Antibiotic Development, Past and Present

ANTIBIOTIC DEVELOPMENT, PAST AND PRESENT

An antibiotic was originally defined in the 1940s as a substance produced by one microorganism which, in low concentrations, inhibited the growth of other microorganisms. This definition necessarily meant that an antibiotic was a naturally occurring substance, a microbial metabolite, so any antimicrobial agent that was manufactured by chemical synthesis fell outside the definition. The use of the term has changed over the years, both because an increasing number of synthetic analogues or derivatives of ‘true’ antibiotics have come on to the market, and because several agents that bear little or no resemblance to natural microbial metabolites have also been developed which, for all practical purposes, mimic traditional antibiotics in their potency, low toxicity and, crucially, systemic action. Consequently, drugs like trimethoprim, metronidazole, imidazole derivatives and fluoroquinolones are commonly referred to as antibiotics, and the term ‘antibiotic’ will be used in this chapter to include these and other agents with systemic antimicrobial activity.

By this broader definition, sulphonamides, introduced into therapy in the 1930s, were the first significant antibiotics and predated penicillin by about 10 years. Although Fleming received the credit for discovering penicillin in 1929, much of the development work was undertaken at Oxford University over the next 10 years, and the onset of the Second World War was the impetus for the American pharmaceutical industry to convert the discovery into a medicine that could be manufactured on a large scale. Benzylpenicillin was the original antibiotic in this class, but in the late 1940s and early 1950s it was joined both by other penicillins and by several other classes of antibiotic that are still in widespread use today, such as tetracyclines, macrolides and aminoglycosides. All of these were ‘true’ antibiotics in the traditional sense, i.e. they were extracted from large volume cultures of Streptomyces bacteria or fungi (in the case of penicillins), but the 1960s saw the advent of semisynthetic antibiotics—penicillins particularly—in which the naturally occurring substance was extracted from the microbial culture, purified and then structurally modified by conventional chemical means. Since then, an increasing number of antibiotics have been totally synthesized.

Although bacterial resistance was a problem that was recognized from the start of the antibiotic era, the international pharmaceutical industry developed new antibiotics steadily throughout the period 1950–1970, so that new drugs regularly became available to replace those to which resistance developed; this ability to keep ahead of the problem lead to a degree of complacency and a belief that the industry would maintain its supremacy indefinitely. The naivety of this assumption became steadily apparent during the remaining years of the century as antibiotic resistance became a major problem and hospital ‘superbugs’ like MRSA (meticillin-resistant Staphylococcus aureus) and ‘C. diff’ (Clostridium difficile) rose to prominence, whilst at the same time the industry diverted research resources away from antibiotics.

Most of the antibiotics developed during the period 1970–2000 were structural modifications of existing ones, and it was not until the new millennium that genuinely new antibiotics like linezolid and quinupristin/ dalfopristin (Synercid) came into use. Unfortunately, though, despite the need for new drugs to treat the superbugs mentioned above and others that have more recently come into prominence, such as multiply resistant tuberculosis (MRTB) and vancomycin-resistant enterococci (VRE), the short duration of therapy and the likelihood of eventual resistance and falling sales mean that the commercial incentive to develop new antibiotics is still much lower than that for drugs treating chronic diseases like diabetes or hypertension, or ‘lifestyle’ problems like obesity. Consequently, the supply of new antibiotics is likely to remain limited, and the use and distribution of those that are developed will be carefully managed to avoid their indiscriminate use which predisposes to resistance development (see Chapter 15 on antimicrobial stewardship). The effects of short durations of therapy (typically 5–10 days for many infections), antimicrobial stewardship policies limiting their prescribing, relatively short patent life, and the likelihood of some degree of resistance eventually developing anyway, all combine to make modern antibiotics very expensive drugs. This trend of escalating cost is starkly illustrated by comparing the UK price differential of more than 700-fold between trimethoprim (from the 1960s) and linezolid (marketed in 2000) (based on a single day’s treatment using current British National Formulary prices).