Beta-Lactam antibiotic-induced leukopenia in severe hepatic dysfunction: risk factors and implications for dosing in patients with liver disease.

PURPOSE: To determine if an association could be established for leukopenia and administration of beta-lactam antibiotic therapy in patients with hepatic dysfunction. If such an association could be found, to determine the incidence, timing, and risk factors for beta-lactam antibiotic-induced leukopenia.

PATIENTS AND

METHODS

Patients with hepatic dysfunction, i.e., liver transplant recipients as well as patients with end-stage liver disease awaiting liver transplantation, seen at our institution between October 1989 and October 1991, who received 7 or more days of antibiotics, were studied in a prospective observational fashion. Complete blood count was determined at baseline and followed until the completion of the antibiotic course or until the resolution of leukopenia in leukopenic patients.

RESULTS

Leukopenia occurred after a mean of 6 days with 23% of the beta-lactam antibiotic courses as compared with 0% with the non-beta-lactam antibiotic courses (p = 0.046). Development of leukopenia correlated with the severity of liver disease. Patients developing leukopenia had worse synthetic hepatic function as evidenced by a lower serum albumin level (p < 0.01), a lower serum cholesterol level (p < 0.05), and a higher prothrombin time (p < 0.01) as compared with the patients without leukopenia. Leukopenic patients had a lower baseline white blood cell count (p < 0.051) and a lower baseline platelet count (p < 0.01) indicative of a greater degree of hypersplenism. Leukopenic patients received a higher mean daily dosage of cephalosporins as compared with nonleukopenic patients.

CONCLUSION

beta-Lactam antibiotics when administered in usually recommended dosages can induce leukopenia in patients with hepatic dysfunction. The probable mechanism is impaired hepatic metabolism of the beta-lactam antibiotics resulting in bone marrow suppression of white cell precursors from excessive antibiotic concentrations. The more severe the hepatic dysfunction, the greater the risk. We propose a reduction in dosages of beta-lactam antibiotics when used in patients with hepatic dysfunction. Finally, we raise the possibility that this adverse drug effect is more common than currently recognized by physicians.