Antimicrobial Chemotherapy

One of the greatest triumphs of modern medicine has been the introduction of a rational system of antimicrobial chemotherapy to combat infectious diseases. Since time immemorial, folk remedies have exploited moulds or mould extracts to treat infections. In the early days of microbiology, attempts were made to use extracts derived from fungal cultures to prevent surgical wound infection.

Joseph Lister used cultures of his own urine to investigate the microbiology of air. He noted that if moulds were present in his cultures, the bacteria that were also there appeared non-motile and degenerate, whereas if bacteria grew without moulds, they were highly motile. Lister concluded that moulds produced a substance or substances that adversely affected the viability of bacteria. He then reasoned that culture filtrates obtained from moulds should prevent infection if used to irrigate surgical wounds. This practice started sixty years before Alexander Fleming described the antibacterial properties of penicillin, produced from a mould that he had originally misidentified.

It was not until the early days of the Second World War that an allied Anglo-American effort overcame the problem of large-scale production and penicillin therapy for human infection was introduced. By the end of the War, penicillin was so plentiful that it was being used to cure cases of gonorrhoea in the allied troops. This was so that they could more quickly be returned to the front line than would otherwise be the case.

After the War, penicillin became generally available. This was not so in the first person to be treated: a policeman with overwhelming staphylococcal sepsis. The antibiotic was in such short supply that it had to be re-purified from the patient's urine. Although in this instance the antibiotic caused relief of the clinical condition, once the supply of penicillin had run out, the staphylococcal infection regained its hold and the patient died.

Penicillin represented the first true antibiotic: a substance produced by one microorganism that, in very small amounts, inhibits or kills other microorganisms.

Antibiotics are the products of microbes that, in dilute solution, inhibit or kill other organisms. Antimicrobial agents include antibiotics and synthetic compounds that have the same effect. Naturally occurring antibiotics may be modified to give semisynthetic derivatives. These often differ from their parent compound in their antimicrobial activity or their pharmacological properties. Often the term 'antibiotic' is applied very loosely and includes antibacterial agents as well, although this is strictly incorrect.

Those agents that kill bacteria are said to be bactericidal and those whose effects are reversible upon removal of the drug are bacteriostatic.

The graphs below show the growth curves for a bacterium treated with two drugs. The upper curve shows the activity of a bacteriostatic drug. The bacterial growth resumes when the drug is withdrawn. The cidal drug, shown in the lower graph, kills bacteria from the time of administration to the culture.

These terms, -cidal and -static, are used to describe the action of disinfectants as well as antibiotics. For example, chloramphenicol is bacteriostatic and gentamicin is bactericidal: phenol is germicidal whereas mercury ions are bacteriostatic.

The development of antibiotics was carried out in parallel with the search for chemical antibacterial agents: artificial compounds that inhibit or kill microbes. Paul Ehrlich described such compounds as magic bullets. The most successful of the early antimicrobial compounds, the sulphonamides, are still in use today.

Chemical structure of sulphamethoxazole, a sulphonamide

Bacteria are good targets for the activity of antimicrobial substances. Aspects of their metabolism are significantly different from that of humans. Antibiotics may act upon bacterial reactions that are not found in human cells. This provides the basis for the selective toxicity of antibiotics, affecting the bacteria but not the human host.

Not all antibiotics are without their side effects. For example, penicillin allergy is very common in humans. The adverse effects of antibiotics are not necessarily associated with their antimicrobial properties. Penicillin allergy is due to the presence of the thiazolidine ring of penicillins. It is the b-lactam ring rather than the thiazolidine ring that is responsible for the antibiotic activity.

The penicillin nucleus showing its amino acid structure and indicating the b-lactam and thiazolidine rings

Fungi and protozoa have a metabolism that is much closer to that of humans than do bacteria, Moreover, viruses are obligate intracellular parasites that depend almost exclusively upon human metabolism for their replication. Consequently, anti-virus, antifungal and anti-protozoal drugs are more limited in their scope and are generally more toxic to humans than are antibacterial drugs.