Comment: Association Between the Prothrombin Time-International Normalized Ratio and Concomitant Use of Antibiotics in Warfarin Users: Focus on Type of Antibiotic and Susceptibility of Bacteroides fragilis to Antibiotics

I read the article by Yagi et al ¹ in your journal with great interest. They investigated the effect of antibiotics use on the prothrombin time-international normalized ratio (PT-INR) in patients receiving warfarin. This study was well designed and contains useful data for all physician because the situation focused on occurs frequently in clinical practice. Here, I would like to comment for the further usefulness and development of this study from the viewpoint of the diversity of microbiota and gene variants of enzymes associated with drug metabolism.

They revealed that antibiotics having susceptibility to Bacteroides fragilis are significantly associated with excessive PT-INR. ¹ When we try to apply this study to clinical practice, it is necessary to make suggestions of optimal dose adjustment of warfarin for stabilization of PT-INR at the time of starting antibiotics. However, prediction of PT-INR is extremely complicated because of the characteristics of the vitamin K–dependent mechanism that is influenced by multiple factors, including intestinal microbiota; single nucleotide polymorphisms (SNPs) of enzyme associated with warfarin metabolism such as CYP2C9, VKORC1, CYP1A2, and CYP3A4; nutrition; and concomitant drugs. ² Regarding microbiota, numerous bacteria are resident and their composition is quite diverse in individuals, depending on race, diseases, or environmental conditions.^3,4 The proportion of Bacteroides spp is known to decreased with obesity and increase with ageing.^5,6 In addition, intestinal bacteria are maintained while interacting with each other, which suggests that production of vitamin K can be affected by not only Bacteroides spp, but also other species. Also, enzymes associated with warfarin metabolism are genetic variants and have a strong influence on PT-INR control. ⁷ Although excessive PT-INR is directly associated with bleeding events that are sometimes lethal, safety system and prediction model based on known contributors are not well established, as a great unmet need.

Breakthroughs in understanding of genomics and microbiota have progressed; however, application to clinical practice is not still realized because the methodology is still developing. In the era of precision medicine, I hope that the results of this study will be confirmed by other larger cohorts and further that the associations with the SNPs of the metabolizing enzymes and microbiomics are minutely investigated by using a national register system. Moreover, identification of major contributing factors and analysis of their quantitative effects to warfarin–PT-INR metabolism will lead to application to mathematical models such as already reported.^7,8 It may be possible to realize to propose a reduction in the dose of warfarin in clinical practice when starting antibiotics. I hope that this study will be a clue to personalized precision medicine in the field of pharmacomicrobiomics and pharmacogenomics and will further progress in the future.