Selective toxicity penicillin

The phenomenon of bacterial resistance to antibiotics was already known by the pioneers of the era of antibiotics, like Paul Ehrlich, who coined the term selective toxicity as the basic principle of antimicrobial therapeutics, as well as Gerhard Domagk, the inventor of the sulfonamide drugs, and Sir Alexander Fleming, the discoverer of the penicillins. When penicillin G was introduced into clinical practice in 1944, as many as 5% of the isolates of Staphylococcus aureus were resistant to penicillin, while 5 years later the percentage was 50%. 

Unfortunately, there are few pure examples of true selective toxicity. Perhaps the best is penicillin. The therapeutic specificity of this antibiotic is based upon the qualitative difference between bacterial cell wall synthesis and mammalian cell membrane synthesis. Synthesis of the former can be inhibited by penicillin while the latter is unaffected. Thus, penicillin is one of the few examples of a drug that can actually cure an illness. A similar example involves the sulfa drugs, which interfere with the synthesis of folic acid, used in nucleic acid formation, in bacteria. While bacteria must synthesize their own folic acid, mammalian cells utilize dietary, preformed folic acid and are not susceptible to interference with its formation. 

Don t harm innocent bystanders The primary goal of antimicrobial therapy is to kill bacteria without harming tissues of the host (Fig. 7.1). Drugs like penicillin, which are effective against certain bacteria, but cause few side effects, have high selective toxicity (i.e., good therapeutic index). In contrast, drugs like amphotericin, which are toxic to human cells at therapeutic doses, have poor selective toxicity. 

Penicillins, cephalosporins, tetracyclines, acrinomvdns These are examples of classes of antibiotics each from a microorganism producing c) otoxic agents. The first three classes are selectively c) otoxic to bacteria, and the fourth cytotoxic to mammalian cancer cells, unfortunately with poor selective toxicity. The penicillins and cephalosporins inhibit bacterial cell wall synthesis, and tetracyclines selectively block protein synthesis at the bacterial ribosome. The actinomycins intercalate in a relative nonselective manner the... 

Much information on the mechanism of action and cross-resistance of purine analogues has been obtained in bacteria, some of which are quite sensitive to certain of these compounds in vitro. There is a great deal of variation in response of the various bacteria to a particular agent and of a particular bacterium to the various cytotoxic purine analogues. Some, if not most, of these differences are probably due to differences in the anabolism of the various compounds. Despite the fact that certain purine analogues have quite a spectrum of antibacterial activity in vitro, none has been useful in the treatment of bacterial infections in vivo because their toxicity is not selective—the metabolic events whose blockade is responsible for their antibacterial activity are also blocked in mammalian cells and thus inhibition of bacterial growth can only be attained at the cost of prohibitive host toxicity. In contrast, the sulpha drugs and antibiotics such as penicillin act on metabolic events peculiar to bacteria. 

Hypersensitivity reactions to antimicrobial drugs or their metabolic products frequently occur. For example, the penicillins, despite their almost absolute selective microbial toxicity, can cause serious hypersensitivity problems, ranging from urticaria (hives) to anaphylactic shock. 

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