Penicillins immunological reactions

Non-IgE-antibody-mediated immunological reactions Modification of erythrocyte surface components due to binding of beta-lactams or their metabolic products is thought to be the cause of the formation of antierythrocyte antibodies and the development of a positive Coombs test implicated in the development of immune hemolytic anemia (211). About 3% of patients receiving large doses of intravenous penicillin (10-20 million units/ day) will develop a positive direct Coombs test (212). However, only a small fraction of Coombs positive patients will develop frank hemolytic anemia (213). Antibody-coated erythrocytes are probably eliminated by the reticuloendothelial system (extravascular hemolysis) (214), or less often by complement-mediated intravascular erythrocyte destruction (215). Another mechanism implicates circulating immune complexes (anti-beta-lactam antibody/beta-lactam complexes), resulting in erythrocyte elimination by an innocent bystander mechanism (82). Similar mechanisms have been implicated in thrombocytopenia associated with beta-lactam antibiotics (216,217). 

Hypersensitivity immunological reactions Hypersensitivity refers to undesirable (damaging, discomfort-producing and sometimes fatal) reactions produced by the normal immune system Penicillins... 

Table 1. Clinical forms of allergic reactions to penicillins immunological parameters... 

Bernreiter M (1959) Electrocardiogram of a patient in anaphylactic shock. JAMA 170 1628 Bierman CW, Van Arsdel PP Jr (1969) Penicillin allergy in children. J Allergy 43 267 Bilezikian SB, Lalei YR, Tsan MF (1976) Immunological reactions involving leukocytes. 

Batchelor FR, Dewdney JM, Weston RD, Wheeler AW (1966) The immunogenicity of cephalosporin derivatives and their cross reaction with penicillin. Immunology 10 21 Batchelor FR, Dewdney JM, Feinberg JG, Weston RD (1967) A penicilloylated protein impurity as a source of allergy to benzyl penicillin and 6-aminopenicillanic acid. Lancet 1 1175... 

Fernstrom AIB (1962) Studies on procaine allergy with reference to urticaria due to procaine penicillin treatment. Acta Derm Venerol 42 79 Fessel WJ (1972) Immunologic reactions in hyperuricemia. N Engl J Med 286 1218 Finke SR, Grieco MH, Connell JT, Smith EC, Sherman W (1965) Results of comparative skin tests with penicilloyl-polylysine and penidllin in patients with penicillin allergy. Am J Med 38 71... 

Whilst this may explain potentially explain many cases, this does not represent the full mechanism which is undoubtedly more complex as not all reactions appear to be immunological. For example, paracetamol is known to form reactive intermediates but yet is not involved in idiosyncratic reactions. Indeed, with some notable exceptions such as the penicillins, many drugs involved in idiosyncratic reactions do not mediate their toxicity through a immune response. 

W8. Warrell, D. A., Perine, P. L., Krause, D. W., Bing, D. H., and McDougal, J. S., Pathophysiology and immunology of the Jarisch-Herxeimer-like reaction in louse-borne relapsing fever Comparison of tetracycline and slow-release penicillin. J. Infect. Dis. 147, 898-909 (1983). 

Many reactions to beta-lactam antibiotics are clearly not immune mediated. These include bleeding disorders, neurotoxicity, and most cases of diarrhea. In addition, many reactions, the pathogenesis of which is still being discussed, clearly depend on the daily and the cumulative dose of beta-lactam antibiotics and hence the duration of treatment. Although the rare, but well-understood, immune hemolysis after penicillin is seen mostly with high-dose and long-term treatment, dose dependency and time dependency point to direct toxicity rather than to immunological mechanisms. Indeed, direct toxic effects of beta-lactam antibiotics on eukaryotic cells and specific interactions with receptor proteins and enzymes have been shown (4) and may underlie particular reactions. 

An immunologically induced hemolytic anemia due to penicillin or its congeners occurs but is rare (44—47). It typically occurs during treatment with high doses (over 10 million units/day) of penicillin for more than 2 weeks (44,45,48). The dose- and time-dependence of this reaction appear to be explained by the underlying mechanism. 

Mechanisms of non-immediate reactions are unclear but may be immunological and non-immunological. Delayed reactions of the IgE type are known (131). Aminopenicillins seem to be an important cause of non-immediate reactions (132-134). The morbilliform rash that begins 1-10 days after amoxicillin can be caused by a delayed cell-mediated immune reaction (135) as can fixed drug eruptions (136,137), toxic epidermal necrolysis (138-140), bullous erythroderma (141), and contact eczema (142). Investigation of these disorders should include delayed readings of skin tests (135). In patients with chronic urticaria, penicillin allergy was demonstrated by cutaneous tests. 

Patients with a history of penicillin allergy should undergo skin testing with both peniciUoyl-polylysine and minor determinant mixtures. Patients with positive skin tests should be treated with another immunologically unrelated compound or should undergo desensitization. The management of patients with a negative skin test but a history of a severe IgE-mediated reaction has to be individualized options include the use of an alternative compound, desensitization, or the controlled administration of a test dose. 

The only drugs which in fact have been shown to be capable of reacting covalently with proteins in vitro and for which such conjugation reactions in vivo appear to be of marked immunologic significance are the jS-lactam antibiotics, penicillins and cephalosporins (for a recent review, see Dewdney 1977). 

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