Showing posts with label ANTIBIOTICS. Show all posts
Showing posts with label ANTIBIOTICS. Show all posts

Friday, May 17, 2013

Tetracyclines antibiotics

7:13 PM by Unknown

3.9 Tetracyclines


The tetracyclines are a conglomerate of broad spectrum orally active actinomycete antibiotics produced by cultures of Streptomyces species, and possessing appreciable therapeutic value. Chlortetracycline was the first bonafide member of this group isolated from Streptomycesaureofaciens and discovered by Duggar in 1948. It was immediately followed by oxytetracycline in 1950 from the cultures of Streptomyces rimosus; and in 1953 tetracycline was eventually discovered in the antibiotic mixture from S. aureofaciens as a minor antibiotic.
tetracycline

Consequently, the intensive and extensive research and development in the selection of mutant strains, and specifically in the manipulations and manifestations to monitor and control both ‘methylation’ and ‘chlorination’ procedures have resulted in the fermentative production of a good number of tetracycline variants, namely: demeclocycline, methacycline, doxycycline, minocycline, lymecycline as given below:
These compounds shall now be discussed individually as under:
3.9.1 Tetracycline
Synonyms Deschlorobiomycin; Tsiklomitsin; Abricycline; Ambramycin; Bio-Tetra; Cyclomycin; Dumocyclin; Tetradecin;
Biological Source It is obtained from a Streptomyces species cultured in an appropriate nutrient medium.
Preparation It may be prepared by removal of chlorine from chlortetracycline and subjecting it to hydrogenation.
Chemical Structure Please see Section 3.9.
Characteristic Features
1. It is obtained as a yellow crystalline powder; odourless, and stable in air.
2. It usually darkens on exposure to strong sunlight.
3. Its potency is seriously affected in solutions of pH < 2.
4. It is destroyed rapidly by alkali hydroxide solutions.
5. It is found to be more soluble than chlortetracycline.
6. It is rather more stable within the physiological and moderately alkaline spectrum of pH.
7. The solutions of tetracycline gets darkened more rapidly than chlortetracycline but less than oxytetracycline.
8. The pH of an aqueous suspension (1 mg . mL–1) ranges between 3.0 to 7.0.
9. Its dissociation constant pKa are: 3.3; 7.7; 7.9.
10. Solubility Profile: 1g is soluble in ~ 2500 mL water; ~ 50 mL ethanol; freely soluble in dilute HCl or alkali hydroxide solutions; and almost insoluble in ether or chloroform.
Uses
1. It is found to be useful in the treatment of toxoplasmosis.
2. The GI side effects are comparatively less than those from chlortetracycline and oxytetracycline but more than from demeclocycline.
3. The plasma half-life ranges between 6 to 11 hours in patients with normal renal function. Tetracycline Hydrochloride [C22H24N2O8.HCl] [Synonyms Achro; Achromycin; Ala Tet; Ambracyn; Ambramicina; Bristaciclina; Cefracycline; Cyclopar; Diocyclin; Hostacyclin;Mephacyclin; Panmycin; Polycycline; Quadracycln; Remicyclin; Sanclomycine; Supramycin; Tetramycin; Topicycline; Totomycin; Unicin.
Characteristic Features
1. The crystals of tetracycline hydrochloride are obtained from butanol + HCl which decomposes at 214°C.
2. Its specific optical rotation [α]D25-257.9° (C = 0.5 in 0.1 N HCl).
3. It is freely soluble in water; soluble in methanol, ethanol; and insoluble in ether and hydrocarbons.
4. The pH of a 2% (w/v) aqueous solution ranges between 2.1-2.3.
3.9.2 Chlortetracycline
Synonyms 7-Chlorotetracycline; Acronize; Aureocina; Aureomycin; Biomitsin; Centraureo; Chrysomykine; Orospray.
Biological Source It is obtained from the substrate of Streptomyces aureofaciens.
Chemical Structure Please refer to Section 9.3.9.
Characteristic Features
1. It is obtained as golden-yellow crystals having mp 168-169°C.
2. It has specific optical rotation [α]D23-275.0° (methanol).
3. It has uvmax (0.1 N HCl): 230, 262.5, 267.5 nm, and (0.1N NaOH): 255, 285, 345 nm.
4. Its solubility in water ranges between 0.5-0.6 mg mL–1, very soluble in aqueous solutions above pH 8.5; freely soluble in the cellosolves, dioxane and carbitol; slightly soluble in methanol, ethanol, butanol, acetone, benzene, ethyl acetate; and almost insoluble in ether and petroleum ether.
Uses
1. It exerts antiamebic activity.
2. It is the first tetracycline antibiotic available for topical application, including ophthalmic purposes.
3. Though its general use has been replaced by other tetracycline antibiotics in human beings, but it is still employed in veterinary medicine.
3.9.3 Oxytetracycline
Synonyms Glomycin; Riomistin; Hydroxytetracycline.
Biological Sources It is an antibiotic substance obtained from the elaboration products of the actinomycete, Streptomyces rimosus, grown on a suitable medium. Oxytetracycline may also be obtained from Streptomyces xanthophaeus.
Chemical Structure Refert to Section 3.9.
Characteristic Features
1. It is obtained as pale yellow to tan, odourless, crystalline powder.
2. It is fairly stable in air, but an exposure to strong sunlight gets darkened.
3. Like tetracycline it also gets deteriorated in solution of pH less than 2, and is quickly destroyed by alkali hydroxide solutions.
4. Its saturated solution is almost neutral to litmus and shows a pH ~ 6.5.
5. Solubility Profile: 1g in 4150 mL water; 100 ml ethanol; > 10,000 ml chloroform; 6250 mL ether; and freely soluble in diluted HCl or alkaline solutions.
6. Stability: Its crystals exhibit no loss in potency on heating for a duration of 4 days at 100°C; whereas the hydrochloride crystals show < 5% inactivation after 4 months at 56°C. It has been observed that the aqueous solutions of the hydrochloride at pH 1.0 to 2.5 are quite stable for at least 30 days at 25°C. It has been observed that the aqueous solutions of the hydrochloride at pH 1.0 to 2.5 are quite stable for at least 30 days at 25°C. However, its solutions at pH 3.0 to 9.0 show no detectable loss in potency on storage at + 5°C for at least 30 days. Half life in hours at aqueous oxytetracycline solutions at 37°C: pH 1.0 = 114; pH 2.5 = 134; pH 4.6 = 45; pH 5.5 = 45; pH 7.0 = 26; pH 8.5 = 33; and pH 10.0 = 14.
Oxytetracycline Hydrochloride [C22H24N2O9.HCl] [Synonyms Alamycin, Duphacycline; Engemycin; Geomycin; Oxlopar; Oxybiocycline; Oxycyclin Oxy-Dumocyclin; Oxytetracid; Oxytetrin; Tetran; Vendarcin]
It is obtained as yellow platelets from water and is found to be extremely soluble in water (1g/mL). It is also soluble in absolute ethanol: 12,000 g/mL; and in 95% (v/v) ethanol: 33,000 g/mL.
Note: Its concentrated aqueous solutions at neutral pH hydrolyze on standing and consequently deposit crystals of oxytetracycline. Oxytetracycline Dihydrate [C22H24N2O9.2H2O] [Synonyms Abbocin; Clinimycin; Oxymycin; Stevacin; Terramycin; Unimycin]
It is obtained as needles from water or methanol which decompose at 181-182°C. Its specific optical rotations are: [α]D25-2.1° (0.1N NaOH); and [α]D25-196.6 (0.1N HCl). It has uvmax (pH 4.5 phosphate buffer 0.1 M): 249, 276, 353 nm (E1%1cm 240, 322, 301). It is found to be soluble in water at 23°C at various pH's: pH 1.2 = 31, 400 g/mL; pH 2.0 = 4600 γ/mL; pH 3.0 = 1400 γ/mL; and pH 9.0 = 38,600 γ/mL. It is soluble in absolute ethanol 12,000 γ/mL and in 95% (v/v) ethanol 200 g/mL.
3.9.4 Demeclocycline
Synonyms Bioterciclin; Declomycin; Deganol; Ledermycin; Periciclina; Demethylchlortetracycline (obsolete).
Biological Source Demeclocycline is related to tetracycline and produced by Streptomyces aureofaciens.
Preparation A suitable strain of S. aureofaciens is grown in an appropriate liquid nutrient medium under controlled experimental parameters of pH, temperature, and extent of aeration. Subsequently, the duly harvested broth is acidified carefully and filtered. The demeclocycline is isolated from the resulting filtrate, either by solvent extraction or by chemical precipitation.
