Lecture №18 Heterocyclic antibiotics: aminoglycosides, macrolides. Polypeptide antibiotics, polyenes and antitumor antibiotics. Fluoroquinolones as antibiotic drugs. prepared ass. Kozachok S.S. Aminoglycosides divided on the following groups: Strepyomycin (separately , NH2- group is substituted); Aminoglycosides (kanamycin, neomycin, gentamycin, monomycin, amikacin); Macrolides (erythromycin, oleandomycin, roxitromycin, claritromicin, dirythromycin, spiramycin, azitromycin); Ansamycin (rifampicin) Strepyomycin sulfate (Streptomycini sulfas) Streptomycin sulfate* (UP) Bis-[N,N’-bis(aminoiminomethyl)-4-O-[5-deoxy-2-O-[2deoxy-2-methylamino)-α-L-glucopyranosyl]-3-С-formylα-L -lyxofuranosyl]-D-streptamine] trisulfate • Streptomycin, discovered in 1944 by the American scientist Waxman. • Obtaining. Microbiological synthesis from Streptomyces griseus actinomycetes. • Streptomycin glycoside consists of the aglycone - streptydin (1,3-diguanidino2,4,5,6-tetraoxicyclohexane) and sugar partdisaccharide streptobiozamine (N-methyl-Lglucosamine and L-streptose). CHARACTERISTICS • White powder. Hygroscopic . Very soluble in water, practically insoluble in ethanol and ether. • Streptomycin has a basic property according to the appearance of the nitrogen containing group (two guanidins and one N-methylamino) that’s why easy creates salts. • In a weak acidic medium streptomycin is stable, but in strong acidic and especially in basic medium it easy hydrolyzes on a streptydin and streptobiozamine, which decomposes on N- methyl-L-glucosamine and L-streptos. Identification • • TLC. Maltol test is caused by the ability of the streptose in a basic medium to convert on a maltol according to the dehydratation and isomerization. At the iron (III) ions interaction in an acidic medium maltol forms the violet products: O O O CHO NaOH, t0C CH3 OH CH3 OH OH OH O Fe3+/3 O FeNH4(SO4)2 H2SO4 CH3 O Maltol (α-methyl-β-oxy-γ-piron) • Sakaguchi reaction on the remnants of guanidines. Formation of a violet-red colour, which appearances in a basic medium under the action of -naphthol and concentrated sodium hypochlorite. O Br OH N C N H R NH • • Molish reaction on carbohydrates (streptos). After acidic hydrolysis the substance does not give reaction with naphthol and concentrated sodium hypochlorite in a basic solution. Yellow colour. It gives the reaction of sulfate. • Un pharmacopoeia reaction : a) Escaping of ammonia by heating of the substance with sodium hydroxide (guanidine residues); b) Weber Reagent (it is oxidized by sodium nitroprusside Na[Fe(CN)5NO]+K3[Fe(CN)6]+NaOH) – red colour (guanidine residues); c) Brown colour with basic potassium tetraiodomerrcurate (Nernst reagent) and red sediment with copper-tartrate reagent– Feling reagent; “silver mirror” reaction (on aldehyde group); d) Condensation with phenols in the presence of concentrated sulfuric acid – aurine dye; e) On the aldehyde group of streptos (with a hydrazine, a semicarbazide – white sediments). Aurine dye red colour Assay • Microbiological method (UP). • Photocolorymetry which is based on the Maltol test. • Cerimetry. Titrant – Cerium sulfate. Indicator – iron (III) chloride. Em = М. m./2 O O O OH - 2e + 2H+ 1 CH3 CH3 O O Ce4++ 1e Ce3+ 2 Storage In the dry place. Application Broad-spectrum antibiotic. Antituberculosis drug. At the treatment of pneumonia, peritonitis, , gonorrhea, brucellosis. Produced in bottles, sealed with rubber stoppers with crimped aluminum caps on 0,25, 0,5 and 1,0 of the active substance in terms of streptomycin-base. Inject inner muscular 0,5-1,0 g on a day. Side effects. Kidney-and oto-toxic, respiratory depression, is rapidly developing resistance (2-3 days). Aminoglycosides The general formula Characteristic. According to the physical properties aminoglycosides antibiotics are powders of white, yellow or creams colors, hydroscopic. Freely soluble in water and practically insoluble or low soluble in the most organic Kanamycin monosulfate (UP) (Kanamycini