Cross-Reactivity of Cefotetan and Ceftriaxone Antibodies, Associated With Hemolytic Anemia, With Other Cephalosporins and Penicillin

Patricia A. Arndt, MS, MT(ASCP)SBB, George Garratty, PhD, FRCPath


Am J Clin Pathol. 2002;118(2) 

In This Article

Abstract and Introduction

Most drug-induced immune hemolytic anemias since the late 1980s have been caused by the second- and third-generation cephalosporins, cefotetan and ceftriaxone, respectively. Cross-reactivity of cefotetan and ceftriaxone antibodies with other cephalosporins or penicillin has been studied only minimally. We tested 7 serum samples previously identified to contain cefotetan antibodies and one serum sample previously identified to contain ceftriaxone antibodies against 9 other cephalosporins, penicillin, and 7-amino-cephalosporanic acid in the presence of RBCs and also used hapten inhibition to indicate cross-reactivity. Serum samples containing cefotetan antibodies showed some cross-reactivity with cephalothin and cefoxitin (and to a much lesser extent with penicillin and ceftazidime). The ceftriaxone antibodies showed very weak cross-reactivity with cefotaxime, cefamandole, and cefoperazone. There was very little cross-reactivity between cefotetan antibodies and the drugs tested in the present study. We have no data to determine whether the in vitro data relate to in vivo reactivity.

Drug-induced immune hemolytic anemia (IHA) occurs rarely, with an estimated incidence of about 1 case per million of the population.[1] In the 1970s, 67% of drug-induced IHA was due to methyldopa and 23% to penicillin.[2] Since the late 1980s, 88% of drug-induced IHA that our laboratory has studied has been due to the second- and third-generation cephalosporins, cefotetan (75%) and ceftriaxone (13%).[3,4]

Table 1 shows that first-generation cephalosporins rarely caused IHA. The clinical and serologic manifestations in these cases were similar to penicillin-induced IHA.[2] In contrast, 3 second-generation cephalosporins and 4 third-generation cephalosporins have been associated with numerous cases of IHA ( Table 1 ). In some cases, severe intravascular hemolysis occurred, which was supported by serologic findings that indicated an "immune complex" mechanism (the patient's serum reacts with untreated RBCs in the presence of drug) rather than the "drug adsorption" mechanism (the patient's serum reacts with drug-coated RBCs). Fatal hemolysis occurred in 1 (33%) of 3 cases due to cefoxitin, 11 (17%) of 64 cases due to cefotetan, and 9 (47%) of 19 cases due to ceftriaxone.

The extent of cross-reactivity of cefotetan and ceftriaxone antibodies with RBCs in the presence of other cephalosporins and penicillin is poorly documented. In a few reports, the patient's serum samples containing cefotetan (n = 9) or ceftriaxone (n = 3) antibodies were tested by the drug adsorption or immune complex methods against 1,[7,10,24] 2,[8,12,25,26] 3,[27] 4,[28] or 5[18] different antibiotics. We present results of testing 7 cefotetan antibody samples and 1 ceftriaxone antibody sample against 9 other cephalosporins, penicillin, and 7-aminocephalosporanic acid, the basis for semisynthetic cephalosporins.


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