The Rise and Fall of Anti-Infectives
Clark, Alice M; Hufford, Charles D, Drug Topics
Very early in the development of chemotherapy, pioneers such as Louis Pasteur, Joseph Lister, and Paul Ehrlich all made contributions to setting the vital and fundamental principles behind our use of anti-infective agents.
The early fundamental emphasis was on chemical substances that were selectively toxic to the microorganisms. The discovery of penicillin in 1929 by Sir Alexander Fleming, and its development in the late 1930s and early 1940s by Fleming, Howard Florey, and Ernst Chain, ushered in the antibiotic era. Also during the same time period, fundamental discoveries were made regarding Prontosil, which led to the introduction of sulfanilamide and the sulfa drugs, another very important class of antimicrobial agents.
We have now had 50-55 years of experience with these two large groups of drugs--antimicrobials and antibiotics. For the purposes of this lesson, we will define an anti-infective as "any agent used to control an infectious disease process." An antimicrobial is defined as a substance other than an antibiotic which inhibits the growth and/or survival of microorganisms. An antibiotic is a product of metabolism or a synthetic/semisynthetic analog of natural substances; when taken in small doses, it antagonizes the growth and/or survival of one or more species of microorganisms without causing serious harm to the host.
With the successful development of the penicillins well in hand by the mid 1940s, the pharmaceutical industry and the scientific communities exploded into the search for other antibiotics. Soil isolates became a major focus, although other bacteria and fungi were also investigated as sources.
Within a short time, streptomycin and the tetracyclines were introduced. These agents were active against a much wider group of microorganisms, although each was significantly more toxic than the penicillins. The use of antibiotics during this time grew at an enormous rate because these agents were highly effective at combating most common infectious diseases and were relatively safe.
The discovery of the cephalosporins and their development during the 1960s and 1970s produced another highly effective group of agents, although the nomenclature and classification systems remain among the most confusing one could imagine.
Continued improvements in the penicillins led to the highly effective, safe, and broadspectrum drugs that are used widely today. Table 1 summarizes the classifications and mechanisms of action of the anti-infectives currently in use.
It was recognized from the very earliest discovery of these drugs that a thorough knowledge of their mechanisms of action would be essential to understanding their effectiveness in combating microorganisms with minimal toxicity to the host. For the most part, the mechanisms of action of these drugs have been elucidated (see Table 1), and it is understood that the more selective an anti-infective is for a molecular target unique to the microorganism, the more likely it is to be relatively free of side effects in the host.
Knowing the mechanisms of action of these agents has also helped us understand how microorganisms can change their enzymatic machinery, with the result that reliable antiinfectives suddenly become ineffective. This development is referred to as microbial resistance.
Microbial resistance is not a new phenomenon. Bacterial resistance to the penicillins was observed within a few years after their introduction. (Staphylococcus aureus, for example, a gram-positive bacterium, rapidly became resistant to treatment with penicillin G.) These observations spurred antibiotic research to develop new penicillins effective against these resistant strains--an effort that was largely successful. As drug-resistant strains developed, effective new agents were introduced, allowing the medical community and the general public to remain oblivious to the looming problem of drug-resistant microorganisms. …