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  ::  Case History
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  Table of Contents     
Year : 2023  |  Volume : 69  |  Issue : 1  |  Page : 46-49

Cefoperazone/sulbactam-induced hemolytic anemia

1 Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
2 Department of Hepatobiliary and Pancreaticosplenic Surgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China

Date of Submission09-Dec-2020
Date of Decision13-Feb-2021
Date of Acceptance31-Mar-2021
Date of Web Publication13-Sep-2021

Correspondence Address:
Dr. H G Wang
Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jpgm.JPGM_1335_20

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 :: Abstract 

Drug-induced hemolytic anemia (DIHA) is a rare complication of drug therapy and usually underdiagnosed. Cefoperazone/sulbactam is a compound prepared from the third generation of cephalosporin and β-lactamase inhibitor. There are limited data of DIHA induced from cefoperazone/sulbactam. A 93-year-old female patient, who had an operation on the biliary tract 3 months ago, was admitted to our hospital with an abdominal infection. After cefoperazone/sulbactam was given as anti-infection treatment, the patient developed hemolytic anemia on the third day. Cefoperazone/sulbactam was discontinued and replaced with meropenem. Subsequently the level of red blood cells, hemoglobin, and hematocrit returned to normal. Clinicians should pay attention to monitoring the possible adverse reactions during the use of cefoperazone/sulbactam and should be aware of the occurrence of DIHA, so as to give timely treatment.

Keywords: Adverse reactions, cefoperazone, drug-related side effects, hemolytic anemia, sulbactam

How to cite this article:
Sun X M, Liu L H, Wu Q, Wang H G. Cefoperazone/sulbactam-induced hemolytic anemia. J Postgrad Med 2023;69:46-9

How to cite this URL:
Sun X M, Liu L H, Wu Q, Wang H G. Cefoperazone/sulbactam-induced hemolytic anemia. J Postgrad Med [serial online] 2023 [cited 2023 Nov 28];69:46-9. Available from:

 :: Introduction Top

Drug-induced hemolytic anemia (DIHA) is a rare complication of drug therapy, which is mostly induced by the second and third generation of cephalosporins. Cefoperazone/sulbactam is a compound preparation of cefoperazone, a third generation of cephalosporin, and sulbactam sodium, a β-lactamase inhibitor.[1] Recently, the abnormal coagulation function caused by cefoperazone/sulbactam has been frequently reported. But there are only two reports of cefoperazone/sulbactam-associated DIHA. Here, we report an abdominal infection in a patient who was treated with intravenous injection of cefoperazone/sulbactam (3 g, q12h) and developed hemolytic anemia that was immune under our suspicion. After the withdrawal of the drug, this adverse reaction subsided. We want to increase the warning of clinicians through this rare case, as it belonged to the most common drugs causing hemolytic anemia but with less attention.