Chemical Structure Refer to section 3.9.
Characteristic Features
Demeclocycline Hydrochloride [C21H21ClN2O8.HCl] [Synonyms: Clortetrin; Demetraciclina; Detravis; Meciclin; Mexocine]
1. It is obtained as yellow, crystalline powder, odourless and having a bitter taste.
2. The pH of 1 in 100 solution is ~ 2.5.
3. It essentially has three distinct dissociation constants, namely: pKa1, 2, 3: 3.3, 7.2, 9.3 attributed by three separate zones in its complex molecule as shown below:
Demeclocycline Hydrochloride
4. Solubility Profile: 1g soluble in ~ 60 mL water; 200 mL ethanol or 50 mL methanol; sparingly soluble in alkali hydroxides or carbonates; and almost insoluble in chloroform.
Uses
1. It is an intermediate-acting tetracycline and causes comparatively a greater extent of phytotoxicity than other members of its class.
2. Its better absorption and slower exeretion by the body render blood levels that distinctly afford certain minor therapeutic advantages than other members of its class.
Demeclocycline Sesquihydrate It has mp 174-178°C (decomposes); and specific optical rotation [α]25D-258° (C = 0.5 in 0.1 N H2SO4).
3.9.5 Methacycline
Synonyms Metacycline, Bialatan; 6-Methylene-5-hydroxytetracycline.
Biological Source It is broad spectrum, semi-synthetic antibiotic related to tetracycline, which is obtained from Streptomyces rimosus.
Preparation It may be prepared by a chemical dehydration reaction from oxytetracycline; besides, it has a methylene function at C-6 position.
Chemical Structure Please refer to Section 3.9.
Characteristic Features
Methacycline Hydrochloride [C22H22N2O8.HCl] [Synonyms Adriamicina; Ciclobiotic;
Germiciclin; Metadomns; Metilenbiotic; Londomycin; Optimycin; Physiomycine; Rindex; Rondomycin]:
1. It is invariably obtained as crystals containing 0.5 mole water and 0.5 mole methanol; and also from a mixture of methanol + acetone + concentrated HCl + ether. It is a yellow crystalline
powder which decompose at ~ 205°C and has a bitter taste.
2. It has uvmax (methanol + 0.1 N HCl): 253, 345 nm (log e 4.37, 4.19).
3. It is found to be soluble in water; sparingly soluble in ethanol; and practically insoluble in chloroform and ether.
Uses
1. The utility of methacycline is particularly associated with good oral absorption.
2. It has a prolonged serum half-life.
3.9.6 Doxycycline
Synonyms Jenacylin; Supracyclin; Vibramycin.
Preparation Methacycline (i.e., 6-deoxy-6-demethyl-6-methylene-5-oxytetracycline) is either dissolved or suspended usually in an inert organic solvent, for instance: methanol and subjected to hydrogenation under the influence of catalytic quantities of noble metals, namely: Rhodium or Palladium to yield a mixture of the 6α-and 6β-methyl epimers. The desired epimer i.e., α-6-deoxy-5-hydroxytetracycline, is subsequently isolated by specific chromatographic methods (US Pat 3,200,149).
Chemical Structure Refer to Section 3.9.
Characteristic Features
Doxycycline Hydrochloride Hemiethanolate Hemihydrate [C22H25Cl N2O8.1/2C2H60.1/2H2O]
[Synonyms Doxycycline hyclate; Azudoxat; Diocimex; Doxatet; Doxychel hyclate; Duradoxal; Hydramycin; Paldomycin; Sigadoxin; Tetradox; Unacil; Vibramycin hyclate; Vibra-Tabs; Zadorin]:
1. It is obtained as light yellow, crystalline powder from ethanol + HCl; and gets charred without melting at ~ 201°C.
2. It has specific optical rotation [α]25D-110°C (C = 1 in 0.01 N methanolic HCl).
3. It has uvmax (0.01N methanolic HCl): 267, 351 nm (log ε 4.24, 4.12).
4. It is found to be soluble in water.
5. Both the inherant ethanol and water of crystallization (1/2 mol of each) are usually lost by subject to drying at 100°C under reduced pressure.
6. Its dissociation constant has three values, namely: pKa 3.4, 7.7, and 9.7 (see demeclocycline).
7. Solubility Profile: It is very slightly soluble in water; freely soluble in dilute acid or alkali hydroxide solution; sparingly soluble in ethanol; and practically insoluble in ether or chloroform.
Uses
1. The 6α-isomer of doxycycline is found to be more active biologically than the corresponding 6β-epimer hydrochloride.
2. It is active against Gram-positive organisms wherein it is almost twice as potent as tetracycline; and having an exception that it is virtually 10 times as potent against Streptomyces viridans.
3. Interestingly, strains of Enterococcus fecalis that are observed to be more resistant to other tetracyclines may prove to be sensitive to this drug.
4. Against Gram-negative organisms it is found to be twice as potent as tetracycline.
5. It is considered to be the drug of first choice for the prophylaxis of traveler’s diarrhea, commonly caused by enterotoxigenic E. coli.
6. It is found to be the best amongst the ‘tetracyclines’ against anaerobes.
7. It is absorbed almost completely i.e., 90 to 100% through oral administration than the rest of tetracyclines, and its absorption does not seem to be retarded by intake of foods.
8. Its plasma-protein binding is almost 93%.
9. Its volume of distribution stands at 0.75 mL g–1.
10. It is found to penetrate rapidly body fluids, cavities and cells.
11. It is invariably eliminated upto 65% through hepatic metabolism, and the balance 35% through biliary/renal exertion.
12. The rate of exertion is rather slow and the half-life is the longest among the ‘tetracyclines’, namely, 12 to 22 hr.
Note: 1. Photosensitization usually takes place more frequently as compared to other shorteracting tetracyclines.
2. Complexation with Ca2+ is to a lesser extent than other tetracyclines; besides, it is not affected by either dairy products or foods.
3.9.7 Minocycline
Synonyms Minocyn.
Biological Source It is a semi-synthetic antibiotic obtained from 6-demethyl tetracycline.
Preparation 6-Demethyl tetracycline is first dissolved in tetrahydrofuran (solvent) containing aliquot quantity of methanesulphonic acid, and is subsequently reacted with dibenzyl azodicarboxylate to form 7-[1, 2-bis (carbobenzoxy) hydrazino]-6-demethyl-tetracycline. The resulting-product is subjected to Pd-catalyzed hydrogenation in the presence of formaldehyde to yield the desired product minocycline.
Chemical Structure Refer to section 3.9.
Characteristic Features
1. It is obtained as bright yellow-orange amorphous solid.
2. Its specific optical rotation [α]25D-116° (C = 0.524).
3. It has uvmax (0.1N HCl): 352, 263nm (log ε 4.16, 4.23); (01 N NaOH) : 380, 243 nm (log ε 4.30; 4.38).
Uses
1. It is readily absorbed from the intestinal tract.
2. It has a slow renal clearance to afford prolonged blood levels; and is normally characterized by relatively lower MICs as compared to other tetracycline antibiotics for certain pathogenic organisms.
Minocycline Hydrochloride [C23H27N2O7.HCl] [Synonyms Klinomycin Minomycin; Veetrin]
Characteristic Features
1. It is obtained as yellow, crystalline powder, odourless, slightly bitter taste and slightly hygroscopic in nature.
2. It is fairly stable in air when protected from light and moisture; however, strong uv-light and/or moist air causes it to darken rather rapidly.
3. Its potency* in solution is primarily affected on account of epimerization.
4. The pH of 1 in 100 solution ranges between 3.5 to 4.5.
5. It distinctly gives rise to four dissociation constant values, namely: pKa12.8; pKa2 5; pKa3 7.8; and pKa4 9.3; mainly due to an additional dimethylamino moiety at e-7 position (compare with demeclocycline, Section 9.4).
--------------------------------------------------------
* Potency: It is equivalent to not less than 785 mcg of minocycline mg–1.

