Severe delayed coagulopathy caused by cefoperazone/sulbactam: A case report

Abstract

This case report described a suspected severe coagulopathy attributed to cefoperazone/sulbactam, and this adverse reaction might be associated with the inhibition of the vitamin K cycle by cefoperazone/sulbactam, leading to vitamin K deficiency within the body. We reported a patient diagnosed with bacterial pneumonia, who received cefoperazone/sulbactam during hospitalization. The patient was administered cefoperazone/sulbactam via intravenous infusion at a dose of 1.5 g every 8 h for a consecutive treatment period of 23 days. On the 26th day, the patient developed a serious adverse reaction characterized by prolonged clotting time. After treatment with vitamin K1, the coagulation parameters significantly improved by the 28th day (prothrombin time decreased by 88.4%, activated partial thromboplastin time decreased by 61.1%, and international normalized ratio decreased by 88.5%). The Naranjo assessment score was 5, suggesting that the patient’s coagulation disorder could be related to the use of cefoperazone/sulbactam. This report highlights that patients at high risk of bleeding should be vigilant about the coagulopathy caused by cefoperazone/sulbactam- and extend the duration of coagulopathy monitoring.

Introduction

Cefoperazone/sulbactam (CPZ/SAM) combines a third-generation cephalosporin with a β-lactamase inhibitor. CPZ exerts its bactericidal effect by inhibiting the biosynthesis of cell wall mucopeptide in susceptible bacteria during the bacterial reproduction period. SAM can protect CPZ from hydrolysis by β-lactamase, enhancing the antibacterial activity and broadening the antibacterial spectrum of CPZ. It exhibits antibacterial effects against most gram-positive cocci, gram-negative bacilli, and anaerobic bacteria, and CPZ/SAM is currently widely used in clinical practice in China. ¹ Adverse effects of CPZ/SAM include coagulation disorders, bleeding, abdominal pain, diarrhea, blood in urine, hemoptysis, skin and mucous membrane congestion, or ecchymosis. Coagulation disorders such as Prothrombin time (PT) and activated partial thromboplastin time (APTT) have also been reported.^2,3 Cases of coagulation disorders induced by CPZ/SAM have been reported, although the number of published articles remains limited. However, similar adverse events continue to occur in clinical practice, highlighting the need for further documentation to raise awareness and inform a broader readership.

Case report

The reporting of this study conforms to Case Report (CARE) guidelines. ⁴ We obtained the patient’s consent to publish this case report, and obtained the written consent. We have deidentified all patient details. An elderly man in his 70s was hospitalized in West China Hospital in October 2024 with intestinal obstruction and gastrointestinal bleeding. He had a body mass index of 22.72, which falls within the normal range. He was hospitalized for bacterial pneumonia 23 days earlier and had received an intravenous infusion of CPZ/SAM at a dosage of 1.5 g every 8 h for 23 days. An abdominal computed tomography (CT) scan suggested the possibility of intestinal obstruction and peritonitis. Based on this, ornidazole injection, 1 g once daily, was administered to control the infection, and esomeprazole injection, 40 mg once daily, was given to inhibit gastric acid secretion. This treatment was continued for 7 days. Given the patient’s history of atrial fibrillation, enoxaparin sodium injection (40 mg once daily; 1 mg of enoxaparin is equivalent to 100 IU of anti-Xa activity) was administered simultaneously to prevent thrombosis, and this treatment lasted for 1 day.

Gastrointestinal bleeding was noted the day after the patient was discharged from the hospital. Upon admission, the patient's coagulation function tests and biochemical examinations showed abnormalities (Figure 1). Immediately after admission, esomeprazole sodium injection (80 mg daily), somatostatin (60 mg daily), and carbazochrome sodium sulfonate injection (60 mg daily) were administered for hemostasis. In addition, amiodarone hydrochloride injection (300 mg) was administered daily for heart rate control, and furosemide injection (20 mg daily) was given for diuresis. Gastroscopy revealed bleeding from a duodenal ulcer, and hemostasis was achieved endoscopically. Two titanium clips were used to stop bleeding in the cardia and body of the stomach.

Figure 1.

Changes in coagulation functional parameters with time after admission. APTT: activated partial thromboplastin time; INR: international normalized ratio; PT: prothrombin time.

