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Comment & Response
July 2014

Supratherapeutic International Normalized Ratios in Warfarin-Treated Patients Who Receive a Highly Potentiating Antimicrobial Course—Reply

Author Affiliations
  • 1Department of Clinical Pharmacy, Kaiser Permanente, Aurora, Colorado
  • 2Department of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Denver
JAMA Intern Med. 2014;174(7):1200-1201. doi:10.1001/jamainternmed.2014.1589

In Reply We thank Daniels and colleagues for their insight and comments regarding our original investigation.1 We agree with their interpretation that patients receiving antibiotics interfering with warfarin metabolism through cytochrome P450 (CYP) enzyme inhibition present a greater risk of excessive anticoagulation than do patients who are sick but do not receive antibiotics. An additional analysis of our data confirms an increased risk of a follow-up international normalized ratio (INR) of 5.0 or greater in the inhibition of CYP metabolism group compared with sick controls (8.6% vs 2.6%, respectively; P < .001).1 The importance of CYP metabolism interactions with warfarin is further underscored in the original analysis of excessive anticoagulation risk across antibiotic mechanism groups. The risk of a follow-up INR of 5.0 or greater was significantly higher in the inhibition of CYP metabolism group compared with the vitamin K disruption group (8.6% vs 3.1%, respectively; P < .017) and between the CYP metabolism group and the no interaction reported group (8.6% vs 2.1%, respectively; P < .017).1 With respect to other highly potentiating antimicrobials, miconazole and voriconazole are rarely used at our institution, and no patients prescribed these medications met study inclusion criteria.1 We did capture information on fluconazole use during our original data collection. Fluconazole administration was documented in 48 patients, with 12.5% of these patients experiencing a follow-up INR of 5.0 or greater. These results are consistent with the other medications included in the inhibition of CYP metabolism group as given in the Table. Including fluconazole in the analysis of antimicrobials inhibiting CYP metabolism increased the proportion of patients experiencing a follow-up INR of 5.0 or greater to 9.6% in this group. Despite the importance of CYP inhibition interactions relative to the other antibiotic and control groups, it is important to note that the mean INR change that we identified remained small, with only about 1 in 10 patients prescribed these agents having a follow-up INR of 5.0 or greater.

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