1、Agranulocytosis During Antibiotic Therapy: Drug Sensitivity or Sepsis?,Anthony V. Pisciotta Department of Hematology, Medical College of Wisconsin, Milwaukee, American Journal of Hematology 42:132-137 (1993)Ri 曹思宏,INTRODUCTION,1957: antibiotic medication: an etiologic factor in agranulocytosis Risto
2、cetin: leukopenia and thrombocytopenia. 1963: AMA Registry of Adverse Drug Reactions an “innocent” drug, concomitantly given with other drugs more likely to be offending. since 1965: agranulocytosis during antibiotic therapy has been reported with increasing frequency,INTRODUCTION,Chloramphenicol: o
3、ne of the first antibiotics to be recognized as a cause of leukopenia. usually part of total bone marrow suppression, which may be a reversible or a permanent feature of aplastic anemia. Shortly thereafter, a group of antibiotics were implicated in selective granulocytopenia (Table I).,INTRODUCTION,
4、It is not certain that leukopenia is truly drug-related as opposed to bone marrow suppression induced by overwhelming sepsis. This study was planned in order to examine the characteristics of agranulocytosis associated with antibiotics.,MATERIALS AND METHODS,Antibiotic-induced agranulocytosis: very
5、rare a prospective analysis of a relationship between drugs and agranulocytosis is not possible. For this reason, 43 previously reported cases from the literature have been examined retrospectively. 27 male, 12 female, 4 gender was unspecified,MATERIALS AND METHODS,MATERIALS AND METHODS,5 cases stud
6、ied by the author were added (Table II).,MATERIALS AND METHODS,suppression of postphagocytosis respiratory burst by the method of McIntyre suppression of trypan blue ejection from PMNs exposed to test serum colony-forming units granulocyte-macrophage (CFU-GM),RESULTS: Clinical Considerations,Many of
7、 the patients who subsequently developed agranulocytosis during antibiotic therapy were severely ill with infection long before they developed hematologic changes. predominant symptoms during the preleukopenic phase appropriate to infection: chills, fever, pain, swelling, and tenderness localized to
8、 the infected area,RESULTS: Clinical Considerations,Agranulocytosis induced by antibiotics displays an incubation period of 20 days, a striking difference from the 40 days required by nonantibiotics.,RESULTS: Clinical Considerations,Four of our patients (Table II) ranged in age from 31 to 69 years a
9、nd received the offending drug for between 3 and 23 days. The fifth received dicloxacillin for 70 days.,Peripheral Blood and Bone Marrow,In each previously reported case, the WBC at nadir varied from 0.5 X 109 / liter (napcillin) to 5.6 X 109 / liter (oxacillin). In all cases, the PMNs were entirely
10、 absent or markedly depleted; 0 0.5 X 109 / liter in cited cases and 0 - 0.4 X 109 / liter in our own five patients.,Peripheral Blood and Bone Marrow,Thus the almost total depletion of PMNs tends to favor the diagnosis of agranulocytosis rather than leukopenia of overwhelming sepsis, with which an i
11、ncreased ratio of PMNs is expected.,Peripheral Blood and Bone Marrow,bone marrow biopsies generally granulocytic aplasia erythrocytic hyperplasia an infiltrate consisting of lymphocytes and plasma cells.,Effect of Rechallenge With Suspected Antibiotics,None of our patients was rechallenged with the
12、suspected antibiotic. Reyes et al. 1 patient: agranulocytosis after 18 days of treatment with carbenicillin. retreated with the same drug three additional times; displayed recurrence 24, 22. and 15 days after treatment was restarted.,Effect of Rechallenge With Suspected Antibiotics,Allo and Silva ag
13、ranulocytosis with cephalosporin in 28 days fell to a latent period of 2 days after the drug and carbenicillin were repeated. Joorabchi and Kohout initial latent period of 23 days with penicillin, fell to 2 days with the second course of treatment.,Effect of Rechallenge With Suspected Antibiotics,Ho
14、mayouni et al. reported ten cases of agranulocytosis after 9-28 days of treatment with cephalosporin. All were rechallenged with a lower dose of the same medication. None of these patients developed a second episode of agranulocytosis.,Effect of Rechallenge With Suspected Antibiotics,Adrouny et al.
15、1patient with agranulocytosis after 1 day of agranulocytosis with vancomycin. Recurrence occurred within 24 h of rechallenge with vancomycin,RESULTS: Possible Mechanisms,Serum from four of our patients suppressed postphagocytosis respiratory burst to 57%. 46%, 37%, and 32% of control values. All sug
16、gested that cytotoxic material was present during agranulocytosis (Fig. 2).,RESULTS: Possible Mechanisms,RESULTS: Possible Mechanisms,In four experiments, acute-phase serum failed to suppress trypan blue ejection, remained between 5% and 10% of leukocyte after exposure to serum. Therefore, consisten
17、t evidence of antibody activity was not found.,RESULTS: Effect of Drug on CFU-GM,Development of CFU-GM was not affected by adding acute-phase serum plus complement alone from four patients. Direct suppression was found with clindamycin in a clindamycin-sensitive patient but not in 15 normal control
18、marrows.,RESULTS: Effect of Drug on CFU-GM,Major suppression was encountered in a concentration of 10 -4 M, which was attenuated as the clindamycin was diluted to 10-8 M (Fig. 4).,Discussion,The association between leukopenia, sepsis, and sensitivity to antibiotics is an unsettled question The blood
19、 picture in overwhelming sepsis is well characterized. Despite severe leukopenia, an increased ratio of granulocytes over lymphocytes is present.,Discussion,idiosyncratic agranulocytosis displays almost complete depletion of PMNs, with lymphocytes remaining as the only persisting representatives of
20、the leukocytes.,Discussion,Any medication administered after the onset of the event is innocent. Agranulocytosis: the drug be given at the same time as the onset, not weeks or months before Even here, some doubt may exist because some cases of agranulocytosis may be dose related.,Discussion,Reyes, P
21、alautke, and Lerner 5 instances of agranulocytosis in two patients sensitive to carbenicillin the latent periods between the start of the drug and rechallenges did not change, suggesting a “nonimmune” event.,Discussion,Joorbachi, Allo and their collaborators first episode occurred after 28 and 23 da
22、ys of treatment second episode of agranulocytosis 2 days after rechallenge with cephalosporin and with penicillin This relationship favors an immunogenic mechanism.,Discussion,The mechanisms underlying drug sensitivity are probably multiple and incompletely expressed. Three basic mechanisms are poss
23、ible. First, peripheral leukocytes or their precursors may be damaged by the drug directly second, by one of its metabolites Third, the drug may stimulate development of an immunogenic clone that alone or together with the drug may cause lysis of PMNs or their precursors.,Discussion,Salama et al. Us
24、ing a sensitive competitive enzyme-linked immunosorbent assay (ELISA), found drug-dependent antibodies in sera during agranulocytosis due to penicillin and dicloxafenac as well as other drugs. These studies suggest that drugs or their metabolites behave as immunologic haptens against the target PMNs.,Discussion,Clearly, the pathogenesis of antibiotic-associated agranulocytosis requires a great deal more work in order to gain a satisfactory understanding.,
