Hypoprothrombinemia and severe perioperative haemorrhagic complications in cardiac surgery patients treated with high-dose cefazolin for infective endocarditis

Abstract

Endocarditis is a serious and common disease that requires prolonged antimicrobial therapy. The recent shortage of oxacillin has led to the use of other antimicrobial agents such as cefazolin to treat endocarditis due to methicillin-sensitive Staphylococcus aureus. We describe four cases of life-threatening haemorrhagic complications (fatal in two cases) in patients treated with high-dose cefazolin. All of these patients with major bleeding presented with hypoprothrombinemia secondary to hypovitaminosis K. This adverse event may be due to inhibition of vitamin K epoxide reductase and/or gamma-glutamyl-carboxylase by the 2-methyl-1,2,3-thiadiazol-5-thiol group of cefazolin. This inhibition may result in hypoprothrombinemia by altering the synthesis of vitamin K-dependent coagulation factors. The increasing use of cefazolin, especially at a high dose and for a prolonged period of time, should be accompanied by regular monitoring of coagulation, including prothrombin index, and vitamin K supplementation.

Introduction

Recent recommendations propose that oxacillin, associated with gentamycin and rifampicin, should be used as first-line treatment for infective endocarditis due to methicillin-sensitive Staphylococcus aureus (MSSA) [1]. The recent shortage of oxacillin forced the French Society of Infectious Diseases to find an alternative antibiotic. Cefazolin (from 80–100 mg.kg⁻¹.day⁻¹) has been proposed as effective therapy for acute endocarditis [2]. Because of an exacerbated inflammatory response, the risk of bleeding during and after cardiac surgery for acute endocarditis remains high. The methyl 5-thiol group present in cephalosporins and released from the molecule in vivo could inhibit vitamin K epoxide reductase. Here, we describe four cardiac surgery patients who were treated with high dose cefazolin for acute endocarditis and developed severe coagulation disorders complicated by major bleeding. Biological tests revealed profound hypoprothrombinemia.