6. Solubility Profile: 1 g in nearly 60 mL water and ~ 70 mL alcohol; soluble in solutions of alkali hydroxides or carbonates; and almost insoluble in chloroform and ether.
Uses
1. Generally, it is found to be 2-4 times as potent as tetracycline against majority of Gram-positive bacteria.
2. It is found to exhibit an equally low-potency against Enterococcus fecalis.
3. It is almost 8 times as potent as tetracycline against Streptococcus viridans.
4. It is 2 to 4 times as potent as tetracycline against Gram-negative organisms.
5. It is now the drug of choice for treating infections caused by Mycobacterium marinum.
Note: It particularly differs from other tetracyclines wherein the bacterial resistance to the drug is not only of low incidence but also of a lower order; which is especially true to staphylococci, in which cross-resistance is observed to be as low as 4%.
6. It is absorbed by the oral route to the extent of 90-100%.
7. Diminution in absorption is caused exclusively by food and milk and substantially by iron preparations and nonsystemic antacids.
8. It is normally protein-bound in plasma between 70-75%.
9. Its ‘volume of distribution’* ranges between 0.14 to 0.7 mLg–1.
10. Its half-life varies between 11 to 17 hours.
3.9.8 Lymecycline
Synonyms Armyl; Ciclolysol; Mucomycin; Tetralisal; Tetramyl; Tetralysal; N-Lysinomethyl tetracycline.
Biological Source It is a semi-synthetic antibiotic related to tetracycline. It is a classic example of an antibiotic developed by qualified chemical modification of the primary amide function at C-2.
Preparation It may be prepared by the method suggested by Tubaro and Raffaldoni.**
Chemical Structure Refer to Section 3.9.
Characteristic Features
Lymecycline Sodium [C29H37N4NaO10]: It has uvmax (CH3OH): 376 nm. It is used as a potent antibacterial agent.
3.9.9 Biosynthesis of Chlortetracycline
The various steps involved in the biosynthesis of chlortetracycline are as stated below:
1. A malonamyl-CoA residue probably caters for as a ‘primer’; and eight such malonate entities undergo stepwise condensations with the addition of C2units and followed by decarboxylation to yield a linear C19 polyketide.
2. Subsequently, the carbonyl-methylene condensations give rise to the tetracyclic pretetramide nucleus.
--------------------------------------------------------
* Volume of Distribution It is pharmacokinetic parameter representing a proportionality constant that relates drug
concentration in a reference fluid, typically plasma, to the amount of drug distributed throughout the body.
** Tubaro and Raffaldoni, Bull. Chim. Farm., 100, 9 (1961).

