TY - JOUR
AU - Rumbaugh, Kelli, A.
AB - Purpose Persistent elevation of prothrombin time (PT) and International Normalized Ratio (INR) values in a patient receiving daptomycin is reported. Summary A morbidly obese 51-year-old man was hospitalized for evaluation for surgical intervention for gallstone pancreatitis and biliary obstruction. Previously prescribed warfarin therapy was withheld due to suspected coagulopathy and an elevated INR (5.1), and warfarin reversal was initiated. After undergoing partial cholecystectomy on hospital day 6, the patient developed sepsis and was treated with i.v. meropenem and daptomycin for vancomycin-resistant Enterococcus infection. Warfarin therapy, which had been resumed after cholecystectomy, was again discontinued on hospital day 12. On the eighth day of daptomycin therapy, the INR remained elevated (2.6) even though the patient had no warfarin exposure for 9 days. On hospital day 21, thromboelastography (TEG) indicated normal whole blood coagulation. Other anticoagulation markers normalized, but the INR remained elevated until daptomycin was discontinued. Daptomycin has been shown to falsely prolong the INR when specific laboratory reagents are used for PT and INR testing, but the specific reagent used in this case has not been previously implicated. Conclusion Daptomycin therapy appeared to cause a false and substantial INR elevation in a patient who had been receiving warfarin. Results of TEG suggested that the INR elevation was an artifact of a drug–laboratory interaction and did not represent an anticoagulated state. The patient’s INR normalized after linezolid was substituted for daptomycin. daptomycin, drug interaction, drug–laboratory test interaction, International Normalized Ratio, prothrombin time, warfarin KEY POINTS Daptomycin therapy may result in a clinically relevant false elevation of the International Normalized Ratio (INR). The drug–laboratory test interaction involving daptomycin and INR appears to be dependent on the specific thromboplastin reagent used, and clinically significant interactions may occur even with thromboplastin reagents not identified through laboratory research. When the INR appears to be elevated in a patient receiving both warfarin and daptomycin, switching to an alternative antibacterial or anticoagulant agent to ensure that therapeutic anticoagulation is both safe and effective may be warranted. Daptomycin is a cyclic lipopeptide antibacterial agent that has rapid bactericidal activity against aerobic and facultative gram-positive microorganisms, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus (VRE).1 The agent was approved by the Food and Drug Administration for the treatment of complicated skin and skin structure infections (cSSSIs) in 2003 and for the treatment of S. aureus bacteremia in 2006. There have been mixed reports in the literature of daptomycin affecting laboratory results for prothrombin time (PT) and International Normalized Ratio (INR). In 16 healthy subjects, administration of daptomycin 6 mg/kg i.v. every 24 hours for 5 days followed by a single oral dose of warfarin sodium 25 mg had no significant effect on the pharmacokinetics of either drug and did not significantly alter the INR.1 In Phase III clinical trials leading to the approval of daptomycin for cSSSIs and bacteremia, however, INR elevation occurred, although rarely, with frequencies of <1.0% and 1.7%, respectively, in the 2 trials.1 Routine postmarketing surveillance of daptomycin has led to the identification of multiple patients at a single hospital who developed an elevated INR in association with daptomycin therapy that could not be explained by changes in concomitant warfarin