On June 9, 1999, the New York Times published a lengthy obituary for Anne Miller, who was 90 when she died. Her claim to fame was that, at the age of 33, she had been one of the first people to be given the new and largely untested antibiotic penicillin. The transformation in her condition, which occurred within days, from a young woman slipping into death to a woman who could sit up in bed, eat meals, and chat with visitors was a stunning demonstration of what was to become commonplace in a new era of medicine. Such seemingly miraculous cures soon led physicians and the public to call antibiotics “miracle drugs”.
The original preparations of penicillin
contained a mixture of four closely related compounds called penicillin F, G, K,
and X. Benzylpenicillin (penicillin G), was chosen for further development
because it exhibited the most attractive properties and because it was possible
to develop a manufacturing process in which Penicillium chrysogenum could
produce benzylpenicillin almost exclusively. Early attempts to modify this
structure relied on presenting the Penicillium mould used to produce penicillin
with different side-chain precursors during the manufacturing process. Later, a
method for removing the side-chain of benzylpenicillin and liberate the
penicillin nucleus, 6-amino-penicillanic acid (6-APA) was discovered. Various
chemical groups could then be added to 6-APA according to the creativity of
medicinal chemists; a large number of compounds, collectively called
semisynthetic penicillins, have been prepared in this way. in figure 1 is
reported the general stucture of penicillins.
Figure 1. General structure of penicillins
Benzylpenicillin revolutionized the treatment of many potentially lethal bacterial infections, such as scarlet fever, puerperal sepsis, bacterial endocarditis, pneumococcal pneumonia, staphylococcal sepsis, meningococcal meningitis, gonorrhoea, syphilis (and other spirochaetal diseases), anthrax, and many anaerobic infections. The overwhelming importance of benzylpenicillin as a major breakthrough in therapy may be gauged from the fact that it remains today the treatment of choice for all these diseases.
Unevitably, resistance has eroded the
value of benzylpenicillin, today nearly all staphylococci and many strains of
gonococci are resistant.
Despite its attractive properties benzylpenicillin has several liabilities:
Subsequent developments have been aimed at overcoming these inherent weaknesses while retaining the attractive properties of benzylpenicillin: high intrinsic activity and lack of toxicity. In figure 2 are reported some important penicillins that have been developed.
The first major success in improving the pharmacological properties of penicillin was achieved with phenoxymethylpenicillin (penicillin V). This compound has properties very similar to those of benzylpenicillin, but it is acid stable and thus achieves better and more reliable serum levels when given orally, at the expense of being marginally less active. Azidocillin, phenethicillin, and propicillin exhibit similar properties, but are not widely used.
antibiotics are rapidly excreted, with plasma half-lives of 1-3hrs.
Benzylpenicillin is even more rapidly eliminated and several strategies have
been developed to maintain effective levels in the body. Oral probenecid
competes for sites of active tubular secretion in the kidney, slowing down the
elimination of penicillin. Another solution is to use insoluble derivatives of
penicillin. These are injected intramuscularly and act as depots from which
penicillin is slowly released. Originally, mixtures of penicillin with oily or
waxy excipients were used, but insoluble salts, such as procaine penicillin,
were later developed. In this way an inhibitory concentration of penicillin can
be maintained in the bloodstream for up to 24 h; extremely insoluble salts, such
as benzathine penicillin, release penicillin even more slowly, but the
concentrations achieved are, of course, correspondingly lower.
Temocillin (Figure 2), a penicillin in which the b-lactam ring carries a methoxy group that renders it stable to most b-lactamases (as in cephamycins), has a peculiar spectrum. It is moderately active against many Gram-negative bacilli, but has no useful activity against Pseudomonas aeruginosa, Gram-positive cocci or anaerobic organisms. It was largely abandoned, but a rise in prevalence of Gram-negative bacilli that produce broad-spectrum b-lactamases has brought to its reintroduction.
A simple carboxyl derivative of benzylpenicillin, carbenicillin (Figure 2), was found to have therapeutically useful activity against P. aeruginosa and was used for a time in high dosage. It has been superseded by ticarcillin (Figure 2), the thienyl variant of carbenicillin and by a group of ureido derivatives of ampicillin, including azlocillin and piperacillin (Figure 2). These antipseudomonal penicillins must be administered by injection, but two prodrugs of carbenicillin, carfecillin, and carindacillin, are also available.
More than 80% of staphylococci isolated
in hospitals are resistant to benzylpenicillin because of their ability to
produce penicillinase. The appearance of these resistant organisms, which often
evolved to serious cross-infection problems, stimulated research to identify new
derivatives that were not susceptible to b-lactamase
hydrolysis. Methicillin wa one of such compounds, with nafcillin, and a group
called isoxazolylpenicillins: oxacillin, cloxacillin, dicloxacillin, and
flucloxacillin (Figure 3). The isoxazolylpenicillins, particularly
flucloxacillin, have good oral bioavailability and are widely used. They are
highly bound to serum proteins, but retain good therapeutic efficacy.
Figure 3. structure of isoxazolylpenicillins
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