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Shutaro Murakami et al
Table 1. Details of Vancomycin Use Calculated by Days of Therapy and TDM-Based Exposure Days Among Each Estimated Renal Function Variablea
2012 2013 2014 2015 2016
2017
Monthly DOT CrCl ≥ 60 mL/min 144.0 (103.5, 155.0) 154.5 (134.3, 176.8) 183.5 (142.3, 199.8) 223.5 (195.3, 257.3) 202.0 (181.0, 256.0) 201.0 (173.3, 224.8) CrCl 30–60 mL/min 77.0 (67.0, 93.8) CrCl < 30 mL/min Dialysis
14.5 (10.8, 24.5) 13.5 (8.8, 23.3)
Monthly
TDM-based ExD CrCl ≥ 60 mL/min 145.0 (108.3, 160.8) 158.0 (137.3, 177.5) 188.5 (154.8, 201.3) 227.5 (195.8, 257.8) 202.5 (182.5, 257.0) 202.5 (175.3, 227.8) CrCl 30–60 mL/min 84.0 (71.5, 102.0) CrCl < 30 mL/min Dialysis
28.0 (16.8, 38.3) 30.0 (21.8, 54.5)
−1.7 (−4.5, −1.0)
78.0 (68.3, 111.8) 22.5 (21.0, 36.3) 40.5 (28.0, 59.5)
Relative difference between DOT and TDM-based ExD, % CrCl ≥ 60 mL/min
CrCl 30−60 mL/min −6.4 (−8.2, −1.4)
−1.4 (−3.4, 0.0) −2.7 (−4.9, −1.4)
86.0 (63.0, 130.3) 128.0 (100.5, 162.5) 106.0 (86.3, 135.8) 103.5 (86.5, 144.8) 26.5 (16.0, 34.8) 63.5 (35.5, 78.8)
35.0 (22.8, 53.3) 43.0 (38.0, 51.8)
−1.7 (−2.4, −1.2) −6.7 (−12.5, −3.7)
−0.2 (−1.9, 0.0) −0.5 (−2.8, 0.0)
53.5 (40.3, 65.5) 50.5 (37.0, 85.5)
−0.5 (−1.0, −0.2) −2.2 (−7.3, −1.3)
52.5 (22.3, 66.5) 52.0 (39.5, 69.5)
−0.9 (−1.7, −0.4) −1.2 (−2.3, 0.0)
CrCl < 30 mL/min −37.9 (−55.1, −28.8) −35.7 (−53.1, −29.1) −19.4 (−39.1, 0.0) −23.1 (−36.4, −9.4) −11.7 (−19.0, −9.1) −20.6 (−26.0, −14.4) Dialysis
−57.2 (−62.1, −53.1) −47.7 (−53.6, −36.6) −47.5 (−52.3, −44.1) −46.5 (−49.1, −36.9) −37.9 (−45.1, −28.2) −41.6 (−49.0, −33.0)
Note. IQR, interquartile range; CrCl, creatinine clearance (Cockcroft-Gault equations); DOT, days of therapy; ExD, exposure days; TDM, therapeutic drug monitoring. aAll data reported as median (IQR).
77.0 (66.8, 107.3) 14.0 (9.8, 26.5) 22.5 (12.8, 30.8)
78.5 (56.0, 114.0) 122.5 (99.3, 163.3) 105.5 (84.5, 127.3) 100.0 (75.8, 144.0) 19.5 (12.5, 27.5) 33.0 (22.5, 40.3)
24.0 (17.5, 34.8) 23.5 (17.8, 33.0)
45.0 (36.5, 57.0) 38.0 (25.3, 42.8)
42.0 (17.5, 49.5) 32.5 (23.0, 37.5)
according to creatinine clearance (CrCl) using Cockcroft-Gault equations: (1) CrCl ≥ 60 mL/min, (2) CrCl 30–60 mL/min, (3) CrCl < 30 mL/min, and (4) dialysis. The paired t test was used to assess the differences between
DOT and TDM-based exposure days. For the statistical analysis, we used Stata version 15.2 software (StataCorp, College Station, Texas). The institutional review board at the study institution approved the study.
Results
Appendices 1 and 2 show the details of TDM and vancomycin use in terms of DOT and TDM-based exposure days during the study period. In general, the median patient days per month were stable at∼19,000. The number of patients receiving at least 1 dose of van- comycin increased during the study period. Since 2014, TDM has been performed twice weekly at the study institution in most patients, except those on a short course of therapy. The mean monthly vancomycin use was 343.5 DOT (standard
deviation [SD], 87.3) and 383.8 TDM-based exposure days (SD, 88.9). The difference between DOT and TDM-based exposure days was−40.3 days (SD, 16.9; P<.001), and the relative difference between DOT and TDM-based exposure days was −10.9% (SD, 4.9%). Among the 4 renal function groups, DOT, TDM-based expo-
sure days, and the absolute and relative differences between the 2 methods varied. For the CrCl ≥ 60 mL/min group, DOT was 187.5 days (SD, 56.1); TDM-based exposure days was 190.7 days (SD, 56.1); the absolute difference between the 2 methods was −3.2 days (SD, 3.9) (P < .001); and the relative difference was −1.8% (SD, 2.7%). For the 60 > CrCl ≥ 30 mL/min group, DOT was 99.4 days (SD, 42.0); TDM-based exposure days was 103.8 days (SD, 41.7); the absolute difference between the 2methods was −4.4 days (SD, 4.9; P < .001); and the relative difference was −5.2% (SD, 7.2%). For the CrCl < 30 mL/min group, DOT was
Discussion
The 2 measures of vancomycin exposure differed significantly; the DOT-based data underestimated vancomycin exposure by ∼10% compared with TDM-based exposure days, which measured only the days of actual exposure. A further difference in vancomycin exposure among patients with CrCl <30 mL/min and those with dialysis was observed, suggesting that using TDM-based exposure days is a better method of assessing the actual duration of exposure in patients with impaired renal function. The difficulty of using exposure days as a measure is its inadequacy to determine the days of exposure between each period of antimicrobial administration, especially when vancomycin is administered at irregular intervals due to renal dysfunction. Although a previous study demonstrated the use of LOT based on the prespecified criteria,4 the method described did not significantly differ from DOT. In contrast, the method used here has the advantage of calculating exposure days based on more frequent assessment of TDM with vancomycin serum concentration values, enabling us to confirm whether the patients were exposed to vancomycin even when the dosing inter- vals were irregular or several days apart. Although TDM-based exposure days probably correlate with DOT, this measure may be more suitable for patients with lower creatinine clearance, elderly patients with labile renal function or intensive care units where significant fluctuation in DOT measurement is expected.
27.4 days (SD, 17.5); TDM-based exposure days was 36.7 days (SD, 20.5); the absolute difference between the 2 methods was −9.3 days (SD, 7.3) (P < .001); and the relative difference was −25.9% (SD, 18.9%).And for the dialysis group,DOT was 27.7 days (SD, 15.5); TDM-based exposure days was 50.7 days (SD, 26.9), the absolute difference between the 2methods was−23.0 days (SD, 14.1; P < .001); and the relative difference was −44.8% (SD, 12.4%). The details of vancomycin exposureamong for each renal functiongroup are shown in Table 1.
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