Cefotetan-induced immune hemolytic anemia following prophylaxis for cesarean delivery.

Second- and third-generation cephalosporins, notably cefotetan, are increasingly implicated in severe, sometimes fatal immunemediated hemolytic anemia. We describe a 26-year-old woman who developed severe hemolytic anemia 2 weeks after receiving a single prophylactic dose of cefotetan during cesarean delivery. The patient's DAT was weakly reactive for IgG and her serum reacted with cefotetan-coated RBCs. The antibody had a titer of 4,096 by antiglobulin testing. The patient required treatment with two units of PRBCs and experienced gradual resolution of hemolysis. Our case emphasizes the need for increased awareness of delayed onset hemolytic anemia following prophylactic use of cefotetan.

Persistence of cefotetan on red blood cells.

BACKGROUND: Cefotetan can cause severe immune hemolytic anemia that may persist long after the drug is discontinued. To study the binding of cefotetan to RBCs, patients who received cefotetan were followed and tested for the presence of antibody to cefotetan. STUDY DESIGN AND METHODS: Patients receiving cefotetan were identified from pharmacy and nursing records. Blood samples obtained for routine hematology tests were analyzed. Cefotetan binding to patients' RBCs was tested using a previously characterized high-titer anticefotetan serum by gel technique. To determine the minimum amount of drug necessary for binding to occur, RBCs were incubated with serial dilutions of cefotetan at pH 7.4. RESULTS: Sixty patients receiving 1 to 25 g i.v. (median, 2 g) of cefotetan were followed for 1 to 123 days (median, 18 days). All were initially positive, for cefotetan on RBCs. Positivity persisted for up to 98 days after the last dose of drug. Fifteen patients became negative during follow-up. The first negative sample occurred at Day 30 to 123. Using the midpoint between the last positive and first negative to estimate of the duration of positivity, we estimate that cefotetan remains RBC-bound for 16.5 to 92 days (median, 67.5 days). During the follow-up period, five patients developed anticefotetan detectable in the serum. Twenty patients receiving other cephalosporin antibiotics showed no specific reactivity of their RBCs with anticefotetan. In vitro studies showed a minimum necessary drug concentration of 1 micromol/L at physiologic pH, which was not significantly altered by RBC pretreatment with ficin, sialydase, or DTT. CONCLUSIONS: Cefotetan is tightly bound to RBCs after intravenous administration and remains detectable for weeks after the last dose. Antibodies to cefotetan may occur in about 8 percent of patients receiving the drug. The minimum necessary concentration for RBC binding is low compared to an estimated plasma concentration of 240 micromol/L from a single i.v. dose of 1 g.

Clinical and laboratory study of an episode of cefotetan-induced severe hemolytic anemia.

BACKGROUND: Cephalosporins are frequently associated with positive direct antiglobulin tests (DAT) and may rarely cause immune hemolytic anemia (IHA). We describe a patient who developed hemolytic anemia while she was receiving intravenous cefotetan. STUDY DESIGN AND METHODS: Immunohematologic studies of drug-dependent antibodies were performed by using cefotetan-treated red blood cells (RBCs) and untreated RBCs in the presence of cefotetan. RESULTS: The patient's serum contained antibodies that reacted with both drug-coated RBCs (adsorption mechanism) and with uncoated RBCs when cefotetan was added to the serum (immune complex mechanism). The prompt recognition of the problem and discontinuation of the drug prevented the onset of renal failure and rapidly resolved the hemolytic reaction. CONCLUSION: Our report underlines the importance of close laboratory and immunohematologic monitoring of patients treated with cephalosporins in order to recognize swiftly any hemolytic reaction due to these antibiotics thus reducing the chance of serious sequelae.

Cross-reactivity of cefotetan and ceftriaxone antibodies, associated with hemolytic anemia, with other: cephalosporins and penicillin.

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-aminocephalosporanic 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.

Cefotetan-induced hemolytic anemia: a case report and review of the literature.

