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]](http://3.bp.blogspot.com/-aKB0stRTwHA/UYtZbmyPvaI/AAAAAAAAF64/WzxjAklZCyQ/s550/50-penicillanic-acid-%255BII%255D.jpg "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
(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:
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.
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* 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.*
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* 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.*
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* 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.
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