Levofloxacin: analogues, review of the main drugs similar to Levofloxacin. Levofloxacin analogs - cheap analogs, substitutes, comparison What helps, indications for use

Antibacterial drugs from the group of fluoroquinolones occupy one of the leading places in the treatment of various bacterial infections, including on an outpatient basis. However, the currently popular ciprofloxacin, ofloxacin, lomefloxacin, pefloxacin have high activity against gram-negative pathogens, moderate activity against atypical pathogens and are inactive against pneumococci and streptococci, which significantly limits their use, especially in respiratory infections.

In the last decade, new drugs from this group began to enter clinical practice - the so-called. new fluoroquinolones, which retain high activity against gram-negative pathogens inherent in their predecessors, and at the same time are much more active against gram-positive and atypical microorganisms. One of these drugs is levofloxacin (tavanic). In terms of chemical structure, it is a levorotatory isomer of ofloxacin. A wide range of antibacterial activity, high safety, convenient pharmacokinetic properties make it possible to use it widely for various infections.

Mechanism of action

Levofloxacin has a fast bactericidal effect, since it penetrates into the microbial cell and, like the first generation fluoroquinolones, inhibits DNA gyrase (topoisomerase II) of bacteria, which disrupts the formation of bacterial DNA. Human cell enzymes are not sensitive to fluoroquinolones, and the latter do not have a toxic effect on the cells of the macroorganism. Unlike the drugs of the previous generation, the new fluoroquinolones inhibit not only DNA gyrase, but also the second enzyme responsible for DNA synthesis, topoisomerase IV, isolated from some microorganisms, primarily gram-positive ones. It is believed that it is the effect on this enzyme that explains the high antipneumococcal and antistaphylococcal activity of new fluoroquinolones.

Levofloxacin has a clinically significant dose-dependent post-antibiotic effect, significantly longer compared to ciprofloxacin, as well as a long-term (2-3 hours) subinhibitory effect.

An increase in the function of polymorphonuclear lymphocytes in healthy volunteers and HIV-infected patients was noted under the influence of levofloxacin. Shown is its immunomodulatory effect on tonsillar lymphocytes in patients with chronic tonsillitis. The data obtained allow us to speak not only about antibacterial activity, but also about the synergistic anti-inflammatory and antiallergic action of levofloxacin.

Spectrum of antimicrobial activity

Levofloxacin is characterized by a wide antimicrobial spectrum, including gram-positive and gram-negative microorganisms, including intracellular pathogens (Table 1).

When comparing the effectiveness of various antibacterial drugs against the causative agents of respiratory infections, it was found that levofloxacin is superior to other drugs in terms of antimicrobial activity. All strains of pneumococcus were susceptible to it, including penicillin-resistant ones, with a relatively lower sensitivity of pneumococci to reference drugs: ofloxacin - 92%, ciprofloxacin - 82%, clarithromycin - 96%, azithromycin - 94%, amoxicillin / clavulanate - 96%, cefuroxime - 80%. All strains of moraxella cataris, Haemophilus influenzae and methicillin sensitive Staphylococcus aureus, 95% of Klebsiella pneumonia strains were also susceptible to levofloxacin.

Resistance

The possibility of widespread clinical use of levofloxacin and other new fluoroquinolones raises the question of the danger of developing resistance to them. Chromosomal mutations are the main mechanism responsible for the resistance of microbes to fluoroquinolones. In this case, there is a gradual accumulation of mutations in one or two genes and a stepwise decrease in sensitivity. The development of clinically significant resistance of pneumococci to levofloxacin is observed after three mutations, and therefore, it seems unlikely. This is confirmed by experimental data: levofloxacin caused spontaneous mutations 100 times less frequently than ciprofloxacin, regardless of the sensitivity of the tested pneumococcal strains to penicillin and macrolides. The widespread use of the drug in recent years in the United States and Japan has not led to an increase in resistance to it. According to K. Yamaguchi et al., 1999, the sensitivity of bacteria to levofloxacin for five years, that is, since the beginning of its widespread use, has not changed and exceeds 90% for both gram-negative and gram-positive pathogens.

The greater risk of developing antibiotic resistance is associated not with pneumococci, but with gram-negative bacteria. At the same time, according to some reports, the use of levofloxacin in intensive care units is not accompanied by a significant increase in the resistance of the gram-negative intestinal flora.

Pharmacokinetics

Levofloxacin is well absorbed in the gastrointestinal tract. Its bioavailability is 99% or more. Since levofloxacin hardly undergoes metabolism in the liver, this contributes to the rapid achievement of its maximum concentration in the blood (much higher than that of ciprofloxacin). So, when volunteers were assigned a standard dose of fluoroquinolone, the values \u200b\u200bof its maximum concentration in the blood when taking levofloxacin were 2.48 μg / ml / 70 kg, ciprofloxacin - 1.2 μg / ml / 70 kg.

After taking a single dose of levofloxacin (500 mg), its maximum concentration in the blood, equal to 5.1 ± 0.8 μg / ml, is reached after 1.3-1.6 hours, while the bactericidal activity of the blood against pneumococci remains up to 6.3 hours, regardless of their sensitivity to penicillins and cephalosporins. For a longer time, up to 24 hours, the bactericidal effect of blood on gram-negative bacteria of the Enterobacteriacae family persists.

The half-life of levofloxacin is 6-7.3 hours. About 87% of the taken dose of the drug is excreted in the urine unchanged over the next 48 hours.

Levofloxacin rapidly penetrates into tissues, while levels of tissue concentrations of the drug are higher than in blood. Especially high concentrations are found in tissues and fluids of the respiratory tract: alveolar macrophages, bronchial mucosa, bronchial secretions. Levofloxacin also reaches high intracellular concentrations.

The long half-life, the achievement of high tissue and intracellular concentrations, as well as the presence of a postantibiotic effect - all this makes it possible to prescribe levofloxacin once a day.

Drug interactions

The bioavailability of levofloxacin decreases when taken simultaneously with antacids, sucralfate, preparations containing iron salts. The interval between taking these medicines and levofloxacin should be at least 2 hours. There were no other clinically significant interactions with levofloxacin.

Clinical efficacy

There are many publications devoted to the results of clinical studies of the effectiveness of the use of levofloxacin. The most significant of them are presented below.

A multicenter, randomized study of 590 patients compared the efficacy and safety of two treatment regimens: levofloxacin IV and / or oral at a dose of 500 mg per day and ceftriaxone IV 2.0 g per day; and / or oral cefuroxime 500 mg twice daily in combination with erythromycin or doxycycline in patients with community-acquired pneumonia. The duration of therapy is 7-14 days. The clinical efficacy was 96% in the levofloxacin group and 90% in the cephalosporin group. Eradication of pathogens was achieved in 98 and 85% of patients, respectively. The incidence of adverse events in the levofloxacin group was 5.8%, and in the comparison group, 8.5%.

Another large randomized trial compared the efficacy of treatment of patients with severe pneumonia with levofloxacin 1000 mg per day and ceftriaxone 4 g per day. During the first days, levofloxacin was administered intravenously, then orally. The results of treatment in both groups were comparable, but in the ceftriaxone group there was a significantly more frequent change of the antibiotic in the first days of treatment - due to insufficient clinical effect.

Comparable results were obtained when comparing the groups of patients treated with levofloxacin and coamoxiclav.

The efficacy of monotherapy with levofloxacin has been studied in more than 1000 patients with community-acquired pneumonia. Clinical and bacteriological efficiency was 94 and 96%, respectively.

Pharmacoeconomic studies have shown that the total costs of treating patients with levofloxacin and a combination of cephalosporin and macrolide are comparable or even slightly lower in the levofloxacin group.

In patients with exacerbation of chronic bronchitis, the effectiveness of treatment with levofloxacin at a dose of 500 mg per day orally and cefuroxime axetil 500 mg orally twice a day was compared. At the same time, the clinical and bacteriological efficacy did not differ depending on the groups and amounted to 77-97%.

Thus, at present, the high efficiency of levofloxacin in respiratory infections of the lower respiratory tract can be considered proven. The results of the studies made it possible to include levofloxacin as a first-line or alternative drug in the treatment regimen for patients with community-acquired pneumonia and exacerbations of chronic bronchitis (Table 2).

In recent years, levofloxacin has become more widely used for other infectious diseases. Thus, there were reports concerning its successful use in patients with acute sinusitis. Levofloxacin is 100% active against the most common bacterial pathogens of this disease; in terms of effectiveness, it is comparable to amoxicillin / clavulanate in large doses and is significantly superior to cephalosporins, cotrimoxazole, macrolides and doxycycline.

Among the causative agents of urological infections, there is an increase in resistance to commonly used antibacterial drugs. Thus, for the period from 1992 to 1996, an increase in the resistance of E. Coli and S. saprophyticus to cotrimoxazole - by 8-16% and to ampicillin - by 20% was noted. Resistance to ciprofloxacin, nitrofurans and gentamicin increased by 2% over the same period. The use of levofloxacin in patients with complicated urinary infections at a dose of 250 mg per day was effective in 86.7% of patients.

Above are the pharmacokinetic parameters of the high content of levofloxacin in tissues. This, along with the antimicrobial spectrum of the drug, served as the basis for its use for the prevention of infectious complications in endoscopic methods of treatment and diagnosis, for example, in retrograde cholangiopancreatography and for perioperative prophylaxis in orthopedics.

