Cefoperazone-induced severe coagulopathy in a patient without classical risk factors: A case report

INTRODUCTION

Cefoperazone is a third-generation cephalosporin frequently combined with sulbactam to enhance its efficacy against beta-lactamase-producing organisms. Despite its clinical effectiveness, cefoperazone carries a unique risk of coagulopathy due to its N-methyl-thio-tetrazole (NMTT) side chain, which inhibits Vitamin K epoxide reductase and disrupts the synthesis of Vitamin K-dependent clotting factors (II, VII, IX, and X).^[1] This case report describes a previously healthy patient who developed significant coagulopathy following cefoperazone therapy for community-acquired pneumonia, emphasizing that this adverse effect can occur even in low-risk populations.

CASE REPORT

A 58-year-old previously healthy male presented to the emergency department with a 5-day history of productive cough with greenish-yellow sputum, high-grade fever, and progressive dyspnea. He reported left-sided pleuritic chest pain and worsening shortness of breath on exertion. The patient’s dietary history was significant for poor nutritional intake over the preceding month due to extended work hours, with irregular meal patterns and limited consumption of Vitamin K-rich foods, including green leafy vegetables and dairy products. He denied any history of bleeding disorders, recent antibiotic use, or anticoagulant therapy.

Physical examination revealed an acutely ill, febrile patient with a temperature of 102.4°F, tachypnea (28 breaths/min), and hypoxemia with oxygen saturation of 88% on room air. Respiratory examination demonstrated bilateral decreased breath sounds with left-sided predominance, diffuse coarse crepitations, and dullness to percussion in the left lower lung zone. Cardiovascular examination showed tachycardia (112 beats/min) but no signs of chronic liver disease or peripheral edema.

Laboratory investigations revealed leukocytosis (18,500 cells/µL), markedly elevated C-reactive protein (156 mg/L), and normal baseline coagulation parameters, including prothrombin time (PT) (13.2 s), international normalized ratio (INR) (1.0), and activated partial thromboplastin time (aPTT) (32 s). Liver and renal function tests were within normal limits. Chest radiograph demonstrated bilateral pulmonary infiltrates with confluent left lung consolidation, left lower lobe involvement, and associated pleural effusion consistent with severe community-acquired pneumonia [Figure 1]. Sputum culture yielded Pseudomonas aeruginosa sensitive to cefoperazone– sulbactam, meropenem, and piperacillin–tazobactam.

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Figure 1:

Chest radiograph (PA view) on admission showing bilateral pulmonary infiltrates with confluent consolidation (arrow) predominantly affecting the left lung, left lower lobe involvement, and associated pleural effusion (arrow) consistent with severe community-acquired pneumonia.

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The patient was initiated on empirical intravenous cefoperazone–sulbactam 2 g every 12 h along with supplemental oxygen, bronchodilators, and supportive care. On day 6 of antibiotic therapy, the patient developed large spontaneous ecchymoses covering extensive areas of bilateral extremities [Figure 2a and b], hematuria with visible blood, and epistaxis requiring nasal packing, without any precipitating trauma. Repeat coagulation studies revealed dramatically prolonged PT (45 s) and elevated INR (3.8), whereas aPTT remained normal (36 s). Fibrinogen, D-dimer, and platelet count were normal, and hemoglobin decreased from 14.2 to 11.5 g/dL. The isolated prolongation of PT and INR without other signs of disseminated intravascular coagulation suggested drug-induced Vitamin K deficiency coagulopathy. The Naranjo Adverse Drug Reaction Probability Scale yielded a score of 7, indicating a probable causal relationship between cefoperazone and coagulopathy. Cefoperazone–sulbactam was immediately discontinued and replaced with intravenous meropenem 1 g every 8 h. Vitamin K1 10 mg was administered intravenously daily for 3 consecutive days. Coagulation parameters began normalizing within 24 h, returning to baseline by day 10 with PT of 13.5 s and INR of 1.0. The ecchymoses resolved progressively over the following week without further bleeding episodes, and hemoglobin stabilized at 11.3 g/dL without transfusion requirement.

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Figure 2:

(a) Extensive spontaneous ecchymosis on the upper extremity on day 6 of cefoperazone therapy, demonstrating drug-induced coagulopathy. (b) Large spontaneous ecchymosis affecting an extensive area of the thigh on day 6 of cefoperazone therapy, demonstrating the severity of cefoperazone-induced Vitamin K-dependent coagulopathy.

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The patient completed a 14-day meropenem course with excellent clinical response. Respiratory symptoms improved significantly, oxygen saturation normalized to 98% on room air by day 12, and follow-up chest radiograph on day 14 showed over 80% clearance of bilateral infiltrates with complete resolution of pleural effusion. He was discharged on day 16 with dietary counseling emphasizing Vitamin K-rich foods and education about the adverse reaction. The detailed timeline of clinical progression, laboratory parameters, and therapeutic interventions is summarized in Table 1. At 4-week follow-up, he remained asymptomatic with normal coagulation studies and complete radiographic resolution of pneumonia.

DISCUSSION

This case illustrates that cefoperazone-induced coagulopathy can occur in apparently low-risk patients with subclinical Vitamin K deficiency. The mechanism involves dual pathways: the NMTT side chain inhibits Vitamin K epoxide reductase, preventing recycling to its active form and blocking gamma-carboxylation of clotting factors, whereas simultaneously suppressing Vitamin K-producing intestinal bacteria, particularly Bacteroides species. This dual mechanism enables rapid coagulopathy development, especially in patients with depleted Vitamin K reserves.^[1,2]Traditional risk factors for cefoperazone-induced coagulopathy include critical illness, renal impairment, hypoalbuminemia below 3.0 g/dL, treatment duration exceeding seven days, daily doses exceeding 6 g, and age over 60 years.^[1,3,4] Our patient possessed none of these characteristics: he was 58 years old with normal renal and hepatic function, normal albumin, moderate illness severity, and received only 4 g daily. The coagulopathy developed on day 6, within the typical 2–8 day window. The probable predisposing factor was 1 month of dietary inadequacy with limited Vitamin K-rich food intake.

A significant limitation is the absence of baseline Vitamin K measurements, preventing definitive confirmation of pre-existing deficiency. However, clinical history, dietary patterns, rapid response to supplementation, and exclusion of alternative causes strongly support this hypothesis.

Prevention strategies should include baseline coagulation studies and nutritional assessment for all patients receiving cefoperazone, prophylactic Vitamin K administration for those with nutritional inadequacy regardless of illness severity, and enhanced monitoring on days 3, 6, and 9 of therapy. Management requires immediate drug discontinuation, Vitamin K supplementation (10 mg intravenously daily for 3 days), alternative antibiotic substitution, and for life-threatening bleeding, fresh frozen plasma or prothrombin complex concentrates.^[5] Our patient’s prompt response to discontinuation and Vitamin K therapy, with coagulation normalization within 72 h, demonstrates the effectiveness of early recognition and appropriate intervention.

CONCLUSION

This case highlights that cefoperazone-induced coagulopathy can occur in patients without traditional risk factors when subclinical nutritional deficiencies exist. Clinicians should maintain high suspicion, conduct thorough dietary assessments, and implement proactive monitoring strategies. Early recognition, prompt cefoperazone discontinuation, and Vitamin K supplementation ensure favorable outcomes. Prophylactic Vitamin K administration should be considered for nutritionally compromised patients receiving cefoperazone therapy.