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Side effects in general and in particular to antiinfective therapy are obviously hardly predictable and a causal relationship is seldom firmly established. The handling of untoward reactions may be improved if a subpopulation which can be identified is at particular risk for a given reaction. A clear assessment of dose and time dependency of untoward reactions is important in this context. Agranulocytosis seen with (i) beta-Lactam-antibiotics, (ii) vancomycin and (iii) amodiaquine can exemplify how simultaneous investigations of epidemiological and experimental aspects lead to identification of a subpopulation at risk.

Seven cases of agranulocytosis and two of liver damage that were probably due to amodiaquine treatment were studied. In five cases agranulocytosis was combined with liver damage, and in one case of primary liver damage moderate neutropenia was present. Three patients died. High total doses or prolonged duration of treatment, or both, appear to favour the occurrence of these reactions. The clustering of five of the seven cases of agranulocytosis within six months in one medical centre indicates that the risk to benefit ratio of amodiaquine for malaria prophylaxis should be re-evaluated.

beta-Lactam antibiotics can induce severe neutropenia by a hitherto unknown mechanism. Fifty cases of beta-lactam antibiotic-induced neutropenia (less than 1,000 neutrophils/mm3) from 17 hospitals were analyzed and compared with 140 literature cases. The incidence of neutropenia was 5%-greater than 15% in patients treated for greater than or equal to 10 days with large doses of any beta-lactam antibiotic but less than 0.1% with shorter duration of therapy. In greater than 95% of cases recovery occurred between one to seven days after withdrawal of beta-lactam antibiotics. Bone marrow aspirates were characterized by a lack of well-differentiated myeloid elements in the presence of numerous immature granulocyte precursors. Nine penicillins and eight cephalosporins inhibited in vitro granulopoiesis in a dose-dependent manner. There was a good correlation between the inhibitory capacity of beta-lactam antibiotics in vitro and the doses inducing neutropenia in vivo. These observations may be relevant for therapy in the granulocytopenic patient.

A patient is presented who developed agranulocytosis while taking amodiaquine for suppressive therapy of malaria. An amodiaquine-dependent granulocytotoxic antibody could be demonstrated in the patient's serum on day 1 after stopping amodiaquine medication. Granulocyte transfusion was ineffective on days 6 and 7, possibly due to the slow elimination of the drug.

Eight patients treated with a total of 220-550 million U penicillin-G developed neutropenia. These cases have been compared with eight patients receiving a similar dose of pencillin-G with no adverse reactions and with eight untreated subjects. All penicillin-treated patients showed raised levels of anti-IgG antibodies and lymphocyte culture stimulation indices. These values were highest in the neutropenia group. Both of the two tests significantly discriminated the three groups. Antineutrophil antibodies could be detected in four of seven neutropenic patients with a staphylococcal-slide-assay while indirect immunofluorescence and microcytotoxicity tests failed to reveal these antibodies. The literature dealing with neutropenias induced by penicillin-G and its congeners is reviewed. We conclude that (1) penicillin-G in doses exceeding a total of 200 million U frequently induces neutropenia, (2) an immune-mediated pathogenesis a highly probable, (3) neutropenia after penicillins is different from two hither-to accepted types of this side effect, (4) sufficiently high amounts of penicillin-G intravenously always induce sensitization against this drug.