The use of levofloxacin in these situations seems promising and requires further study.

Safety

Levofloxacin is considered one of the safest antibacterial drugs. However, there are a number of limitations in its appointment.

In patients with impaired liver function, it is not necessary to correct the dose of the drug, but impaired renal function with a decrease in creatinine clearance (less than 50 ml / min) requires a decrease in the dose of the drug. Additional administration of levofloxacin after hemodialysis or outpatient peritoneal dialysis is not required.

Levofloxacin is not used in pregnant and lactating women, children and adolescents. The drug is contraindicated in patients who have a history of adverse reactions to treatment with fluoroquinolones.

In elderly and senile patients, when taking levofloxacin, there was no increased risk of developing unwanted side reactions and no dose adjustment was required.

Controlled clinical studies have shown that adverse reactions with the use of levofloxacin are rare and for the most part are not serious. There is a relationship between the dose of the drug and the incidence of ND: with a daily dose of 250 mg, their frequency does not exceed 4.0-4.3%, with a dose of 500 mg / day. - 5.3-26.9%, at a dose of 1000 mg / day. - 22-28.8%. The most common symptoms of gastrointestinal dyspepsia were nausea and diarrhea (1.1-2.8%). With intravenous administration, redness of the injection site is possible, sometimes the development of phlebitis is observed (1%).

Dosing

Levofloxacin is available in two forms: for intravenous administration and oral administration. It is used at 250-500 mg once a day, with severe infections, it is possible to prescribe 500 mg twice a day. With community-acquired pneumonia, the duration of treatment is 10-14 days, with exacerbation of chronic bronchitis - 5-7 days.

Table 1. Spectrum of antimicrobial activity of levofloxacin

Highly active

• S. pneumoniae
• Streptococci
• Staphylococci
• Chlamydia
• Mycoplasma
• Legionella
• H. parainfluenzae
• M. catarrhalis
• K. pneumoniae
• B. pertussis
• Yersinia
• Salmonella
• Citrobacter spp.
• E. coli
• Enterobacter spp., Acinetobacter spp.
• P. mirabilis, vulgaris
• Neisseria spp.
• C. perfringens
• B. urealyticus

Moderately active

• Enterococci
• Listeria
• Peptococcus
• Peptostreptococcus
• S. spp.
• S. marcescens
• H. influenzae
• P. aeruginosa

Inactive

• C. difficile
• Pseudomonas spp.
• Fusobacteria
• Mushrooms
• Viruses
• M. morgani

Note!

• Levofloxacin has a wide spectrum of action, including most gram-positive and gram-negative pathogens, including intracellularly located
• In contrast to previously used fluoroquinolones, levofloxacin is highly active against gram-positive cocci, including pneumococci resistant to penicillin and erythromycin. In addition, levofloxacin is more active against atypical pathogens. Levofloxacin has convenient pharmacokinetic properties: high bioavailability, long half-life, which allows it to be used once a day, creates high tissue and intracellular concentrations
• The drug is not metabolized in the liver, has no unwanted drug interactions; does not require dose adjustment in elderly patients. Levofloxacin is well tolerated and is one of the safest antibacterial drugs
• It seems promising to use the drug for infections of the urinary tract, skin and soft tissues, for the prevention of complications in surgery
• The presence of two forms of the drug - for parenteral and oral administration - makes it possible to use it in a stepwise therapy mode, which, along with the possibility of a single dose, greatly facilitates the work of medical staff and is convenient for the patient

In diseases of the ENT organs and bronchi, four main groups of antibiotics are used. These are penicillins, cephalosporins, macrolides and fluoroquinolones. They are convenient because they are available in tablets and capsules, that is, for oral administration, and they can be taken at home. Each of the groups has its own characteristics, but for all antibiotics there are admission rules that must be followed.

• Antibiotics should only be prescribed by a doctor for certain indications. The choice of antibiotic depends on the nature and severity of the disease, as well as on what drugs the patient received earlier.
• Antibiotics should not be used to treat viral diseases.
• The effectiveness of the antibiotic is assessed during the first three days of its administration. If the antibiotic works well, you should not interrupt the course of treatment before the time recommended by your doctor. If the antibiotic is ineffective (symptoms remain the same, fever persists), inform your doctor. Only the doctor decides on the replacement of the antimicrobial drug.
• Side effects (eg, mild nausea, bad taste in the mouth, dizziness) do not always require immediate discontinuation of the antibiotic. Often, only a dose adjustment of the drug or additional administration of drugs that reduce side effects is sufficient. The measures for overcoming the side effects are determined by the doctor.
• Diarrhea may develop as a consequence of taking antibiotics. If you have heavy loose stools, see your doctor as soon as possible. Do not try to treat antibiotic-related diarrhea yourself.
• Do not reduce the dose of the medicine prescribed by your doctor. Low doses of antibiotics can be dangerous because they are more likely to develop resistant bacteria.
• Strictly observe the time of taking the antibiotic - the concentration of the drug in the blood must be maintained.
• Some antibiotics need to be taken before meals, others after. Otherwise, they are absorbed worse, so do not forget to check with your doctor about these features.

Cephalosporins

Features: broad-spectrum antibiotics. They are mainly used intramuscularly and intravenously for pneumonia and many other serious infections in surgery, urology, gynecology. Of the drugs for oral administration, only cefixime is now widely used.

• They cause allergies less frequently than penicillins. But a person who is allergic to the penicillin group of antibiotics can develop a so-called cross-allergic reaction to cephalosporins.
• Can be used by pregnant women and children (each drug has its own age restrictions). Some cephalosporins are approved from birth.

Allergic reactions, nausea, diarrhea.

Main contraindications:

Trade name of the drug	Price range (Russia, rub.)
Active substance: Cefixime
Panzef (Alkaloid) Suprax(various products) Ceforal Solutab (Astellas)		A widely used drug, especially in children. The main indications for the appointment are tonsillitis and pharyngitis, acute otitis media, sinusitis, uncomplicated urinary tract infections. Suspension is allowed from 6 months, capsules - from 12 years. Breastfeeding women on the days of taking the drug are recommended to stop breastfeeding for a while.

Penicillins

Basic indications:

• Angina
• Exacerbation of chronic
• Sharp medium
• Exacerbation of chronic
• Community-acquired pneumonia
• Scarlet fever
• Skin infections
• Acute cystitis, pyelonephritis and other infections

Features:are low-toxic antibiotics with a wide spectrum of action.

The most common side effects are:allergic reactions.

Main contraindications:individual intolerance.

Important information for the patient:

• Drugs in this group are more likely to cause allergies than other antibiotics. An allergic reaction to several drugs from this group is possible. If you develop a rash, hives, or other allergic reactions, stop taking the antibiotic and see your doctor as soon as possible.
• Penicillins are one of the few groups of antibiotics that can be used by pregnant women and children from a very young age.
• Drugs containing amoxicillin reduce the effectiveness of birth control pills.

Trade name of the drug	Price range (Russia, rub.)	Features of the drug that are important for the patient to know
Active substance: Amoxicillin
Amoxicillin(various manuf.) Amoxicillin DS(Mekofar Chemical-Pharmaceutical) Amosin (Synthesis JSC) Flemoxin Solutab (Astellas) Hikontsil (KRKA)		A widely used antibiotic. Especially suitable for the treatment of sore throats. It is used not only for respiratory tract infections, but also in treatment regimens for gastric ulcer. Well absorbed when taken orally. It is usually used 2-3 times a day. However, it is sometimes ineffective. This is due to the fact that some bacteria are capable of producing substances that destroy this drug.
Active substance: Amoxicillin + clavulanic acid
Amoxiclav (Lek) Amoxiclav Kviktab (Lek dd) Augmentin (GlaxoSmithKline) Panclave (Hemofarm) Flemoklav Solutab(Astellas) Ecoclave (Avva Rus)		Clavulanic acid protects amoxicillin from resistant bacteria. Therefore, this drug is often prescribed to people who have already been treated with antibiotics more than once. It is also better for treating sinusitis, kidney, biliary tract, and skin infections. It is usually used 2-3 times a day. More often than other drugs in this group, it causes diarrhea and liver dysfunction.

Macrolides

Main indications:

• Mycoplasma and chlamydia infection (bronchitis, pneumonia in people over 5 years old)
• Angina
• Exacerbation of chronic tonsillitis
• Acute otitis media
• Sinusitis
• Exacerbation of chronic bronchitis
• Whooping cough

Features:antibiotics, used mainly in the form of tablets and suspensions. Acting slightly slower than other antibiotics groups. This is due to the fact that macrolides do not kill bacteria, but stop their reproduction. Relatively rarely cause allergies.

The most common side effects are:allergic reactions, abdominal pain and discomfort, nausea, diarrhea.

Main contraindications:individual intolerance.

Important information for the patient:

• The resistance of microorganisms to macrolides is rapidly developing. Therefore, you should not repeat the course of treatment with drugs of this group for three months.
• Some of the drugs in this group can interfere with the activity of other drugs, and may be less absorbed when they interact with food. Therefore, before using macrolides, you must carefully study the instructions.

