomplicated cystitis), uncomplicated upper urinary tract infection (acute uncomplicated pyelonephritis), complicated urinary tract infection (with or without pyelonephritis), urosepsis, urethritis, special forms (prostatitis, epididymitis and orchitis) [1]

In various regions of the world, UTIs account for up to 2-6% of visits to doctors, while 80-90% of those who apply are women. Urinary tract infections in the United States are the reason for visiting a doctor for about 7 million patients a year, and for 2 million patients they are the reason for hospitalization. The incidence in the Russian Federation is up to 36 million cases per year.

Based on the results of the all-Russian multicenter study “SONAR” (2005), data on the prevalence of uncomplicated UTI in the Russian Federation, the Republic of Belarus, Kazakhstan and Kyrgyzstan were analyzed. The results obtained indicate that at the age of 18–20 years, about 20% of women had a history of at least one episode of UTI, and in older age groups there is an increase in incidence [2].

Among all urinary tract infections, the leading place is occupied by cystitis, which is the most common disease encountered in the medical practice of doctors of various profiles. An important feature of inflammatory diseases of the urinary tract in women is their frequent combination with infection of the reproductive system due to the peculiarities of the anatomical and functional structure of the external genitalia and cyclic hormonal changes. The role of sexually transmitted urogenital infection in the etiology of urethritis and cystitis in women is now generally accepted, which also determines the tendency for frequent recurrent UTIs. According to the literature, recurrence of cystitis within six months after the initial episode occurs in approximately one third of patients [3, 4]. The combination of infections of the urinary and reproductive systems, the frequent recurrent nature of cystitis significantly worsens the quality of life of a woman and increases the number of cases of temporary disability, largely determining the social and economic significance of this disease.

To select optimal empirical therapy, it is extremely important to know the current characteristics of UTI pathogens. The largest international study ECO-SENS revealed the following patterns: the most common pathogens of chronic cystitis are gram-negative enterobacteria, mainly E. coli-80%, in 8.2% of cases Proteus spp. is identified, in 3.7% - Klebsiella spp., in 3% - Staphylococcus saprophyticus, in 2.2% - Enterobacter spp., in 0.7% - Pseudomonas aeruginosa [5]. Similar studies were also conducted in the Russian Federation - UTIAP I (1998–1999), UTIAP II (2000–2001), UTIAP III (2004–2005). As a result of these studies, it was established that in the Russian Federation, acute cystitis was caused by Escherichia coli in 85.9% of cases, Klebsiella spp. in 6.0%, Proteus spp. in 1.8%, Staphylococcus saprophyticus in 1.6% , in 1.2% - Pseudomonas aeruginosa, etc. Dysbiosis of the genital tract, chlamydial, mycoplasma and trichomonas infections can also play a significant role in the development of cystitis. In addition, recently there has been an increase in the number of diagnosed urogenital infections caused by Candida spp., which may be a consequence of the uncontrolled use of antibacterial agents [6].

The diagnosis of cystitis, as a rule, does not present any particular difficulties due to the characteristic clinical picture. The main symptoms indicating the presence of inflammation of the mucous membrane of the bladder are signs of dysuria: frequent urination, accompanied by discomfort, pain, burning during urination; frequent urge to urinate; nocturia; feeling of incomplete emptying of the bladder; the appearance of blood in the urine at the end of urination, etc. Clinical diagnosis of cystitis, along with routine examination methods, such as a general urine test, a clinical blood test, a bacteriological analysis of urine, should include an ultrasound examination of the bladder and kidneys, identification of pathogens of sexually transmitted infections (PCR), and, if indicated, morphological methods (cystoscopy with biopsy). To exclude concomitant diseases in women, an examination by a gynecologist is necessary.

Despite the huge number of effective antibiotics, the problem of treating women with UTIs is far from being resolved. The increasing resistance of major uropathogens to many antimicrobial drugs constantly raises debate about the choice of an effective method for treating these diseases. According to current recommendations for the treatment of infectious diseases, the pathogen must be identified and its sensitivity profile to antibiotics determined before starting therapy. However, when treating patients with acute clinical manifestations of UTI, in most cases, obtaining timely data on the sensitivity profile of uropathogens is not always possible. In addition, an important condition for the successful treatment of UTIs and the prevention of recurrent infections is the creation of not only high concentrations of the antibiotic in the blood, but also ensuring the maintenance of high levels of drugs in the mucous membrane of the bladder, since the leading role of interstitial and even intracellular localization of uropathogenic strains of E. coli has been proven in the development of UTIs, in particular cystitis [7, 8]. Studies have shown that fluoroquinolones (FQ) and nitrofurantoin exhibit the greatest activity against intracellularly localized uropathogens, while the activity of penicillins, aminoglycosides, fosfomycin and cotrimoxazole against uropathogenic strains of E. coli localized intracellularly is low [9].