dosage or other clinical factors.2 Prescribing information for daptomycin was updated (effective date, February 12, 2007) to address the potential for false prolongation of PT and elevation of INR when certain recombinant thromboplastin reagents are used for these assays.1 Recommendations to address this drug–laboratory test interaction include assessing PT and INR from specimens collected when the daptomycin concentration is at a trough, using alternative methods (with different reagents) to measure PT and INR, and examining other potential causes of abnormally elevated PT or INR results. Although observed in postmarketing surveillance and in vitro studies, INR elevation in association with daptomycin use has not yet been described in the clinical literature. Here we report a case of clinically relevant INR elevation in a surgical patient receiving daptomycin for abdominal sepsis. Case report A 51-year-old Caucasian man (weight, 225 kg; height, 172.7 cm) with a history of morbid obesity, congestive heart failure (CHF), atrial fibrillation, hypertension, type 1 diabetes mellitus, and chronic kidney disease requiring hemodialysis was transferred to a medical center from a referring hospital for possible surgical intervention for gallstone pancreatitis and biliary obstruction. He had several hospital admissions in the past year for a urinary tract infection, biliary infection, and vancomycin-resistant enterococcal bacteremia. The patient’s home medications included diltiazem hydrochloride 180 mg orally daily, metoprolol tartrate 50 mg orally twice daily, hydralazine hydrochloride 25 mg orally every 8 hours, bumetanide 2 mg orally twice daily, warfarin sodium 7.5 mg orally daily, tamsulosin 0.4 mg orally daily, omeprazole 40 mg orally daily, tramadol hydrochloride 50 mg every 4 hours orally as needed for pain, and regular insulin injected subcutaneously per sliding scale. On the day of hospital admission, the patient had an elevated INR value (5.1) (Table 1); this was thought to be due to warfarin therapy and the contributing factors of decreased nutrition and drug interaction. The patient reported that he had nausea, vomiting, and minimal oral intake for 2 days prior to presentation at the referring hospital. Additionally, the patient had received 24 hours of therapy with metronidazole at the referring hospital, with no apparent change in the warfarin dosage. The patient had no signs or symptoms of bleeding. However, due to the prospect of surgical intervention, the apparent coagulopathy was reversed with 2 units of fresh frozen plasma (FFP) and 10 mg of oral phytonadione. Over the next 4 days, during which warfarin was withheld, the patient’s INR normalized to 1.2; an additional unit of FFP and an additional dose of phytonadione 10 mg i.v. were given during this interval. The patient underwent laparoscopic partial cholecystectomy on hospital day 6. He received 2 units of packed red blood cells (PRBCs) in the operating room. On hospital day 8, warfarin sodium was restarted at 7.5 mg daily and was bridged with an i.v. heparin infusion. The INR on day 8 was 1.3; it increased to 2.8 by hospital day 13, after 5 doses of warfarin sodium 7.5 mg. Table 1 Coagulation Values During Hospital Staya Hospital Day PT (sec) INR aPTT (sec) Warfarin Sodium Dose (mg) Agents Affecting Coagulation Heparin Route VRE Treatment Medications Interacting With Warfarin 1 53.6 5.1 …b None Phytonadione 10 mg p.o., FFP 2 units Subcut. None None 2 33.3 3.4 … None FFP 1 unit Subcut. None Metronidazole, ciprofloxacin 3 25.4 2.4 … None Phytonadione 10 mg i.v. Subcut. None Metronidazole, ciprofloxacin 4 18.1 1.6 35.9 None None I.V. None Metronidazole, ciprofloxacin 5 14.8 1.2 