3. Importantly, methylation at the C-6 position of the pretetramide is normally regarded an initial step in the biosynthesis of most tetracyclines; however, this particular step is usually left out in the creation of the naturally occurring dimethyl tetracyclines.
4. Hydroxylation at the C-4 position followed by dearomatization to produce a 4-keto intermediate appears to precede 7-chlorination.
5. It is necessary that halogenation should precede introduction of the 4-amino group, which is methylated in a stepwise manner.
6. Terminal reactions in the biosynthetic sequence are carried out in two stages: first, hydroxylation at C-6 position; and secondly, reduction of double bond in ring B.
7. It is, however, interesting to absence that the presence of a 7-halogen substituent evidently blocks 5-hydroxylation.
The various steps involved in the biosynthesis of chlortetracycline may be summarized as given below:
biosynthesis of chlortetracycline

Sunday, May 12, 2013

Polypeptide Antibiotics

8:34 AM by Unknown

3.8 Polypeptide Antibiotics


Interestingly, a plethora of polypeptides of bacterial origin that are found to comprise of D- and L-amino acids, do exert a marked and pronounced antibiotic activity. It is, however, pertinent to mention here that these specific antibiotics have two inherent major anomalies, namely: first, very poor absorption from the intestinal tract; and secondly, possess high degree of nephrotoxicity* when used systemically. Generally, the polypeptide antibiotics exert a predominantly Gram-positive spectrum; however, there are a few-exceptions that are solely active against Gram-negative organisms, such as: the strongly basic polymyxins.
It has been observed that these polypeptide antibiotics have a tendency to occur as mixtures of very close structurally related compounds. Nevertheless, the exact composition of commercial mixtures depend to a great extent upon the skilful usage of selected strains of producing organisms.
Besides, a precise and reliable strength of therapeutic response against certain susceptible organisms is exclusively based on the quantitative microbial assay.
The various important members of ‘polypeptide antibiotics’ are, namely: cycloserine; polymyxin-B; colistin (polymixin-E), bacitrasin; vanomycin; and teichoplanin, which shall now be treated separately as under:
3.8.1 Cycloserine
Synonyms Closina; Farmiserina; Micoserina; Orientomycin; Oxamycin; Seromycin; PA-94.
Biological Sources It is a polypeptide antibiotic substance produced by Streptomyces garyphalus sive orchidaceus.**
Preparation It may also be synthesized by the method of Stammer et al.***
Chemical Structure
Cycloserine
D-4-Amino-3-isoxazolidinone; C3H6N2O2.
Characteristic Features
1. It is obtained as crystals that decompose at 155-156°C.
2. Its specific optical rotations are: [α]D23 + 116° (C = 1.17); [α]25546 + 137° (C = 5 in 2N NaOH).
3. It has uvmax : 226 nm (E1%1cm 402).
4. Its aqueous solutions have a pH 6.
5. It is fairly soluble in water; and slightly soluble in methanol and propylene glycol.
6. It is found to form salts readily with acids and bases.
7. Its aqueous solutions buffered to pH 10 with Na2CO3 may be stored without any loss of activity upto a duration of one week between 0-10°C (i.e., at refrigerated temperatures).
Uses
1. It exhibits a fairly broad spectrum of activity; however, its therapeutic efficacy is exclusively associated with its inherent inhibitory effect on Mycobacterium tuberculosis.
2. It precisely inhibits alanine racemase, which action precludes the incorporation of D-alanine strategically into the pentapeptide side-chain of the specific murein* component of bacterial cell walls. Perhaps this unique features is solely responsible for its antibiotic activity.
3. It is invariably regarded as an ‘antibiotic of second choice’; and is frequently used in conjunction with isoniazid in the control, management and treatment of tuberculosis who usually fail to respond to the first-line agents.**
4. It is readily absorbed orally and is subsequently exerted quickly through the kidneys (i.e., newly 50% without any metabolic alteration whatsoever).

------------------------------------------------------
* A toxic substance that causes damage to kidney tissues.
** Kuehl, Jr. et al. J. Am. Chem. Soc., 77, 2344, (1955).
*** Stammer et al. J. Am. Chem. Soc., 77, 2346, (1955).

3.8.2 Polymixin B
Polymyxins represent a group of cycle polypeptide antibiotics produced by various species of Bacillus. However, polymyxins A to E were primarily isolated from Bacillus polymyxa. Subsequently, it was shown that both polymyxin B and polymycin E (or colistin) were mixtures of two components each. The structures of polymyxin B1 and polymyxin B2; and polymyxin E1 (colistin A) and polymyxin E2 (colistin B) are as given below:
Polymixin
Actually, these molecules essentially contain ten amino acids, of which six happen to be L-α-, γ-diaminobutyric acid (L-Dab), having a fatty acid*** strategically bonded to the N-terminus; besides, a cyclic peptide portion meticulously designed via an amide bond located in between the γ-amino of one of the Dab-residues and the carboxyl terminus. Interestingly, the γ-amino functions
of the remaining Dab residues distinctly attribute a rather strong basic property to the various
antibiotics. This particular characteristic feature confers detergent-like properties and perhaps permits
them to either get bound or cause damage to bacterial membranes.
Characteristic Features
Polymyxin Hydrochloride
1. It is obtained as nearly colourless powder that gets decomposed at 228-230°.
2. It has specific optical rotation [α]D23-40° (C = 1.05).
3. It is very soluble (> 40%) in water and methanol; the solubility decreases considerably in higher alcohols; and almost insoluble in ethers, esters, ketones, hydrocarbons and the chlorinated solvents.
4. It usually gives rise to water insoluble salts with the help of a host of precipitants, such as: helianthic acid (C7H9O4) picric acid; and Reinacke salt.
picric acid; and Reinacke salt
Polymyxin B: It is a mixture of Polymyxins B1 and B2. The mixture also contains minimal amounts of the more toxic polymyxins A, C and D. Both polymyxins B1 and B2 essentially possess a cyclopeptidic structure and comprise of six residues of α, γ-diaminodutyric acid (DABs). However, the latter characteristic feature affords an exceptionally strong basic property to the polymixin antibiotics.
It has specific optical rotation [α]5461-106.3° (1N. HCl).
Uses
1. It is used topically in ointments (usually 5000 or 10,000 Units/g) and ophthalmic solutions (10,000 Units/ml).
2. It was employed formerly for control, management and treatment of infections of the intestinal tract caused by Shigella, Pseudomonas aeruginosa, and E. coli.
Polymyxin B Sulphate [Synonyms Aerosporin; Mastimyxin;]: It is the sulphate salt of a substance produced by the growth of Bacillus polymyxa (Prazmowski) Mignla belonging to the natural order Bacillaceae. It has a potency of not less than 600 Units of polymyxin B. mg–1, calculated on the anhydrous basis.
Preparation The filtered broth obtained from the fermentation process (section 3.7) is eventually treated with a ‘certified dye’, and the resulting polymyxin B-dye salt complex thus precipitated is collected by means of filtration, washed with water and finally treated with an alcoholic solution of a lower aliphatic amine sulphate. The polymyxin B sulphate thus produced is filtered off and subsequently purified and lypholized. Polymyxin B is a mixture of polymyxin B1 (C56H98N16O13),and polymyxin B2 (C55H96N16O13) the only vital point of difference is nothing but the composition of the N-acyl moiety (see Section 3.8.2).
Characteristic Features
1. It is a white to buff-coloured powder; either odourless or having a very faint odour.
2. It has dissociation constant pKa 8 to 9.
3. Its solutions are either slightly acidic or are neutral to litmus (pH 5 to 7.5).
4. It is found to be freely soluble in water; and slightly soluble in alcohol.
Uses
1. The antimicrobial spectrum of activity of polymyxin B sulphate for its in vitro and in vivo profile is solely restricted to Gram-negative organisms, namely: Aerobacter, Escherichia, Haemophilus, Klebsiella, Pasteurella, Pseudomonas, Salmonella, Shigella, most Vibrio and Yesinia; all strains of Pr. providencia and most of Serratio marceseens are found to be unaffected by this antibiotic.
2. It is used topically either for the treatment or the prevention and treatment of external ocular infections caused by susceptible microorganisms, especially Ps aeruginosa.
3. In topical therapy, it is invariably combined with neomycin, gramicidin and bacitracin.
4. It also forms an integral component in glucocorticoid ophthalmological topical preparations.
Note: Substances like soap, which is a triglyceride of fatty, acids, and hence specifically antagonize cationic surface-active agents, is found to impair the activity of the antibiotic.
Polymyxin B Sulphate mixture with Trimethoprim [Synonyms Polytrim]: The combination of polymyxin B sulphate with trimethoprim enhances the overall antibacterial profile rather than each one used alone.
Polymycin B1 [C56H98N16O13]
Polymyxin B1 Pentahydrochloride [C56H98N16O13.5HCl]: It is obtained as a white powder. It has specific optical rotation [α]D25-85.11° (C = 2.33 in 75% ethanol).
Polymycin B2 [C55H96N16O13]: It has specific optical rotation [a]225461-112.4° (2% acetic acid).


