A. P. Ball

The Semi-Synthetic Penicillins

The separation of 6-APA from its side chain by amidase (fig. 1) has allowed a very wide variety of new side chains to be attached to the nucleus semi-synthetically giving rise to different therapeutic properties, including acid resistance as with the Phenoxymethylpenicillins, penicillinase resistance as with methicillin and the isoxazolyl penicillins, and a wider antibacterial spectrum as with ampicillin, amoxycillin, epicillin, hetacillin and carbenicillin (fig. 2).

The Management of Tuberculosis

This subject has recently been admirably reviewed by Seaton (1978). As he says, all forms of tuberculosis should be treated in the same way, preferably with a chest physician in charge with experience in the problems of the management of antituberculosis chemotherapy. He further points out that this is true of tuberculosis presenting to surgeons, as early diagnosis will often prevent unnecessary surgery. There seems little doubt that drugs alone will be successful in the management of almost all cases of tuberculosis, irrespective of the system involved, provided certain prin-ciples are adhered to. Initially adequate specimens should be sent to the laboratory so that Mycobacterium tuberculosis can be cultured, identified, and its pattern of drug resistance, if any, estimated. This will take 6 to 8 weeks; during this time treatment should be commenced with drugs to which the organism is likely to be sensitive. This primary regimen is continued for at least 8 weeks, or until the drug sensitivities are known. Thereafter 2 drugs are given. Such treatment reduces infectivity quickly by a rapid kill of the organisms and prevents resistance. Careful supervision, probably initially as an inpatient, but more importantly with outpatients, should ensure that the patient is taking the drugs; all the oral drugs should be taken on a fasting stomach. Obvious close contacts should be screened for evidence of tuberculosis.

Peptide Antibiotics (Polymyxin B and Polymyxin E)

Of the five polymyxins, A, B, C, D and E, originally isolated from a spore-bearing bacillus called variously B. aerosporus and B. polymyxa (Garrod et al., 1973), only two have found clinical usefulness, namely polymyxin B, usually in the form of the sulphate, and polymyxin E (colistin), either as the sulphate or sodium sulphomethate. They are basic polypeptides which are soluble in water and methanol and fairly heat stable.

The Urinary Antiseptics

A large number of derivatives of nitrofurfurane exhibit antibacterial properties, but few of these have been found commercially or therapeutically acceptable. Nitrofurazone is used as a cream or ointment for the topical treatment of skin, vaginal, ear or eye infections, and furazolidone has been used for the prophylaxis and treatment of gastrointestinal infections and ‘travellers’ diarrhoea’. The most widely used of these compounds is nitrofurantoin which is of value in the management of urinary tract infections.

Co-trimoxazole (Trimethoprim-sulphamethoxazole)

Trimethoprim is a synthetic agent, related to the antimalarial drug pyrimethamine and was first described in 1962. Whilst retaining some antimalarial activity, trimethoprim has powerful antibacterial properties. This latter effect is due to blockade of bacterial folic acid synthesis, and a combination of trimethoprim with a sulphonamide has a strongly synergistic antibacterial effect. Trimethoprim is used in combination with sulphamethoxazole (SMZ) which has similar pharmacokinetic characteristics. The combination of TMP and SMZ in a ratio of 1:5 is known as co-trimoxazole.

Fusidic Acid (Sodium Fusidate)

This steroid antibiotic derived from Fusidium coccineum fungus is chemically related to cephalosporin P1. The acid forms colourless crystals which are sparingly soluble in water compared with the sodium salt, sodium fusidate, which is highly water soluble.

The Natural Penicillins — Benzylpenicillin (Penicillin G) and Phenoxymethylpenicillin (Penicillin V)

The two so-called natural penicillins are both produced biosynthetically from Penicillium chrysogenum by fermentation. Benzylpenicillin (penicillin G) is formed if phenylacetic acid is added to the culture medium and Phenoxymethylpenicillin (penicillin V) is formed when phenoxyacetic acid is added. Deacylation of penicillin G is brought about by amidase enzymes of bacterial origin which split off the side chain leaving the ‘penicillin nucleus’ or 6-aminopenicillanic acid (6-APA). The ‘new’ or semi-synthetic penicillins (section 4) are derived by grafting different side chains onto 6-APA so conferring widely differing pharmacological and antibacterial properties. The 6-APA nucleus itself consists of a thiazolidine ring fused to a β-lactam ring. This structure is converted into bacteriologically inert penicilloic acid by the enzyme β-lactamase or penicillinase which splits open the β-lactam ring (fig. 1). Some of the semisynthetic penicillins possess bulky side chains which by stearic hindrance mechanisms protect the β-lactam ring from penicillinase; both of the natural penicillins and semisynthetic penicillins such as ampicillin which possess less heavy side chains, remain entirely vulnerable to penicillinase action.

Chemotherapy of Gram-negative Bacillary Infections

The importance of Gram-negative bacillary infections is twofold. First these infections are often endogenous and so extremely common; secondly, if the infection results in bacteraemia, a serious or even fatal outcome is likely. Three American studies (Spittel et al., 1956; Finland et al., 1959; McCracken and Shinefield, 1966) testify to the increasing frequency over the past 4 decades of serious Gram-negative bacillary infections, both in adults and neonates, and to their persisting high mortality despite the advent of chemotherapy. Although there is some evidence of a return in the importance of Gram-positive organisms (Williams et al., 1976) infections with Gramnegative bacilli remain a serious problem.

Antibacterial Drugs in Obstetrics and Gynaecology

Since the thalidomide disaster in the 1950’s there has been an increasing awareness of the possible intrauterine effects of drugs, especially those taken in the early months of pregnancy. For this reason many pregnant women will be reluctant to take drugs, and their fears must be alleviated before any therapy is prescribed. However, circumstances will arise when antibacterial drugs will be required. At the outset, it should be explained to the patient, that the drug chosen has been shown clearly to have no specific effects on the fetus, either in animal experiments or in human experience.

Mecillinam and Pivmecillinam

Mecillinam is a new antibiotic derived from the 6-aminopenicillanic acid (6-APA) nucleus and synthesised from penicillin G. However, it is not classed as a penicillin, the difference being in the substitution of an amidino group in the 6 position in the β-lactam ring. This chemical manipulation affords the drug interesting new properties which are strikingly different from those of the penicillins in antibacterial activity and mode of action. Unfortunately mecillinam shares with the penicillins — except those in the isoxazolyl group — the disadvantage of being broken down by β-lactamase. This leaves an open β-lactam ring and a bac-teriologically inert substance. It also raises the possibility that the formation of a penicilloate can lead to hypersensitivity reactions (Leading Article, 1976). Pivmecillinam is the orally absorbed ester of mecillinam (fig. 3). An appraisal of mecillinam is given in the supplement of the Journal of Antimicrobial Chemotherapy (July, 1977).