 :: Case History Top

A 93-year-old woman was admitted to our hospital complaining of abdominal pain with nausea and vomiting for 3 days and fever at 38.5°C for 2 days. Three months ago, she underwent laparoscopic biliary tract exploration and cholecystectomy for cholangiolithiasis with cholangitis, cholecystolithiasis with cholecystitis, and obstructive jaundice, and recovered well after the operation. After admission to our hospital, her vital signs were normal. Complete blood count showed white blood cell count (WBC) 11.72 × 109/L (normal 3.5–9.5 × 109/L), percentage of neutrophil count (NE) 86.0% (normal 40%–75%), red blood cell count (RBC) 3.24 × 1012/L (normal 3.8–5.1 × 1012/L), hemoglobin (Hb) 110 g/L (normal 115–150 g/L), hematocrit (HCT) 32.8% (normal 35–45%), and platelet (PLT) 225 × 109/L (normal 125–350 × 109/L). Biochemical tests showed total bilirubin 100.6 μmol/L (normal 5–21 μmol/L), direct bilirubin 69.3 μmol/L (normal 0–6 μmol/L), indirect bilirubin (IBIL) 31.3 μmol/L (normal 3.4–17.1 μmol/L), and lactate dehydrogenase (LDH) 222 U/L (normal 120–250 U/L). Computed tomography (CT) examination indicated that there was an abdominal infection with negative results of bacterial culture. Based on the above evidence, she was diagnosed with abdominal infection, choledochectasia post biliary surgery, jaundice, and abnormal liver function. On the day of admission, the clinicians gave her cefoperazone/sulbactam (3.0 g, q12h, ivgtt [intravenously guttae]) as an anti-infective treatment. On the third day, her RBC, Hb, and HCT decreased slightly, and the values were 3.10 × 1012/L, 108 g/L, and 31.8%, respectively. After 1 month of anti-infective therapy, the infection improved, and the WBC and NE also decreased [Figure 1]a and [Figure 1]b. Meanwhile, her RBC, HCT, and Hb continued to decrease [Figure 1]d, [Figure 1]e, [Figure 1]f. PLT showed a trend of fluctuation [Figure 1]c. There was no significant change in LDH, and there was a delayed ascent in IBIL [Figure 2]. The laboratory test results ruled out the possibility of megaloblastic anemia, iron-deficiency anemia, or other kinds of anemia, and CT showed no abdominal bleeding, so she was diagnosed with hemolytic anemia on Day 34. We checked the duration of the administrated drugs [Table 1]. The drugs given before the decrease in RBC, HCT, and Hb (at Day 1 and Day 2) were cefoperazone/sulbactam, omeprazole for injection, polyene phosphatidylcholine, alanyl glutamine, nadroparin calcium, esmolol, and potassium chloride. Only cefoperazone/sulbactam was continuously administered until Day 34. Meanwhile, we looked up the labels and considered that it may be related to cefoperazone/sulbactam. We stopped cefoperazone/sulbactam immediately on Day 34. Although the anemia was Grade 3 as assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, the decrease of Hb did not reach the level for initiating treatment. Because we considered it was an adverse drug reaction, we stopped the drug for observation. The WBC was on the rise [Figure 1]a, and the patient still had intermittent fever at this time with pathogenic bacteria cultured in the bile. We gave her meropenem injection instead of cefoperazone/sulbactam to continue the anti-infective treatment. After withdrawing cefoperazone/sulbactam, the levels of RBC, HCT, and Hb rebounded and returned to normal after 20 days. Then, we reviewed this case. The patient had no medical history or family history of glucose-6-phosphate dehydrogenase (G6PD) deficiency that may induce nonimmune hemolytic anemia. We suspected that this hemolytic anemia might be due to immunological factors caused by cefoperazone/sulbactam.
Figure 1: Changes in blood test reports during the use of cefoperazone/sulbactam (the left side of the arrow) and after withdrawal of it, replaced by meropenem (the right side of the arrow) [a-f]

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Table 1: Details of drug administration

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Figure 2: Changes of serum indirect bilirubin (IBIL) during the use of cefoperazone/sulbactam (the left side of the arrow) and after withdrawal of it, replaced by meropenem (the right side of the arrow)