FQs have been widely used as empirical therapy for UTIs of any location, including cystitis. However, a frequent argument against the widespread use of PCs is the growth of resistant strains of microorganisms to them. In Russia, the level of resistance of uropathogenic E. coli to fluoroquinolones, according to various studies, ranges from 4.3 to 12.9%, averaging about 7–8%. From the point of view of clinical practice, it is important that resistance in most microorganisms to PC develops quite slowly; these antibiotics are quickly and well absorbed from the intestine, creating high concentrations in the urine that remain for quite a long time at a level significantly exceeding the minimum inhibitory concentration (MIC) for the main causative agents of uncomplicated UTIs. PCs are also widely used for infectious and inflammatory diseases of the female genital organs, the main pathogens in which are Chlamydia trachomatis, Mycoplasma spp., Ureaplasma urealyticum, Neisseria gonorrhoeae, Streptococcus spp., Escherichia coli, Haemophilusin fluenzae, etc., as well as anaerobes such as Prevotellaspp. and Peptostreptococcus.

For infectious and inflammatory diseases of UTI caused by Trichomonas vaginalis, drugs of the nitroimidazole group are widely used with fairly high efficiency.

We assessed the effectiveness of complex therapy with the new combination drug Combiflox®, which has a wide spectrum of antibacterial activity, in the treatment of women with uncomplicated UTI.

Combiflox® is a combined antiprotozoal drug with antibacterial activity. The effect of the drug is due to ofloxacin, which is a broad-spectrum antimicrobial agent from the group of fluoroquinolones, and ornidazole, a 5-nitroimidazole derivative that has antiprotozoal and antimicrobial effects. The summarized spectrum of action of these drugs is presented in Table No. 1.

The release form of the drug is film-coated tablets, which is very important for its use in outpatient practice. Both ofloxacin and ornidazole are well absorbed from the gastrointestinal tract. Bioavailability of ofloxacin – 95%, ornidazole – 90%. Plasma protein binding of ofloxacin is 25%, ornidazole is 13%. TCmax - for ofloxacin 1-2 hours, for ornidazole - 3 hours. About 5% of ofloxacin is metabolized in the liver and 75-90% of it is excreted unchanged by the kidneys, about 4% - with bile. Ornidazole is metabolized in the liver and excreted 60-70% in the form of metabolites, 4% unchanged by the kidneys and 20-25% by the intestines.

The main indication for the use of this drug is mixed bacterial infections caused by sensitive gram-positive and gram-negative microorganisms in association with anaerobic microorganisms and/or protozoa, and these are, first of all, infections of the lower urinary tract (cystitis, urethritis), genital and pelvic organs (endometritis, salpingitis, oophoritis, cervicitis, parametritis, prostatitis, colpitis, orchitis, epididymitis).

Contraindications to the drug are epilepsy (including a history), age under 18 years, pregnancy and lactation, hypersensitivity to the components of the drug.

MATERIALS AND METHODS

We assessed the effectiveness of this drug at the urology department of OJSC Polyclinic Medroskontrakt. The study included 54 patients with a laboratory-verified diagnosis of cystitis. The median age was 27.5 years (minimum age - 18 years, maximum - 57 years). During the study, 3 patients dropped out of the study for various reasons not related to taking the study drug. Thus, effectiveness was assessed based on treatment results in 51 participants. Inclusion criteria: verified diagnosis of cystitis, absence of use of any antibacterial drugs or immunomodulators during the last month, sensitivity of the culture revealed during bacteriological examination to the components of the drug Combiflox®. Exclusion criterion: the presence of multidrug-resistant flora during bacteriological examination of urine. Diagnosis criteria: comprehensive examination, including laboratory diagnostics (general urine test, complete blood count, biochemical blood test, bacteriological urine culture, PCR diagnostics for sexually transmitted infections, examination of a smear from the vagina and cervical canal), filling out a urination diary, Ultrasound of the kidneys and bladder; examination by a gynecologist. Microbiological examination of urine was carried out before the start and 2-3 weeks after the end of treatment. The role of the pathogen was considered clinically significant when more than 104 CFU/ml of uropathogenic bacteria were detected. The results of bacteriological examination of urine showed that 73% of UTIs were caused by Escherichia coli, 18% by Enterococcus faecalis & cloacae, the rest were caused by various gram-negative bacteria, such as Proteus spp., Klebsiella spp., Staphylococcus saprophyticus, Pseudomonas aeruginosa, etc. Resistance was detected mainly to amoxicillin, cefotaxime, erythromycin.

Table 1. Total spectrum of action of the combination drug Combiflox®

The study participants were divided into three groups: Group I – 21 patients (41%) with a diagnosis of “exacerbation of chronic cystitis”; Group II – 14 patients (27%) diagnosed with “acute cystitis”; Group III – 16 patients (31%) who developed cystitis in combination with vaginal dysbiosis or sexually transmitted infection (Trichomonas vaginalis, Chlamydia trachomatis, Gardnerella vaginalis, Mycoplasma hominis, Ureaplasma urealyticum). All patients were treated with Combiflox® at a dosage of 1000/400 mg/day in two doses, the total duration of the course of therapy was on average 5-10 days.