Trade name of the drug	Price range (Russia, rub.)	Features of the drug that are important for the patient to know
Active substance: Azithromycin
Azithromycin(various manuf.) Azitral(Shreya) Azitrox (Pharmstandard) Azicide (Zentiva) Zetamax retard (Pfizer) Z factor (Veropharm) Zitrolide (Valenta) Zitrolide forte (Valenta) Sumamed (Teva, Pliva) Sumamed forte(Teva, Pliva) Hemomycin (Hemofarm) Ecomed (Avva Rus)	168,03-275 80-197,6	One of the most commonly used drugs in this group. Better tolerated and well absorbed. Unlike other macrolides, it inhibits the growth of Haemophilus influenzae, which often causes otitis media and sinusitis. Preferably taken on an empty stomach. It circulates in the body for a long time, therefore it is taken 1 time per day. Possible short courses of treatment as prescribed by the doctor: from 3 to 5 days. If necessary, it can be used with caution during pregnancy. Contraindicated in severe liver and kidney dysfunction.
Active substance: Erythromycin
Erythromycin(various manuf.)	26,1-58,8	A long-used antibiotic, and therefore some bacteria are resistant to it. Nausea is caused somewhat more often than other representatives of this group of antibiotics. It inhibits the work of liver enzymes that are responsible for the destruction of other drugs. Therefore, some drugs interact with erythromycin are retained in the body and cause toxic effects. It is very important to use the drug on an empty stomach. Can be used during pregnancy and lactation.
Active substance: Clarithromycin
Clarithromycin(various manuf.) Klabaks (Ranbaxi) Klabaks OD (Ranbaxi) Klacid(Abbott) Klacid SR (Abbott) Fromilid(KRKA) Fromilid Uno(KRKA) Ecozitrin (Avva Rus)	773-979,5 424-551,4	It is used not only for the treatment of respiratory tract infections, but also in treatment regimens for peptic ulcer disease to destroy the bacteria Helicobacter pylori. It is active against chlamydia, therefore it is often included in the treatment regimens for sexually transmitted diseases. Side effects and drug interactions are similar to those of erythromycin. Not used in children under 6 months of age, during pregnancy and lactation.
Active substance: Midecamycin / midecamycin acetate
Macropen (KRKA)	205,9-429	A classic macrolide antibiotic often used in suspension form to treat infections in children. Well tolerated. It is advisable to take it 1 hour before meals. It is quickly excreted from the body, therefore the minimum frequency of admission is 3 times a day. Drug interactions are less likely. During pregnancy, it can be used only in exceptional cases; it is not used during breastfeeding.
Active substance: Roxithromycin
Rulid(Sanofi-Aventis)	509,6-1203	Well absorbed, well tolerated. Indications and side effects are standard. Does not apply during pregnancy and lactation.

Fluoroquinolones

Main indications:

• Severe otitis externa
• Sinusitis
• Exacerbation of chronic bronchitis
• Community-acquired pneumonia
• Dysentery
• Salmonellosis
• Cystitis, pyelonephritis
• Adnexitis
• Chlamydia and other infections

Features:powerful antibiotics, most often used for severe infections. They can disrupt the formation of cartilage, and therefore are contraindicated for children and expectant mothers.

The most common side effects are:allergic reactions, pain in tendons, muscles and joints, pain and discomfort in the abdomen, nausea, diarrhea, drowsiness, dizziness, increased sensitivity to ultraviolet rays.

Main contraindications: individual intolerance, pregnancy, breastfeeding, age up to 18 years.

Important information for the patient:

• Oral fluoroquinolones should be taken with a full glass of water, and in total during the treatment period, drink at least 1.5 liters per day.
• For complete assimilation, you must take the drugs at least 2 hours before or 6 hours after taking antacids (remedies for heartburn), iron, zinc, bismuth preparations.
• It is important to avoid sunburn while using drugs and for at least 3 days after the end of treatment.

Trade name of the drug	Price range (Russia, rub.)	Features of the drug that are important for the patient to know
Active substance: Ofloxacin
Ofloxacin(various products) Zanocin (Ranbaxi) Zanocin OD(Ranbaxi) Zoflox (Mustafa nevzat ilach sanai) Ofloxin (Zentiva) Tarivid (Sanofi-Aventis)		Most often used in urology, gynecology. For respiratory tract infections, it is not used in all cases. It is indicated for sinusitis, bronchitis, but not recommended for angina and pneumococcal community-acquired pneumonia.
Active substance: Moxifloxacin
Avelox (Bayer)	719-1080	The most powerful antibiotic in this group. It is used for severe acute sinusitis, exacerbations of chronic bronchitis and community-acquired pneumonia. It can also be used in the treatment of drug-resistant forms of tuberculosis.
Active substance: Ciprofloxacin
Ciprofloxacin(various products) Cyprinol (KRKA) Tsiprobay (Bayer) Tsiprolet (Dr. Reddy's) Tsipromed (Promed) Tsifran (Ranbaxi) Tsifran OD(Ranbaxi) Ecocifol (Avva Rus)	46,6-81 295-701,5	The most widely used drug from the group of fluoroquinolones. Has a wide spectrum of action, including against pathogens of severe infections. The indications are the same as for ofloxacin.
Active substance: Levofloxacin
Levofloxacin (various products) Levolet (Dr. Reddy's) Glevo (Glenmark) Lefokcin (Shreya) Tavanik(Sanofi-Aventis) Flexid(Lek) Floracid (Valenta, Obolenskoe) Haileflox (Heiglans Laboratories) Ecolevid (Avva Rus) Eleflox (Ranbaxi)	366-511 212,5-323	The drug has a very broad spectrum of action. It is active against all pathogens of the respiratory tract. It is especially often prescribed for pneumonia and sinusitis. It is used when penicillins and macrolides are ineffective, as well as in cases of severe bacterial diseases.

Remember, self-medication is life-threatening, consult your doctor for advice on the use of any medications.

For citation:Belousov Yu.B., Mukhina M.A. Clinical pharmacology of levofloxacin // BC. 2002. No. 23. S. 1057

RSMU

IN Currently, fluoroquinolones (FQ) are considered as an important group of chemotherapeutic drugs within the class of quinolones - DNA gyrase inhibitors, characterized by high clinical efficacy (including oral use), wide indications for use and constitute a serious alternative to other broad-spectrum antibiotics. More than 15 drugs of the PC group have been created, several new active compounds are undergoing clinical research in order to obtain more effective drugs against gram-positive microorganisms, mycobacteria, anaerobes, and atypical pathogens. An important challenge is also the development of drugs with a minimal risk of side effects and high clinical efficacy.

Among PCs, two groups of drugs are currently distinguished: earlyor old (norfloxacin, ciprofloxacin, ofloxacin, pefloxacin, lomefloxacin, etc.) and newor late (levofloxacin, sparfloxacin, gatifloxacin, gemifloxacin, etc.).

Ofloxacin has been used for over 15 years, has high efficacy, good tolerance, low level of side effects and the absence of significant drug-drug interactions. From the point of view of stereochemistry, ofloxacin is a racemic mixture of two optically active isomers: levorotatory (L-isomer, L-ofloxacin) and dextrorotatory (D-isomer, D-ofloxacin).

The levorotatory isomer of ofloxacin - L-ofloxacin is currently known as levofloxacin (LF)... The drug was developed in the late 1980s in Japan and was proposed for use after multicenter clinical trials conducted in Europe, America, and Asia. In Russia, levofloxacin was registered and approved for use in 2000 under the trade name Tavanik (oral and parenteral forms).

Levofloxacin is 8-128 times more active than D-ofloxacin. Two main groups play an important role in the chemical structure of Lf: 4-methyl-piperazinyl, which increases absorption when the drug is taken orally, increases its activity against gram-negative bacteria, lengthens the half-life, and the oxazine ring, which causes an expansion of the spectrum of activity against gram-positive bacteria, as well as lengthening the half-life. Levofloxacin is characterized by 2 times more activity than ofloxacin, and, therefore, is not inferior in activity to ciprofloxacin.

Levofloxacin has a unique, almost 100% oral bioequivalence. The pharmacokinetic profile of Lf is similar to that of ofloxacin. The half-life is 4-8 hours, that is, more than that of ciprofloxacin, T max - 1.5 hours (like ciprofloxacin and ofloxacin), C max - 5.1 mg / l (that is, 4 times more than that of ciprofloxacin), which practically corresponds to C max for parenteral administration in an equivalent dose. Levofloxacin dissolves almost 10 times better than ofloxacin.

Spectrum of activity

Levofloxacin, like other PCs, has a bactericidal type of action and a broad antimicrobial spectrum. PCs are active against most enterobacteria, gram-negative bacilli (Haemophilus influenzae, including b-lactamase-producing strains) and gram-negative cocci (gonococcus, meningococcus, moraxella, including b-lactamase-producing strains), as well as Pseudomonas aeruginosa. Early PCs (ciprofloxacin, ofloxacin) have some activity against staphylococci and even less against streptococci and enterococci, in contrast to new PCs, including levofloxacin, highly active against Staphylococcus aureus (except for methicillin-resistant strains), staphylococcus aureus, including staphylococcus aureus (Tables 1, 2). The MIC range of Lf in relation to staphylococci is 0.06-64 mg / L (with a MIC of 90 0.25-16 mg / L), in relation to pneumococci, the MIC range is 0.25-0.2 mg / L. Antipneumococcal activity does not depend on the degree of sensitivity to penicillin. Levofloxacin is somewhat less active against enterococci, although for some strains the MIC values \u200b\u200bare 0.5-1 mg / l. The drug is highly active against Listeria monocitogenes, Сorinebacterium diphtheriae... Intracellular pathogens (chlamydia, mycoplasma, legionella) are susceptible to all PCs. Some new PCs are active against anaerobes, Lf - partially. Of particular interest is the activity of Lf against mycobacteria. The activity of Lf against rickettsia, bartonella and some other microorganisms is being studied.