Cefotetan disodium-induced hemolytic anemia has been reported previously, and some of these cases have been severe or fatal. We describe a case of severe hemolytic anemia that occurred in an 80-year-old woman who received cefotetan prophylactically after surgery for a small bowel obstruction. Eight days after the first dose of cefotetan, the patient developed a severe Coomb test-positive hemolytic anemia. Using flow cytometry, we demonstrated cefotetan-specific antibodies in her posttreatment serum, which were detectable at a serum dilution up to 1:10 000. The patient received corticosteroid therapy and blood transfusions, with improvement of her hematologic parameters, but died 54 days after admission for respiratory failure. To our knowledge, this is the first use of flow cytometry for the detection of cefotetan-induced red blood cell antibodies. This technique offers a sensitive, rapid, objective method for detecting drug-induced antibodies.

Serology of antibodies to second- and third-generation cephalosporins associated with immune hemolytic anemia and/or positive direct antiglobulin tests.

BACKGROUND: First-generation cephalosporins rarely caused immune hemolytic anemia (IHA). Second- and third-generation cephalosporins, especially cefotetan and ceftriaxone, are increasingly associated with severe, sometimes fatal IHA. STUDY DESIGN AND METHODS: Samples from 53 patients with drug-induced IHA and/or positive direct antiglobulin test (DAT) were tested. Patients' sera were tested against drug-treated red cells (RBCs) and untreated or enzyme-treated RBCs, with and without the addition of drug solution. Eluates from patients' RBCs were tested against drug-treated and untreated RBCs. RESULTS: Forty-three patients had antibodies to cefotetan, 8 to ceftriaxone, 1 to cefoxitin, and 1 to cefotaxime. All patients had a positive DAT; only anticefoxitin and anti-cefotetan were demonstrable in RBC eluates. Sera containing anti-cefoxitin, anti-cefotaxime, and anti-cefotetan reacted with drug-treated RBCs (100%) and untreated or enzyme-treated RBCs in the presence of drug (98% or 100%, respectively). All of the ceftriaxone antibodies reacted with untreated or enzyme-treated RBCs in the presence of drug, but those tested did not react with ceftriaxone-treated RBCs. In addition to cefotetan-dependent antibodies, 19 (44%) and 14 (33%) of 43 sera contained drug-independent antibodies when tested with and without the presence of a polyethylene glycol potentiator, respectively. CONCLUSION: Cefotetan is by far the most common cause of drug-induced IHA. All cefotetan antibodies and the single examples of cefoxitin and cefotaxime antibodies reacted with drug-coated RBCs, and most, in contrast to the reactions of antibodies to first-generation cephalosporins (e.g., cephalothin), also reacted with RBCs (not treated with drug) in the presence of the drug. Ceftriaxone antibodies reacted only by the latter mechanism. Drug-independent antibodies (i.e., those reacting without any drug being present) were detected in 33 to 44 percent of patients' sera containing cefotetan antibodies, depending on the sensitivity of the method used.

Cefotetan-induced immunologic thrombocytopenia.

Profound thrombocytopenia accompanied by a severe coagulopathy developed in an elderly female patient being treated with cefotetan while undergoing surgery for closure of a perforated gastric ulcer. During the acute phase of the bleeding diathesis, the patient had a platelet count of 12 x 10(9)/l, a prothrombin time of 88 s (normal 10.0-11.8 s) and a PTT of 105 s (normal 23.0-37.0 s). Potent IgG cefotetan-dependent anti-platelet antibodies, which also were weakly reactive with ampicillin, were detected in the patient's serum using immunofluorescence and a recently developed protein A-agarose rosette forming assay. Unlike typical cephalosporin- and penicillin-induced antibodies that react with cells pretreated with drug, this antibody only reacted with platelets in the presence of exogenous drug. Failure of the antibody to react with drug-coated platelets suggests the possibility that, in this patient, sensitization to cefotetan involved mechanisms other than formation of typical hapten-carrier complexes normally described for members of the cephalosporin family of antibiotics. This appears to be the first definitive report that cefotetan, or any other cephalosporin derivative, can induce immunologic thrombocytopenia.