On the evening of the third day after admission, the patient’s PT, international normalized ratio (INR), and APTT were severely prolonged, whereas fibrinogen (FIB) and blood platelet (PLT) count remained unchanged (Figures 1 and 2). Based on prior research, delayed onset is defined as the development of coagulation disorders more than 20 days after drug administration. ³

Figure 2.

Changes in coagulation functional parameters with time after admission. FIB: fibrinogen; PLT: blood platelet.

The patient immediately received an intramuscular injection of vitamin K₁ (10 mg once daily). Two units of suspended red blood cells were infused simultaneously, totaling five units. After the coagulopathy, tests were performed for toxic drugs such as methamphetamine, 3,4-methylenedioxymethamphetamine, ketamine, morphine, heroin, and organic pesticides, and drug poisoning was excluded. In addition, immunological and genetic disease examinations were performed, excluding hereditary coagulation disorders. The patient’s coagulation factor V activity was elevated (154.0%), coagulation factor activity was elevated (271.2%), and other factors were within normal limits. During the treatment period, the patient had no fever, and no other antibiotics were used. Four days after treatment with vitamin K₁, the patient’s PT, INR, and APTT returned to normal.

Discussion

Long-term and high-dose use of CPZ/SAM may lead to a disorder in the synthesis of vitamin K and thus cause coagulopathy. Specifically, CPZ/SAM contains a structure similar to N-methylthiotetrazole. This similarity allows it to competitively bind to γ-glutamyl carboxypeptidase, blocking vitamin K and causing disordered synthesis. CPZ/SAM-induced coagulopathy occurs due to interference with vitamin K synthesis, which subsequently reduces the production of vitamin K-dependent factors II, VII, IX, and X. Moreover, CPZ (a component of CPZ/SAM) is primarily excreted through bile. Critically, bile reduces vitamin K-producing gut bacteria, such as Escherichia coli and Bacteroides. Together, these effects significantly reduce vitamin K synthesis. ⁵ Regarding clinical prevalence, a study using machine learning models reported that the incidence of coagulation disorders related to cefazolin sodium, CPZ/SAM, cefminol sodium, amoxicillin/SAM sodium, and piperacillin/tazobactam sodium was 2.4%, 5.4%, 1.5%, 5.5%, and 4.8%, respectively. ⁶ Furthermore, recent research indicates that CPZ/SAM is more likely to cause coagulation disorders than CPZ-tazobactam. This finding suggests that SAM may play a synergistic role with CPZ in hypoprothrombinemia. ⁷

Enoxaparin treatment was stopped after 1 day. A 10-day interval elapsed from the cessation of enoxaparin use to the development of coagulation disorders. The main anticoagulant effect of enoxaparin is achieved by enhancing the inhibition of coagulation factor Xa and thrombin through antithrombin, thereby exerting its antithrombotic function. However, enoxaparin can achieve the peak of anti-Xa activity within 3–5 h after administration, and its half-life is related to the dosage, with a maximum of 5 h. ⁸ Furthermore, no studies have reported coagulation abnormalities caused by enoxaparin lasting for more than 20 days. Therefore, we do not consider enoxaparin to be the cause. Other medications that could affect coagulation function between admission and the onset of coagulation disorders include esomeprazole, furosemide, and amiodarone. Omeprazole may affect anticoagulant efficacy by inhibiting CYP2C19 enzyme activity, interfering with the metabolism of antiplatelet drugs such as clopidogrel. Rare adverse reactions include thrombocytopenia, but the incidence is extremely low. ⁹ According to previous research, among loop diuretics, torsemide rather than furosemide may cause bleeding events and prolonged PT. ¹⁰ Amiodarone may prolong clotting time and increase the risk of bleeding by inhibiting vitamin K-dependent coagulation factors II, VII, IX, and X. However, cases of coagulation disorders caused by amiodarone are often cotreated with warfarin.^11,12