36.8 None None I.V. None Metronidazole, ciprofloxacin 6 15.0 1.2 75.0 None PRBCs 2 units I.V. None Metronidazole, ciprofloxacin 7 15.0 1.2 100.5 None None I.V. None Metronidazole, ciprofloxacin 8 15.4 1.3 53.2 7.5 None I.V. None Metronidazole 9 16.1 1.3 61.0 7.5 None I.V. None None 10 17.0 1.4 66.3 7.5 None I.V. None None 11 19.6 1.7 83.5 7.5 None I.V. None None 12 24.8 2.3 177.2 7.5 None None None None 13 28.7 2.8 … None None None None None 14 38.5 4.1 … None None None Daptomycin None 15 51.5 6.0 … None Phytonadione 10 mg i.v. None Daptomycin None 16 28.2 2.6 … None FFP 1 unit None Daptomycin None 17 24.1 2.2 … None None None Daptomycin None 18 25.5 2.4 … None FFP 1 unit None Daptomycin None 19 30.5 3.0 … None None None Daptomycin None 20 27.4 2.6 … None None Subcut. Daptomycin None 21 27.1 2.6 46.9 None None Subcut. Daptomycin None 22 26.0 2.5 45.9 None None I.V. Linezolid None 23 23.5 2.2 49.5 None None I.V. Linezolid None 24 22.3 2.0 51.4 7.5 None I.V. Linezolid None 25 20.8 1.7 46.5 7.5 None I.V. Linezolid None 26 21.3 1.9 56.8 7.5 None I.V. Linezolid None 27 24.4 2.3 59.4 7.5 None I.V. Linezolid None 28 24.3 2.3 … 7.5 None None Linezolid None 29 24.7 2.3 … 7.5 None None Linezolid None 30 25.8 2.4 … 7.5 None None Linezolid None 31 25.9 2.5 … 7.5 None None Linezolid None 32 25.0 2.4 … 7.5 None None Linezolid None 33 25.9 2.5 … 7.5 None None Linezolid None 34 25.3 2.4 … 7.5 None None Linezolid None 35 25.8 2.4 … 7.5 None None Linezolid None 36 … … … 7.5 PRBCs 1 unit None Linezolid None 37 26.5 2.5 … 7.5 None None Linezolid None 38 … … … 7.5 None None Linezolid None Hospital Day PT (sec) INR aPTT (sec) Warfarin Sodium Dose (mg) Agents Affecting Coagulation Heparin Route VRE Treatment Medications Interacting With Warfarin 1 53.6 5.1 …b None Phytonadione 10 mg p.o., FFP 2 units Subcut. None None 2 33.3 3.4 … None FFP 1 unit Subcut. None Metronidazole, ciprofloxacin 3 25.4 2.4 … None Phytonadione 10 mg i.v. Subcut. None Metronidazole, ciprofloxacin 4 18.1 1.6 35.9 None None I.V. None Metronidazole, ciprofloxacin 5 14.8 1.2 36.8 None None I.V. None Metronidazole, ciprofloxacin 6 15.0 1.2 75.0 None PRBCs 2 units I.V. None Metronidazole, ciprofloxacin 7 15.0 1.2 100.5 None None I.V. None Metronidazole, ciprofloxacin 8 15.4 1.3 53.2 7.5 None I.V. None Metronidazole 9 16.1 1.3 61.0 7.5 None I.V. None None 10 17.0 1.4 66.3 7.5 None I.V. None None 11 19.6 1.7 83.5 7.5 None I.V. None None 12 24.8 2.3 177.2 7.5 None None None None 13 28.7 2.8 … None None None None None 14 38.5 4.1 … None None None Daptomycin None 15 51.5 6.0 … None Phytonadione 10 mg i.v. None Daptomycin None 16 28.2 2.6 … None FFP 1 unit None Daptomycin None 17 24.1 2.2 … None None None Daptomycin None 18 25.5 2.4 … None FFP 1 unit None Daptomycin None 19 30.5 3.0 … None None None Daptomycin None 20 27.4 2.6 … None None Subcut. Daptomycin None 21 27.1 2.6 46.9 None None Subcut. Daptomycin None 22 26.0 2.5 45.9 None None I.V. Linezolid None 23 23.5 2.2 49.5 None None I.V. Linezolid None 24 22.3 2.0 51.4 7.5 None I.V. Linezolid None 25 20.8 1.7 46.5 7.5 None I.V. Linezolid None 26 21.3 1.9 56.8 7.5 None I.V. Linezolid None 27 24.4 2.3 59.4 7.5 None I.V. Linezolid None 28 24.3 2.3 … 7.5 None None Linezolid None 29 24.7 2.3 … 7.5 None None Linezolid None 30 25.8 2.4 … 7.5 None None Linezolid None 31 25.9 2.5 … 7.5 None None Linezolid None 32 25.0 2.4 … 7.5 None None Linezolid None 33 25.9 2.5 … 7.5 None None Linezolid None 34 25.3 2.4 … 7.5 None None Linezolid None 35 25.8 2.4 … 7.5 None None Linezolid None 36 … … … 7.5 PRBCs 1 unit None Linezolid None 37 26.5 2.5 … 7.5 None None Linezolid None 38 … … … 7.5 None None Linezolid None a PT = prothrombin time, INR = International Normalized