Antibiotics clinical use

Most of the fermentation and isolation processes for manufacture of the tetracyclines are described in patents (71,72). Manufacture begins with the cultivated growth of selected strains of Streptomjces in a medium chosen to produce optimum growth and maximum antibiotic production. Some clinically useful tetracyclines (2—4) are produced directly in these fermentations others (5—7) are produced by subjecting the fermentation products to one or more chemical alterations. The purified antibiotic produced by fermentation is used as the starting material for a series of chemical transformations (59). 

The total U.S. antibiotic market for 1990 was about 4.73 biUion, 233 million of that was tetracyclines. The development of the semisynthetic P-lactam antibiotics (see Antibiotics, P-LACTAMs) and emergence of resistance to the tetracyclines has steadily diminished the clinical usefulness of tetracyclines. 

The phleomycin, bleomycin and related families are widespectrum antibiotics containing the pyrimidine (987) in addition, they have antineoplastic activity and bleomycin is already in clinical use for certain tumours. They were isolated about 1956 from Streptomyces verticillus, and in addition to the pyrimidine portion the molecules contain an amide part (R ) and a complicated part (R ) consisting of polypeptide, an imidazole, two sugars, a bithiazole and a polybasic side chain which can vary widely phleomycin and bleomycin differ by only one double bond in the bithiazole section (78MI21303). The activity of such antibiotics is increased by the addition of simple heterocycles (including inter alia pyrimidines and fused pyrimidines) and other amplifiers (82MI21300). 

Table 1 Examples of Clinically Useful Cephalosporin Antibiotics...

Treatment of 14 with hydrogen and a catalyst converts it to a mixture of epimeric 6-deoxy-5-oxytetracyclines (15 and 16), each of which is active as an antibiotic. The more active isomer has the natural tetracycline configuration of the methyl group at Ce and is in clinical use as a 6-deoxyoxytetracycline (15). ... 

One of the most popular orally active penicillins in present clinical use is amoxicillin (12). Its oral effectiveness and broad spectrum of activity against common pathogens as well as its better absorption than its closest precedent competitor, ampicillin (14), largely accounts for this. Higher blood and tissue levels of antibiotics is another means of dealing with resistance. In an attempt to achieve yet further improvements in oral bioavailability and hence blood and ti.ssue levels of amoxicillin, the prodmg fumoxicillin (13) is prepared from amoxicillin (12) by treatment with furfural [3]. The imine moiety is less basic than the primary amine so that the isoelectric point of fumoxicillin is more on the acid side than is that of amoxicillin. 

That bacterial resistance predates the era of clinical use of antibiotics by several hundred millions of years is the recent result of genomic sequence data mining from antibiotic-producing microorganisms. These are supposed to be the inventors of antibiotic resistance genes which they had developed to protect themselves from the lethal action of their own antibiotics [4]. 

Like penicillins, cephalosporins are (3-lactam antibiotics and interfere with bacterial cell wall synthesis. A very large number of cephalosporins are available for clinical use. They differ in their route of administration and clinical use. 

Thiatetracyclines contain a sulphur atom at position 6 in the molecule. One derivative, thiacycline, is more active than minocycline against tetracycline-resistant bacteria. Despite toxicity problems affecting its possible clinical use, thiacycline could be the starting point in the development of a new range of important tetracycline-type antibiotics. 

Staphylococcus aureus is less sensitive to erythron rdn than are pneumococci or haemolytic streptococci, and there may be a rapid development of resistance, especially of staphylococci, in vitro. However, in vivo with successM short courses of treatment, resistance is not usually a serious clinical problem. On the other hand, resistance is likely to develop when the antibiotic is used for long periods. 

Benzylpenicillin is produced as various salts according to its intended use, whether as an input to semisynthetic /3-lactam antibiotics manufacture or for clinical use in its own right. 

Bacterial resistance to antibiotics has been recognized since the first drugs were introduced for clinical use. The sulphonamides were introduced in 1935 and approximately 10 years later 20% of clinical isolates of Neisseria gonorrhoeae had become resistant. Similar increases in sulphonamide resistance were found in streptococci, coliforms and other bacteria. Penicillin was first used in 1941, when less than 1 % of Staphylococcus aureus strains were resistant to its action. By 1947,3 8% of hospital strains had acquired resistance and currently over 90% of Staph, aureus isolates are resistant to penicillin. Increasing resistance to antibiotics is a consequence of selective pressure, but the actual incidence of resistance varies between different bacterial species. For example, ampicillin resistance inEscherichia coli, presumably under similar selective pressure as Staph, aureus with penicillin, has remained at a level of 30-40% for mai years with a slow rate of increase. Streptococcus pyogenes, another major pathogen, has remained susceptible to penicillin since its introduction, with no reports of resistance in the scientific literature. Equally, it is well recognized that certain bacteria are unaffected by specific antibiotics. In other words, these bacteria have always been antibiotic-resistant. 

Enyzme catalysis is thus essential for all life. Hence the selective inhibition of critical enzymes of infectious organisms (e.g., viruses, bacteria, and multicellular parasites) is an attractive means of chemotherapeutic intervention for infectious diseases. This strategy is well represented in modem medicine, with a significant portion of antiviral, antibiotic, and antiparasitic drugs in clinical use today deriving their therapeutic efficacy through selective enzyme inhibition (see Table 1.1 for some examples). 

The aim of this review is to summarize the available pharmacology and safety data on this nonsystemic antibiotic as well to outline its current and potential clinical use. 

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