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Research Letter |

Change in International Normalized Ratio Among Patients Treated With Dicloxacillin and Vitamin K Antagonists FREE

Anton Pottegård, MScPharm, PhD1; Daniel P. Henriksen, MD, PhD2; Kenneth G. Madsen, BScMed1; Maja Hellfritzsch, MD1; Per Damkier, MD, PhD1; Tore B. Stage, MScPharm1
[+] Author Affiliations
1Clinical Pharmacology, University of Southern Denmark, Odense
2Department of Clinical Chemistry and Pharmacology, Odense University Hospital, Odense, Denmark
JAMA. 2015;314(3):296-297. doi:10.1001/jama.2015.6669.
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Published online

A challenge in the use of vitamin K antagonists (VKAs) is the potential for drug-drug interactions, resulting in insufficient or excessive anticoagulation. Solid data are lacking for most alleged interactions. In case reports,13 the commonly used antibiotic dicloxacillin has been reported to lower the anticoagulant effect of warfarin, the most used VKA.

Patients currently taking warfarin were identified via the anticoagulant database Thrombobase, a clinical database of all VKA-treated patients (N ≈ 7400) followed up by 3 outpatient clinics and 50 general practitioners in Funen, Denmark. All international normalized ratios (INRs) are recorded.

We included all patients who filled a prescription for dicloxacillin while receiving warfarin therapy between March 1998 and November 2012 (as ascertained via the population-based prescription register Odense Pharmacoepidemiological Database). Registry-based studies are exempt from ethical review in Denmark.

Measures of INR were grouped by the week relative to dicloxacillin exposure. For individuals with multiple measurements in rapid succession (≤5 days between measurements), only the first measurement was included.

We compared the last INR measurement before dicloxacillin exposure with the first measurement within weeks 2 to 4 after dicloxacillin exposure. To retain the paired nature of the data, we excluded individuals without an INR measurement within this postexposure period and the analysis was performed using a paired t test.

Furthermore, we assessed the use of dicloxacillin among patients taking another VKA, phenprocoumon. To assess the potential for confounding by indication, we performed similar analyses among patients taking warfarin and phenoxymethylpenicillin or amoxicillin.

A 2-sided P value of <.05 was considered statistically significant. Analyses were performed using Stata version 13.1 (StataCorp).

Of 519 patients taking warfarin and initiating treatment with dicloxacillin (Figure 1), 236 met inclusion criteria. Patients most commonly filled prescriptions for 30 dicloxacillin tablets (89%; range, 30-100 tablets). The median age was 68 years (interquartile range, 59-77 years) and 61% were male. The main indications for anticoagulant treatment were atrial fibrillation (56%) and heart valve replacement (22%).

Place holder to copy figure label and caption
Figure 1.
Patients Treated With a Vitamin K Antagonist in Denmark
Graphic Jump Location

Median INR levels with corresponding percentiles over time relative to dicloxacillin exposure are displayed in Figure 2. The mean INR level prior to dicloxacillin exposure was 2.59 (95% CI, 2.50-2.68) compared with 1.97 (95% CI, 1.90-2.05) 2 to 4 weeks after dicloxacillin exposure, a mean decrease of 0.62 (95% CI, 0.50-0.74; P < .001). In total, 61% (n = 144) experienced subtherapeutic INR levels (<2.0) within 2 to 4 weeks after dicloxacillin treatment.

Place holder to copy figure label and caption
Figure 2.
Median International Normalized Ratio Levels Over Time Among Users of Warfarin Exposed to Dicloxacillin
Graphic Jump Location

Among patients taking phenprocoumon (n = 64), mean INR levels were 2.61 (95% CI, 2.46-2.76) before exposure to dicloxacillin compared with 2.30 (95% CI, 2.12- 2.48) after exposure, a mean decrease of 0.31 (95% CI, 0.11-0.51; P = .003). The proportion with subtherapeutic INR levels after dicloxacillin exposure was 41% (n = 26).

Analyses for phenoxymethylpenicillin among patients taking warfarin (n = 539) showed mean INR levels of 2.52 (95% CI, 2.46-2.58) before exposure compared with 2.62 (95% CI, 2.54- 2.69) after exposure, a mean increase of 0.10 (95% CI, 0.01-0.19; P = .03). Corresponding INR levels for amoxicillin (n = 266) were 2.58 (95% CI, 2.50-2.66) compared with 2.72 (95% CI, 2.62-2.81), a mean increase of 0.14 (95% CI, 0.03-0.26; P = .01).

We found an association between dicloxacillin treatment and a decrease in INR levels among patients taking either warfarin or phenprocoumon.

