Incidence of β-lactam-induced delayed hypersensitivity and neutropenia during treatment of infective endocarditis

Background: Long-term parenteral beta-lactam treatment is often complicated by adverse reactions that necessitate drug withdrawal. Objective: To evaluate the incidence and mechanism of beta-lactam adverse reactions during an 8-year period in all episodes of suspected infective endocarditis in patients treated at a university-affiliated institution. Methods: Patients with 215 consecutive episodes of beta-lactam treatment for 10 days or more were prospectively enrolled during 2 periods, January 1984 through December 1988 and January 1993 through December 1995, and compared with 51 episodes of vancomycin hydrochloride treatment for 10 days or more. Incidents of adverse reactions, such as fever, rash, or neutropenia, were registered. Neutrophil counts, eosinophil counts, and penicillin antibodies were studied. Patients with delayed adverse reactions to penicillin G sodium were rechallenged with penicillin v potassium. Results: Incidence of delayed adverse reactions during treatment was 33% with beta-lactams compared with 4% with vancomycin. Rates of adverse event for beta-lactams increased continuously from treatment day 15 to day 30. A 6-fold difference in capacity to induce adverse events was found with different beta-lactams. Penicillin G induced neutropenia in 14% and any adverse event in 51% of treated episodes. Mean daily doses significantly influenced the frequency of adverse events. Occurrence of hemagglutinating penicillin antibodies was significantly related to patients whose penicillin-treated episodes were complicated with adverse events. Patients with delayed adverse reactions to penicillin G were safely rechallenged with penicillin. Conclusions: Incidence of delayed adverse reactions to beta-lactams increases sharply when parenteral treatment is extended beyond 2 weeks. Penicillin G is the most frequent inducer of adverse reactions among p-lactams studied. An immunological reaction mediated by antibodies to the penicilloyl determinant may be involved in the pathogenesis, possibly enhanced by a dose-related toxic trigger mechanism. beta-Lactam-induced neutropenia followed a uniform pattern, occurring after, on average, 21 days of treatment, and might be due to both immunologic and toxic effects of treatment. Patients with a late adverse reaction to penicillin can safely be re-treated with penicillin, although they should remain under close surveillance if treatment extends beyond 2 weeks.