Cefotetan

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.

Cefotetan (formerly ICI 156834 and YM09330) is a 7-methoxy cephalosporin possessing some advantageous antimicrobial spectrum, safety, and pharmacokinetic characteristics compared with other so-called second-generation cephalosporins. The published literature was reviewed and the cefotetan quantitative susceptibility testing data from nearly 31,000 isolates was tabulated. Against 15,769 enteric bacilli, cefotetan was observed to have a potency and spectrum more closely resembling a third-generation cephalosporin and markedly superior to cefoxitin. The mean of all MIC 90s reported for the Enterobacteriaceae ranged from 0.06 to 13 micrograms/ml except for citrobacter species, E. cloacae, Enterobacter species, and C. freundii. The mean MIC 50 for all 22 recorded species was in the susceptible range. Cefotetan was very effective against B. catarrhalis, H. influenzae, and pathogenic Neisseria species. However, cefotetan and cefoxitin were not active against Pseudomonas species, Acinetobacter species, and some rarely isolated species. Cefotetan was moderately active against the staphylococci (mean MIC 50, 7.6 to 26 micrograms/ml) and streptococci (mean MIC 50, 0.9 to 6.6 micrograms/ml). The coagulase-negative staphylococcus species generally had higher cefotetan and cefoxitin minimum inhibitory concentrations compared with the S. aureus isolates. Oxacillin-resistant staphylococci were resistant to cefotetan. The enterococci, JK group diphtheroids, Corynebacterium species, and L. monocytogenes isolates were resistant. A review of 4,751 strict anaerobes showed cefotetan to have a very comparable activity and spectrum to cefoxitin. The 1,291 B. fragilis strains had a mean MIC 50 and MIC 90 of 5.4 and 23 micrograms/ml, respectively. These values were slightly superior to cefoxitin when tested in parallel. More elevated minimum inhibitory concentrations were observed for other B. fragilis group species for cefoxitin and cefotetan. The mean cefotetan MIC 90 for all other anaerobic bacteria except the Eubacterium species and Lactobacillus species predict favorable clinical efficacy. The beta-lactamase stability of cefotetan is very similar to that of other 7-methoxy cephalosporins. Cefotetan also inhibits Type Ia cephalosporinases with high enzyme affinity and is an inducer of these beta-lactamases, although cefotetan is not rapidly hydrolyzed. Synergy between cefotetan and numerous other antibiotics has been reported, but antagonism has also been occasionally observed.

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.