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

Gi Hyue Park, Seungyeon Kim, Min Soo Kim, Yun Mi Yu, Gun Hee Kim, Jeong Sang Lee, Euni Lee, Gi Hyue Park, Seungyeon Kim, Min Soo Kim, Yun Mi Yu, Gun Hee Kim, Jeong Sang Lee, Euni Lee

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.

Keywords: bleeding; cephalosporins; hypoprothrombinemia; prothrombin time.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Flow chart of the study selection process.
Figure 2
Figure 2
Risk of bias in the included randomized controlled studies.
Figure 3
Figure 3
Forest plots of odds ratio for bleeding, PT prolongation, and hypoprothrombinemia associated with NMTT-cephalosporin compared with non-NMTT-cephalosporin. NMTT, N-methylthiotetrazole side chain. a Multiple control groups from the study were treated independently in the meta-analysis.
Figure 4
Figure 4
Subgroup analyses of hypoprothrombinemia and each NMTT-cephalosporins. NMTT, N-methylthiotetrazole side chain. a Multiple control groups from the study were treated independently in the meta-analysis.

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