Life-Threatening Bleeding in a Patient Treated with Cefonicid

TO THE EDITOR:

Although cephalosporins are generally considered to be safe and well-tolerated antimicrobial agents, they may have several adverse hematologic effects, including hemolytic anemia, neutropenia, thrombocytopenia, and coagulation defects. Compounds with an N-methyl-thiotetrazole (NMTT) side chain (such as moxalactam, cefotetan, or cefamandole) have been associated with a higher incidence of bleeding [1]. Free NMTT inhibits vitamin K epoxide reductase, thus interfering with the carboxylation of several factors in the coagulation cascade [2]. Cefonicid is a second-generation cephalosporin that does not contain an NMTT chain and that is usually considered free of hemorrhagic adverse effects. We describe a patient who developed life-threatening bleeding after two doses of cefonicid.

A 68-year-old woman was seen in the emergency department because of hemorrhagic diathesis. One year earlier, she had received a biologic (Hancock) valve prosthesis because of severe aortic stenosis and regurgitation. One month after surgery, the patient had an ischemic stroke. Coagulation variables were normal, and she began receiving acenocoumarol. The dose was adjusted according to periodic controls. During the following months, her prothrombin index ranged from 27% to 48% (international normalized ratio, 1.7 to 3.3) while she received 18 mg of acenocoumarol per week. Two weeks before admission, her prothrombin index was 28% (international normalized ratio, 3.3). She had a history of kidney stones and took enalapril to control hypertension. One week before admission, she experienced pain in the left kidney area, which was treated with acetaminophen and hyoscine. A few days later, fever appeared, and cefonicid was prescribed (1 g/d). Two days later, multiple hematomas, hematuria, and melena developed. Her status deteriorated rapidly.

On admission the patient was hypotensive and icteric and had extensive hematomas. Her physical examination was otherwise unremarkable. She had gross hematuria and frank melena. A complete blood count showed 19 000 leukocytes, a hemoglobin concentration of 5 g/dL, and 40 000 platelets. Her partial thromboplastin time was 129 seconds (control, 27 seconds), and her prothrombin index was less than 5%. Fibrinogen levels and thrombin time were normal. She received intravenous crystalloids, ranitidine, ciprofloxacin, vitamin K, 4 units of plasma, and 4 units of packed red blood cells. The next day, her partial thromboplastin time and prothrombin index were normal, and she showed no evidence of active bleeding. An ultrasonographic scan showed kidney stones, and Escherichia coli grew in a urine culture. Blood cultures were negative. An echocardiogram showed no evidence of endocarditis.

Cefonicid is usually well tolerated and, unlike NMTT-containing cephalosporins, does not generally interfere with the synthesis of coagulation factors, even in patients with cirrhosis [3]. Nevertheless, a patient with low prothrombin levels and skin hematomas apparently related to cefonicid therapy was recently described [4]. A MEDLINE search of articles published from 1986 to 1994 found no other reports of hemorrhagic diathesis associated with cefonicid use. Infections and low vitamin K levels are risk factors for antibiotic-related bleeding [5]; thus, it seems likely that anticoagulant therapy and urinary tract infection predisposed this patient to hemorrhage. Prophylactic therapy with vitamin K has been proposed to decrease the incidence of hemorrhage in high-risk patients receiving antibiotics. Because it is not appropriate in patients receiving anticoagulants, therapy with NMTT-containing cephalosporins should not be used in such patients. This case emphasizes the need for frequent monitoring of anticoagulation levels even when safe cephalosporins are prescribed.

• Copyright ©2004 by the American College of Physicians