Pathogen resistance

In the past decade, the following pathogens have been noted to be resistant to fluoroquinolones in the United States: MRSA, enterococci, Pseudomonas sp.In subsequent years, an increase in the resistance of Salmonella, Shigella, Acinetobacter sp., Campilobacter sp.and gonococcus. The selection of Lf-resistant strains of Staphylococcus aureus is observed much less frequently than to ciprofloxacin. There are known data on resistance of pneumococci to FH. One of the lowest levels of pneumococcal resistance is noted for LF (overall 0.5% in 1997-2000 in the USA and Canada). Formation of resistance to levofloxacin is possible, but currently resistance to the drug develops most slowly and does not cross with other antibiotics .

In the past decade, the following pathogens have been noted to be resistant to fluoroquinolones in the United States: MRSA, enterococci. In the following years, an increase in the resistance of Salmonella, Shigella, and Gonococcus has been reported. The selection of Lf-resistant strains of Staphylococcus aureus is observed much less frequently than to ciprofloxacin. There are known data on resistance of pneumococci to FH. One of the lowest levels of pneumococcal resistance is noted for LF (overall 0.5% in 1997-2000 in the USA and Canada). The formation of resistance to levofloxacin is possible, however, at the present time.

Pharmacokinetics

Levofloxacin has some pharmacokinetic advantages over other PCs. This is determined by the resistance of the molecule to transformation and metabolism in the patient's body. Levofloxacin, like ciprofloxacin, gatifloxacin, trovafloxacin and ofloxacin, exists in oral and parenteral forms and can be used for step therapy , unlike other FH, available only in oral form.

Long T 1/2 allows Lf to be administered once a day , which increases patient compliance. The oral bioavailability of Lf reaches 100% and does not depend on food intake, which also makes it convenient to use. The majority of PCs are excreted in a double way (via the kidneys and liver). In contrast, Lf is excreted mainly through the kidneys (90%), which requires dose adjustment in severe renal failure. However, the absence of metabolism by enzymes of the cytochrome p450 system determines the absence of interaction with warfarin and theophylline and other significant drug interactions. In a clinical and pharmacological study, the mutual influence with the simultaneous appointment of LF with nonsteroidal anti-inflammatory, antidiabetic, antiarrhythmic drugs of I and III classes, theophylline, warfarin, cyclosporine and cimetidine was not noted (Simpson I., 1999).

Levofloxacin is metabolized by only 5%. About 35% of Lf binds to serum proteins, and therefore the drug is well distributed in tissues. It should be emphasized that PC, including LF, perfectly penetrate into various tissues, creating high concentrations in the kidneys, prostate, female genital organs, bile, gastrointestinal tract organs, bronchial secretions, alveolar macrophages, pulmonary parenchyma, bones, as well as in the cerebrospinal fluid, therefore these drugs can be widely used for infections of almost any localization. In addition, good intracellular penetration ensures their activity against atypical pathogens.

The clinical efficacy of LF with a single administration of 250-500 mg / day is an essential advantage of the drug, however, with generalized infectious processes proceeding in a severe form, LF is prescribed twice.

Side effects and tolerance

Side effects of levofloxacin and other PCs are known from European and other international studies. In Europe, more than 5000 patients underwent the study, and approximately 130 million Lf prescriptions were made worldwide during trials.

Levofloxacin proved to be the safest PC with a low level of hepatotoxicity (1/650000). Levofloxacin, along with ofloxacin and moxifloxacin, is safer in terms of pathological effects on the central nervous system. The cardiovascular negative effect of LF was observed much less frequently than with the use of other FH (1/15 million prescriptions, for sparfloxacin - in 1-3% of cases). Diarrhea, nausea, and vomiting are the most common side effects associated with Lf, but they are much less common than other FH. The frequency of side effects of LF and other PCs is presented in table. 3.

It has been shown that an increase in the dose of Lf to 1000 mg / day does not lead to an increase in the number of side effects, and their probability does not depend on the patient's age.

In general, the level of adverse reactions associated with Lf is the lowest among PCs, and the tolerability of Lf can be regarded as very good.

Levofloxacin for lower respiratory tract infections

Community-acquired pneumonia

Community-acquired pneumonia is one of the most common diseases with a serious prognosis. The incidence of pneumonia in Europe ranges from 2 to 15 cases per 1000 people per year. According to A.G. Chuchalin, the prevalence of pneumonia among the adult population of Russia is 5-8 per 1000 people. In the United States, there are 2-3 million cases of community-acquired pneumonia annually, for which about 10 million medical visits are made annually. According to the Central Scientific Research Institute of Health of the Ministry of Health of the Russian Federation, more than 1.5 million adults suffer pneumonia in Russia every year.

The general mortality rate in pneumonia is about 20-30 cases per 100 thousand people per year. Mortality among outpatients with a low degree of risk is no more than 1%, and in patients hospitalized with pneumonia - up to 14% (in critically ill patients up to 30-40%) (Fine et al. 1999).

Pneumococcus remains the most common causative agent of community-acquired pneumonia - 30.5% (20-60%). In young and middle age groups, there are often Mycoplasma pneumoniae (5-50%) and Chlamydia pneumoniae(5-15%). In older age groups, these pathogens are less common (1-3%). Legionella is a rare causative agent of pneumonia (4.8%), but it causes up to 10% of cases of severe pneumonia. Legionella pneumonia is the second most fatal after pneumococcal disease. H. influenzaemore often causes pneumonia in smokers or against the background of chronic bronchitis (3-10%) and, according to some data, in Russia it ranks second in the etiology of severe pneumonia. Family members Enterobacteriaceae(E.coli, K.pneumoniae) are found in patients with risk factors (diabetes mellitus, circulatory failure, etc.) in 3-10% of cases. Moraxella catarrhalis allocated in 0.5% of cases Relatively rarely isolated Str. pyogenes, Chl. psittaci, Coxiella burnetii and others. In severe pneumonia, a relatively large proportion of bacterial agents is Staphylococcus aureus, the probability of its detection increases with age or after the flu (3-10%), while the mortality rate can reach 50%. In 50% of cases, it is not possible to isolate the pathogen, and in 2-5% of cases, a mixed infection is detected.

Over the past years, a rapid increase in the resistance of pneumonia pathogens to antibacterial drugs has been observed throughout the world. The proportion of pneumonia caused by pneumococcal strains resistant to penicillin (up to 51.4%) and cephalosporins, as well as to macrolides (to erythromycin up to 45.9%), tetracyclines and co-trimoxazole increased significantly. Moreover, in some regions, macrolide resistance prevails over penicillin resistance. In some countries, the incidence of penicillin resistance of pneumococci can be as high as 60%. Large-scale studies of resistance of pneumococci to penicillin have not been conducted in our country. According to local studies in Moscow, the frequency of resistant strains is 2%, strains with intermediate sensitivity - about 20%. The resistance of pneumococci to penicillin is not associated with the production of β-lactamases, but with the modification of the target of the antibiotic in the microbial cell - penicillin-binding proteins; therefore, inhibitor-protected penicillins are also inactive against these pneumococci. Resistance of pneumococci to penicillin is usually accompanied by resistance to I-II generation cephalosporins, macrolides, tetracyclines, co-trimoxazole.

The problem of resistance of pneumococcus to antibiotics in Russia is not yet as relevant as in the West, but it should be remembered that the resistance of strains varies in each region. Risk factors for the development of resistance are old age and childhood, comorbidities, previous antibiotic therapy, and stay in nursing homes.

The resistance of Haemophilus influenzae to penicillins reaches 10%, and its resistance to new macrolides is growing.

Antibiotic therapy for pneumonia, in the vast majority of cases empirical, requires the use of drugs with a wide spectrum of action. When choosing a method of treatment, the severity of the disease and risk factors are taken into account. Empiric therapy should always cover pneumococcus, consider the use of antibiotics active against mycoplasma and legionella during an influenza epidemic - S. aureus, and in elderly patients - Enterobacteriaceae.It is generally accepted for severe community-acquired pneumonia to begin treatment with a combination of antibiotics consisting of a macrolide and an agent active against gram-negative enterobacteria, such as cephalosporin. In addition, current guidelines recommend the use of the latest PCs for the treatment of community-acquired pneumonia requiring hospitalization.