The principal strength of this study is the large number of patients taking warfarin and exposed to dicloxacillin, representing nonselected patients from everyday clinical settings.

The main weakness is the lack of data on the underlying infection. In Denmark, dicloxacillin is primarily used against impetigo, soft tissue, and skin infections due to Staphylococcus aureus. Infections have been reported to increase INR,4 which is supported by our results for phenoxymethylpenicillin and amoxicillin. Such an effect would bias our results in the opposite direction of that observed for dicloxacillin.

Other limitations include the potential lack of representativeness of the population from 1 Danish region and the lack of data on clinical outcomes.

A biologically plausible rationale for the finding is through dicloxacillin activation of pregnane X receptor, resulting in induction of CYP3A45 and probably CYP2C9,6 which catalyze the metabolism of warfarin.

Physicians should be aware that dicloxacillin treatment may cause a significant decrease in INR levels among patients taking VKAs.

Section Editor: Jody W. Zylke, MD, Deputy Editor.

Corresponding Author: Anton Pottegård, MScPharm, PhD, Clinical Pharmacology University of Southern Denmark, JB Winsløws Vej 19, 2 DK-5000 Odense C, Denmark (apottegaard@health.sdu.dk).

Author Contributions: Dr Pottegård had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: All authors.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: All authors.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Pottegård, Henriksen, Stage.

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Additional Contributions: We thank Jesper Hallas, MD, Kim Brøsen, MD, and Henrik Horneberg, BA (all with Clinical Pharmacology, University of Southern Denmark), for valuable comments on the manuscript. No financial compensation was provided.

Mailloux  AT, Gidal  BE, Sorkness  CA.  Potential interaction between warfarin and dicloxacillin. Ann Pharmacother. 1996;30(12):1402-1407.
PubMed
Lacey  CS.  Interaction of dicloxacillin with warfarin. Ann Pharmacother. 2004;38(5):898.
PubMed   |  Link to Article
Khalili  H, Nikvarz  N, Najmeddin  F, Dashti-Khavidaki  S.  A probable clinically significant interaction between warfarin and cloxacillin: three case reports. Eur J Clin Pharmacol. 2013;69(3):721-724.
PubMed   |  Link to Article
Self  TH, Oliphant  CS, Reaves  AB, Richardson  AM, Sands  CW.  Fever as a risk factor for increased response to vitamin K antagonists: a review of the evidence and potential mechanisms. Thromb Res. 2015;135(1):5-8.
PubMed   |  Link to Article
Yasuda  K, Ranade  A, Venkataramanan  R,  et al.  A comprehensive in vitro and in silico analysis of antibiotics that activate pregnane X receptor and induce CYP3A4 in liver and intestine. Drug Metab Dispos. 2008;36(8):1689-1697.
PubMed   |  Link to Article
Chen  Y, Goldstein  JA.  The transcriptional regulation of the human CYP2C genes. Curr Drug Metab. 2009;10(6):567-578.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.
Patients Treated With a Vitamin K Antagonist in Denmark
Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Median International Normalized Ratio Levels Over Time Among Users of Warfarin Exposed to Dicloxacillin
Graphic Jump Location

Tables

References

Mailloux  AT, Gidal  BE, Sorkness  CA.  Potential interaction between warfarin and dicloxacillin. Ann Pharmacother. 1996;30(12):1402-1407.
PubMed
Lacey  CS.  Interaction of dicloxacillin with warfarin. Ann Pharmacother. 2004;38(5):898.
PubMed   |  Link to Article
Khalili  H, Nikvarz  N, Najmeddin  F, Dashti-Khavidaki  S.  A probable clinically significant interaction between warfarin and cloxacillin: three case reports. Eur J Clin Pharmacol. 2013;69(3):721-724.
PubMed   |  Link to Article
Self  TH, Oliphant  CS, Reaves  AB, Richardson  AM, Sands  CW.  Fever as a risk factor for increased response to vitamin K antagonists: a review of the evidence and potential mechanisms. Thromb Res. 2015;135(1):5-8.
PubMed   |  Link to Article
Yasuda  K, Ranade  A, Venkataramanan  R,  et al.  A comprehensive in vitro and in silico analysis of antibiotics that activate pregnane X receptor and induce CYP3A4 in liver and intestine. Drug Metab Dispos. 2008;36(8):1689-1697.
PubMed   |  Link to Article
Chen  Y, Goldstein  JA.  The transcriptional regulation of the human CYP2C genes. Curr Drug Metab. 2009;10(6):567-578.
PubMed   |  Link to Article
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