monosulfas) • Composition of Kanamycin is aglucone 2deoxystreptomine (meso-1,3-diamino-4,5,6trioxycyclohexan) and two saccharates - 3-amino-3-deoxyD-glucose and 6-аmino-6-deoxy-D-glucose. • Drug is obtained by the fermentation of Streptomyces kanamycetis at 27-29 оС and рН=7, the environment that contains starch and soy flour. From the environment Kanamycin A, B and C is extracted by an ionchangers.The list toxic Kanamycin A has, that’s why it composes the mass of the drug Kanamycin monosulfate (94 %). • The semi-synthetic analog of Kanamycin is amikacin sulfate. Its main difference from kanamycin is a present of 4-аmino-L-2-oxybtyl radical. Except aglucone 2- deoxy-Dstreptamine amikacin has 2-deoxy-L-streptamine. Amykacin sulfate (Amyсаcini sulfas) NH2 CH2NH2 OH O CH2OH OH O OH OH O O * 2 H2SO4 OH OH OH HN NH2 C O C H C H2 C H2 NH2 • Neomycin like Kanamycin is a mixture of two stereoisomers В and С. Aglucone – 2-deoxystreptamine ties three saccharides. • The drug is obtained from the liquid Streptomyces fradiae culture by the carboxylic cation exchange resins. In 1949 neomycin was the first obtained by Waxman and le Shatelye. • Monomycin sulfate drug is a mixture of monomycins that are produced by Actinomyces circulatus var. monomicini. The difference of the monomycin chemical structure from neomycin is a present in 6’ position – СН2ОН group (paramosa) exept – CH2NH2. • Gentamycin is similar to kanamycin. It is a metabolizing product of Micromonospora purpurea. It is a mixture of: Neomycin sulfate (Neomycini sulfas) H2C Monomycin sulfate (Monomycini sulfas) OH O OH OH NH2 NH2 OH H2N CH2 O NH2 O HO CH2 *nH2SO4 O O OH O OH NH2 OH Gentamycin sulfate (Gentamycini sulfas) Aminoglycoside’s identification Physical constants: melting temperature, UV- and Proton Nuclear Magnetic Resonanse-spectroscopy, TLC, Liquid chromatography. Reaction on the aliphatic amino-group of Kanamycin monosulfate – at the heating with a ninhydrin solution observed violet color. Melting temperature of Kanamycin picrate. They give reaction of sulfate. Bial’s reaction (pentose opening). For the identification of Kanamycin monosulfate and neomycin sulfate using a color reaction with a alcohol solution of an orcyn (methylresorcinol) and concentrated hydrochloric acid at the present of iron (III) chloride. Solution gets green color. After acidic hydrolysis kanamycin and amikacin give the reaction of the reducing saccharides (Feling reagent. Nernst, Tolens). Amykacin according to the amide group forms color complexes with the hard metal’s salts (reaction with cobalt nitrate after sodium hydroxide neutralization – violet). Amikacin at the heating with concentrated mineral acids forms from the saccharides 5-aminomethylfurfural, which gives the colour reaction with antron: Assay Microbiological method (UP). Polarimetry (gentamycin sulfate). Photocolorimetry. Absorption spectroscopy in UV- and visible region. Storage Protection from light. Application Broad spectrum antibiotics. For the treatment of the gastrointestinal tract diseases, tuberculosis and infectious skin diseases, sepsis, urinary tract infections. Kanamycin monosulfate – bottle on 0,5 and 1,0 g. Inner muscular injection 5-7 days. H.d.d. – 2 g Gentamycin sulfate – Solution for injection.: exports producing. 40 or 80 mg 2,0 ml №10; national (Ukrainian) producing 4% 1,0 or 2,0 ml №10; cream 0,1% 15 г; eye oinment 0,3% 5,0 g. Average day’s dose – 3 mg/kg, 2-3 times, inner muscular injection. Amykacin – КМ – bottle on 0,1 and 0,25 g. Average day’s dose 15 mg/kg by 2 times inner muscular injections. Tergynan – vaginal tablets (ternidazole, neomycin sulfate, nystatin , prednisolone). Side effects – Kidney-and oto-toxic action, allergy and others. Lincomycins In medical practical using Lincomycin hydrochloride and clindamycin Lincomycin hydrochloride (Lyncomycini hydrochloridum) (UP) CH3 CH3 N C3H7 C Monohydrate methyl-6,8-dideoxyO 6-[(2S,4R)-1-ethyl-4-propylpyrrolidinyl-2-carboxamido]1-thio-D-erythro-α-D-galactooctopyranoside