Warfarin Interactions With Antibiotics in the Ambulatory Care Setting

JAMA Internal Medicine (Impact Factor: 13.12). 01/2014; 174(3). DOI: 10.1001/jamainternmed.2013.13957
Source: PubMed


The effect of antibiotic coadministration on the international normalized ratio (INR) in a relatively stable, real-world warfarin population has not been adequately described. Case reports and studies of healthy volunteers do not account for the potential contribution of acute illness to INR variability.Objective
To compare the risk of excessive anticoagulation among patients with stable warfarin therapy purchasing an antibiotic (antibiotic group) with the risk in patients purchasing a warfarin refill (stable controls) and patients with upper respiratory tract infection but not receiving an antibiotic (sick controls).Design, Setting, and Participants
A retrospective, longitudinal cohort study evaluated patients receiving warfarin between January 1, 2005, and March 31, 2011, at Kaiser Permanente Colorado, an integrated health care delivery system. Continuous data were expressed as mean (SD) or median (interquartile range). Multivariable logistic regression analysis was used to identify factors independently associated with a follow-up INR of 5.0 or more. A total of 5857 (48.8%), 5579 (46.5%), and 570 (4.7%) patients were included in the antibiotic, stable control, and sick control groups, respectively. Mean age was 68.3 years, and atrial fibrillation was the most common (44.4%) indication for anticoagulation.Exposures
Warfarin therapy with a medical visit for upper respiratory tract infection or coadministration of antibiotics.Main Outcomes and Measures
Primary outcomes were the proportion of patients experiencing a follow-up INR of 5.0 or more and change between the last INR measured before the index date and the follow-up INR.Results
The proportion of patients experiencing an INR of 5.0 or more was 3.2%, 2.6%, and 1.2% for the antibiotic, sick, and stable groups, respectively (P < .001, antibiotic vs stable control group; P < .017, sick vs stable control group; P = .44, antibiotic vs sick control group). Cancer diagnosis, elevated baseline INR, and female sex predicted a follow-up INR of 5.0 or more. Among antibiotics, those interfering with warfarin metabolism posed the greatest risk for an INR of 5.0 or more.Conclusions and Relevance
Acute upper respiratory tract infection increases the risk of excessive anticoagulation independent of antibiotic use. Antibiotics also increase the risk; however, most patients with previously stable warfarin therapy will not experience clinically relevant increases in INR following antibiotic exposure or acute upper respiratory tract infection.