Fluoroquinolones have a broad spectrum of antimicrobial activity. These drugs show natural activity against almost all potential pathogens of community-acquired pneumonia. However the use of early FH (ciprofloxacin, ofloxacin, pefloxacin) with community-acquired pneumonia was limited due to their weak natural activity against the main causative agent of pneumonia - S. pneumoniae... The values \u200b\u200bof the minimum inhibitory concentrations (MIC) of early PC in relation to pneumococcus are from 4 to 8 μg / ml, and their concentration in the bronchopulmonary tissue is much lower, which is not enough for successful therapy. Cases are described when PC therapy for pneumococcal pneumonia did not bring success. According to other data, it is possible to create a high tissue concentration of these drugs, sufficient for adequate antipneumococcal activity. This is confirmed by the clinical and bacteriological efficacy of ciprofloxacin in the treatment of pneumonia and other infections of the lower respiratory tract, which is not inferior to standard therapy with b-lactam antibiotics. The proven efficacy of PCs in lower respiratory tract infections makes it possible to determine their place in the treatment of community-acquired pneumonia. In patients under 65 years of age, non-smokers, without serious chronic diseases, the causative agent of community-acquired pneumonia in 80% of cases is pneumococcus and other streptococci, less often atypical microorganisms. Fluoroquinolones in this category of patients are an alternative for the treatment of moderate to severe pneumonia, for example, in case of allergy to penicillins. In patients over 65 years of age, heavy smokers, suffering from serious chronic somatic diseases, alcoholism, the causative agents of pneumonia are mainly gram-negative pathogens, namely H. influenzae, M. catarrhalis, Klebsiella spp., in a third of cases pneumococcus, often atypical pathogens. Fluoroquinolones are the drugs of choice in this category of patients, especially in outpatient treatment, since they can be administered orally in case of moderate disease with a single dose per day, which increases the compliance of elderly patients. In the treatment of pneumonia requiring hospitalization, the advantage of PC is the possibility of using stepwise therapy, which significantly improves the pharmacoeconomic aspects of treatment.

Against the background of the growing resistance of key pathogens of respiratory infections to antibiotics (in particular, the spread of strains S.pneumoniaeresistant to penicillin and macrolides), new or so-called respiratory fluoroquinolones (levofloxacin, moxifloxacin, gatifloxacin). New PCs have an increased, in comparison with classical fluoroquinolones (ofloxacin, ciprofloxacin), activity against S.pneumoniae... It should also be emphasized that the high antipneumococcal activity of new PCs is observed regardless of the sensitivity of pneumococcus to penicillin and / or to macrolides. The superiority of new PCs is also obvious in relation to atypical pathogens ( M.pneumoniae, C. pneumoniae, L.pneumophila). And, finally, these antibiotics "inherited" the high activity of classical PCs against H.influenzae and M.catarrhalis... There is no doubt that the new PCs are an acceptable alternative to macrolides, amoxicillin / clavulanate, and oral cephalosporins in the treatment of community-acquired pneumonia. The obvious advantages of new PCs should be added to the possibility of taking them once a day and using them as part of stepwise therapy.

In the studies conducted to date, including incl. and patients with severe and (or) prognostically unfavorable course of the disease, convincing evidence was obtained of superior or at least comparable clinical and microbiological efficacy of Lf monotherapy compared to traditional combined treatment (cephalosporins + macrolides). This circumstance, as well as the excellent safety profile, confirmed by many years of wide clinical application, and the obvious economic advantages of monotherapy, explain the presence of Lf in modern treatment regimens for community-acquired pneumonia. Levofloxacin occupies a prominent place in modern treatment regimens for adult patients with community-acquired pneumonia not subject to hospitalization (Frias J., 1998; Bartlett J.G., 2000), as well as in a hospital setting (Frias J., 2000; Mandell L.A., 1997)

In community-acquired pneumonia, the clinical efficacy of LF exceeded the efficacy of therapy with ceftriaxone, cefuroxime (including in combination with erythromycin or doxycycline) and amounted to 96 and 90%, bacteriological efficacy - 98 and 85%, respectively; the differences were statistically significant (File T.M., 1997).

According to I. Harding (2001), levofloxacin was more effective in the treatment of community-acquired pneumonia than clarithromycin, benzylpenicillin, ceftriaxone, amoxicillin / clavulanic acid.

In a randomized, double-blind, multicenter study in 518 patients with community-acquired pneumonia, a comparative analysis of the clinical efficacy of Lf and amoxicillin / clavulanate was carried out. Clinical efficacy when taking 500 mg of LF once a day was 95.2%, when taking Lf 500 mg 2 times a day - 93.8%, and when taking amoxicillin / clavulanate 625 mg 3 times a day - 95.3 %.

A multicenter, open-label, randomized trial compared the efficacy of Lf and ceftriaxone in combination with erythromycin in patients with community-acquired pneumonia at high risk of poor outcome. For 132 patients who received Lf, the drug was initially administered intravenously (500 mg once a day), then orally at the same dose for 7-14 days. In the comparison group, 137 patients received intravenous or intramuscular ceftriaxone (1-2 g 1 time per day) and intravenous erythromycin (500 mg 4 times a day), followed by a switch to oral administration of amoxicillin / clavulanate (875 mg 2 times a day) together with clarithromycin (500 mg 2 times a day). Clinical efficiency in group 1 was 89.5%, in group 2 - 83.1%. Thus, Lf monotherapy is not inferior in efficiency to traditional combined treatment in patients with a high probability of death.

In another multicenter randomized study in 456 patients with community-acquired pneumonia (group 1 - 226 patients received levofloxacin, group 2 of 230 patients received ceftriaxone and / or cefuroxime axetil), the clinical and microbiological efficacy of LF administered intravenously (500 mg once a day) was studied and / or orally (500 mg once a day), in comparison with ceftriaxone administered intravenously (1.0-2.0 g 1-2 times a day) and / or cefuroxime axetil administered orally (500 mg twice a day) day). In addition, based on the specific clinical situation, 22% of patients in the second group were prescribed oral erythromycin (1 g 4 times a day). The clinical and microbiological efficacy of Lf monotherapy was significantly higher than the traditional treatment regimen. Thus, clinical success in patients of group 1 was 96%, in patients of group 2 - 90%, and the frequency of eradication of the pathogen in microbiologically examined patients was 98% and 85%, respectively.

The role and place of LF in the sequential therapy of community-acquired pneumonia versus conventional therapy have been studied in a large-scale Canadian study ( CAPITAL Study), which included 1743 patients. The M.J. scale was used to decide on the place of treatment and the method of administration of the drug. Fine et al., 1997. If the patient's final assessment did not exceed 90 points, then the treatment was carried out at home with the appointment of LF (500 mg 1 time / day, orally) for 10 days. If the final score was 91 or more points, then the patient was hospitalized and initially LF (500 mg 1 time / day) was administered intravenously. Upon reaching steady state (ability to swallow food, negative blood cultures, body temperature 38.0 ° C, respiratory rate<24/мин, частота сердечных сокращений <100/мин), лечение продолжалось с назначением оральной формы ЛФ (500 мг 1 раз/сутки). Использовали унифицированные критерии для выписки больного из стационара: возможность приема антибиотика внутрь; число лейкоцитов периферической крови < 12x109/л; стабильное течение сопутствующих заболеваний; нормальная оксигенация крови.

As a result, there were no significant differences in the rate of readmission, mortality and quality of life among patients who received LF as part of a stepwise therapy or with standard treatment. At the same time, the introduction of stepwise therapy for LF led to an 18% decrease in bed-days for this nosological form and a reduction in costs by $ 1,700 (per patient).

The clinical efficacy and safety of LF and some new macrolides (azithromycin, clarithromycin) in the treatment of community-acquired pneumonia were compared using a meta-analysis of randomized controlled trials. The rate of complete clinical recovery was clearly higher with the use of LF (78.9%) than macrolides (azithromycin - 57%, clarithromycin 63.3%). A higher incidence of adverse drug effects was noted with the use of Lf - 36.6% (azithromycin - 12.6%, clarithromycin - 27.1%), but, according to the authors, the safety profile of Lf practically does not differ from macrolides, and levofloxacin can be recommended as an effective agent in the treatment of community-acquired pneumonia.

The presented data allow us to conclude that clinical and microbiological efficacy of monotherapy with levofloxacin is not less than that of traditional treatment regimens for community-acquired pneumonia .

A large number of studies have confirmed not only the clinical advantage of Lf, but also its economic superiority over other antibacterial drugs.

In a study conducted at Talakhasa Medical Center, it was shown economic advantage of using LF in the treatment of community-acquired pneumonia in comparison with traditional parenteral therapy. Estimated savings averaged $ 111 per patient.

In a multicenter, randomized controlled trial, conducted in 19 Canadian hospitals, the economic outcome of treating adult patients with community-acquired pneumonia was assessed. Hospitals were divided into two groups: using the investigational approach and those using conventional standard therapy. The investigated method of management included the use of Lf as the antibiotic of choice, and the use of the Pneumonia Severity Scoring Index (PSSI), according to which patients were divided into 5 classes and the question of the method of treatment (outpatient or inpatient) was decided. In hospitals using the conventional approach, decisions about hospitalization, choice of antibiotic (excluding Lf) and other decisions were made by the treating physician. The analysis included 716 patients according to the study method and 1027 patients according to conventional therapy. In hospitals with the studied method, there were fewer hospitalizations than in hospitals with conventional therapy (46.5% and 62.2%, respectively, p \u003d 0.01), there was also a decrease in the length of stay of patients in the hospital by an average of 1.6 days and savings of $ 457-994 per patient, without compromising clinical effectiveness and quality of life.

A study by the INOVA healthcare system has shown that levofloxacin is a cost-effective alternative to ciprofloxacin for infectious diseases of various locations (upper and lower respiratory tract, urinary tract, skin and soft tissues, etc.) and that the use of disease risk criteria (PSI) can reduce the frequency of justifiable hospitalizations for community-acquired pneumonia, which also leads to cost savings. In addition, experience has demonstrated the economic and clinical benefits of using step therapy.

