The Association Between Cephalosporin and Hypoprothrombinemia: A Systematic Review and Meta-Analysis

Abstract

Cephalosporins that contain the N-methylthiotetrazole side chain (NMTT-cephalosporin) have been reported to be associated with coagulation-related adverse events; however, a comprehensive evaluation regarding the association is lacking. A systematic review and meta-analysis were conducted to assess the safety profile of NMTT-cephalosporins with respect to hypoprothrombinemia and bleeding. The MEDLINE, Embase, Cochrane, and RISS databases were systematically searched for clinical studies up to October 2018. The association between NMTT-cephalosporins and hypoprothrombinemia was estimated using an odds ratio (OR) with a 95% confidence interval (CI). A total of 15 studies on cefamandole, cefoperazone, cefotetan, cefmetazole, and moxalactam were identified and included in the meta-analysis. Hypoprothrombinemia (OR 1.676, 95% CI 1.275–2.203) and prothrombin time (PT) prolongation (OR 2.050, 95% CI 1.398–3.005) were significantly associated with NMTT-cephalosporins, whereas bleeding was not (OR 1.359, 95% CI 0.920–2.009). Subgroup analyses revealed that cefoperazone (OR 2.506, 95% CI 1.293–4.860), cefamandole (OR 3.247, 95% CI 1.083–9.733), and moxalactam (OR 3.367, 95% CI 1.725–6.572) were significantly associated with hypoprothrombinemia. An Antimicrobial Stewardship Program led by a multidisciplinary team could play a critical role in monitoring cephalosporin-related hypoprothrombinemia or PT prolongation in patients with underlying clinical conditions at risk for bleeding. The multidisciplinary team could also assist in communicating the potential safety concerns regarding NMTT-cephalosporin use with healthcare professionals to decrease the risk of adverse events.

Latamoxef‐induced coagulation disorders: Incidence and risk factors

“…The results were in accordance with the earlier findings, which showed that latamoxef might increase coagulation disorders. 1,[8][9][10] However, the bleeding events were rarely seen in our study, which showed no difference between the latamoxef group and ceftazidime group. This was in keeping with the study conducted by Park et al, which did not find the correlation of bleeding and the usage of NMTT-cephalosporins.…”

“…Subgroup analyses revealed that latamoxef (OR 3.367, 95% CI 1.725-6.572) was obviously associated with hypoprothrombinaemia. 1 Calandra et al evaluated the tolerance of latamoxef in 158 patients, two of whom experienced haemoperitoneum or gastrointestinal haemorrhage. 11 Fainstein investigated 268 cancer patients who received β-lactam antibiotics, 3 of 28 patients treated with latamoxef, and tobramycin developed severe coagulation abnormalities and suffered haemorrhage.…”

“…This was in keeping with the study conducted by Park et al, which did not find the correlation of bleeding and the usage of NMTT-cephalosporins. 1 Nevertheless, some reported the latamoxef-induced haemorrhagic events. 4,8,9,11,12 The possible reasons were as follows.…”

“…Latamoxef is a broad‐spectrum oxacephem antibiotic widely used in moderate to severe infections such as respiratory, intra‐abdominal or urinary tract infections. Latamoxef has an N‐methylthiotetrazole (NMTT) side chain which was thought to be a key structure to induce vitamin K deficiency, hypoprothrombinemia, thrombocytopenia and bleeding 1 . Cefoperazone, which also carries an NMTT structure, was linked with a higher risk of hypoprothrombinemia, with the reported incidence ranging 4%–68% 2 .…”

“…Cefoperazone, which also carries an NMTT structure, was linked with a higher risk of hypoprothrombinemia, with the reported incidence ranging 4%–68% 2 . Several researchers noticed that latamoxef could induce prolonged prothrombin time (PT) or activated partial thromboplastin time (APTT) 1,3 . However, there were very few Asian patients till now.…”