title: Dose-dependent artificial prolongation of prothrombin time by interaction between daptomycin and test reagents in patients receiving warfarin: a prospective in vivo clinical study.
abstract: BACKGROUND
  Daptomycin has been reported to cause artificial prolongation of prothrombin time (PT) by interacting with some test reagents of PT. This prolongation was particularly prominent with high concentrations of daptomycin in vitro. However, whether this prolongation is important in clinical settings and the optimal timing to assess PT remain unclear.
  
  
  METHODS
  A prospective clinical study was conducted with patients who received daptomycin for confirmed or suspected drug-resistant, gram-positive bacterial infection at a university hospital in Japan. PT at the peak and trough of daptomycin was tested using nine PT reagents. Linear regression analyses were used to examine the difference in daptomycin concentration and the relative change of PT-international normalized ratios (PT-INR).
  
  
  RESULTS
  Thirty-five patients received daptomycin (6 mg/kg). The mean ± standard deviation of the trough and peak concentrations of daptomycin were 13.5 ± 6.3 and 55.1 ± 16.9 μg/mL, respectively. Twelve patients (34%) received warfarin. With five PT reagents, a significant proportion of participants experienced prolongation of PT-INR at the daptomycin peak concentration compared to the PT-INR at the trough, although the mean relative change was less than 10%. None of the participants clinically showed any signs of bleeding. A linear, dose-dependent prolongation of PT was observed for one reagent [unadjusted coefficient β 3.1 × 10-3/μg/mL; 95% confidence interval (CI) 2.3 × 10-5-6.3 × 10-3; p = 0.048]. When patients were stratified based on warfarin use, this significant linear relationship was observed in warfarin users for two PT reagents (adjusted coefficient β, 6.4 × 10-3/μg/mL; 95% CI 3.5 × 10-3-9.3 × 10-3; p < 0.001; and adjusted coefficient β, 8.3 × 10-3/μg/mL; 95% CI 4.4 × 10-3-1.2 × 10-2; p < 0.001). In non-warfarin users, this linear relationship was not observed for any PT reagents.
  
  
  CONCLUSIONS
  We found that a higher concentration of daptomycin could lead to artificial prolongation of PT-INR by interacting with some PT reagents. This change may not be clinically negligible, especially in warfarin users receiving a high dose of daptomycin. It may be better to measure PT at the trough rather than at the peak daptomycin concentration.
authors.affiliation: Department of Infectious Diseases, University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Saito
authors.affiliation: Department of Infectious Diseases, University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. shatake-tky@umin.ac.jp.|Division of General Internal Medicine, Division of Infectious Diseases, Jichi Medical University Hospital, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi, 329-0498, Japan. shatake-tky@umin.ac.jp.
authors.forename: Shuji
authors.initials: S
authors.lastname: Hatakeyama
authors.affiliation: Department of Infectious Diseases, University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Hashimoto
authors.affiliation: Department of Infectious Diseases, University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Takumitsu
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Department of Infectious Diseases, University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Jubishi
authors.affiliation: Department of Clinical Laboratory, University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kaneko
authors.affiliation: Department of Clinical Laboratory, University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kume
authors.affiliation: Department of Pharmacy, University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Takehito
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Department of Pharmacy, University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Department of Infectious Diseases, University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yotsuyanagi
mesh_terms: D000368:Aged; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000627:therapeutic use*; D000925:Anticoagulants / Q000627:therapeutic use*; D001424:Bacterial Infections / Q000188:drug therapy; D017576:Daptomycin / Q000378:metabolism / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005189:False Positive Reactions; D005260:Female; D006785:Hospitals, University; D006801:Humans; D007202:Indicators and Reagents / Q000378:metabolism*; D007564:Japan; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011517:Prothrombin Time; D014859:Warfarin / Q000627:therapeutic use*
chemical_list: D000900:Anti-Bacterial Agents; D000925:Anticoagulants; D007202:Indicators and Reagents; D014859:Warfarin; D017576:Daptomycin
keywords: Daptomycin; Drug resistance; Gram-positive infections; High dose; Prothrombin time; Warfarin