---------------------------------------
* Murien: Chloride (Cl–).
** Rifampin and Rifabutin.
*** 6-Methyloctanoic acid; or 6-Methylheptanoic acid.

3.8.3 Colistin
Synonyms Polymyxin E; Colimycin; Coly-Mycin; Colisticina; Totazina.
Biological Source It is a cyclopolypeptide antibiotic produced by Bacillus colistinus (Aerobacillus colistinus) first isolated from Japansese soil). It is comprised of colistins A, B and C.*
colistins A, B
DAB = α,β-diamobutyric acid
Polymyxin E1(Colistin A)       :  R = (+)-6-Methyloctanoyl
Polymyxin E2                                              :   R = 6-Methylheptanoyl
Uses This antibiotic has more or less the same spectrum and therapeutic application as that of polymyxin B.
Colistin Sodium Methanesulphonate [C58H105N16Na5O28S5] [Synonyms Colistimethate sodium; Alficetin; Methacolimycin]: It is the injectable form of colistin. It is soluble in water and fairly stable in the dry form. It is inactive in itself but releases active polymyxin in the body.
Colistin Sulphate [Synonyms Malimyxin; Multimycine]: It is mostly used either orally or topically.
Colistin Formaldehyde-Sodium Bisulphite*: It is obtained as crystals that decompose between 290-295°. It is found to be soluble in water; and slightly soluble in methanol, ethanol, acetone and ether.
Polymyxin E1 [C53H100N16O13] [Synonym Colistin A]: It has specific optical rotation [α]225461-93.3° (2% acetic acid).
Polymyxin E2 [C52H98N16O13]: It has specific optical rotation is [α]225461-94.5° (2% acetic acid).
Note: The use of methacolimycin nowadays is rarely justified on account of the availability of less toxic alternative antibiotics.

---------------------------------------
* Suzuki et al., J. Biodiem. (Tokyo), 54, 25 (1963).

3.8.4 Bacitracin
Synonyms Altracin; Ayfivin; Fortracin; Penitracin; Topitracin; Zutracin.
Biological Source It is a polypeptide antibiotic complex produced by Bacillus subtilis and licheniformis (family: Bacillaceae).** The commercial bacitracin is found to be a mixture of at least nine bacitracins. The purification of bacitracin may be affected by ‘carrier displacement method’.
Chemical Structure The major component of the mixture is ‘Bacitracin A’, which is essentially a dodecylpeptide having five of its amino-acid-residues arranged strategically in a cyclic structure as shown below:
Bacitracin A
Characteristic Features
1. It is obtained as a Grayish-white powder having a very bitter taste, odourless and hygroscopic in nature.
2. It is found to be soluble in water and ethanol; and almost insoluble in ether, chloroform, and acetone.
3. It is fairly stable in acid solution and unstable in alkaline solutions.
4. It affords a loss in potency most probably on account of the transformation of bacitracin A to bacitracin F, and the latter does not have any antimicrobial activity.
5. Its solutions undergo rapid deterioration at room temperature, and ultimately affords precipitation.
6. Its activity is significantly negated by salts of many of the heavy metals.
7. Its aqueous solutions invariably retain their potency for several weeks when stored in a refrigerator.
Uses
1. It is found to be effective exclusively against Gram-negative organisms.
2. Its applications are more or less limited to such infections only which may be treated either by topical application or by local infiltration.
3. It is significantly effective topically in the control, management and treatment of the following cutaneous bacterial infections where the pathogenic organism is specifically bacitracin-sensitive, such as: impetigo-contagiosa; falliculitis; pyoderma; ecthyma; furunculosis; decubitus, ulcer; infectious eczematoid dermatitis; scabies and dermatophytosis.
4. Bacitracin also finds its applications in the treatment of various ophthalmological conditions.
5. Its zinc salt invariably is preferred for topical therapy; and is the form most often incorporated into combinations.
6. It is mostly combined with neomycin and polymyxin B sulphate.
Note: 1. Due to the relatively high incidence of nephrotoxicity (albuminuria, cylindruria, azotemia, accumulation of drug) which essentially follows its parenteral administration precludes systemic usage except in life-endangering staphylococcal infections, such as: pneumonia, empyema, particularly in infants wherein other antibiotics have proved to be either ineffective or in the treatment of antibioticassociated (pseudomembranous)-enterocolitis caused by Cl difficile.
2. Development of bacterial resistance is much less frequent and slower for bacitracin as compared to penicillin, and for most organisms it is found to be almost nil.
-----------------------------------
* Koyama et al. Japan. pat. 57, 4898 (1957).
** Anker et al. J. Bacteriol. 55, 249 (1948).