Ratio, aPTT = activated partial thromboplastin time, VRE = vancomycin-resistant Enterococcus, FFP = fresh frozen plasma, I.V. = intravenous infusion, Subcut. = subcutaneous, PRBCs = packed red blood cells. b Not available or not measured. View Large Table 1 Coagulation Values During Hospital Staya Hospital Day PT (sec) INR aPTT (sec) Warfarin Sodium Dose (mg) Agents Affecting Coagulation Heparin Route VRE Treatment Medications Interacting With Warfarin 1 53.6 5.1 …b None Phytonadione 10 mg p.o., FFP 2 units Subcut. None None 2 33.3 3.4 … None FFP 1 unit Subcut. None Metronidazole, ciprofloxacin 3 25.4 2.4 … None Phytonadione 10 mg i.v. Subcut. None Metronidazole, ciprofloxacin 4 18.1 1.6 35.9 None None I.V. None Metronidazole, ciprofloxacin 5 14.8 1.2 36.8 None None I.V. None Metronidazole, ciprofloxacin 6 15.0 1.2 75.0 None PRBCs 2 units I.V. None Metronidazole, ciprofloxacin 7 15.0 1.2 100.5 None None I.V. None Metronidazole, ciprofloxacin 8 15.4 1.3 53.2 7.5 None I.V. None Metronidazole 9 16.1 1.3 61.0 7.5 None I.V. None None 10 17.0 1.4 66.3 7.5 None I.V. None None 11 19.6 1.7 83.5 7.5 None I.V. None None 12 24.8 2.3 177.2 7.5 None None None None 13 28.7 2.8 … None None None None None 14 38.5 4.1 … None None None Daptomycin None 15 51.5 6.0 … None Phytonadione 10 mg i.v. None Daptomycin None 16 28.2 2.6 … None FFP 1 unit None Daptomycin None 17 24.1 2.2 … None None None Daptomycin None 18 25.5 2.4 … None FFP 1 unit None Daptomycin None 19 30.5 3.0 … None None None Daptomycin None 20 27.4 2.6 … None None Subcut. Daptomycin None 21 27.1 2.6 46.9 None None Subcut. Daptomycin None 22 26.0 2.5 45.9 None None I.V. Linezolid None 23 23.5 2.2 49.5 None None I.V. Linezolid None 24 22.3 2.0 51.4 7.5 None I.V. Linezolid None 25 20.8 1.7 46.5 7.5 None I.V. Linezolid None 26 21.3 1.9 56.8 7.5 None I.V. Linezolid None 27 24.4 2.3 59.4 7.5 None I.V. Linezolid None 28 24.3 2.3 … 7.5 None None Linezolid None 29 24.7 2.3 … 7.5 None None Linezolid None 30 25.8 2.4 … 7.5 None None Linezolid None 31 25.9 2.5 … 7.5 None None Linezolid None 32 25.0 2.4 … 7.5 None None Linezolid None 33 25.9 2.5 … 7.5 None None Linezolid None 34 25.3 2.4 … 7.5 None None Linezolid None 35 25.8 2.4 … 7.5 None None Linezolid None 36 … … … 7.5 PRBCs 1 unit None Linezolid None 37 26.5 2.5 … 7.5 None None Linezolid None 38 … … … 7.5 None None Linezolid None Hospital Day PT (sec) INR aPTT (sec) Warfarin Sodium Dose (mg) Agents Affecting Coagulation Heparin Route VRE Treatment Medications Interacting With Warfarin 1 53.6 5.1 …b None Phytonadione 10 mg p.o., FFP 2 units Subcut. None None 2 33.3 3.4 … None FFP 1 unit Subcut. None Metronidazole, ciprofloxacin 3 25.4 2.4 … None Phytonadione 10 mg i.v. Subcut. None Metronidazole, ciprofloxacin 4 18.1 1.6 35.9 None None I.V. None Metronidazole, ciprofloxacin 5 14.8 1.2 36.8 None None I.V. None Metronidazole, ciprofloxacin 6 15.0 1.2 75.0 None PRBCs 2 units I.V. None Metronidazole, ciprofloxacin 7 15.0 1.2 100.5 None None I.V. None Metronidazole, ciprofloxacin 8 15.4 1.3 53.2 7.5 None I.V. None Metronidazole 9 16.1 1.3 61.0 7.5 None I.V. None None 10 17.0 1.4 66.3 7.5 None I.V. None None 11 19.6 1.7 83.5 7.5 None I.V. None None 12 24.8 2.3 177.2 7.5 None None None None 13 28.7 2.8 … None None None None None 14 38.5 4.1 … None None None Daptomycin None 15 51.5 6.0 … None Phytonadione 10 mg i.v. None Daptomycin None 16 28.2 2.6 … None FFP 1 unit None Daptomycin None 17 24.1 2.2 … None None None Daptomycin None 18 25.5 2.4 … None FFP 1 unit None Daptomycin None 19 30.5 3.0 … None None None Daptomycin None 20 27.4 2.6 … None None Subcut. Daptomycin None 21 27.1 2.6 46.9 None None Subcut. Daptomycin None 22 26.0 2.5 45.9 None None I.V. Linezolid None 