Natural penicillins
Narrow spectrum penicillinase susceptible
Penicillinase-Resistant Penicillins
Other extended spectrum penicillins


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.
Moreover, pneumococci exhibiting reduced susceptibility to benzylpenicillin are increasingly prevalent. Such strains are of two types: those for which the minimum inhibitory concentration (MIC) of benzylpenicillin is increased from the usual value of about 0.02 mg/l to 0.1-1 mg/l, and those for which the MIC exceeds 1 mg/l. The former are sufficiently sensitive to enable the antibiotic to be successfully used in high dosage, except in pneumococcal meningitis.

Despite its attractive properties benzylpenicillin has several liabilities:

  • it exhibits a restricted antibacterial spectrum;

  • it causes hypersensitivity reactions in a small proportion of persons to whom it is given;

  • it is inactivated by gastric acidity when administered orally;

  • it is eliminated from the body at high rate by the kidneys;

  • it is hydrolysed by b-lactamases produced by many bacteria, including staphylococci.

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.

Figure 2. Structure of some important penicillins

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.

Most b-lactam 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.
Broadening the spectrum of benzylpenicillin to include Gram-negative bacteria was achieved for the first time by adding an amino group to the side-chain to form ampicillin (Figure 2). Ampicillin shows lower activity than benzylpenicillin against Gram-positive cocci and is equally susceptible to staphylococcal b-lactamase. In contrast, it displays greatly improved activity against clinically important enterobacteria, including Escherichia coli, Salmonella enterica, and Shigella spp. as well as against Haemophilus influenzae. Ampicillin has relatively poor oral bioavailability, but some prodrugs, such as pivampicillin regain good absorption. Such compounds are split by tissue esterases in the intestinal mucosa to release ampicillin during absorption. Improved absorption has also been more simply achieved by a minor modification to the molecule to produce amoxicillin (Figure 2).

Replacement of the amido group at position 6 of the penicillanic acid with an amidino group (N-CH=N), provided a significant change in the spectrum of activity. The only penicillin of this type to become available, mecillinam (known as amdinocillin in the USA), is active against ampicillin-sensitive enterobacteria and some of the more resistant Gram-negative rods. Unfortunately, mecillinam (Figure 2) displays no useful activity against Gram-positive cocci. It is poorly absorbed when given orally, but pivmecillinam, its prodrug form, displays sufficient bioavailability.

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.
Resistance to penicillinase-stable penicillins is caused not by inactivating enzymes, but by alterations to the penicillin target (PBP2'). Staphylococci of this type were originally characterized by resistance to methicillin but resistance extends to all b-lactam agents and often accompanies resistance to gentamicin and other antibiotics (multiresistant staphylococci). Particularly troublesome are methicillin-resistant Staphylococcus aureus strains (MRSA), which cause persistent problems in some healthcare settings; certain strains have a propensity to spread to give rise to epidemics.

Figure 3. structure of isoxazolylpenicillins


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