3.8.5 Vancomycin
Synonyms Vancocin; Vncoled; Lyphocin (Lyphomed).
Biological Source It is an amphoteric glycopeptide antibiotic substance produced by Streptomyces orientalis (Family: Streptomycetaceae) from Indonesian and Indian soil that essentially inhibits bacterial nucleopeptide biosynthesis by formation of complexes.
Chemical Structure The structure of the primary component of the mixture has been established beyond any reasonable doubt to be a complex tricyclic aglycone linked glycosidically to glucose and vincosamine functions. The vancomycin molecule essentially contains one free carboxylic acid moiety, two chloro substituted aromatic residues, and seven amide bonds, one of which is a prominent primary-amide.
The apparently novel feature of vancomycin is the tricyclic structure exclusively generated by three phenolic oxidative coupling reactions.
vancomycin
Preparation It is produced by the submerged fermentation process as described earlier under penicillins.
Characteristic Features
Vancomycin Monohydrochloride [C66H75Cl2N9O24.HCl] [Synonyms Lyphocin; Vancor;]:
1. It is obtained as white solid, free-flowing powder, odourless and having a bitter-taste.
2. It has uvmax (H2O): 282 nm (E1%1cm 40).
3. Its solubility in water is more than 100 mg. ml–1.
4. It is found to be moderately soluble in dilute methanol; and insoluble in the higher alcohols, acetone and ether.
5. Its solubility in neutral aqueous solutions is enhanced by low concentrations of urea.
6. The acidic solutions precipitate out the antibiotic on addition of either NaCl or (NH4)2 SO4.
Uses
1. It has a Gram-positive antibacterial spectrum.
2. It specifically acts on bacterial cell walls by inhibiting murein biosynthesis by virtue of its complexation with the D-alanyl-D-alanine precursor and hence is bactericidal, which eventually renders it particularly useful in serious infections besides in the immunocompromised patients.
3. It also exerts to a certain extent the ‘secondary modes of action’ i.e., enhancing cytoplasmic membrane permeability and impairing RNA synthesis.
4. Vancomycin hydrochloride is widely recommended for the control, management and treatment of serious infections, such as: septicemia, endocarditis, wound infections caused by Gram-positive bacteria, specifically in those patients who are allergic to β-lactam antibiotics.
5. Vancomycin HCl is also found to be effective in Enterococcus faecalis strains that are inadequately controlled and managed by β-lactam antibiotics.
6. Vancomycin is not absorbed orally; however, oral administration is usually recommended for the treatment of staphylococcal-enterocolitis and antibiotic-associated pseudomembranous colitis produced by Clostridium difficile.
7. IM administration is rather painful and very often associated with local necrosis; therefore, systemic therapy with vancomycin makes use of IV-infusion extended over a span of 20 to 30 minutes.
Note:
 (i) It is irritating to tissue and hence may cause thrombophlebitis, or pain at the site of injection and neurosis takes place if extravasted; also produces chills, fever, occasional urticaria and maculopapular rashes with hypotension (Red Man’s Syndrome), nephrotoxicity and ototoxicity and, rarely, thrombocytopenia and neuropathy.
(ii) Recently, the plasmid-mediated resistant strains of enterococcus have virtually clamped restriction for the use of vancomycin in hospitals with a view to control the spread of resistance.
3.8.6 Teicoplanin
Synonyms Tiecoplanin A2; Teichomycin A2; Targocid; Targosid; MDL-507.
Biological Source It is a glycopeptide antibiotic complex produced by Actinoplanes teichomyceticus nov. sp.; structurally related to vancomycin and comprised of a mixture of five teicoplanins, which essentially differ only in the nature and length of the fatty acid-chain attached to the sugar residue.
Characteristic Features
1. It is obtained as an amorphous powder having mp 260°C (decomposes).
2. It has uvmax in 0.1 N HCl 278 (E1%1cm 53); and in 0.1 N NaOH: 297 (E1%1cm 74).
3. It is found to be soluble in aqueous solution at pH 7.0; partially soluble in methanol, ethanol; and insoluble in dilute mineral acids, and also in non-polar organic solvents.
The various physical parameters of the five major components of teicoplanin are as follows:
(i) Teicoplanin A2-1: (C88H95Cl2N9O33): It is a white amorphous powder which darkens at 220°C and decomposes at 255°C.
(ii) Teicoplanin A2-2: (C88H97Cl2N9O33): It is a white amorphous powder, darkens at 210°C and gets decomposed at 250°C.
(iii) Teicoplanin A2-3: (C88H97Cl2N9O33): It is a white amorphous powder, darkens at 210°C and decomposed at 250°C.
(iv) Teicoplanin A2-4: (C88H99Cl2N9O33): It is a white amorphous powder, darkens at 210°C and gets decomposed at 250°C.
(v) Teicoplanin A2-5: (C89H99Cl2N9O33): It is a white amorphous powder, darkens at 210°C and gets decomposed at 250°C.
Uses
1. Teicoplanin has almost similar antibacterial profile to vancomycin (Section 9.3.8.5), but possesses a longer duration of action, and may be administered by IM as well as IV injection.
2. It is also employed against Gram-positive pathogens that are resistant to established antibiotics.
3. The ‘Red-Neck Syndrome’ as observed upon rapid administration of vancomycin is rarely seen, besides the incidence of autoxicity also seems to be reduced considerably.

Thursday, May 9, 2013

Penicillins antibiotic

1:15 AM by Unknown

3.7 Penicillins

Alexander Fleming observed in 1928 during the course of examination of certain culture plates in the laboratory of St. Mary’s Hospital, London, that the lysis of the staphylococcus organisms takes place by a contaminating mold. Subsequently, the mold was subcultured in a sterile broth under aseptic condition; and it was revealed that it resulted into a powerful, nontoxic antibacterial product.
Fleming baptized this substance as ‘penicillin’ based on its parent organism Penicillium notatum that eventually paved the way for the creation of the so called ‘generation of the antibiotic’—a historic remarkable landmark in the field of medicine derived from the natural products. ‘Penicillin’ categorically symbolizes a host of vital and significantly prominent antibiotic substances produced by the growth of different Penicillium species or by various semi-synthetic or synthetic means.
In general, the penicillins are nomenclatured in the literature invariably as the derivatives of:
(a) (2S-cis) -4-thia-1-azabicyclo-(3, 2, 0) heptane-2-carboxylic acid [I]; (b) 3, 3-dimethyl-7-oxoderivative of [I] and also known by its trivial name penicillanic acid [II]; and (c) α-carboxamido derivative of it [III], here only the ‘R’ of the α-carboxamido moiety is identified ultimately, as depicted below:
penicillanic acid [II]
In actual practice, one comes across three different types of penicillins, such as:
(a) Biosynthetic Penicillins: These are usually accomplished by the introduction of various acids, amines or amides directly incorporated into the medium in which the mold is being developed thereby leading to the ultimate production of a spectrum of biosynthetic penicillins which essentially differ only in ‘R’ in III. By adopting this unique well-developed and articulated process dozens of biosynthetic penicillins have been prepared with a view to obtain newer molecules that have an edge over penicillin G with regard to various physical parameters, microbiological or pharmacological characteristics.
It is pertinent to mention here that in 1958 an altogether new dimension was added to update and boost up the on-going development of penicillins. Methods were devised for modifying the very ‘penicillin nucleus’ thereby making it feasible to biosynthesize penicillins which earlier could note be accomplished in a just normal medium. The concerted efforts made by the researchers resulted into the formation of plethora of altogether new series of medicinally potent substances that were often found to be more acid-stable, more-penicillinase resistant or had a wider antibacterial spectrum.
(b) Commercial Penicillins: In fact, a major portion of the commercial penicillin is pure crystalline penicillin G. It is invariably obtained in the fermentation liquors along with variable quantities of penicillin K and F and relatively smaller amount of others. However, penicillin G is eventually separated from the other congeners during the process of purification. Nevertheless, the commercial process of producing penicillins is observed to suppress, to some extent, the inherent natural tendency of the mold to give rise to penicillins other than the desired penicillin G by the introduction of a precursor of G, such as: phenylacetic acid, phenylacetamide, phenylethylamine or such other chemical entities containing the ‘phenylacetyl’ radical, that is incorporated directly into the penicillin G molecule. It is worth while to state here that penicillin G enjoys the additional advantage of being crystallized out more easily than K or F.
(c) Salts of Penicillins: From the figures I, and II and III it is quite evident that penicillin are acids. The potassium salt is more prevalent and hence predominates in actual usage, with the sodium salt next. The inherent acidic moiety may be exploited skillfully and judiciously to combine penicillinswith various bases, namely: procaine, benzathine, to design and evolve rather insoluble salts, for repository application, or for the objective of minimising solubility so as to render the substance more resistant to gastric acid in the stomach.
3.7.1 Classification and Spectrum
Initially, penicillins were classified either on the basis of pseudohistorical categories, or according to various numbered “generation”, very much identical to the classification of the ‘cephalosporins’ (section 3.3). In fact, it is rather more convenient and beneficial as well to classify them according to a well-defined chemical and antimicrobial designations, namely:
(i) Natural Penicillins (best streptococcal and narrow spectrum)
(ii) Penicillinase-resistant Penicillins (antistaphylococcal)
(iii) Aminopenicillins (improved Gram-negative: H. influenzae, Enterococcus, Shigella, Salmonella)
(iv) Extended-spectrum (antipseudomonal) penicillins
(v) Beta Lactamase Combinations (expand spectrum to staph, beta-lactamase producers)
It will be worthwhile to treat a few important penicillin drugs individually from each category in the sections that follow:
3.7.1.1 Natural Penicillins
A. Penicillin G Potassium
Synonyms Crystapen; Cosmopen; Eskacillin; Forpen; Hylenta; Hyasorb; Monopen; Notaral; Pentid.
Preparation It is prepared by the interaction of 6-amino-penicillanic acid and phenyl acetyl chloride in an inert organic solvent.
Chemical Structure Please refer to section 3.7.1.
Characteristic Features
1. It is obtained as colourless or white crystals, or a white crystalline powder, odourless or practically so; moderately hygroscopic and gets decomposed between 214-217°C.
2. Humidity and moisture accelerates decomposition.
3. It has specific optical rotation [α]D22 + 285-310° (C = 0.7).
4. It is not appreciably affected either by air or by light.
5. The solutions usually deteriorate at room temperature, but solutions stored lower than 15°C remain stable for several days.
6. It gets rapidly inactivated by acids and alkalies, and also by oxidizing agents.
7. The pH (aqueous solution 30 mg.mL–1) 5 and 7.5.
8. The dissociation constant pKa (acid) 2.8.
9. Solubility Profile: It is found to be very soluble in water, saline TS or dextrose solutions; soluble in ethanol (but is inactivated by this solvent), glycerol and several other alcohols.
10. Penicillin G Potassium 1 mg ≡ 1595 U.S.P. Penicillin Unit or International Unit (IU).
Uses
1. It is still recommended as an important and useful drug for the treatment of many Gram-positive organisms, such as streptococci, pneumococci, gonococci, and meningococci infections.
2. It is mostly destroyed by gastric juice and is, therefore, not given by oral route, and is best administered as IM or IV injection.
3. The K-salt as such has no advantage over the corresponding Na-salt except when high doses are used in patients on sodium restriction e.g., blood-pressure patients.
4. The K-salt also avoids the incidence of hypokalemic alkalosis which occasionally takes place during prolonged treatment with high doses of penicillins.
5. The half-life ranges between 0.5 to 0.7 hour; except 2.5 to 10 hour in renal failure or after probenecid.