23 23.5 2.2 49.5 None None I.V. Linezolid None 24 22.3 2.0 51.4 7.5 None I.V. Linezolid None 25 20.8 1.7 46.5 7.5 None I.V. Linezolid None 26 21.3 1.9 56.8 7.5 None I.V. Linezolid None 27 24.4 2.3 59.4 7.5 None I.V. Linezolid None 28 24.3 2.3 … 7.5 None None Linezolid None 29 24.7 2.3 … 7.5 None None Linezolid None 30 25.8 2.4 … 7.5 None None Linezolid None 31 25.9 2.5 … 7.5 None None Linezolid None 32 25.0 2.4 … 7.5 None None Linezolid None 33 25.9 2.5 … 7.5 None None Linezolid None 34 25.3 2.4 … 7.5 None None Linezolid None 35 25.8 2.4 … 7.5 None None Linezolid None 36 … … … 7.5 PRBCs 1 unit None Linezolid None 37 26.5 2.5 … 7.5 None None Linezolid None 38 … … … 7.5 None None Linezolid None a PT = prothrombin time, INR = International Normalized Ratio, aPTT = activated partial thromboplastin time, VRE = vancomycin-resistant Enterococcus, FFP = fresh frozen plasma, I.V. = intravenous infusion, Subcut. = subcutaneous, PRBCs = packed red blood cells. b Not available or not measured. View Large Two days later the patient became septic from a urinary or abdominal source of infection. He was transferred to the surgical intensive care unit and was treated empirically with meropenem 1,000 mg i.v. every 12 hours (infused over 3 hours) and daptomycin 1,350 mg (6 mg/kg) i.v. every 48 hours due to his history of VRE infection. A urine culture obtained at that time was positive for ampicillin- and vancomycin-resistant Enterococcus faecium. Daptomycin was continued for treatment of VRE urinary tract infection, and meropenem was continued for treatment of a presumed intraabdominal infection. At the time of daptomycin initiation on day 14, the patient’s INR was 4.1. On day 15, the INR was 6.0 despite withholding of warfarin since the last administered dose on day 12. Phytonadione 10 mg was administered i.v. on day 15, and the INR decreased but never reached a normal level. On day 16, 1 unit of FFP was administered. The INR decreased from 2.6 on day 16 to 2.2 on day 17. An additional unit of FFP was administered on day 18 prior to intravascular line placement. At that time, the INR was 2.4; the INR was 3.0 on day 19. On the eighth day of daptomycin therapy (hospital day 21), the INR remained elevated (2.6) even though the patient had not been exposed to warfarin for 9 days. Laboratory values indicating liver function were monitored throughout this time; values for aspartate transaminase, alanine transaminase, alkaline phosphatase, and total bilirubin all remained within normal limits. On hospital day 21, thromboelastography (TEG) was performed to assess the efficiency of whole blood coagulation in the setting of an elevated INR; the TEG 5000 Thromboelastograph Hemostasis Analyzer System (Haemonetics Corporation, Braintree, MA) was used. Most results were within normal limits (Table 2), indicating normal coagulation properties despite an elevated INR. Table 2 Thromboelastography Results on Hospital Day 21a Parameter Clot Characteristic Measured Reference Range Patient Value Reaction time (R) Time to initial fibrin formation 5–10 min 4.8 min Kinetic time (K) Time to achieve set level of clot strength 1–3 min 1.2 min α Angle Rate of clot formation 43–72° 73.4° Maximum amplitude (MA) Overall stability and strength of clot 50–70 mm 65.0 mm Shear elastic modulus strength (G) Clot strength and overall platelet function 4.5–11.0 kdyn/sec 9.3 kdyn/sec Parameter Clot Characteristic Measured Reference Range Patient Value Reaction time (R) Time to initial fibrin formation 5–10 min 4.8 min Kinetic time (K) Time to achieve set level of clot strength 1–3 min 1.2 min α Angle Rate of clot formation 43–72° 73.4° Maximum amplitude (MA) Overall stability and strength of clot 