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    • "A number of worldwide studies have been conducted to examine the response to warfarin therapy in both ambulatory and hospital settings (Doecke et al., 1991; Brigden et al., 1998; Fang et al., 2006; Clark et al., 2014). Response to warfarin therapy is patient specific; however, various factors have been reported to alter warfarin response and target INR such as older age, disease states, warfarin dose and influence of other medications (Doecke et al., 1991; Brigden et al., 1998; Demirkan et al., 2000; Hylek et al., 2001; Froom et al., 2003; Torn et al., 2005; Fang et al., 2006; Clark et al., 2014). Conflicting results have been reported for some of these factors such as age, gender and concurrent disease states (Fihn et al., 1996; Demirkan et al., 2000; Sivrikaya et al., 2013). "
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    ABSTRACT: The objective of this study was to investigate the influence of simultaneous factors that potentially keep patients far from achieving target INR range at discharge in hospitalized patients. Prospective cross-sectional observational study conducted at the Cardiology Department and Intensive Care Unit (ICU) of the Assiut University Hospitals. One-hundred and twenty patients were enrolled in the study from July 2013 to January 2014. Outcome measures were discharge INRs, bleeding and thromboembolic episodes. Bivariate analysis and multinomial logistic regression were conducted to determine independent risk factors that can keep patients outside target INR range. Patients who were newly initiated warfarin on hospital admission were given low initiation dose (2.8 mg ± 0.9). They were more likely to have INR values below 1.5 during hospital stay, 13 (27.7%) patients compared with 9 (12.3%) previously treated patients, respectively (p = .034). We found that the best predictors of achieving below target INR range relative to within target INR range were; shorter hospital stay periods (OR, 0.82 for every day increase [95% CI, 0.72–0.94]), being a male patient (OR, 2.86 [95% CI, 1.05–7.69]), concurrent infection (OR, 0.21 [95% CI, 0.07–0.59]) and new initiation of warfarin therapy on hospital admission (OR, 3.73 [95% CI, 1.28–10.9]). Gender, new initiation of warfarin therapy on hospital admission, shorter hospital stay periods and concurrent infection can have a significant effect on discharge INRs. Initiation of warfarin without giving loading doses increases the risk of having INRs below 1.5 during hospital stay and increases the likelihood of a patient to be discharged with INR below target range. Following warfarin dosing nomograms and careful monitoring of the effect of various factors on warfarin response should be greatly considered.
    Full-text · Article · Feb 2015 · Saudi Pharmaceutical Journal
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    • "Clark et al investigated the interactions between warfarin and antibiotics in the ambulatory care setting and concluded that acute upper respiratory tract infection could increase the risk of excessive anticoagulation independent of antibiotic use and antibiotics could also increase the risk. However, most patients on previously stable warfarin therapy will not experience clinically relevant increases in INR following exposure to antibiotic or acute upper respiratory tract infection.50 For patients receiving warfarin and LVX concomitantly, caution is advised regarding potential changes in INR values; however, it is not necessary to seek alternatives to LVX for the sake of avoiding a drug interaction with warfarin. "
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    ABSTRACT: Personalized medicine should be encouraged because patients are complex, and this complexity results from biological, medical (eg, demographics, genetics, polypharmacy, and multimorbidities), socioeconomic, and cultural factors. Levofloxacin (LVX) is a broad-spectrum fluoroquinolone antibiotic. Awareness of personalized therapeutics for LVX seems to be poor in clinical practice, and is reflected in prescribing patterns. Pharmacokinetic-pharmacodynamic studies have raised concerns about suboptimal patient outcomes with the use of LVX for some Gram-negative infections. Meanwhile, new findings in LVX therapeutics have only been sporadically reported in recent years. Therefore, an updated review on personalized LVX treatment with a focus on pharmacokinetic concerns is necessary. Relevant literature was identified by performing a PubMed search covering the period from January 1993 to December 2013. We included studies describing dosage adjustment and factors determining LVX pharmacokinetics, or pharmacokinetic-pharmacodynamic studies exploring how best to prevent the emergence of resistance to LVX. The full text of each included article was critically reviewed, and data interpretation was performed. In addition to limiting the use of fluoroquinolones, measures such as reducing the breakpoints for antimicrobial susceptibility testing, choice of high-dose short-course of once-daily LVX regimen, and tailoring LVX dose in special patient populations help to achieve the validated pharmacokinetic-pharmacodynamic target and combat the increasing LVX resistance. Obese individuals with normal renal function cleared LVX more efficiently than normal-weight individuals. Compared with the scenario in healthy subjects, standard 2-hour spacing of calcium formulations and oral LVX was insufficient to prevent a chelation interaction in cystic fibrosis patients. Inconsistent conclusions were derived from studies of the influence of sex on the pharmacokinetics of LVX, which might be associated with sample size and administration route. Children younger than 5 years cleared LVX nearly twice as fast as adults. Patients in intensive care receiving LVX therapy showed significant pharmacokinetic differences compared with healthy subjects. Creatinine clearance explained most of the population variance in the plasma clearance of LVX. Switching from intravenous to oral delivery of LVX had economic benefits. Addition of tamsulosin to the LVX regimen was beneficial for patients with bacterial prostatitis because tamsulosin could increase the maximal concentration of LVX in prostatic tissue. Coadministration of multivalent cation-containing drugs and LVX should be avoided. For patients receiving warfarin and LVX concomitantly, caution is needed regarding potential changes in the international normalized ratio; however, it is unnecessary to seek alternatives to LVX for the sake of avoiding drug interaction with warfarin. It is unnecessary to proactively reduce the dose of cyclosporin or tacrolimus when comedicated with LVX. Transporters such as organic anion-transporting polypeptide 1A2, P-glycoprotein, human organic cation transporter 1, and multidrug and toxin extrusion protein 1 are involved in the pharmacokinetics of LVX. Personalized LVX therapeutics are necessary for the sake of better safety, clinical success, and avoidance of resistance. New findings regarding individual dosing of LVX in special patient populations and active transport mechanisms in vivo are opening up new horizons in clinical practice.
    Full-text · Article · Mar 2014 · Therapeutics and Clinical Risk Management
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    ABSTRACT: The prevalence of mesenteric venous thrombosis has increased over the past 2 decades with the routine use of contrast-enhanced computed tomography (CT) in patients presenting with abdominal pain and those with portal hypertension. Concurrent with increasing recognition, routine and frequent use of anticoagulation has reduced the need for surgical intervention and improved outcome in these patients. Acute thrombosis often presents with abdominal pain, whereas chronic disease manifests either as an incidental finding on CT or with features of portal hypertension. Contrast-enhanced CT diagnoses about 90% of cases. The presence of collateral circulation and cavernoma around a chronically thrombosed vein differentiates chronic from acute disease. The superior mesenteric vein is often involved, whereas involvement of the inferior mesenteric vein is rare. Associated portal venous thrombosis can be seen if the disease originates in the major veins instead of the small vena rectae. Thrombophilia and local abdominal inflammatory conditions are common causes. Management is aimed at preventing bowel infarction and recurrent thrombosis. Anticoagulation, the mainstay of management, has also been safely used in patients with cirrhosis and portal hypertension. This review discusses the pathogenesis of thrombosis of mesenteric veins, the diagnosis and differentiation from arterial ischemia, the emergence of the JAK2 (Janus kinase 2) sequence variation as a marker of thrombophilia and myelodysplastic neoplasms, and new anticoagulants. Algorithms for the management of acute and chronic mesenteric venous thrombosis are provided to help readers understand and remember the approach to the management of acute and chronic mesenteric venous thrombosis.
    Full-text · Article · Mar 2013 · Mayo Clinic Proceedings
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