At the same time, the patients received anti-inflammatory therapy (suppositories with non-steroidal anti-inflammatory drugs 50 mg 2 times a day for 3-5 days) and were prescribed herbal diuretics.

Clinical monitoring was carried out throughout the entire treatment period. The results of the therapy were assessed based on an assessment of the dynamics of complaints, an objective examination, monitoring of laboratory parameters (general urine analysis on the 3rd, 5th, 10th day of treatment), filling out a urination diary by patients, and assessing treatment tolerability. Laboratory (bacteriological and PCR diagnostics, if necessary) quality control of treatment was carried out 2-3 weeks after completion of the drug Combiflox®.

RESULTS

Group I – patients with exacerbation of chronic cystitis. Assessing the results of the treatment over time: on the third day – a decrease in dysuria, a decrease in the frequency of urination, an improvement in laboratory parameters over time (preservation of slight leukocyturia); on days 5-10 – reduction or complete disappearance of complaints, normalization of laboratory parameters. The prescribed therapy was well tolerated by the patients. Two patients (3.9%) developed side effects from the gastrointestinal tract (nausea, upset stool) associated with taking the antibacterial drug. The clinical effectiveness of the drug in the group was 85% (18 patients); according to the results of complete laboratory control, the microbiological effectiveness was 90% (19 patients). In two patients, due to persistent changes in laboratory parameters and identified resistance of the uropathogen to the drug, the drug was replaced.

Group II – patients with acute cystitis. Evaluation of the results of the treatment over time: on the 2-3rd day, a decrease in the number of complaints, a decrease in the frequency of urination, an improvement in laboratory parameters over time (preservation of slight leukocyturia); 5-10 days – complete disappearance of complaints, normalization of laboratory parameters. The prescribed therapy was well tolerated by the patients; no side effects associated with taking the antibacterial drug were noted. According to the control results, the clinical effectiveness and eradication of the pathogen was 92% (13 patients). In one patient, the antibacterial drug was changed due to insufficient effect of the therapy.

Group III – patients with cystitis in combination with a sexually transmitted infection. Assessing the results of the treatment over time: on the third day - a decrease in dysuria, a decrease in the number of complaints, a decrease in the frequency of urination, an improvement in laboratory parameters over time (preservation of slight leukocyturia); 5-10 days – complete disappearance of complaints, normalization of laboratory parameters. The prescribed therapy was well tolerated by the patients. One patient (6.2%) developed side effects from the gastrointestinal tract (nausea, heartburn, bitterness in the mouth) associated with taking the antibacterial drug. According to the control results, the clinical effectiveness and eradication of the pathogen was 93% (15 patients). In one patient, antibacterial therapy was changed due to repeated isolation of the STD pathogen in tests.

In all groups, the majority of patients (46 patients - 90%) showed signs of clinical improvement within 3-5 days from the start of treatment - relief of dysuria and pain, reduction in the frequency of urination. Further therapy showed the effectiveness of treatment in all groups, microbiological effectiveness was 92% (47 patients). During a control bacteriological study and PCR diagnostics performed 2-3 weeks after completion of treatment, in patients with a good clinical effect from the treatment, pathogen growth in the urine and STI pathogens were not detected. The effectiveness of the therapy is presented in Figure 1.

Rice. 1. The effectiveness of the therapy

Side effects from the use of the drug Combiflox® were noted in 3-6% of patients in all groups (Fig. 2). It should be noted that the above-described phenomena had an extremely low degree of severity and were easily corrected conservatively.

Rice. 2. Side effects of drug therapy

CONCLUSIONS

The data presented show that Combiflox® is an effective antibacterial drug with systemic action, convenient for use, with a wide range of indications and fairly well tolerated. Therapy for uncomplicated lower urinary tract infection should be etiological and pathogenetic and, depending on the clinical form of cystitis, treatment should be comprehensive and individual.

Currently, the main principles of rational antibacterial therapy for urogenital infections in women are the ability of the antibiotic not only to quickly penetrate the organs of the genitourinary system affected by inflammation, but also to create therapeutically effective concentrations in the urine and cervico-vaginal secretions. The method of administration, the dosage regimen of the antibiotic, as well as its spectrum of action should contribute to its maximum microbiological effectiveness, the creation of the required concentration at the site of inflammation and its maintenance at the required level until a stable therapeutic effect.

Thus, today, drugs of the fluoroquinolone group, which belong to the broad-spectrum antibacterial drugs and retain their leading position, are the drugs of choice in the treatment of urogenital infections. The use of these drugs in synergy with drugs from other groups makes it possible to increase their clinical effectiveness by expanding the spectrum of antimicrobial activity and reduce the number of prescribed drugs.

LITERATURE

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