CSF if the meninges are inflamed. Penicillins are organic acids and their rapid clearance from plasma is due to secretion into renal tubular fluid by the anion transport mechanism in the kidney. Renal clearance therefore greatly exceeds the glomerular filtration rate (127 ml/min). The excretion of penicillin can be usefully delayed by concurrently giving probenecid which competes successfully for the transport mechanism. Dosage of penicillins may should be reduced for patients with severely impaired renal function.

Adverse effects. The main hazard with the penicillins is allergic reactions. These include itching, rashes (eczematous or urticarial), fever and angioedema. Rarely (about 1 in 10 000) there is anaphylactic shock which can be fatal (about 1 in 50 000-100 000 treatment courses). Allergies are least likely when penicillins are given orally and most likely with local application. Metabolic opening of the (3-lactam ring creates a highly reactive penicilloyl group which polymerises and binds with tissue proteins to form the major antigenic determinant. The anaphylactic reaction involves specific IgE antibodies which can be detected in the plasma of susceptible persons.

There is cross-allergy between all the various forms of penicillin, probably due in part to their common structure, and in part to the degradation products common to them all. Partial cross-allergy exists between penicillins and cephalosporins (a maximum of 10%) which is of particular concern when the reaction to either group of antimicrobials has been angioedema or anaphylactic shock. Carba-penems (meropenem and imipenem-cilastatin) and the monobactam aztreonam apparently have a much lower risk of cross-reactivity.

When attempting to predict whether a patient will have an allergic reaction, a reliable history of a previous adverse response to penicillin is valuable. Immediate-type reactions such as urticaria, angio-oedema and anaphylactic shock can be taken to indicate allergy, but interpretation of maculopapu-lar rashes is more difficult. Since an alternative drug can usually be found, a penicillin is best avoided if there is suspicion of allergy, although the condition is undoubtedly overdiagnosed and may be transient (see below).

When the history of allergy is not clear-cut and it is necessary to prescribe a penicillin, the presence of IgE antibodies in serum is a useful indicator of reactions mediated by these antibodies, i.e. immediate (type 1) reactions. Additionally, an intradermal test for allergy may be performed using standard amounts of a mixture of a major determinant (metabolite) (benzylpenicilloyl polylysine) and minor determinants (such as benzylpenicillin), of the allergic reaction; appearance of a flare and weal reaction indicates a positive response. The fact that only about 10% of patients with a history of 'penicillin allergy' respond suggests that many who are so labelled are not, or are no longer, allergic to penicillin.

Other (nonallergic) adverse effects include diarrhoea due to alteration in normal intestinal flora which may progress to Clostridium difficile-associated diarrhoea. Neutropenia is a risk if penicillins (or other ß-lactam antibiotics) are used in high dose and usually for a period of longer than 10 days. Rarely the penicillins cause anaemia, sometimes haemolytic, and thrombocytopenia or interstitial nephritis. Penicillins are presented as their sodium or potassium salts which are inevitably taken in significant amounts if high dose of antimicrobial is used. Physicians should be aware of this unexpected source of sodium or potassium, especially in patients with renal or cardiac disease. Extremely high plasma penicillin concentrations cause convulsions. Co-amoxiclav and flucloxacillin given in high doses for prolonged periods in the elderly may cause hepatic toxicity.

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