Another large, multicenter, prospective, open-label, randomized, actively controlled phase III trial included 310 outpatients and 280 inpatients with community-acquired pneumonia who were prescribed levofloxacin or cefuroxime axetil (intravenous or oral). The economic evaluation was carried out for outpatients only. The economic benefit of LF was found to be $ 233 per patient (p \u003d 0.008).

A study conducted at the University of Texas Cancer Center has shown that the use of levofloxacin is safe, effective and cost-effective in the treatment of community-acquired pneumonia in adults compared with β-lactam antibiotics and clarithromycin. In this study, the sensitivity to the studied antibiotics was determined using the MIC and a high level of resistance of the main pathogens of pneumonia (pneumococcus, Haemophilus influenzae, moraxella) to b-lactams, an increase in the resistance of atypical pathogens to macrolides and, in contrast, a low level of resistance to LF. Frequent cases of allergic reactions to β-lactams in comparison with Lf and the good tolerance of the latter also showed its advantage. The second study examined the question of optimal antibiotic therapy for community-acquired pneumonia in patients with various comorbid conditions (COPD, diabetes, chronic heart failure, alcoholism, staying in nursing homes, working on livestock farms, etc.). As a result, among all PCs, only levofloxacin was recommended for the management of community-acquired pneumonia.

In the next study, the replacement of other PCs with levofloxacin was studied in pneumonia and infections of other localization. Microbiological studies, clinical and pharmacoeconomic assessments were carried out. As a result, the replacement by a more expensive drug (levofloxacin) with cheaper ones (ofloxacin, ciprofloxacin) turned out to be more profitable.

Chronic bronchitis in the acute phase

According to a study by C.A. DeAbate (1997), the clinical and bacteriological efficacy of Lf when taken in a dose of 500 mg once a day for 5-7 days is comparable to a 7-10-day intake of cefuroxime at a dose of 250 mg 2 times a day. Clinical efficiency was 94.5 and 92.6%, bacteriological - 97.4 and 92.6%, respectively.

According to M.P. Habib (1998), the clinical and bacteriological efficacy of a single dose of 500 mg of Lf for 5-7 days is comparable to a 7-10-day intake of cefaclor at a dose of 250 mg 3 times a day. Clinical efficiency was 91.6 and 85%, bacteriological - 94.2 and 86.5%, respectively.

Nosocomial pneumonia

In the etiology of nosocomial pneumonia, gram-negative flora predominates ( Klebsiella sp., P. mirabilis, E. coli, H. influensae, P. aeruginosa). From gram-positive flora are found S. aureus, less often pneumococci, often multi-resistant strains. Fluoroquinolones have long been successfully used in the treatment of this pathology. Given the antimicrobial spectrum of Lf, its appointment for nosocomial pneumonia may be fully justified. However, for suspected or confirmed infection P. aeruginosa requires combination antibiotic therapy, usually with antipseudomonal β-lactam antibiotics to prevent the development of resistance.

Conclusion

The experience of using levofloxacin convincingly proves that it is a highly effective drug, comparable in its degree of effectiveness with other new fluoroquinolones. Almost equally, levofloxacin is effective against both gram-positive and gram-negative aerobic flora, and also has high activity against atypical pathogens. Levofloxacin has almost ideal pharmacokinetic parameters and two dosage forms, oral and parenteral, which allows you to maximize the dose and therapy regimens and use it as part of supernatant therapy. The high bactericidal activity of levofloxacin in combination with high values \u200b\u200bof maximum concentrations, good penetration into tissues, and AUC indicators provides the maximum therapeutic effect.

Among other drugs of the PC group, levofloxacin has the best tolerance with a low level of side effects.

Currently, levofloxacin is successfully used mainly for lower respiratory tract infections. However, given the wide antimicrobial spectrum, optimal pharmacokinetic parameters, good tolerance, levofloxacin can be used for infections of almost any localization (sinusitis, infections of the urinary tract, skin and soft tissues, small pelvis, intra-abdominal infections, severe generalized infections, intestinal infections, infections transmitted sexually, etc.).

The formation of resistance to levofloxacin is possible, however, at present, resistance to the drug develops most slowly and does not cross with other antibiotics.

Along with high clinical efficacy, levofloxacin undoubtedly has pharmacoeconomic advantages, which is important in the modern healthcare system.

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The traditional approach to the management of patients with severe or prognostically unfavorable lower respiratory tract infections (primarily pneumonia) involved parenteral administration of antibiotics throughout the entire period of hospitalization. Moreover, in

A. I. Sinopalnikov, Professor, State Institute for Advanced Training of Doctors of the Ministry of Defense of the Russian Federation;
V. K. Duganov, Main Military Clinical Hospital named after N. N. Burdenko, Moscow

The traditional approach to the management of patients with severe or prognostically unfavorable lower respiratory tract infections (primarily pneumonia) involved parenteral administration of antibiotics throughout the entire period of hospitalization. At the same time, to a certain extent, the alternative possibility of prescribing antibiotics in oral dosage form, which have a wide spectrum of antimicrobial activity, high oral bioavailability and are as effective as parenteral forms of antibacterial drugs, was ignored. However, with the advent of new oral antibiotics, characterized by an excellent pharmacokinetic profile and safety, and an improvement in our knowledge of pharmacodynamic predictors of the effectiveness of antibiotic therapy, it became possible to prescribe more frequently oral antibiotics even in severe infectious processes, including the respiratory tract.

Of particular interest is the concept of the so-called stepwise therapy, which involves a two-stage use of antibacterial drugs: the transition from parenteral to non-parenteral (usually oral) route of administration as soon as possible, taking into account the clinical condition of the patient and without compromising the final effectiveness of treatment.

The main idea of \u200b\u200bstepwise therapy is obvious benefits for the patient, doctor and hospital (reduction of the length of hospital stay and transfer to treatment at home, psychologically more comfortable; minimization of the risk of nosocomial infections; reduction of costs associated with the lower cost of oral antibiotics, elimination of additional costs on the introduction of the drug in parenteral form, etc.) while maintaining the high quality of medical care - corresponds to modern recommendations for the management of patients with community-acquired pneumonia, rightly emphasizing that at present the provision of highly effective / high-quality medical care should be carried out in the most economical way.

Stepwise antibiotic therapy for pneumonia was first introduced in 1985, when F. Shann et al. have successfully used sequential administration of chloramphenicol in parenteral and then oral dosage forms in children of Papua and New Guinea. However, in fairness, it must be said that only two years later R. Quintiliani et al. presented the scientific rationale for this new approach to the use of antibacterial drugs.

In the implementation of the concept of stepwise antibiotic therapy, it is necessary to take into account several factors, namely, "patient factor", "pathogen factor" and "antibiotic factor" (Table 1).

Obviously, stepwise antibiotic therapy is not just a mechanical substitution of a parenteral drug for an oral one. First of all, taking into account the clinical feasibility, the appropriate timing of this replacement should be determined. In this case, the main conditions for a safe transition to oral therapy should be the following:

Usually, the latter include the achievement of apyrexia, a decrease in cough and the severity of other respiratory symptoms, a significant decrease in the number of peripheral blood leukocytes, etc. So, in particular, one of the widely popularized criteria for switching to oral antibiotic therapy for respiratory infections are: a decrease in cough, others respiratory symptoms; normal body temperature when measured sequentially at 8-hour intervals; a tendency to normalize the number of leukocytes in the peripheral blood; absence of gastrointestinal absorption disorders (J. A. Ramirez, 1995).

In general, based on the analysis of available studies to assess the efficacy and safety of stepwise therapy for lower respiratory tract infections (first of all, community-acquired pneumonia), the following conditions can be distinguished for switching to an oral antibiotic:

• achieving clinical improvement against the background of initially administered intravenous antibiotic therapy;
• the patient has no known risk factors for an unfavorable prognosis of community-acquired pneumonia: condition after splen-ectomy, chronic alcoholism, intellectual-mnestic status disorders, significant deviations from the norm of instrumental and laboratory test indicators: tachypnea\u003e 30 / min, systolic blood pressure 38.3 ° C , arterial hypoxemia 9 / l or hyperleukocytosis\u003e 30x109 / l, renal failure (residual urea nitrogen\u003e 20 mg / dl); multilobe pneumonic infiltration, rapid progression of focal-infiltrative changes in the lungs, destruction of lung tissue, the need for mechanical ventilation, metastatic “screenings” of infection (brain abscess, etc.), signs of a severe course of the infectious process (metabolic acidosis, septic shock, respiratory distress syndrome in adults, etc.).

In this case, the time of transition from intravenous to oral route of antibiotic administration varies, as a rule, from 48 to 72 hours. According to some publications, the next 48 hours appears to be the optimal time frame for deciding whether to switch to an oral antibiotic.

A simple, at first glance, scheme of stepwise antibacterial therapy of lower respiratory tract infections can sometimes be difficult to implement, since the patient may be in the field of view of doctors of various specialties (hence the widest possible popularization of modern recommendations for the management of patients with community-acquired pneumonia becomes extremely important). In this context, one should take into account the possible peculiarities of the “doctor-patient” cooperation. And, finally, it is necessary to take into account the fact that in some patients there is a slow regression of the clinical and radiological picture of the disease, which means that before switching to oral therapy, an analysis of the possible causes of the protracted course of community-acquired pneumonia should be carried out.

