A Curious Case of Elevated INR; Artificial Rise of PT/INR by Telavancin

Matthew J Lopez; Derek Amanatullah, MD, PhD; Robert Gosselin, CLS; Munish C Gupta, MD; Malathi Srinivasan, MD

University of California, Davis Medical Center; Sacramento, CA

Learning Objectives 1. Consider medication side effects as a possible cause of

increased INR 2. Utilize proper testing protocols when measuring INR in

the setting of telavancin use.

Case Description:

HPI: 61yo female with severe scoliosis s/p T4-sacrum posterior spinal fusion in August 2009 Recurrent MRSA positive abscesses and spine osteomyelitis Resistant to vanco, dapto, PNC, b-lactams after therapy Sensitive to telavancin (Astellas Pharma, Deerfield, IL), a new lipoglycopeptide Admitted for hardware replacement, started on telavancin Pre-op lab work: INR = 2.5. Previously, INR = 1.0 PMH: No history of bleeding or coagulation disorders. No nutritional deficiencies. No coumadin or anticoagulants. Physical Exam: Unremarkable. No bruising or ecchymoses. Labs: Coagulation studies : (all normal) aPTT 29.6 Thrombinogen 92 Factor V 118, Factor VII 166, Factor X 153 Hospital Course: Hospital Day 1: INR = 2.5 Hospital Day 2: INR = 2.0. Vitamin K 1mg given Hospital Day 3: INR = 1 Hospital Day 4: INR = 2.4

Hospital Day 5: Anticoagulation team consulted and medications reviewed. Telavancin can interfere with certain INR reagents, confirmed by in vitro testing. Alternative reagent used, and INR normalized

Hospital Day 8: INR = 1.0 with new reagent in assay. Hospital Day 9: Surgery performed successfully without complications.

Telavancin at a glance:

A lipoglycopeptide antibiotic approved by the FDA in 2009 Semi-synthetic derivative of vancomycin Indications: complicated skin and skin structure infections (cSSSI) caused by: S. aureus (MRSA and MSSA); Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus group, or Enterococcus faecails (vancomycin- susceptible isolates only) No reported resistance…yet Provides a new alternative to vancomycin, linezolid, tigecycline, and daptomycin Exerts concentration dependent bactericidal activity. Inhibits cell wall synthesis of Gram positive bacteria by interfering with cross linking of peptidoglycan Dosed at 10 mg/kg IV qd over 60 min for 7-14 days t½ 8.0 +/- 1.5 hrs Notable side effects: nausea/vomiting, QT prolongation, reversible renal dysfunction. Unknown teratogenic effects.

Discussion:

While the incidence of hospital associated MRSA is decreasing, community acquired MRSA infections are increasing. 2004 (most recent year with CDC available data): 1. 11 million visits for skin infections caused by S. aureus. 2. Of these, 78% were caused by CA-MRSA. Telavancin 1. Provides a new treatment option for highly resistant MRSA. 2. Can cause elevated INR measurements, when using standard reagents. True INR can be obtained 2 different ways: 1. Use of an alternative reagent that is not affected by telavancin. Our institution uses RecombiPlasTin 2G (older reagent). 2. The manufacturer recommends drawing blood samples immediately before the next daily dose of telavancin.

References: 1.Kim DH, Spencer M, Davidson SM, Li L, Shaw JD, Gulczynski D, Hunter DJ, Martha JF, Miley GB, Parazin SJ, Dejoie P, Richmond JC. Institutional prescreening for detection and eradication of methicillin-resistant Staphylococcus aureus in patients undergoing elective orthopaedic surgery. J Bone Joint Surg Am 2010;92-9:1820-6. 2.Naimi TS, LeDell KH, Como-Sabetti K, Borchardt SM, Boxrud DJ, Etienne J, Johnson SK, Vandenesch F, Fridkin S, O'Boyle C, Danila RN, Lynfield R. Comparison of community- and health care-associated methicillin-resistant Staphylococcus aureus infection. JAMA 2003;290-22:2976-84. 3.Astellas Pharma US I. Telavancin Package Insert. Deerfield, IL: Aseellas Pharma US, Inc., 2009. 4.Bamford E, Bowen R. A capillary whole blood method for measuring the INR. Clinical Laboratory Haematology 2000;22:279-85. 5.Corey GR, Stryjewski ME, Weyenberg W, Yasothan U, Kirkpatrick P. Telavancin. Nat Rev Drug Discov 2009;8-12:929-30. 6.Barriere SL, Goldberg MR, Janc JW, Higgins DL, Macy PA, Adcock DM. Effects of telavancin on coagulation test results. Int J Clin Pract 2011. 7.Shaw JP, Cheong J, Goldberg MR, Kitt MM. Mass balance and pharmacokinetics of [14C]telavancin following intravenous administration to healthy male volunteers. Antimicrob Agents Chemother 2010;54-8:3365-71. 8.Shaw JP, Seroogy J, Kaniga K, Higgins DL, Kitt M, Barriere S. Pharmacokinetics, serum inhibitory and bactericidal activity, and safety of telavancin in healthy subjects. Antimicrob Agents Chemother 2005;49-1:195-201. 9. Wong SL, Barriere SL, Kitt MM, Goldberg MR. Multiple-dose pharmacokinetics of intravenous telavancin in healthy male and female subjects. J Antimicrob Chemother 2008;62-4:780-3. 10.Center for Disease Control. “MRSA statistics.” http://www.cdc.gov/mrsa/statistics/index.html. Sep 24 2011.

Figure 2: The relationship of increasing serum telavancin levels with measured INR using two different INR reagents, Innnovin and RecombiPlasTin 2G – which contain different phospholipids (PL). When Innovin is used the INR falsely increases, while INR measurement with RecombiPlasTin 2G is not affected.

Figure 1. Hospital day 1 (3/1/11) shows a elevated INR at 2.51. Vitamin K was given on day 2, which was initially believed to be responsible for the normal INR seen on day 3. INR was measured with the Innovin (Dade Behring, Liederbach, Germany) reagent until day 8. INR was measured with the alternative reagent, RecombiPlasTin 2G (Instrumentation Laboratory, Bedford, MA), on days 8 and 9, reflecting the true INR.

Hospital Course

in vitro testing

Hospital Day

Vit K given

Blood drawn before

telavancin administration

INR tested with RecombiPlasTin

2G reagent

First day of Telavancin

administration

Surgery performed w/o

bleeding complications

7.0

8.9

27.2

466 140

4.4

104

26

21

0.86 123

PT/INR testing

Why does telavancin affect one reagent but no the other?

Short answer: Exact mechanism unconfirmed, however…. Long answer:

Telavancin is known to bind to the artificial phospholipids in the INR assay reagent solution. Different reagents contain different PL, and reagent characterization is proprietary information (we cannot access exact PL configuration).

Ca: 8.2 Mg: 2.0

Coagulation

Cascade

Figure 4: The extrinsic pathway is trigged when platelet poor plasma is added to reagent (Ca, TF, & artificial PL). After clotting, INR is measured by changes in optical density. Telavancin competitively binds artificial PL in solution, slowing optical density change.

Figure 3: Intrinsic and extrinsic coagulation cascade. The INR assay tests the extrinsic pathway.

Fibrinogen (I) Fibrin ( Ia )

TF

II