Cross-Reactivity of Cefotetan and Ceftriaxone Antibodies

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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.

Cite this: Cross-Reactivity of Cefotetan and Ceftriaxone Antibodies, Associated With Hemolytic Anemia, With Other Cephalosporins and Penicillin - Medscape - Aug 01, 2002.

Table 1. Cephalosporins Associated With Immune Hemolytic Anemia*
	No. of Cases	Mechanism	References
First-generation
Cephalothin	5	DC	Garratty^[3]
Cefazolin	1	DC	Garratty^[3]
Cephalexin	1	DC	Manoharan and Kot^[5]
Second-generation
Cefamandole	1	DC	Garratty^[3]
Cefoxitin	3	DC, IC	Garratty,^[3] Arndt et al^[4]
Cefotetan	64	DC, IC, AA	Garratty,^[3] Arndt et al,^[4] Badon et al,^[6] Johnson et al,^[7] Stroncek et al,^[8] Naylor et al,^[9] Moes and MacPherson,^[10] Marques et al,^[11] Ray et al,^[12] Chai et al^[13]
Third-generation
Cefotaxime	2	DC, IC	Garratty^[3]
Ceftriaxone	19	IC	Garratty,^[3] Arndt et al,^[4] Longo et al,^[14] Maraspin et al,^[15] Meyer et al,^[16] Viner et al,^[17] Seltsam and Salama,^[18] Falezza et al^[19]
Ceftazidime	2	DC, IC	Garratty,^[3] Fueger et al^[20]
Ceftizoxime	4	IC, DC	Shammo et al,^[21] Endoh et al,^[22] Calhoun et al^[23]

Table 1. Cephalosporins Associated With Immune Hemolytic Anemia*
	No. of Cases	Mechanism	References
First-generation
Cephalothin	5	DC	Garratty^[3]
Cefazolin	1	DC	Garratty^[3]
Cephalexin	1	DC	Manoharan and Kot^[5]
Second-generation
Cefamandole	1	DC	Garratty^[3]
Cefoxitin	3	DC, IC	Garratty,^[3] Arndt et al^[4]
Cefotetan	64	DC, IC, AA	Garratty,^[3] Arndt et al,^[4] Badon et al,^[6] Johnson et al,^[7] Stroncek et al,^[8] Naylor et al,^[9] Moes and MacPherson,^[10] Marques et al,^[11] Ray et al,^[12] Chai et al^[13]
Third-generation
Cefotaxime	2	DC, IC	Garratty^[3]
Ceftriaxone	19	IC	Garratty,^[3] Arndt et al,^[4] Longo et al,^[14] Maraspin et al,^[15] Meyer et al,^[16] Viner et al,^[17] Seltsam and Salama,^[18] Falezza et al^[19]
Ceftazidime	2	DC, IC	Garratty,^[3] Fueger et al^[20]
Ceftizoxime	4	IC, DC	Shammo et al,^[21] Endoh et al,^[22] Calhoun et al^[23]

Table 2. Titration Results for Six Cefotetan Antibody Samples Tested Against RBCs Treated With the Various Drugs*
Drug	Normal Plasma Pool	Cefotetan Antibody Sample
Drug	Normal Plasma Pool	1	2	3	4	5	6
Cefotetan	<20	200,000	20,000	20,000	20,000	20,000	2,000
7-Aminocephalosporanic acid	0	<10	<2	<2	<2	<2	<2
Cefamandole	0	40	2	<2	2	2	<2
Cefazolin	0	<10	2	<2	2	<2	<2
Cefepime	0	20	2	<2	<2	<2	<2
Cefoperazone	0	<10	2	<2	<2	<2	<2
Cefotaxime	0	20	2	<2	2	2	<2
Cefoxitin	0	5,120	640	320	1,280	80	160
Ceftazidime	0	<10	<2	<2	<2	<2	<2
Ceftriaxone	<20	<20	<20	<20	<20	<20	<20
Cephalothin	<20	5,120	320	160	320	80	20
Penicillin	0	320	2	2	40	2	<2
None	0	<10	<2	<2	<2	<2	<2

Table 3. Titration Results of Testing Three Cefotetan Antibody Samples and One Ceftriaxone Antibody Sample Against Enzyme-Treated RBCs in the Presence of 1 mg/mL Solutions of the Drugs by the "Immune Complex" Method*
Drug	Cefotetan Antibody Sample			Ceftriaxone Antibody Sample
Drug	2	4	7	Ceftriaxone Antibody Sample
Cefotetan	20/10,240	<20/1,280	<20/1,280	0/0/0
Ceftriaxone	0/0	0/0	0/0	80/5,120/640
7-Aminocephalosporanic acid	0/0	0/0	0/0	0/0/0
Cefamandole	0/0	0/0	0/0	0/ ¹/₂+/¹/₂+
Cefazolin	0/0	0/0	0/0	0/0/0
Cefepime	0/0	0/0	0/0	0/0/0
Cefoperazone	0/0	0/0	0/0	0/1+/0
Cefotaxime	0/0	0/0	0/0	1+/1+/2+
Cefoxitin	0/0	0/0	0/0	0/0/0
Ceftazidime	0/0	0/0	0/0	0/0/0
Cephalothin	0/1+	0/0	0/0	0/0/0
Penicillin	0/0	0/0	0/0	0/0/0

Table 4. Hapten-Inhibition Results (Antiglobulin Test)*
Drug	Cefotetan Antibody Sample 2			Cefotetan Antibody Sample 4
Drug	0.1	1.0	10.0	0.1	1.0	10.0
Cefotetan	2+	2+	M+	2+	2+	M+
7-Aminocephalosporanic acid	2+	2+	2¹/₂+	2+	2+	2+
Cefamandole	2+	3+	2+	2+	2+	2+
Cefazolin	2+	2¹/₂+	2+	2+	2+	2+
Cefepime	2+	2+	2+	2+	2+	2+
Cefoperazone	2+	2+	2+	2+	2+	2+
Cefotaxime	2+	2+	2+	2+	2+	2+
Cefoxitin	2+	2+	2+	2+	2+	2+
Ceftazidime	2+	2+	M+	2+	2+	2+
Ceftriaxone	2+	2+	2+	2+	2+	2+
Cephalothin	2+	2+	¹/₂+	2+	2+	1+
Penicillin	2¹/₂+	2+	2+	2+	2+	2+

Table 5. Results of Cefotetan Antibodies Tested Against Other Cephalosporin-Treated RBCs
Drug	Johnson et al^[7]	Stroncek et al^[8]	Moes and MacPherson^[10]	Ray et al^[12]	Eckrich et al^[25]	Ogburn et al^[26]	Chenoweth et al^[27]	Present Study
Cephalothin	--	--	--	--	+	--	--	+
Cephalexin	--	(+)	--	--	--	--	--	--
Cefazolin	--	--	0	0	--	--	0	0
Cefadroxil	--	--	--	--	--	+	--	--
Cefotaxime	--	--	--	--	--	--	0	(+)
Ceftriaxone	+	--	--	--	--	--	--	0
Penicillin	--	--	--	0	0	+	+	+

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

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