(P-373) Cefoperazone and the Risk of Bleeding: A Systematic Review and Network Meta-analysis

Background: Cefoperazone is a third-generation cephalosporin. It has a wide spectrum activity against many bacterias. Serious bleeding cases is a major concern for many years with cefoperazone.

Objectives: To investigate the risk of bleeding with cefoperazone in comparison to ceftriaxone, ceftazidime and cefotaxime which are registered cephalosporins in Saudi Arabia with the same indication.

Methods: A search was conducted in PubMed, Cochrane and Google Scholar for relevant studies in English language from inception to October 2020. Search terms and strategies included the following: (Cefoperazone OR Ceftriaxone OR Cefotaxime OR Ceftazidime AND Hemorrhage OR Haemorrhage, bleeding OR blood loss OR bleeding time abnormal OR bleeding time prolonged OR Hypoprothrombinemia OR bleeding anvoultary). In addition, we conducted a Bayesian Network Meta-analysis to compare the risk of bleeding between cefoperazone and the other cephalosporins.

Results: We included four studies (a randomized clinical trial (RCT), a retrospective cohort, a nested case-control and a review article). In a RCT, Hypoprothrombinemia was reported in three cefoperazone users out of 60 and in one ceftriaxone user out of 50.
In a retrospective cohort, Hypoprothrombinemia was found statistically higher among cefoperazone users versus ceftazidime (adjusted OR 5.7, 95%CI 2.5-13.2) and among cefoperazone users versus ceftizoxime or cefotaxime users (adjusted OR 7.2, 95%CI 2.9 -18).
While in a nested control study compared between cefoperazone and reference antibiotics, found a statistically higher risk of bleeding among cefoperazone users compared to reference antibiotics users (aOR 4.57, 95%CI 2.63-7.95).
Based on the network meta-analysis that we conducted including the two observational studies, the fixed-effect model showed a statistically significant low risk of bleeding in cefuroxime, flomoxef, and cefoxitin vs cefoperazone. However, the random effect model did not show a difference between the medications included in the analysis.

Conclusions: The available data suggested a potential safety signal of bleeding among cefoperazone users, which needed further evaluation by well-designed pharmacoepidemiological studies. However, the risk of hypoprothrombinemia had a significant association with cefoperazone.