50–70 mm 65.0 mm Shear elastic modulus strength (G) Clot strength and overall platelet function 4.5–11.0 kdyn/sec 9.3 kdyn/sec a On day 21, International Normalized Ratio was 2.6, with last warfarin dose given on day 12. View Large Table 2 Thromboelastography Results on Hospital Day 21a Parameter Clot Characteristic Measured Reference Range Patient Value Reaction time (R) Time to initial fibrin formation 5–10 min 4.8 min Kinetic time (K) Time to achieve set level of clot strength 1–3 min 1.2 min α Angle Rate of clot formation 43–72° 73.4° Maximum amplitude (MA) Overall stability and strength of clot 50–70 mm 65.0 mm Shear elastic modulus strength (G) Clot strength and overall platelet function 4.5–11.0 kdyn/sec 9.3 kdyn/sec Parameter Clot Characteristic Measured Reference Range Patient Value Reaction time (R) Time to initial fibrin formation 5–10 min 4.8 min Kinetic time (K) Time to achieve set level of clot strength 1–3 min 1.2 min α Angle Rate of clot formation 43–72° 73.4° Maximum amplitude (MA) Overall stability and strength of clot 50–70 mm 65.0 mm Shear elastic modulus strength (G) Clot strength and overall platelet function 4.5–11.0 kdyn/sec 9.3 kdyn/sec a On day 21, International Normalized Ratio was 2.6, with last warfarin dose given on day 12. View Large Activated partial thromboplastin time (aPTT) values on hospital days 21 and 22 were elevated (46.9 and 45.9 seconds, respectively; reference range, 23.8–32.0 seconds) but below target levels for heparin therapy. The institution’s low-dose heparin protocol (used for treatment of acute coronary syndromes and atrial fibrillation) targets a goal aPTT of 60–80 seconds, which is calibrated by the laboratory to anti–factor Xa levels of 0.3–0.7 IU/mL. The aPTTs were measured in the setting of subcutaneous heparin administration on days 20 and 21 for venous thromboembolism prophylaxis and suspicion of false INR elevation. On hospital day 22, daptomycin was replaced with linezolid to avoid daptomycin influencing the INR. Over the next 3 days, the INR drifted downward to 1.7. Warfarin sodium (7.5 mg daily) was resumed on day 24, when the INR was 2.0. The remainder of the hospital stay was uneventful. The patient’s INR was maintained within the desired range at a warfarin sodium dosage of 7.5 mg daily until his discharge on hospital day 38. Outpatient follow-up of the INR was performed by the patient’s primary care provider, and INR values were not available for review at the time of writing. The patient’s elevated INR was not associated with any bleeding events. He received 2 units of PRBCs due to intraoperative blood loss on hospital day 6. He received 1 additional unit of PRBCs on hospital day 36 in response to a hemoglobin concentration of 6.7 g/dL, which was thought to be associated with frequent blood collection for laboratory tests and not with acute bleeding. The patient’s complete blood count was checked daily throughout the hospital stay, and hemoglobin and hematocrit values remained above standard transfusion thresholds of 7 g/dL and 21%, respectively, on all other days. Discussion False INR elevation in the presence of daptomycin exposure has been demonstrated in vitro but has not been reported in clinical practice in the literature. Thromboplastin reagents used for determination of PT and INR are composed of tissue factor, derived from recombinant human and rabbit sources, that is reconstituted into phospholipid vesicles.3 Tissue factor is the protein responsible for triggering the extrinsic pathway of the clotting cascade. Daptomycin is thought to falsely prolong PT by inserting into the phospholipid of the reagent, thus interfering with the clotting reaction.2 Results of in vitro