Penicillins
Penicillins
Penicillins
Penicillins
(Abstracted from: Remington-The Science and Practice of Pharmacy Vol. II., 20th edn., 2000)

B. Penicillin V
Synonyms Acipen-V; Distaquaine V; Fenospen; Meropenin; Oracilline; Oratren; V-Cillin.
Biological Source It is obtained by the addition of phenoxyacetic acid to the Penicillium chrysogenum culture using yeast autolyzate as a source of nitrogen, as shown below:
Penicillins V
Chemical Structure Please refer to Section 3.7.1.
Characteristic Features
1. It is obtained as crystals that get decomposed between 120-128°.
2. It is found to be failry stable in air upto 37°C.
3. It is relatively stable to acid.
4. It has uvmax: 268, 274 nm (ε 1330, 1100).
5. Solubility Profile It is found to be soluble in water at pH 1.8 (acidified with HCl) = 25 mg/ 100 ml; soluble in polar organic solvents; and almost insoluble in vegetable oils and in liquid petrolatum.
Uses
1. Phenoxymethylpenicillin (Penicillin V) enjoys the greatest advantage of being recognized as ‘acid-resistant, which is solely due to the introduction of an electron-withdrawing heteroatom (i.e., O-atom of phenoxy-moiety) into the side-chain.
2. It is, therefore, suitable for oral administration.
3. It is specifically recommended for respiratory tract infections and tonsilitis.
Penicillin V Potassium Salt [C16H17KN2O5S] [Synonyms Antibiocin; Apsin VK; Arcacin; Beromycin; Betapen VK; Calciopen; Cliacil; Compocillin VK; Distakaps V-K; Dowpen VK; Fenoxypen; Ledercillin VK; Penavlon V; Pen-Oral; Stabicilline; Uticillin VK; Vepen; Suspen]
It is soluble in water; and has specific optical rotation [α]D25+ 223° (C = 0.2).
Uses It exhibits an antibacterial spectrum very identical to that of penicillin G against Grampositive bacteria but this is less potent and effective against Gram-negative bacteria. Its biological half-life is about 0.5 to 1 hour.
3.7.1.2 Penicillinase-resistant Penicillins
A. Cloxacillin
Biological Source Cloxacillin is a semi-synthetic antibiotic related to penicillin; and is the chlorinated derivative of oxacilline which contains an isoxazole group.
Preparation 6-APA is acylated with 3-(o-chlorophenyl)-5-methyl-4-isoxazolecarboxylic acid. The resulting cloxacillin is subsequently purified by recrystallization.
Chemical Structure Please refer to section 3.7.1.
Characteristic Features
Cloxacillin Sodium Monohydrate: [C19H17ClN3NaO5S.H2O] [Synonyms Bactopen; Cloxapen; Cloxypen; Gelstaph; Orbenin; Methocillin-S; Prostaphlin-A; Staphybiotic; Tegopen]
1. It is obtained as a white, odourless crystalline powder having a bitter taste and decompose at 170°C.
2. It is stable in light; and is slightly hygroscopic in nature.
3. It has specific optical rotation [α]D20 + 163° (C = 1 in water).
4. The pH of 1% aqueous solution is 6.0-7.5.
5. Its dissociation constant pKa (COOH) is 2.7.
6. It is found to be soluble in water, methanol, ethanol, pyridine and ethylene glycol; and slightly soluble in chloroform.
Uses
1. It is penicillinase-resistant penicillin (antistaphylococcal) which is administered orally.
2. It is a first-choice agent against penicillin-resistant Staphylococcus aureus.
B. Nafcillin
Biological Source It is a semi-synthetic antibiotic related to penicillin bearing essentially a maphthamido moiety.
Preparation 6-APA is first acylated by treatment with 2-ethoxy-1-naphthoyl chloride in an anhydrous organic solvent containing triethylamine. An aqueous extract of this product is admixed with a water-immiscible solvent and nafcillin is precipitated by the addition of H2SO4. The crude product may be recrystallized from chloroform.
Chemical Structure Please refer to Section 3.7.1.
Characteristic Features
Nafcillin Sodium [C21H21N2NaO5S]: [Synonyms Nafcil; Naftopen; Unipen]
1. It is obtained as white to yellowish white powder having not more than a slight characteristic odour.
2. It is freely soluble in water or chloroform; and soluble in alcohol.
Uses
1. It is considered as a preferred drug given through IV for staphylococci.
2. It is a penicillinase-resistant penicillin, the use of which is restricted to the treatment of infections caused by penicillinase-producing cocci (mostly staphylococci).
Note: After oral administration serum levels are low and invariably unpredictable, hence the oral route is not recommended.
3.7.1.3 Aminopenicillins
A. Amoxicillin
Synonyms Amoxycillin; Amocilline; Amolin; Amopenixin; Amoram; Amoxipen; Anemolin; Aspenil; Betamox; Cabermox; Delacillin; Efpenix; Grinsil; Helvamox; Optium; Ospamox; Pasetocin; Penamox; Penimox; Piramox; Sawacillin; Sumox.
Biological Source It is a semi-synthetic antibiotic related to penicillin with side-chain containing a basic amino moiety.
Preparation It may be prepared by carrying out the acylation of 6-aminopenicillanic acid with D-(-)-2-(p-hydroxyphenyl) glycine.
Chemical Structure Please refer to Section 3.7.1.
It is usually obtained as its trihydrate product.
Characteristic Features
Amoxicillin Trihydrate [C16H19N3O5S.3H2O]: [Synonyms Alfamox; Almodan; Amoxidin;
Amoxypen; Clamoxyl; Cuxacillin; Flemoxin; Ibiamox; Moxaline; Polymox; Robamox; Sigamopen; Silamox; Trimox; Utimox; Zamocillin].
1. It is obtained as fine, white to off-white, crystalline powder, bitter taste.
2. Exposure to high humidity and temperature beyond 37°C adversely affect the stability of amoxicillin.
3. It has specific optical rotation [α]D20 + 246° (C = 0.1).
4. It has uvmax (ethanol): 230, 274 nm (ε 10850, 1400); (0.1N HCl) : 229, 272 nm (ε 9500, 1080); (0.1N KOH): 248, 291 (ε 2200, 3000).
5. Solubility Profile: In mg . ml–1: water 4.0; methanol 7.5; absolute ethanol 3.4. It is found to be insoluble in hexane, benzene, ethyl acetate and acetonitrile.
Uses
1. Its antibacterial spectrum is very much similar to that of Ampicillin, except that its activity is less against Streptococcus; N. meningitidis; Clostridium; Salmonella; and Shigella.
2. It is found to be more acid stable than ampicillin and absorption is not affected appreciably by food intake.
3. It is the drug of choice for various infections caused by Enterococcus faecalis (enterococcus) Branhamella catarrhalis or Bacteroides fragilis (mild to moderate infections).
4. It is an alternate drug for infections by penicillinase-producing Staphylococcus (combined with clavulanic acid), N. gonorrhoeae (with probenecid), E. coli (with clavulanic acid) or Pasteurella multicida (with clavulanic acid).
Note: It cannot be given parenterally in conditions with severe infections.
B. Ampicillin
Synonyms Albipen; Amfipen; Ampipenin; Bonapicillin; Britacil; Doktacillin; Domicillin, Dumopen; Nuvapen; Omnipen; Penicline; Tokiocillin
Biological Source It is orally active, semi-synthetic antibiotic which is structurally related to penicilline i.e., penicillin with side-chain having a basic amino function.
Preparation The outline of the synthesis is that 6-APA is appropriately acylated with D-glycine under specific experimental parameters. Kajfez et. al., in 1976 put forward an alternate method of synthesis.*
Chemical Structure Please see Section 3.7.1. It is mostly obtained as its trihydrate product.
Characteristic Features
1. It is obtained as crystals that get decomposed between 199–202°C.
2. It has specific optical rotation [α]D23 + 287.9° (C = 1 in water).
3. It is found to be sparingly soluble in water.
Uses
1. It is the first aminopenicillin antibiotic which exhibits its in vitro spectrum against Grampositive cocci very much similar to but usually somewhat less effective than that of penicillin G, with an exception that it is somewhat effective against Enterococcus faecalis (enterococcus).
2. It is 1/20 as effective against Streptococcus pyogenes.
3. It is the drug of choice for treatment of infections due to sensitive strains of Strep Group B, Enterococcus faecalis (combined with gentamycin); Listeria monocytogenes (with or without gentamycin); E. coli (with or without gentamycin); and Prot mirabilis, and Salmonella (not typhi).
4. It is employed invariably as an alternative drug against Kl pneumoniae (with sulbactam), indolepositive Proteus (M. morganii, Pr vulgaris and Providencia rettegri; with sulbactam), Salmonella typhi, Shigella, Gardnerella vaginalis, H. influenzae (serious infections; initially combined with chloramphenicol) or Nocardia.
Note: 1. A good number of these organisms rapidly acquire resistance by elaboration of penicillinase, hence it is invariably administered in combination with sublactam.
2. It causes allergic reactions typical of other penicillins and is found to be five-times as allergenic as penicillin G.
Ampicillin Sodium [C16H18Na3O4S] [Synonyms Alpen-N; Amcill-S; Ampicin; Cilleral; Omnipen-N; Penbritin-S; Pentrex; Polycillin-N; Synpenin; Viccillin.]
Preparation It is prepared by first dissolving ampicillin in a suitable organic solvent, and secondly by precipitating it as its sodium salt by the addition of sodium accetate.
Characteristic Features
1. It is obtained as white to off-white, crystalline powder, hygroscopic in nature; the L(+) form decomposes at about 205°C.
2. Its dissociation constants are pKa1 2.66; pKa2 7.24.
3. L(+) form has specific optical rotation [α]D20 + 209° (C = 0.2 in water).
4. It is found to be very soluble in water, isotonic NaCl or dextrose solutions.
5. It has been observed that L(+) form is less active as an antibiotic than the corresponding D(–) isomer.
Uses It is employed for IM or IV administration; and its actions and uses are similar to Ampicillin.
---------------------------------------------
* F. Kajfez et al., J. Heterocycl. Chem., 13, 561, (1976)