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 :: Discussion Top

In this case, the patient had symptoms of hemolytic anemia. We considered that cholangitis and cholecystitis resulted in a high value of IBIL at the beginning. Once the infection was controlled, IBIL decreased between Day 4 and Day 30, and then showed a reactive increase beyond the normal range probably associated with hemolytic anemia. After withdrawing cefoperazone/sulbactam, the level of IBIL descended to normal. By comparing the time of the hemolytic anemia with the course of each drug as well as analyzing the known adverse drug reactions, we considered that cefoperazone/sulbactam was the trigger that induced hemolytic anemia. We used the Naranjo method to evaluate the possibility of the adverse drug reaction (ADR) and found that the score was 6, which indicated a “probable” relationship.[2] The details of Naranjo score are shown in [Table 2]. The patient did not have G6PD deficiency and had been given cefoperazone/sulbactam 3 months ago without any adverse events. When cefoperazone/sulbactam was administered the second time during this admission, hemolytic anemia occurred at once. For the above reasons, we strongly suspected that the DIHA was immune. DIHA can be divided into two categories: immune and nonimmune. Nonimmune hemolytic anemia is often accompanied by G6PD deficiency, which is more common in males because of the linked X chromosome. Drugs such as chloramphenicol, ciprofloxacin, glimepiride, ribavirin, and sulfonamides are a common trigger of hemolysis in patients with G6PD deficiency.[3] DIHA is always associated with second- and third-generation cephalosporins.[4] Sulbactam also can cause DIHA by nonimmunologic protein adsorption method.[5] There were two women in the previous reports who had DIHA related to cefoperazone/sulbactam with the same dose. The first patient was treated with multiple antimicrobial agents successively and then developed DIHA.[6] Here we focus on the comparison with the second case. In the second case, DIHA was induced by cefoperazone/sulbactam. The patient was undergoing surgical excision of atrial myxoma with normal Hb, HCT, and RBC levels. On the second day of cefoperazone/sulbactam therapy (3 g, q12h), laboratory test results showed a slight reduction in Hb, HCT, and RBC, and an increase in PLT.[7] The patient received cefoperazone/sulbactam for 8 days, and the levels of Hb, HCT, RBC, and PLT were 58 g/L, 0.192 L/L, 2.29 × 1012/L, and 550 × 109/L, respectively. Then the clinicians discontinued cefoperazone/sulbactam and performed RBC transfusion (2 units) for 3 days. After 1 week, the condition improved, and the patient was discharged. The dose and frequency of cefoperazone/sulbactam administration, Hb, HCT, and RBC changes in the patient were similar to our case. But in our case, the patient was given longer cefoperazone/sulbactam with infection and had a fluctuating rise in PLT. And the condition was handled by discontinuing the suspected drug and giving a close observation. The prognosis of the patients with Hb, HCT, and RBC was similar. The limitation of our report is that DAT or Coombs test was not done to help determine the diagnosis and mechanism of DIHA. But the symptoms and signs, family history, second administration, and drug classes all pointed to immune hemolytic anemia. However, whether the hemolytic anemia was immune or nonimmune, it was still a severe adverse event that cannot be ignored. As cefoperazone/sulbactam is widely used in clinical practice, we report this ADR so as to alert clinical attention to DIHA and to enable timely examination. Only a few teams have worked on the research of DIIHA before. With the development of new drugs, DIHA should not be overlooked.
Table 2: Naranjo score

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Declaration of patient consent

The authors certify that appropriate patient consent was obtained.

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Conflicts of interest

There are no conflicts of interest.

 :: References Top

Iakovlev VP. [Sulperazone--a combined form of cefoperazone with sulbactam]. Antibiot Khimioter 1995;40:55-70.  Back to cited text no. 1
Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45.  Back to cited text no. 2
Harcke SJ, Rizzolo D, Harcke HT. G6PD deficiency: An update. JAAPA 2019;32:21-6.  Back to cited text no. 3
Garratty G. Immune hemolytic anemia associated with drug therapy. Blood Rev 2010;24:143-50.  Back to cited text no. 4
Arndt PA, Leger RM, Garratty G. Positive direct antiglobulin tests and haemolytic anaemia following therapy with the beta-lactamase inhibitor, tazobactam, may also be associated with non-immunologic adsorption of protein onto red blood cells. Vox Sang 2003;85:53.  Back to cited text no. 5
Baek EJ, Lee S, Kim S, Choi HK, Kim HO. A case of immune hemolytic anemia induced by ceftizoxime and cefobactam (sulbactam/cefoperazone). Korean J Lab Med 2009;29:578-84.  Back to cited text no. 6
Zhou L, Bao J, Ma J. Hemolytic anemia and reactive thrombocytosis associated with cefoperazone/sulbactam. Front Pharmacol 2019,10:1342.  Back to cited text no. 7


  [Figure 1], [Figure 2]

  [Table 1], [Table 2]


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