Interaction of daptomycin with two recombinant thromboplastin reagents leads to falsely prolonged patient prothrombin time/International Normalized Ratio results

Abstract

A cluster of patients experiencing elevations of International Normalized Ratio without clinical bleeding in temporal association with daptomycin therapy was identified during postmarketing safety surveillance. A common element was the thromboplastin reagent used for the laboratory assay. The present study evaluated the effect of daptomycin on measured prothrombin time using commercially available thromboplastin reagent kits commonly used in the United States. Thirty reagent kits were obtained. Daptomycin was added to pooled normal human plasma samples to achieve final concentrations of 0-200 microg/ml. Quality control ranges were established for each reagent kit using normal and abnormal control plasmas. Triplicate assays of the prothrombin time were performed on the daptomycin-spiked plasma samples using each of the 30 kits. The activated partial thromboplastin time and thrombin time were also assessed. Statistical comparisons of interest were performed using analysis of variance with the Bonferroni t-test for multiple comparisons; alpha = 0.05 was used. Addition of daptomycin to human plasma samples dose-dependently prolonged measured prothrombin times when two recombinant thromboplastin reagents were utilized. The findings were statistically and clinically significant. No clinically meaningful effect was observed with the other reagents. The activated partial thromboplastin time and thrombin time were not affected. Prolonged International Normalized Ratio patient values were an artifact caused by the interaction of daptomycin with the in-vitro prothrombin time test reagent; an in-vivo anticoagulant effect was not observed. Healthcare providers should consider a possible drug-laboratory test interaction if prolonged prothrombin time or elevated International Normalized Ratio values are observed in patients receiving daptomycin.

Effects of Oritavancin on Coagulation Tests in the Clinical Laboratory

“…Similar to effects observed in other studies with telavancin and daptomycin (4,6), the coagulation test elevations are likely a function of variable interactions of oritavancin with the proprietary phospholipidcontaining reagents needed to initiate coagulation in the test systems. For example, the highest tested concentration of oritavancin (46.6 g/ml) in vitro had no effect on the PT/INR result determined using the STA-Neoplastine CI Plus reagent, but increases of 7.0% to 8.9% in the PT/INR result were observed using the other two reagents.…”

“…Participants received a single oritavancin infusion of 1,200 mg over 3 h. Plasma samples were collected at 0, 3,6,12,18,24,48,72,96, and 120 h after the start of oritavancin infusion and were stored at Ϫ20°C until coagulation testing and the pharmacokinetic analysis were performed. The primary objective of the study was to determine the time to resolution of test interference (mean, median, minimum, and maximum values), defined as the interval from the start of the oritavancin infusion to the time the result for all participants returned to the normal reference range or below the subject's baseline value for each coagulation test.…”

“…Previous studies have shown that some lipoglycopeptide or lipopeptide antibiotics (e.g., telavancin and daptomycin) may artificially prolong phospholipid-dependent coagulation test results (4)(5)(6)(7). Although these agents do not interfere with the coagulation system in vivo, their interference with coagulation assays can confound monitoring of hemostasis in the clinical setting.…”

Dose-dependent artificial prolongation of prothrombin time by interaction between daptomycin and test reagents in patients receiving warfarin: a prospective in vivo clinical study

“…It is licensed for use against skin and soft tissue infections and bloodstream infection by gram-positive pathogens. Since its use was first approved in the USA in 2003, several reports have shown that prothrombin time (PT) was prolonged in daptomycin users, especially those who were on warfarin [2, 3]. This prolongation was considered artificial because those patients did not show evidence of bleeding [3].…”

“…Since its use was first approved in the USA in 2003, several reports have shown that prothrombin time (PT) was prolonged in daptomycin users, especially those who were on warfarin [2, 3]. This prolongation was considered artificial because those patients did not show evidence of bleeding [3]. In addition, daptomycin does not interfere with cytochrome P450 and thus it is unlikely to interact with warfarin in vivo [4].…”