Benzylpenicillin (1942) is produced by growing one of the penicillium moulds in deep tanks. In 1957 the penicillin nucleus (6-amino-penicillanic acid) was synthesised and it became possible to add various side-chains and so to make semisynthetic penicillins with different properties. It is important to recognise that not all penicillins have the same antibacterial spectrum and that it is necessary to choose between a number of penicillins just as it is between antimicrobials of different structural groups, as is shown below.
A general account of the penicillins follows and then of the individual drugs in so far as they differ.
Mode of action. Penicillins act by inhibiting the enzymes (Penicillin Binding Proteins, PBPs) involved in the crosslinking of the peptidoglycan layer of the cell wall which protects the bacterium from its environment; incapable of withstanding the osmotic gradient between its interior and its environment the cell swells and ruptures. Penicillins are thus bactericidal and are effective only against multiplying organisms because resting organisms are not making new cell wall. The main defence of bacteria against penicillins is to produce enzymes, P-lactamases, which open the (3-lactam ring and terminate their activity. Other mechanisms that have been described include modifications to PBPs to render them unable to bind (3-lactams, reduced permeability of the outer cell membrane of Gramnegative bacteria, and possession of pumps in the outer membrane which remove (3-lactam molecules that manage to enter. Some particularly resistant bacteria may possess several mechanisms that act in concert. The remarkable safety and high therapeutic index of the penicillins is due to the fact that human cells, while bounded by a cell membrane, lack a cell wall. They exhibit time-dependent bacterial killing (see p. 203).
Pharmacokinetics. Benzylpenicillin is destroyed by gastric acid and is unsuitable for oral use. Others, e.g. Phenoxymethylpenicillin, resist acid and are absorbed in the upper small bowel. The plasma t'/2 of penicillins is usually < 2 h. They are distributed mainly in the body water and enter well into the
1 While not strictly a penicillin, it has a similar spectrum of action including some antipseudomonal activity.
(natural penicillins) beniytpenicillin, p hen oxy me thy I pcniciltin An «staphylococcal penicillins doxacTIIrn flucloxaciilin (¡i-lactamase resistant:)
Broad spectrum ampicillin, amoxicillin.
Monobactam (active only aztreonam against Gram-negative bacteria) Antipseudomonal
Penicil)in-(i-lactamase eo-amoxiclav, inhibitor combinations piperacillin-tazobactam, ticarcillln-clavulanate Carbapenems moropenem, imipenem-cilastatin
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