hydrochloride HO C H N H C H O OH * HCl * H2O OH SCH3 OH • Lincomycin hydrochloride– used at sepsis, staphylococ infections, acute and chronic osteomyelitis, purulent skin infections, otitis. Externally at purulent diseases of skin and soft tissue. Intravenous, inner muscular injection. Once dose - 0,5 g, day dose – 1,5 g. Capsules on 0,25 g №20; solution for injection 30% 1,0 or 2,0 № 10. Contraindications – severe liver and kidney disease, myasthenia gravis. Clindamycin (Dalacin) – broad-spectrum ANT. Capsule on 150 and 300 mg № 16; solution for injection 150 mg/ml 2,0 or 4,0 № 1; vaginal cream and suppositories. Macrolides antibiotics They contain a lactone ring with 12-17 carbon atoms, it ties with amino carbohydrates (for the amino glycosides type) and neutral sugars. Reserve antibiotics. Modern classification 1. 14 – members: natural (erythromycin, oleandomycin); prodrug (esther and erythromycin salts, oleandomycin esthers); semi-synthetic (roxithromycin, clarithromycin, dirithromycin, josamycin, its active metabolite is 14-hydroxi clarithromycin). 2. 15 – members: semi-synthetic (additional nitrogen atom – azalides - azithromycin (sumamed) 3. 16 – members: natural (spiramycin (rovamycin), midecamycin (macropen), semi-synthetic (midecamycin acetate (miocamycin). In medical practice the most often used : It is now known about 100 macrolide antibiotics, the 1. Erythromycin phosphate general formula: 2. 3. 4. 5. 6. 7. (altrocin –S); Spiramycin (rovamycin, rovalen); Midecamycin(macropen); Roxithromycin (roxide, rulid, renicin, rovenal); Josamycin (wilprafen ); Clarithromycin (fromilid , klabax , clacid ); Azithromycin (Azitrox, Azithro, Zithromax , sumamed ). Erythromycin(Erythromycinum) • Erythromycin is produced from a strain of the actinomycete Saccharopolyspora erythraea.. • Erythromycin consists of aglucone erythrolide (14-members lactone) and two sugars: cladynos (3-methyl-3-methoxy-2,6didedeoxyhexopyranos) and deamine (pycrocin, 3dimethylamino-4,6- didedeoxyhexopyranos). Cladynos splits off at the interaction with eryehromycin with 0,5 М НСl solution at the cold, and deamine – at the interaction with eryehromycin with 6 М НСl solution. • Erythromycin – white crystalline substance bitter on taste, melting at 190-193 оС, soluble in water, freely soluble in ethanol, acetone and chloroform. With concentrated H2SO4 gives red-brown color, and with concentrated HCl – orange color that transfers into red after puple. • 1mg of Erythromycin equals 1000 U.A. Oleandomycin phosphate Oleandomycini phosphas H3C CH3 O O OH H3C OH N O O OCH3 H3C H3C CH3 *H3PO4 CH3 H2C O OH O O O CH3 CH3 CH3 Azithromycin (UP) (Azithromycinum) H3C CH3 O O HO H3C O N O CH3 H3C H3C OH H3CO CH3 OH H 3C CH3 O OH O • OH N H 3C CH3 CH3 CH3 Identification: IRspectroscopy • Assay: Liquid chromotography • Erythromycin is available in enteric-coated tablets, slow-release capsules, oral suspensions, ophthalmic solutions, ointments, gels, and injections. • Erythromycin tablets on 100000 and 250000 U.A. are used for the treatment of pneumonia, scarlatina, angina, anthrax etc. For the local using at the infection wounds, burns, trophic exulcerates, trachoma, bedsores there is recommended an ointment Unguentum erythromycini, its 1 g contains 10000 U.A. • Other antibiotics-macrolides are produced as oral medicine forms. • Macrolide antibiotics are used by prescription, determine the sensitivity to this group and compared with a sensitivity to other groups as well as macrolides quickly develop resistance. If antibioticsmacrolides are not used continuously, the sensitivity of the microorganism to them restored. Ansamycin’s antibiotics At the core of the structure is aromatic ring, coupled with macrocyclic aliphatic chain, called Anza-chain. Aliphatic chain does not contain the lactone bonds that are typical for macrolide’s antibiotics, it attaches to the core with the amide nitrogen atom. The following antibiotics belong to ansamycin’s : rifampicin, streptovaricin, tolipomicin, galomicin, naphtomicin etc. Rifampicin and its semi-synthetic analogs are used as medicines [3-(4methyl-1-piperazinyliminomethyl)- rifampicin ], rifabutin , rifampitin and the combine drugs. Ansamycin’s antibiotics have broud-spectrum action and a high efficiency. Prescribed in the cases where other antibiotics are ineffective. Used for the treatment of all forms of tuberculosis, diseases of gastrointestinal tract and pyogenic infections on the doses of 0,3-0,45 g. Microorganisms very quick develop the resistance to Rifampicin. Rifampicin’s general formula and radicals Polyenes antibiotics Polyenes antibiotics have an antifungal activity. They are mixtures of substances that are very close in structure. Molecule of each component consists of the aglycone having macrocyclic structure, and amino sugars, connected by a glycosidic bond. Polyene structure of the aglycone has 6-7 double bonds and 35-40 carbon atoms. In medical practice the following medicines used: nystatin, Amphotericin В, levorin, trihmicin, candocidin, mycoheptin , griseofulvin , amphoglucamin , etc. Application. For the treatment of candidiasis, dermatomycoses, trichomoniasis, fungal diseases. The modern antifungal medicines – imidazole derivatives: Ketoconazole (1-2%), Oxiconazole (mifungar), Intraconazole (orungal); allylamine: Terbinafine (lamisil, terbisil, exifine); triazol derivatives : Fluconazole (diflucan, micosyst). Nystatin Nystatinum tablets, ointment , suppository CH3 O OH NH2 OH O H3C CO OH CH3 O HO H3C OH OH OH OH O O OH OH OCH3 OH O OCH 3 • Griseofulvin Griseofulvinum tablets, liniment O O H3CO Cl CH3 Nystatin (Nystatinum) (UP) • Identification: UV-, ІR-spectroscopy; Substance + concentrated hydrochloric acid – brown color; Substance + concentrated sulfuric acid – brown color that transfers into a violet; Liquid chromatography. • Assay: Microbiological method • For a substance that is designed to produce medicines for oral use must be withstanded the test on abnormal toxicity. Amphotericin В O Amphotericinum B OH CH3 amphomin, amphotret, fungizome, fungizone NH2 OH O H3C CH3 O HO H3C OH OH OH OH O O OH CO OH OH OH • Yellow or yellow-orange powder. Hygroscopic . Sensitive to the action of light and temperature. It is easy inactivated in acid and base medium. • Application - systemic and deep mycoses (blastomycosis, criptococoz), mold mycosis, chronic and granulomatous forms of candidiasis. Intravenous injection, inhalation and topical (cream). Used only in hospital settings: a highly toxic drug, capable to cumulation, kidney throtoxic, causes the reducing of potassium quantity in a blood. Polypeptides antibiotics Polypeptides antibiotics according to their amino acids composition, chemical structure are different from other peptides (proteins). Amino acids associate in a cycle. In medical practice the following medicines used: Gramicidin S, Polymyxin M . Storage. Protection from light. Application. According to a high toxicty of polypeptides the are applied outside, at the internal using they cause hemolysis of erythrocytes. At the heavy septic and gastroenteric diseases (as enemas), when other antibiotics are uneffective, for washing of purulent wounds, ulcers, bedsores, rinse of throat. Gramicidin S has the spermocidic action (as paste). Gramidin (tablet fro resorb) – Gramicidin S 1,5 mg and lidocaine h/ch 10 mg. Sofradex (drops eye/ears) – gramicidin 0,05 mg, neomycin 5,0 mg, Dexamethason 0,5 mg. Gramicidin S (Gramicidin S) Gramicidin S is produced from a bacterial strain of the Bacillus brevis, which are in the soil. The first it was obtained in USA. Antineoplastic antibiotics In 1940 actinomycin was obtained by the american scientist Waxman, and in 1952 there was determined the antineoplastic action of the substance. Antitumor antibiotics that are used in medical practice can be divided into derivatives: tetracycline (doxorubicin hydrochloride); Aurelic acid (olivomycin); Anthracycline (rubomycin); Quinoline-5,8-dion (Вruneomycin ). For the analysis of these drugs physical, physical-chemical and chemical methods are used. Storage. In a well stoppered container in a dry place, protected from light at room temperature. Doxorubicin hydrochloride(UP) Doxorubicini hydrochloridum Adriblastin O OH O OH OH • Crystalline orange-red powder. Hygroscopic. OCH3 • Identifiction: ІRspectroscopy, gives the reaction of chloride ions. • Assay: OH Liquid chromatography H O * HCl OH O CH3 NH2 O O Olivomycin А CH3 O O O H3C C OCH3 O OH OCH3 O OH CH3 O OH O OH OH OH CH3 O O CH CH3 O OH CH3 OH C O O O CH3 H 3C O CH3 O • Rubomycin hydrochloride O OH COCH3 OH • Вruneomycin *HCl O OCH3 OHC 3 OH O H3CO O OH NH2 N COOH N H2N O H2N CH3 OH OCH3 OCH3 Olivomycin А – yellow powder with a green tint. Hygroscopic. Freely soluble in water, alcohol, practically insoluble in chloroform, ether. Storage as a toxic substance at below 20 оС. Using intravenous injection or local (oinmant). Вruneomycin (streptonigrin) – brown crystalline powder. Practically insoluble in water, alcohol, soluble in DMFA, pyridine. Storage as a toxic substance at below 20 оС in a dark place. Using intravenous injection as a sodium salt, hypodermic injection – necrosis. Rubomycin h/ch – red powder. Hygroscopic. Freely soluble in water, alcohol, slightly soluble in chloroform. The color of medicine in acidic medium– red, in basic – blue. Storage as a toxic substance at below 20 оС. Using intravenous injection, inner muscular injection or hypodermic injection – necrosis. 6 – Fluoroquinolones Antibiotics of a 4-quinoline derivatives, which in the 6-th position contain Fluorine atom, and in the 7-th position - piperazine cycle. Their precursors such as derivatives of quinoline and naphtiridin, are started to use in 60 years of ХХ century. The first representative of this class is nalidyxone acid (nevigramon, negram) and its analogs is a pipemіdine acid (pipemidine, palin, urosept, pimidel). These drugs are characterized primarily by the activity to gramnegative microorganisms, the rapid development of resistance to these antibiotics causing their using only for infectious diseases of the urinary tract. Nalidyxone acid (belongs to naphtiridines): Fluoroquinolones began to be introduced into medical practice in 80 years of the last century. Introduction of fluorine atoms in the molecule of quinoline derivatives and naphtiridin leds to a group of drugs with fundamentally new pharmacological properties. Fluoroquinolones are a highly active antimicrobial compounds, which are used at severe infections of the different etiology and localization (respiratory tract infections, skin and soft tissues, bones and joints, gastrointestinal tract, postoperative infections, other chronic inflammatory processes). The mechanism of fluoroquinolones action: they affect on the metabolism of bacterial DNA by inhibiting the enzyme in bacterial cells, DNA gyrase, which controls the structure and function of DNA. Inhibition of DNA gyrase leads to destruction of the bacteria (bactericidal effect). Antibacterial activity of quinolones is also connected with the effect on RNA synthesis of bacteria and bacterial proteins, the stability of membranes and other vital processes of the bacterial cells. Quinolones have a high effect on aerobic gramnegative bacteria and have little effect on anaerobic bacteria. They are rapidly absorbed from the gastrointestinal tract and are effective at the inside administration. Quinolones inhibit the oxidazing enzymes of liver and can increase the effects of drugs (increase the side effects of theophylline). The quinolones activity increases when administered in their molecules of two (lomefloxacin) or three (hemafloxacin) fluorine atoms. Replacement of the ethyl radical in norfloxacin on cyclopropyl leads to the increasing of the substances activity (ciprofloxacin) by 3-8 times. Some drugs of this group after extensive clinical using have been banned because of serious side effects. Fluoroquinolones classification