C. Bacampicillin
Biological Source It is a semi-synthetic antibiotic related to penicillin. It is an acyloxymethyl ester through the thiazolidine carboxyl moiety (i.e., a ‘prodrug’), and is duly hydrolyzed to ampicillinby esterases in the gut.
Chemical Structure Please refer to Section 3.7.1.
Characteristic Features
Bacampicillin Hydrochloride [C21H27N3O7S.HCl]: [Synonyms Ambacamp; Ambaxin; Bacacil; Bacampicine; Spectrabid.]
1. It is obtained as white crystals from a mixture of acetone and petroleum ether having mp 171-176°C. (decomposes).
2. It has specific optical rotation [α]D20 + 161.5°; and also reported as + 173° (Bodin).
3. The pH of a 2% (w/v) aqueous solution ranges between 3 to 4.5.
4. Solubility Profile: It is found to be soluble 1g in 15ml. water, 7ml. alcohol and 10 ml. chloroform.
Uses
1. It is an oral prodrug converted to ampicillin in vivo.
2. It is an improved version of aminopenicillin with modified and enhanced Gram-negative activity against H. influenzae, Enterococcus, Shigella and Salmonella.
3.7.1.4 Extended-Spectrum Penicillins The various typical examples of extended-spectrum(antipseudomonal) penicillins are carbenicillin and ticarcillin wherein the penicillins contain an additional-COOH moiety in the side-chain and their overall activity is certainly broad-spectrum.
Another type of extended-spectrum penicillins essentially include the acylureido penicillins, namely: Mezlocillin and Piperacillin, which are found to be much more active against Pseudomonas aeruginosa together with other Gram-negative organisms, such as: Klebsiella pneumoniae andHaemophilus influenzae.
These aforesaid antibiotics shall now be discussed in the sections that follows:
A. Carbenicillin
Biological Source It is a semi-synthetic antibiotic related to penicillin that essentially has an additional carboxylic function present in the side-chain.
Chemical Structure Please refer to Section 3.7.1.
Preparation First of all the starting esters may be prepared by acylating 6-aminopenicillanic acid (i.e., 6-APA) with monoesters of phenylmalonic acid. The resulting esters are subsequently hydrolyzed with the help of an appropriate esterase, for instance: α-chymotrypsin or pancreatin, and extracting the liberated acid with a suitable organic solvent.
Characteristic Features
Carbenicillin Disodium [C17H16Na2O6S]: [Synonyms Anabactyl; Carbapen; Carbecin; Geopen; Hyoper; Microcillin; Pyocianil; Pyopen.]
1. It is obtained as white to off-white, crystalline powder having a bitter taste, odourless; and hygroscopic in nature.
2. The pH of a 1% (w/v) aqueous solution is 8.0.
3. It gives rise to two distinct values for dissociation constant viz., pKa1 2.76 and pKa2 3.50.
4. Solubility Profile: 1 g in 1.2 ml water; 2.5 ml ethanol; and almost insoluble in chloroform and ether.
Uses
1. It is a carboxy benzyl penicillin with enhanced antibacterial profile against non-β-lactamase producing Gram-negative bacilli, precisely Pseudomonas aeruginosa.
2. It has been observed that the D-and L-isomers actually show very slight differences in their biologic activity, besides they undergo rapid interconversion when in solution; hence, most logically the racemic mixture is employed invariably.
3. It may be safely administered to a maximum extent of 4 g per day so as to obtain serum concentration exceeding 50-60 mcg ml–1, which concentrations normally inhibit most Pseudomonas aeruginosa strains.
4. It has been observed that the clinical efficacy may be increased appreciably by the combination therapy of carbenicillin disodium either with tobramycin or gentamycin in their respective full therapeutic dosages.
Note: There is an obvious possibility of a chemical interaction between aminoglycosides and β-lactam antibiotics, whereby the amino moieties of the aminoglycoside molecules afford to attack the β-lactam ring, ultimately result into the formation of a covalent adduct and finally the inactivation of the antibiotics. This serious drawback is easily overcome by their administration through different routes.
5. It is particularly effective in UTIs by virtue of its attainment of very high urine levels through IM.
B. Ticarcillin
Biological Source It is a broad-spectrum, semi-synthetic antibiotic related to penicillin; and it also essentially has an additional carboxylic function at alpha position in the side-chain.
Chemical Structure Please refer to section 3.7.1.3.
Preparation It may be prepared by the conversion of 2-(3-thienyl) malonic acid monobenzyl ester to the corresponding acid chloride which is subsequently condensed with 6-APA, followed by hydrogenation to convert the ester to the free acid.*
---------------------------
* Belgian, Pat 646,991.
Characteristic Features
Ticarcillin Disodium [C15H14N2Na2O6S2] [Synonyms Aerugipen, Monapen; Ticar; Ticarpen; Ticillin]
1. It is obtained as creamy-white, hygroscopic non-crystalline powder.
2. It is found to be quite unstable in an acidic medium.
3. It has dissociation constant pKa (acid form) 2.44 and 3.64.
4. The pH of a concentrated solution (> 100 g. mL–1) is approximately 7.0.
5. Its aqueous solutions are relatively stable; and the acidic solutions comparatively unstable.
Uses
1. Its antibacterial profile very much resembles to that of Carbenicillin (Section 3.7.1.4.A).
2. It is found to be twice as active against Ps aeruginosa.
3. Though it has an inherent tendency to develop resistance readily; however, with many infections the resistance is obviated by inclusion of clavulanic acid.
4. For the treatment, control and management of Gram-negative infections, it is invariably combined with either gentamycin (Section 3.1.2) or tobramycin (see section 3.1.7) so as to enhance activity and delay resistance to an appreciable extent.
C. Mezlocillin
Biological Source It is a semisynthetic, broad-spectrum antibiotic related to penicillin and azlocillin; and belong to the class of acylureido penicillins.
Chemical Structure Please refer to Section 3.7.1.
Characteristic Features
Mezlocillin Sodium Monohydrate [C21H24N5NaO5S2.H2O] [Synonyms Baycipen; Baypen; Mezlin]:
1. It is obtained as either yellowish-white powder or as pale yellow crystalline substance.
2. It has dissociation constant pKa 2.7.
3. It is found to be soluble in water, methanol and DMF; and insoluble in acetone nd ethanol.
Uses
1. It is one of the most active penicillins against Ps aeruginosa, with a potency almost at par with gentamycin.
2. It is found to be more potent against Klebsiella and a host of other enteric bacilli than is carbenicillin and ticarcellin (A and B above).
3. It is employed frequently as an ‘alternative drug’ against infections caused by Acinetobacter, Bacteroidis fragilis (G.I. strains), Enterobacter, E. coli, Kl pneumoniae, Morganella morganii, Pr vulgaris, Providencia rettegeri, Ps aeruginosa (UTIs) or Serratia.
D. Piperacillin
Biological Source It is a broad spectrum semi-synthetic antibiotic related to penicillin bearing essentially an acylureido function.
Chemical Structure Please refer to Section 3.7.1.
Characteristic Features
Piperacillin Sodium [C23H26N5NaO7S] [Synonyms Isipen; Pipril Pentcillin; Pipracil]: It is obtained as white crystals having mp 183-185°C (decomposes). 1g gets dissolved in approximately 1.5 ml water or methanol, and 5 ml of ethyl alcohol.
Uses
1. It is an extended-spectrum (antipseudomonal) penicillin.
2. It is usually administered IV.
3. Its activities are very much similar to mezlocillin sodium (sec C above).
3.7.1.5 Beta-Lactamase Combinations β-Lactamases are the enzymes that help in opening up the β-lactam rings of penicillins, cephalosporins and also the related compounds exclusively at the β-lactam bond. Generally, the β-lactamases may be classified into three major categories, namely:
(a) Substrate selectivity and inhibition,
(b) Acidity/basicity of the enzyme protein, and
(c) Intra-and extracellular location of enzyme.
Penicillinases are the enzymes which get excreted exclusively from the bacterium and the genes located on plasmids. These are broadly regarded as Type II β-lactamases; and are essentially responsible for the penicillin-resistant Gram-positive organisms, Gram-negative cocci, besides a host of Gram-negative bacilli.
It has been observed that the penicillinase-resistant penicillins usually get bound to the penicillinases; however the actual dissociation of the ‘drug’-enzyme complex is rather quite rapid.
In actual practice, they have been successfully supplanted by three substances, namely: clavulanic acid, sulbactam and tazobactam. All these are regarded as newer breeds of β-lactamase inhibitors that specifically acylate the enzymes by creation of a ‘double-bond’ (greater electronic bondage) and consequently afford dissociation very slowly, thereby significantly enhancing the potency of the penicillins against certain organisms and ultimately increase their therapeutic efficacy.
The combination of b-lactamase inhibitors with other antibiotics helps to expand the spectrum of the antibiotic to a significant extent which may be observed evidently by carrying out the in vitro studies.
There are three important b-lactamase inhibitors duly recognized, namely: clavulanic acid, sulbactam, and tazobactam, which shall now be discussed individually and also the combinations with antibiotics which are available commercially in the sections that follow:
A. Clavulanic Acid
Synonyms MM 14151
Biological Source It is a β-Lactamase inhibitor, and an antibiotic obtained as a fermentation product of Streptomyces clavuligerus, structurally related to the penicillins. Clavulanic acid enjoys the status of being the first ever reported naturally occurring fused β-lactam containing oxygen.*
----------------------------
* J. Antibiot., 29, 668, 1976
Chemical Structure Please refer to Section 3.7.1.
Characteristic Features
Clavulanate Potassium [C8H8KNO5]: It is obtained as a white powder having a bitter taste. 1g is soluble in 2.5 ml of ethanol or in less than 1 ml of water.
Uses
1. The sulphur at position 1 of the β-lactam ring has been strategically replaced by oxygen (less electro negative); and also there is an ethylidene function present at position 2, that significantly increases reactivity with the typical exopenicillinases of Staphylococcus aureus and Epidermatitis and the Gram-negative β-lactamases of the Richmond Types II and III (Haemophilus, Niesseria,
E. coli, Salmonella and Shigella), IV (Bacteroides, Klebsiella and Legionella) and V. Interestingly, these are all plasmid-mediated enzymes; and the chromosomally mediated enzymes are not inhibited at all.
2. It is absorbed well orally, but is also suitable for parenteral administration. The half-life is about 1 hour.
Clavulanate Amoxicillin Trihydrate (i.e., combination of potassium salt with amoxicillin trihydrate).
Synonyms Augmentin; Amoksiklav; Co-Amoxiclav; Ciblor; Klavocin; NeO-Duplamox.
Uses
1. It is a β-lactam antibiotic with a β-lactamase inhibitor.
2. It extends the in vitro activity of amoxicillin to include β-lactamase producing strains of H. influenzae, E. coli; Pr. Mirabilis; and S. aureus.
Note:
(a) It is pertinent to mention here that it may not extend the spectrum to various bacteria not usually killed by amoxicillin (such as: Pseudomonas aeuruginosa) in the absence of β-lactamase resistance.
(b) Clavulanate Ticarcillin Disodium (i.e., combination of potasium salt with ticarcillin disodium):
Synonyms Betabactyl; Timentin.
Uses
1. It is employed for parenteral treatment of UTIs, skin and soft tissue, and lower respiratory tract infections, and sepsis caused due to suceptible bacteria.
2. The combination exerts an appreciable increase in activity that takes place against particularly the β-lactamase-producing strains of S. aureus, H. influenzae, gonococcus, E. coli, and Klebsiella.
Note: It fails to inhibit the β-lactamases generated by majority of strains of pseudomonas, Enterobacter and certain other Gram-negative bacilli; besides, β-lactamaseproducing strains of those bacteria which eventually remain resistant to ticarcillin.
B. Sulbactam
Synonyms Penicillanic acid sulfone; Penicillanic acid 1, 1-dioxide; CP-45899.
Biological Source It is also a semi-synthetic β-lactamase inhibitor; and is structurally related to the penicillins.
Preparation 6-APA is diazotized to result into the formation of the unstable diazo derivative, which is subsequently and rapidly converted to the corresponding 6, 6-dibromo compound by carrying out the reaction in the presence of bromine. Finally, the resulting product is subjected to catalytic hydrogenolysis of the bromine atoms from the product.*
Chemical Structure Please refer to Section 3.7.1.
Characteristic Features
1. It is obtained as white crystalline solid having mp 148-151°C.
2. It has specific optical rotation [α]D20 + 251° (C = 0.01 in pH 5.0 buffer).
3. It is found to be soluble in water.
Sulbactam Sodium [C8H10NNaO5S] [Synonyms Betamaze; Unasyn; CP-45899-2.]
Uses
1. It shows greater activity against Type-I β-lactamases than clavulanic acid, but fails to penetrate the cell walls of Gram-negative organisms.
2. It also exert its own feeble antibacterial activity.
3. It is absorbed by the oral route but is also suitable for parenteral administration.
Sulbactam Ampicillin [i.e., mixture of sodium salt with ampicillin sodium]: [Synonyms Bethacil (inj.); Loricin; Unacid; Unacin (inj.)]
Uses It extends the antibacterial profile of ampicillin to include b-lactamase-producing strains of Acinetobacter, Bacteroides, besides other anaerobes, such as: Branhamella, Enterobacter, E. coli, Klebsiella, Neisseria, Proteus, and Staphylococcus.
C. Tazobactam
Synonyms CL-298741; YTR –830H.
Biological Source It is a β-lactamase inhibitor and structurally related to the penicillins. It also supplants the general approach of expanding the antibacterial spectrum of certain antibiotic(s) (e.g., piperacillin sodium) to include some β-lactamase-producing strains.
Chemical Structure Please see section 9.3.7.1.
Characteristic Features
Tazobactam Sodium [C10H11N4NaO­S] [Synonyms YTR-830; CL-307579]: It is an amorphous solid having mp > 170°C (decomposes).
Tazobactam Piperacillin [i.e., mixture of tazobactam sodium with piperacillin sodium]
[Synonyms Tazocilline; Tazocin; Zosyn;]: The combination product is administered by IV-infusion over 30 minutes duration. The usual total daily dose is usually 12 grammes of piperacillin and 1.5 grammes of tazobactam gives as 3.375 gramms every 6 hours. It is found to be active Vs more Gram-negative bacilli.
------------------------------
* J. Org. Chem., 47, 3344, 1982.

Subscribe to: Posts ( Atom )