To date, we have a very limited number of controlled clinical trials confirming the high efficacy and safety of stepwise therapy for lower respiratory tract infections (Table 2). Nevertheless, the available data provide a strong argument in favor of switching to oral antibiotics as early as possible when an adequate clinical and / or laboratory response is achieved against the background of initial intravenous therapy for community-acquired pneumonia.

When choosing a drug for oral administration in the framework of stepwise therapy, preference should be given to those antibiotics that demonstrate an identical or similar spectrum of antimicrobial activity to antibiotics administered parenterally. At the same time, most doctors feel more comfortable if the transition occurs to the oral form of the same antibiotic (on the contrary, the very fact that in some cases the corresponding antibiotic is not available in the oral dosage form may postpone the planned "switch"). Of particular importance is the dosing regimen corresponding to high or, conversely, low compliance. Additional benefits in this regard are acquired by antibiotics taken 1 or 2 times a day. The requirements for oral antibiotics should also include high bioavailability, an acceptable safety profile, and a minimum level of drug interactions.

All these requirements, especially in the context of the treatment of community-acquired pneumonia, are best met by levofloxacin - among the new or so-called respiratory fluoroquinolones.

First, like other new or "respiratory" fluoroquinolones (moxifloxacin, gatifloxacin, gemifloxacin), levofloxacin has a broad spectrum of activity against all potential pathogens of community-acquired pneumonia, including Streptococcus pneumoniae (regardless of their sensitivity to penicillin and / or macrolide atypical pathogens and gram-negative bacilli.

Secondly, levofloxacin is characterized by attractive pharmacokinetic parameters: almost absolute bioavailability after oral administration (\u003e 99%); achievement of high and predictable concentrations in the bronchial mucosa, fluid lining the bronchial epithelium, alveolar macrophages, polymorphonuclear leukocytes, exceeding the concentration in blood serum.

Thirdly, levofloxacin is available in dosage forms for intravenous and oral administration, and is prescribed once a day.

Fourth, levofloxacin has an acceptable safety profile comparable to that of the reference drugs. So, in particular, levofloxacin is characterized by insignificant phototoxicity, the absence of serious adverse events from the central nervous system, is not metabolized by the enzymes of the cytochrome P450 system, which means that it does not interact with warfarin, theophylline and, in general, is characterized by a minimum degree of drug interactions. When taking levofloxacin, lengthening of the corrected QT interval and clinically significant hepatotoxicity were not established. Since the registration of levofloxacin in the USA in 1997 (it has been used in Japan since 1993), a vast experience of successful clinical use of this antibiotic has been accumulated all over the world, covering more than 150 million patients. This circumstance is especially important, since the specific problems of individual fluoroquinolones (temafloxacin, trovafloxacin, grepafloxacin, clinafloxacin, lomefloxacin, sparfloxacin) could create an image of "toxic antibiotics" for the whole class.

To date, in the course of well-organized controlled studies, numerous evidences have been obtained of a close or superior clinical and / or microbiological efficacy of levofloxacin in comparison with comparison antibiotics in the framework of stepwise therapy for community-acquired pneumonia. In one of the studies in patients with community-acquired pneumonia, the clinical / microbiological efficacy and safety of levofloxacin administered intravenously (500 mg once a day) and / or orally (500 mg once a day) was studied in comparison with ceftriaxone (1.0 -2.0 g 1-2 times a day) and (or) cefuroxime axetil (500 mg 2 times a day). In addition, based on the specific clinical situation, patients randomized to the ceftriaxone ± cefuroxime axetil group could be prescribed erythromycin or doxycycline. This addition turned out to be very relevant, since according to the results of serological examination, Chlamydia pneumoniae, Mycoplasma pneumoniae and Legionella pneumophila were detected in a significant number of patients (in 101, 41 and 8 patients, respectively). In both groups, the duration of antibiotic therapy did not exceed 12 days. At the same time, 2% of patients received levofloxacin only in parenteral dosage form, 61% - by mouth, and 37% - as part of stepwise therapy. In the comparison group, parenteral, oral and sequential cephalosporins were prescribed in 2, 50 and 48% of cases, respectively.

Comparative analysis showed that the clinical and microbiological efficacy of monotherapy with levofloxacin (which was also prescribed as part of stepwise therapy) was significantly higher than traditional treatment regimens for community-acquired pneumonia (ceftriaxone ± cefuroxime axetil ± erythromycin or doxycycline) with a comparable frequency of adverse events - 5, 8 and 8.5%, respectively. Moreover, this superiority was in no way associated with the known advantage of fluoroquinolone over cephalosporins in relation to "atypical" pathogens (Table 3). Another study investigated the comparative efficacy of levofloxacin in sequential therapy (500 mg 2 times a day) and ceftriaxone (4.0 g 1 time per day) in patients with severe community-acquired pneumonia. The evidence of the initially severe condition of the patients was a comparable number of patients in both groups with an integral APACHE II score\u003e 15 points (21%), as well as a mortality rate of 7%. In the group receiving levofloxacin, all patients received at least 4 doses of the drug intravenously, and the majority of patients (87%) eventually switched to taking the antibiotic by mouth.

The data obtained indicated comparable clinical and microbiological efficacy of levofloxacin and ceftriaxone in the treatment of severe community-acquired pneumonia (Table 4), although there were significantly more cases of ceftriaxone withdrawal due to early clinical ineffectiveness (p \u003d 0.05).

The role and place of levofloxacin in the stepwise therapy of community-acquired pneumonia versus conventional therapy was studied in the large-scale Canadian study (CAPITAL Study), which included 1743 patients, followed up in 20 centers. To resolve the issue of the place of treatment and the method of administration of the drug, the well-known prognostic scale M.J. Fine et al., 1997. If, according to this scale, the patient's final score in points did not exceed 90, then the treatment was carried out at home with the appointment of levofloxacin (500 mg once a day, orally) for 10 days. If the final score in points was 91 or more, then the patient was hospitalized, and initially levofloxacin (500 mg 1 time / day) was administered intravenously (the first dose within the next 4 hours after the patient sought medical help). Subsequently, upon reaching a stable state (the ability to swallow food and liquid, negative results of blood cultures, body temperature

criteria for switching to an oral antibiotic;

peripheral blood leukocyte count 9 / l;

stable course of concomitant diseases;

normal oxygenation (when breathing room air SaO 2\u003e 90%) for patients with concomitant chronic obstructive pulmonary disease at pO 2\u003e 60 mm Hg. Art.

As the analysis of the results of the study showed, there were no significant differences in the rate of readmission, mortality and quality of life (SF-36 rating scale) among patients with community-acquired pneumonia who received levofloxacin as part of stepwise therapy or standard treatment. The introduction of stepwise therapy with levofloxacin led to a decrease in the length of hospital stay by an average of 1.7 days, an 18% decrease in bed-days for this nosological form, and a reduction in costs by US $ 1,700 (per patient).

Finally, the results of another multicenter, open-label, randomized, comparative study were recently published to investigate the clinical and microbiological efficacy of levofloxacin and ceftriaxone in combination with erythromycin in patients with community-acquired pneumonia at high risk of adverse outcome. The evidence of the initially severe condition of the patients was the corresponding values \u200b\u200bof the final point assessment on the APACHE II scale, which were 15.9 ± 6.29 in the group of patients receiving levofloxacin, and 16.0 ± 6.65 in the comparison group. Patients receiving levofloxacin (n \u003d 132) received the drug initially intravenously at a dose of 500 mg once a day, and then the antibiotic was continued in an oral dosage form (500 mg once a day) for 7-14 days. In the comparison group (n \u003d 137), patients were injected intravenously or intramuscularly with ceftriaxone (1-2 g 1 time per day) and intravenous erythromycin (500 mg 4 times a day), followed by a switch to oral administration of amoxicillin / clavulanate (875 mg 2 times a day). day) in combination with clarithromycin (500 mg 2 times a day).

Integral clinical (cases of cure and clinical improvement) and microbiological efficacy were comparable in both groups (Table 5).

Since most of the previously published works analyzed cases of community-acquired pneumonia with a low risk of adverse outcome, it is obvious that this study provides unique information indicating that monotherapy with levofloxacin is at least as effective as the traditional combined treatment “ceftriaxone + erythromycin "category of patients with a high probability of death.

As mentioned above, such properties of levofloxacin as the possibility of administering the drug in parenteral and oral dosage forms, proven clinical efficacy in the treatment of respiratory tract infections, almost absolute bioavailability, safety, lack of clinically significant drug interactions, good oral tolerance, long dosing interval create the image of the "ideal" antibiotic for the stepwise therapy of community-acquired pneumonia. And in the studies carried out to date, including patients with a severe and (or) prognostically unfavorable course of the disease, convincing evidence has been obtained of superior or at least comparable clinical and microbiological efficacy of levofloxacin monotherapy in comparison with the traditional combined treatment (cephalosporins + macrolides). This circumstance, as well as an excellent safety profile, confirmed by many years of wide clinical use, and the obvious economic advantages of monotherapy explain the presence of levofloxacin in modern treatment regimens for community-acquired pneumonia, especially in a hospital setting (Fig.).

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Article provided by the company
"Aventis Pharma" in Ukraine,
published in the Russian Medical Journal (2001, vol. 9, no. 15).