We referred to the Naranjo assessment scale, and the patient’s score was 5, indicating a high probability between CPZ/SAM and coagulopathy. According to the Naranjo assessment scale, there are previous case reports of similar cases (1 point), the adverse reaction occurred after the use of CPZ/SAM (2 points), the use of vitamin K₁ relieved the symptoms (1 point), and the patient’s laboratory test results confirmed the abnormal coagulation function (1 point). Therefore, the comprehensive score shows that the patient’s Naranjo assessment scale result is “very likely” (5 points). ¹³ We also referred to the Uppsala Monitoring Center (UMC) method, and the causal relationship grade was “probably related.” Finally, based on the nomogram for predicting CPZ/SAM-induced hypoprothrombinaemia by Bai H, we evaluated the risk of this adverse drug reaction in this patient. ¹⁴ The assessment results showed that the patient’s total score was 105 points, indicating a relatively high probability of the risk of hypoprothrombinaemia due to CPZ/SAM.

Moreover, the coagulopathy caused by CPZ/SAM is different from that caused by other drugs. In previous studies, PT, APTT, and INR showed significant increases in patients with coagulation disorders caused by CPZ/SAM.^7,15 In our case, PT and INR increased significantly. APTT showed minimal increase, but after the administration of vitamin K₁, all three indicators decreased significantly to normal levels. Interestingly, the patient’s FIB did not change significantly, which aligns with previous findings that CPZ/SAM disrupts vitamin K metabolism and synthesis, impairing the synthesis of vitamin K-dependent clotting factors while not affecting the synthesis and secretion of clotting factors. ¹⁶ β-lactam drugs can usually lead to thrombocytopenia, including piperacillin, cefuroxime, piperacillin/tazobactam, and ampicillin/clavulanic. Some case reports showed that thrombocytopenia is a rare but serious adverse reaction in patients administered CPZ/SAM, which may not respond to standard drug treatment.^17,18 No significant change in PLT was observed in our patient. This may be related to blood transfusion and the low probability of this adverse reaction.

Coagulopathy induced by CPZ/SAM can be challenging to detect, as the adverse effects may not occur immediately after CPZ/SAM use. ¹⁶ The coagulopathy usually emerges 6.6 ± 3.2 days after CPZ/SAM use and can be delayed up to 19 days. ³ Compared with previous CPZ/SAM-induced coagulopathy cases, the time to first detection of the adverse reaction in this patient was significantly prolonged to 26 days. As CPZ/SAM inhibits vitamin synthesis, such adverse reactions often appear delayed. In a retrospective study, patients developed coagulation disorders as early as the second day of treatment, with 195 cases recorded between the 2nd and 19th days, accounting for about 99% of the cases. ³

In our case, the patient received CPZ/SAM at a dose of 4.5 g daily, which is below the commonly reported dangerous dose of 6 g daily. ¹⁹ However, continuous use for over 10 days, advanced age (>65 years), and anticoagulant use were bleeding risk factors.^20,21 Prior to admission, the patient had been bedridden and maintained on a fasting diet for an extended period. Moreover, his advanced age and history of blood transfusion may have contributed to prolonged coagulation times. Nevertheless, we conclude that CPZ/SAM was the primary factor responsible for the severe coagulation abnormality observed. Additionally, we could not establish an association between CPZ/SAM and intestinal obstruction in this patient. Vitamin K₁ supplementation is recommended to prevent adverse events like secondary coagulation risks in high-bleeding-risk patients on CPZ/SAM. CPZ/SAM dosage, duration of use, advanced age, renal insufficiency, fasting state, and liver damage are independent risk factors for CPZ/SAM-induced coagulopathy.^22,23 As vitamin K₁ is not currently routinely used to prevent bleeding after CPZ/SAM treatment in clinical practice, we recommend that high-risk patients have their coagulation function monitored earlier and for a longer duration. Alternatively, prophylactic supplementation with vitamin K₁ may be considered to prevent coagulopathy.

Conclusion

In this case, we report a case of vitamin K‑dependent coagulopathy induced by CPZ/SAM. The patient had been treated with CPZ/SAM for 23 days and developed coagulopathy following hospitalization for gastrointestinal bleeding. The patient’s APTT, PT, and INR were all significantly prolonged and rapidly returned to normal levels following the administration of vitamin K₁. Although coagulopathy caused by CPZ/SAM is rare, we recommend that cephalosporins be chosen cautiously for patients at high risk of bleeding when providing anti-infective therapy. If there is a clinical need to use such drugs, patients’ coagulation function should be monitored early and over an extended period.