The first generation Pefloxacin (Abactal, Unikpef, Peflox-400); Norfloxacin (Norbactin, Negaflox, Nalicin, Norilet, Renor) is the active metabolite of pefloxacin The second generation Ciprofloxacin (Ciprinol, Ciprobay, Cyprohexal, Cyprolet, Cyfran, Ciprom, Cipronat); Ofloxacin (Zinocin, Oflohexal, Ofloxin, Geoflox, Zanocin, Zoflox, Tarivil,); Lomefloxacin (Lomaley, Maxacvin, lomflox, Oxacin) The third generation Levofloxacin (Locsof, Tavanic, Leflox) – left rotation isomer of ofloxacin; Moxifloxacin (Avelox); Gatifloxacin (Zicvin, Terbis); Sparfloxacin (Omniflox). • Norfloxacin Norfloxacinum • Ofloxacin Ofloxacinum O O F HN N COOH F COOH N H3C C2H5 N N N O CH3 1-ethyl-6-fluor-1,4-dihydro-4-оxо7-(1’-piperazinyl)-3quinolinecarboxylic acid (±) 3-methyl- 7-оxo-9-fluor-10(4’-methyl-1’- piperazinyl)-2,3dihydro-7Н-pirido-1,4benzoxazine -6- carboxylic acid • Ciprofloxacin h/ch (UP 1.2) Ciprofloxacini hydrochloridum • Lomefloxacin Lomefloxacinum O O F COOH F COOH H3C HN N N * HCl * H2O H 2C HN N N F CH C2H5 CH2 1-cyclopropyl-6-fluorine-4-оxo-7(piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid hydrochloride 1-ethyl-6,8-difluorine-7-(3’methyl-1’- piperazinyl)-4оxo-1,4-dihydro-3quinolinecarboxylic acid Fluoroquinolones characters Pale yellow crystalline powder, norfloxacin and ciprofloxacin - hygroscopic. Very slightly or practically insoluble in water, soluble in alcohol and acetone. Norfloxacin is a photosensitive. Chlorides of ofloxacin and ciprofloxacin are soluble in water and practically insoluble in alcohol, acetone and methylene chloride. Fluoroquinolones identification IR, UV spectroscopy, TLC. Heterocyclic nitrogen atom is determined by Dragendorff’s reagent, picric acid. Oxo-group is identified by the reactions of the formation of oxime’s precipitation (reaction with hydroxylamine), thiosemicarbazone (reaction with thiosemicarbazide) phenylhydrazone (reaction with phenylhydrazine). Chlorides containing salts give the reaction of chloride. Formation of the chelate complexes of a dark-red color with Fe3+ ions: For the determining of fluorine atom the mineralization is carried out in order to obtain the F- ion, a) after pre-mineralization with a mixture for sintering. The residue was dissolved at pH 4,0-5,0, to add a solution of calcium chloride, observed opalescence (precipitate CaF2): 2F- + Ca2+ → CaF2↓ b) After the combustion with oxygen in the presence of hydrogen peroxide. Fluorides are formed discolor red solution of iron (III) thiocyanate: Fe(SCN)6 + 6F- → [FeF6]3- + 3(SCN)b) after the mineralization of the substance under the influence of molten sodium metal. Fluorides destroy the zirconium-alizarin red complex, according to that extract a free alizarin is a yellow color: Extracted at this case a white precipitate zirconium (IV) fluoride is dissolved at the same time in excess of fluoride with the formation of a colorless anion [ZrF6]2-. Assay 1. Acidimetry in a non-aqueous medium, a direct titration. Ем=М.m. 2. Hydrogen chloride salts are determined by a liquid chromatography . Storage Protection from light. Side effects; Fluoroquinolones cause photosensibilization (sensitivity to light), so we can not at the time of acceptance of this group of drugs irradiate with UVand sunlight. Accumulation in the skeletal system - can not use for children under 15 years old, pregnant, during lactation. Producing; Pefloxacin– tabl. on 04 g; ampulla on 5 ml (0,4g). Norfloxacin and Lomefloxacin – tabl. on 0,4 g. Ofloxacin – tabl on 0,2 g. Ciprofloxacin – tabl. on 0,25 g; 0,5 g; 0,75 g; 0,2% solution for infusion on 50, 100 ml; 1% solution for injection аmpulla 10 ml. Eye-ear drops 0,3%. Cifran SТ – ciprofloxacin 500 mg + tinidazole 600 mg. Levofloxacin – tabl. 0,25 g; 0,5g №5; solution for infusion 0,5 g on 100 ml №1. Moxifloxacin – tabl. 0,4 g №5; solution for infusion 0,4 g on 250 ml №1. Gatifloxacin – tabl. 0,2 and 0,4 g №10; solution for infusion 0,4 g on 200 ml №1. Sparfloxacin - tabl. 0,2 g №10. Thanx for attention