studies suggested that false elevation of PT or INR in the presence of daptomycin is dependent on the specific thromboplastin reagent used for laboratory testing.2,4–6 Over 30 different thromboplastin reagents are commercially available. Only 4 of these reagents have been implicated in INR elevation associated with daptomycin use in the literature: (1) International Standard rTF/95 (available from the World Health Organization), (2) HemosIL RecombiPlasTin, (3) Hemoliance RecombiPlasTin, and (4) HemosIL RecombiPlasTin 2G (the latter 3 products are manufactured by Instrumentation Laboratory, Bedford, MA).2,4–6 It has been postulated that the specificity of daptomycin’s effect with the use of different thromboplastin reagents may be related to the type and/or configuration of the phospholipid incorporated into the reagent.7 The thromboplastin reagent used by the laboratory at the admitting institution was STA Neoplastine Cl+ (Diagnostica Stago, Inc., Parsippany, NJ), which contains tissue factor derived from rabbit brain; false INR elevation has not been reported with the use of this specific reagent. In fact, Webster et al.2 examined this reagent in the laboratory setting and did not find an association with INR elevation in the presence of daptomycin. The reported case suggests that clinically relevant interactions between daptomycin and thromboplastin reagent in vivo may not always be demonstrable with in vitro tests. We evaluated this potential drug–laboratory test interaction with the Drug Interaction Probability Scale (DIPS), which is designed to measure an interaction between 2 products.8 Points were assigned on the basis of previous reports of this interaction, the known properties of thromboplastin reagents, the timing of the event in relation to daptomycin initiation and discontinuation, and the lack of alternative causes, giving a final DIPS score of 6, which indicated a probable drug interaction. Other potential causes of INR elevation were considered in the patient, but none were identified. The patient’s liver function test results were normal and had not changed from baseline. The patient was not bleeding, as hemoglobin and hematocrit levels were stable throughout the hospitalization, and no blood products were administered except as described previously. The patient received ciprofloxacin and metronidazole for gallstone pancreatitis on hospital days 2–7; however, his INR was 1.2 on the last day of this dual therapy. No other medications known to significantly increase INR values were administered. The patient was maintained on a clear liquid diet with nutrition drinks (Boost, Nestlé Health Science, Epalinges, Switzerland), and this did not change over the period of time examined. The patient had a history of compensated CHF, and he was free from exacerbation of this disorder for the duration of hospitalization. In the case presented here, daptomycin therapy was associated with persistently elevated INR values despite discontinuation of warfarin and administration of i.v. phytonadione. Analysis of the patient’s blood by TEG revealed normal coagulation parameters despite an INR of 2.6, suggesting that INR elevation was an artifact of a drug–laboratory interaction and did not represent an actual state of anticoagulation. The utility of TEG for detecting coagulopathy in patients receiving warfarin has been questioned,9 but investigators have also confirmed the adequacy of TEG for determining coagulopathy in this population.10 Point-of-care INR and chromogenic factor Xa testing were not available at the admitting institution. Thus, TEG was employed as the best possible alternative to standard PT and INR testing in the case described. Product