ANTIBACTERIAL DRUGS

For the student of pharmacy, these compounds are of utmost importance and in the UK are usually studied outside the field of pharmacognosy. For this reason, and because space precludes the in-depth treatment afforded by other works available to readers, an introduction only is given below.

Sources

Waksman’s 1951 definition of antibiotics was limited to substances produced by microorganisms. The term ‘antibacterial’ is consequently used to include those active compounds prepared synthetically or isolated from higher plants. Most of the clinically used antibiotics are produced by soil microorganisms or fungi but many examples of antibacterial agents from the other groups have been recorded and are mentioned below.

History

The first scientific recording of antibiotic activity was made by Louis Pasteur, who in 1877 reported that animals injected with an inoculation containing Bacillus anthracis and certain other common bacilli failed to develop anthrax.

In 1881, Tyndal in his Essays on the Floating Matter of the Air in Relation to Putrefaction and Infection reported that in some tubes containing a nutritive infusion and bacteria which had become contaminated also with Penicillium glaucum, the bacteria lost their ‘transilatory power and fell to the bottom of the tube’. Tyndal attributed this phenomenon to the cutting off of the oxygen supply to the bacteria by the pellicles formed by the mould. Ten years after Pasteur’s discovery, Emmerich (1887) accidentally discovered that a guinea-pig which had previously been injected with Streptococcus erysipelatis failed to develop cholera when injected with virulent cultures of Vibrio cholerae. He immediately recognized the significance of the discovery and was able to prevent anthrax in experimental animals by administering S. erysipelatis prior to the injection of B. anthracis.

Bouchard (1889) noticed that Pseudomonas aeruginosa prevented the development of anthrax in the rabbit; this observation was extended in scope by Woodhead and Wood (1889), who found that sterilized cultures of P. aeruginosa exerted the same protective effect against anthrax. The lytic action of certain Actinomycetes on various microorganisms was observed by Brunel. Emmerich with his colleague Low further studied the protective action of culture filtrates of P. aeruginosa; they concentrated these cell-free filtrates to 1/10th of their original volume and demonstrated that they destroyed Corynebacterium diphtheriae, staphylococci, streptococci, the pneumococcus, the gonococcus, Vibrio cholerae and Shigella paradysenteria in vitro. The active principle present in this preparation has now been isolated and purified and its structure determined. The recognition of the phenomenon of antibiosis had now been established but in 1928 Fleming noted the inhibition of bacteria by a colony of Penicillium notatum that had developed as a contaminant on a Petri dish. He advocated in his paper (Fleming, 1929) the possible clinical use of the substance formed by the Penicillium culture.

The advent of World War II launched a large-scale programme for the production and testing of the substance now known as penicillin, and the resources of industry and academic institutions were devoted to the study of this substance and the search for other antibiotics. This led to the discovery of streptomycin, aureomycin, chloromycetin and many other antibiotics involving notably various species of Streptomyces. High-yielding strains of Penicillium chrysogenum which produce little pigment have now replaced P. notatum for penicillin manufacture. Preferential synthesis of benzylpenicillin is achieved by the addition of phenylacetic acid to the fermentation medium.

Clinical use

Of the antibiotics in clinical use, most are of bacterial or fungal origin (Table 30.1). Among the bacteria, the genus Streptomycesis particularly noteworthy, as it produces antibiotics such as streptomycin, chloramphenicol, chlortetracycline, tetracycline, erythromycin and neomycin. The penicillins, griseofulvin (an antifungal agent) and cephalosporins are of fungal origin.

Table 30.1 Some clinically important antibiotics

Types and examples	Sources	Notes
Penicillins	Various Penicillium spp.	Based on β-lactam structure with various side-chains mainly at position 6
Benzylpenicillin (Penicillin G)	Suitable strains of P. notatum	Acts by interfering with the synthesis of bacterial cell membranes. Inactivated by bacterially produced penicillinases
Phenoxymethyl penicillin (Penicillin V)	As above, with phenoxyacetic acid added to the culture medium	Unlike benzyl penicillin it is resistant to acid gastric juice
Semisynthetic penicillins	By enzymatic removal of side-chain of penicillin and re-esterification with other acids	Have modified properties of penicillin G such as acid resistance, penicillinase resistance (flucloxacillin), broad-spectrum activity (ampicillin) and antipseudomonal activity (ureidopenicillins)
Cephalosporins		Core structure similar to that of the penicillins and based on 7-aminocephalosporic acid
Cephalosporin C	Cephalosporium acremonium	Has only moderate antibacterial activity
Modified cephalosporins	Side-chain substitution—see text	They have a higher degree of resistance to staphylococcal penicillinase compared with the penicillins. Wide spectrum of activity against Gram-negative bacteria
Tetracyclines
Tetracycline, chlortetracycline, oxytetracycline and others	Streptomyces spp., S. aureofaciens, S. rimosus	Broad-spectrum antibiotics to which bacterial resistance has greatly increased. Bacteriostatic rather than bactericidal. Most commonly prescribed for chronic bronchitis
Chloramphenicol	S. venezuelae: now by synthesis	Because of its toxicity chloramphenicol should be reserved for life-threatening diseases such as typhoid fever, meningitis, infections of Haemophilus influenzae and other conditions where no other antibiotic is effective. Widely used as eye drops
Aminoglycosides	Various soil organisms	All are bactericidal and active against many Gram-negative and some Gram-positive organisms
Streptomycin	Strains of Streptomyces griseus and other spp.	Discovered shortly after penicillin, streptomycin was used for the treatment of tuberculosis. Resistance was rapidly developed by the tubercle bacilli and it is now little used
Gentamicin	Micromonospora purpurea	The most widely used of the aminoglycosides; BP drug is a mixture of various gentamicin sulphates. Used in a variety of preparations
Neomycin	Selected strains of Streptomyces fradiae	Not used systemically. Administered prior to colonic surgery to suppress bowel flora. Topical applications. Eye preparations
Macrolides
Erythromycin	Certain strains of Streptomyces erythreus which produce principally erythromycin A	An alternative therapy for penicillin-hypersensitive patients
Nystatin	Streptomyces spp.	A polyene macrolide used for local treatment of the fungus Candida albicans
Peptides	Principally Bacillus spp.	Composed of a polypeptide chain linked to another group such as a long-chain fatty acid
Bacitracin	B. subtilis, B. licheniformis	In combination with other antibiotics it is used principally to treat skin infections
Polymyxin B	B. polymyxa	Effective against Gram-negative organisms particularly Pseudomonas aeruginosa. Included in bladder instillations, eye and ear drops and as other topical preparations
Colistan (Polymyxin E)	B. colistinus	Uses include bowel sterilization regimens
Cytotoxic antibiotics
Actinomycin D, daunorubicin and others	Various Streptomyces spp.	Anticancer therapy