Today in otolaryngology and pulmonology, various antibacterial agents are considered one of the main drugs. Due to their high efficiency, drugs from the fluoroquinolone group are quite often prescribed for the treatment of ENT diseases and respiratory infections. In this article we will try to figure out which is better than levofloxacin or ciprofloxacin. To give a thorough answer, one should dwell in more detail on the features of the use of each of these drugs separately.

Ciprofloxacin belongs to the classical fluoroquinolones, which have broad indications for use in respiratory infections of the lower respiratory tract and ENT pathology. Clinical experience shows that this drug is active against gram-negative bacteria, staphylococci and atypical pathogens (chlamydia, mycoplasma, etc.). At the same time, Ciprofloxacin is not effective enough for diseases caused by pneumococci.

The selection of the optimal drug for the treatment of any disease should be dealt with exclusively by a highly qualified doctor.

Indications

As a broad-spectrum antibacterial drug, Ciprofloxacin has been successfully used in the treatment of patients suffering from respiratory infections of the respiratory tract and ENT pathology. For what diseases of the respiratory system and diseases of the ear, throat, nose, this drug from the group of classic fluoroquinolones is used:

1. Acute and chronic bronchitis (at the stage of exacerbation).
2. Pneumonia caused by various pathogenic microorganisms.
3. Inflammation of the middle ear, sinuses, throat, etc.

Contraindications

Like most drugs, Ciprofloxacin has its own contraindications. In what situations this representative of classical fluoroquinolones cannot be used in the treatment of respiratory diseases and ENT pathology:

• Allergic reaction to Ciprofloxacin.
• Pseudomembranous colitis.
• Childhood and adolescence (until the end of the formation of the skeletal system). The exception is children with pulmonary cystic fibrosis who have developed infectious complications.
• Pulmonary anthrax.

In addition, patients with the following disorders and pathological conditions have restrictions on the use of Ciprofloxacin:

• Progressive atherosclerotic lesions of the blood vessels of the brain.
• Severe cerebral circulation disorders.
• Various heart diseases (arrhythmia, heart attack, etc.).
• Decreased levels of potassium and / or magnesium in the blood (electrolyte imbalance).
• Depressive state.
• Epileptic seizures.
• Severe central nervous system disorders (eg, stroke).
• Myasthenia gravis.
• Serious malfunction of the kidneys and / or liver.
• Advanced age.

Side effects

According to clinical practice, adverse reactions in the prevailing majority of patients taking fluoroquinolones are infrequent. Here are the undesirable effects that occur in about 1 in 1000 patients taking Ciprofloxacin:

• Dyspeptic disorders (vomiting, pain in the abdomen, diarrhea, etc.)
• Decreased appetite.
• Feeling of heartbeat.
• Headache.
• Dizziness.
• Recurrent sleep problems.
• Changes in basic blood parameters.
• Weakness, fatigue.
• Allergic reaction.
• Various skin rashes.
• Painful sensations in muscles and joints.
• Functional disorders of the kidneys and liver.

Do not buy Levofloxacin or Ciprofloxacin without first talking to your healthcare professional.

special instructions

With extreme caution, Ciprofloxacin is prescribed to patients who are already taking medications leading to a prolongation of the QT interval:

1. Antiarrhythmic drugs.
2. Antibiotics from the macrolide group.
3. Tricyclic antidepressants.
4. Antipsychotics.

Clinical observations show that Ciprofloxacin enhances the effect of hypoglycemic drugs. With their simultaneous use, careful monitoring of blood glucose should be carried out. It is recorded that drugs that reduce acidity in the gastrointestinal tract (antacids), and which contain aluminum and magnesium, reduce the absorption of fluoroquinolones from the digestive tract. The interval between the use of an antacid and an antibacterial drug should be at least 120 minutes. I would also like to note that milk and dairy products can affect the absorption of Ciprofloxacin.

In case of an overdose of the drug, it is possible to develop headache, dizziness, weakness, convulsive attacks, dyspeptic disorders, functional disorders of the kidneys and liver. There is no specific antidote. The stomach is washed, activated charcoal is given. If necessary, symptomatic therapy is prescribed. Closely monitor the patient's condition until complete recovery.

Levofloxacin

Levofloxacin belongs to the third generation fluoroquinolones. Possesses high activity against gram-negative bacteria, pneumococci and atypical pathogens of respiratory infections. Most pathogens that show resistance (resistance) to the "classic" second-generation fluoroquinolones may be sensitive to more modern drugs such as Levofloxacin.

Food intake does not affect the absorption of Ciprofloxacin or Levofloxacin. Modern fluoroquinolones can be taken either before or after meals.

Indications

Levofloxacin is a broad-spectrum antibacterial drug. It is actively used for the following diseases of the respiratory system and ENT organs:

• Acute or chronic inflammation of the bronchi (at the stage of exacerbation).
• Inflammation of the paranasal sinuses (sinusitis, sinusitis, etc.).
• Infectious and inflammatory processes in the ear, throat.
• Pneumonia.
• Infectious complications of cystic fibrosis.

Contraindications

Despite the fact that Levofloxacin belongs to the new generation of fluoroquinolones, this drug can not be prescribed in all cases. What are the contraindications to the use of Levofloxacin:

• Allergic reaction to the drug or its analogues from the fluoroquinolone group.
• Serious kidney problems.
• Epileptic seizures.
• Tendon damage associated with previous fluoroquinolone therapy.
• Children and adolescents.
• Periods of childbearing and breastfeeding.

Levofloxacin should be prescribed with extreme caution in elderly patients.

Side effects

As a rule, all adverse reactions are classified according to the severity and frequency of occurrence. Let's list the main undesirable effects from taking Levofloxacin that may occur:

• Problems with the functioning of the gastrointestinal tract (nausea, vomiting, diarrhea, etc.).
• Headaches.
• Dizziness.
• Allergic reactions (skin rash, itching, etc.).
• The level of essential liver enzymes rises.
• Drowsiness.
• Weakness.
• Pain in muscles and joints.
• Tendon damage (inflammation, tears, etc.).

Self-administration of Levofloxacin or Ciprofloxacin without the permission of the attending physician can have serious consequences.

special instructions

Since the likelihood of joint damage is high, Levofloxacin is not prescribed in childhood and adolescence (up to 18 years), with the exception of extremely severe cases. When using antibacterial drugs for the treatment of elderly patients, it should be borne in mind that this category of patients may have impaired renal function, which is a contraindication for prescribing fluoroquinolones.

During therapy with Levofloxacin, patients who have previously suffered a stroke or severe traumatic brain injury may develop epileptic seizures (convulsions). If you suspect the presence of pseudomembranous colitis, you should immediately stop taking Levofloxacin and prescribe the optimal course of therapy. In such situations, it is strongly discouraged to use drugs that inhibit intestinal motility.

Although rare, there may be cases of tendon inflammation (tendonitis) when using Levofloxacin. Older patients are more prone to this kind of adverse reactions. Concomitant use of glucocorticosteroids significantly increases the risk of tendon ruptures. If you suspect a tendon lesion (inflammation, rupture, etc.), fluoroquinolone therapy is stopped.

In case of an overdose of this drug, symptomatic therapy should be carried out. The use of dialysis in such cases is ineffective. There is no specific antidote.

During therapy with Levofloxacin, it is not recommended to engage in activities that require increased concentration of attention and quick reactions (for example, driving). In addition, due to the risk of developing photosensitization, refrain from excessive exposure of the skin to ultraviolet rays.

Which drug to choose?

How to determine which is better than Levofloxacin or Ciprofloxacin? Of course, only an experienced specialist can make the best choice. Nevertheless, when choosing a drug, it is necessary to rely on 3 main aspects:

• Efficiency.
• Safety.
• Availability.

A good drug is one that is not only effective, but also less toxic and available. In terms of effectiveness, Levofloxacin has its advantages over Ciprofloxacin. Along with the preserved activity against gram-negative pathogenic microorganisms, Levofloxacin has a more pronounced antibacterial effect against pneumococci and atypical pathogens. Nevertheless, it is inferior to Ciprofloxacin in activity against the pathogen Pseudomonas (P.) aeruginosa. It has been noted that pathogens that are resistant to Ciprofloxacin may be sensitive to Levofloxacin.

The type of pathogen and its sensitivity to antibacterial agents are decisive when choosing the optimal fluoroquinolone (in particular, Ciprofloxacin or Lefovloxacin).

Both drugs are well absorbed in the intestine when taken orally. Food has practically no effect on the absorption process, with the exception of milk and dairy products. They are convenient to use because they can be prescribed 1-2 times a day. Regardless of whether you take Ciprofloxacin or Levofloxacin, in rare cases, unwanted side reactions may develop. As a rule, dyspeptic disorders (nausea, vomiting, etc.) are noted. Some patients taking second or third generation fluoroquinolones complain of headache, dizziness, weakness, increased fatigue, and sleep disturbance.

In elderly patients, especially with glucorticosteroid therapy, tendon ruptures are possible. Due to the risk of developing joint lesions, fluoroquinolones are limited in use during periods of gestation and breastfeeding, as well as during childhood.

Currently, for most patients, the price aspect is of paramount importance. A package of Ciprofloxacin tablets costs about 40 rubles. Depending on the dosage of the drug (250 or 500 mg), the price may fluctuate, but not significantly. More modern Levofloxacin will cost you an average of 200-300 rubles. The price will depend on the manufacturer.

At the same time, the final decision as to which is best for the patient, Ciprofloxacin or Levofloxacin, is made exclusively by the attending physician.