labeling for daptomycin states that measuring INR during times of serum daptomycin trough concentrations may mitigate the probable interaction described here.1 In the case described, the blood sample for INR measurement was collected during a daptomycin trough on hospital day 22 only, but the INR result of 2.5 was only slightly lower than an INR measured earlier in the daptomycin dosing interval (a value of 2.6 on day 21). Transition from daptomycin to linezolid in this patient was associated with a reduction in the INR and enabled the reliable use of values to monitor warfarin therapy. Conclusion Daptomycin therapy appeared to cause a false and substantial INR elevation in a patient who had been receiving warfarin. Results of TEG suggested that the INR elevation was an artifact of a drug–laboratory interaction and did not represent an anticoagulated state. The patient’s INR normalized after linezolid was substituted for daptomycin. Disclosures The authors have declared no potential conflicts of interest. References 1 Cubicin (daptomycin for injection) package insert . Whitehouse Station, NJ ; Merck Sharp & Dohme ; 2016 . 2 Webster PS Oleson FB Paterson DL et al. Interaction of daptomycin with two recombinant thromboplastin reagents leads to falsely prolonged patient prothrombin time/International Normalized Ratio results . Blood Coagul Fibrinolysis . 2008 ; 19 : 32 – 8 . Google Scholar Crossref Search ADS PubMed 3 Smith SA Morrissey JH . Properties of recombinant human thromboplastin that determine the International Sensitivity Index (ISI) . J Thromb Haemost . 2004 ; 2 : 1610 – 6 . Google Scholar Crossref Search ADS PubMed 4 Van den Besselaar A Tripodi A . Effect of daptomycin on prothrombin time and the requirement for outlier exclusion in International Sensitivity Index calibration of thromboplastin . J Thromb Haemost . 2007 ; 5 : 1975 – 6 . Google Scholar Crossref Search ADS PubMed 5 Van den Besselaar A Breukink E Koorengevel MC . Phosphatidylglycerol and daptomycin synergistically inhibit tissue factor-induced coagulation in the prothrombin time test . J Thromb Haemost . 2010 ; 8 : 1429 – 30 . Google Scholar Crossref Search ADS PubMed 6 Yamada T Kato R Oda K et al. False prolongation of prothrombin time in the presence of a high blood concentration of daptomycin . Basic Clin Pharmacol Toxicol . 2016 ; 119 : 353 – 9 . Google Scholar Crossref Search ADS PubMed 7 Cawthern K Bottenus R Rawal D Triscott M . The impact of phospholipid composition on the interference caused by the antibiotic daptomycin in thromboplastin reagents . J Thromb Haemost . 2007 ; 5 ( suppl 2 ): P-W-017 . 8 Horn JR Hansten PD Chan LN . Proposal of a new tool to evaluate drug interaction cases . Ann Pharmacother . 2007 ; 41 : 674 – 80 . Google Scholar Crossref Search ADS PubMed 9 Dunham CM Rabel C Hileman BM et al. TEG and RapidTEG are unreliable for detecting warfarin-coagulopathy: a prospective cohort study . Thromb J . 2014 ; 12 : 4 . Google Scholar Crossref Search ADS PubMed 10 Schmidt DE Homstrom M Majeed A et al. Detection of elevated INR by thromboelastrometry and thromboelastrography in warfarin treated patients and healthy controls . Thromb Res . 2015 ; 135 : 1007 – 11 . Google Scholar Crossref Search ADS PubMed Copyright © 2018 by the American Society of Health-System Pharmacists, Inc. All rights reserved.
TI - False prolongation of International Normalized Ratio associated with daptomycin
JO - American Journal of Health-System Pharmacy
DO - 10.2146/ajhp170098
DA - 2018-03-01
UR - https://www.deepdyve.com/lp/oxford-university-press/false-prolongation-of-international-normalized-ratio-associated-with-BeG97nedT5
SP - 269
VL - 75
IS - 5
DP - DeepDyve
ER -