Background : Due to the relatively high renal toxicity of vancomycin injection (VCM), setting an initial dose that achieves a trough that ranges between 10 and 20 μg/mL on day 3 is important to ensure safety and minimize side-effects, especially for patients with low renal function. To address these issues, the revised 2016 Therapeutic Drug Monitoring (TDM) Guidelines for Antimicrobial Agents (GL2016) proposed the use of a renal function-based, estimate glomerular filtration rate (eGFR) nomogram for setting the dose of VCM in Japan. Methods : Our hospital introduced the use of the GL2016 in September 2016 for the patients administered VCM. After setting the initial VCM dose using 1 ) a conventional VCM analysis software and 2 ) the GL2016 eGFR nomogram, the measured trough values on day 3 were compared and evaluated in this study. Results: With the VCM analysis software, th e mean measured trough value in the a-total group (n = 53) was 12.8 ± 4.7 μg/mL. With the eGFR nomogram, the mean measured trough value in the b-total group (n = 13) was 9.6 ± 4.6 μg/mL. However, when the different severities of renal function were compared, the mean measured trough value was more significantly lower in the b-1 group than in the a-1 group among subjects with G2 and above (eGFR ≥ 60 mL/min/1.73 m2), but it was similar between the a-2 group and the b-2 group among subjects with G3 and below (eGFR < 60 mL/min/1.73 m2). The proportion of subjects reaching the various trough ranges shows similar tendency. Conclusions: These data suggested that the measured trough value on day 3 was generally lower when the initial dose was established using the eGFR nomogram based on the GL2016, and this was especially prominent among patients with normal renal function. As for subjects with low renal function, the trough values were relatively high while ensuring safety.
The Therapeutic Drug Monitoring (TDM) Guidelines for Antimicrobial Agents were created by the Japan Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring to ensure that clinical physicians and pharmacists in Japan deliver efficient and appropriate TDM of antimicrobial agents and to provide high quality medical care to patients [
Vancomycin (VCM), which is a drug against methicillin-resistant Staphylococcus aureus, is the most commonly used antimicrobial agent in Japan. However, VCM has numerous side effects that are primarily associated with kidney damage. Therefore, to strike a balance between clinical efficacy and safety, setting the initial dosage and measurement of the trough value on day 3 is mandatory during TDM [
In this study, after setting the initial VCM dose, we evaluated and compared the measured trough values between 1) an estimate glomerular filtration rate (eGFR) nomogram, as proposed by the GL2016 and 2) a VCM analysis computer software (VCM-soft), which was used prior to the introduction of the GL2016 [
The a-total group comprised 53 subjects who used VCM-Soft for initial dose setting between January 2014 and August 2016. The b-total group comprised 13 subjects who used the initial dose setting proposed by the eGFR nomogram (
Subjects who received prophylactic administration or those who discontinued the administration prior to measuring the initial blood concentration were excluded.
The measured trough values for each of the a and b groups, including the renal function groups, were compared. The trough value ranges were set to 1) less than 10 μg/mL, 2) between 10 and 15 μg/mL, 3) between 15 and 20 μg/mL, and 4) 20 μg/mL and above; the percentage of patients who reached these ranges were compared and evaluated.
In general, an initial target trough value of 10 to 15 μg/mL as the dose setting after VCM administration is ideal although the trough value of 15 to 20 μg/mL is also acceptable.
This study has been approved by the Committee for Clinical Scientific Research of Tohoku Medical and Pharmaceutical University Hospital as No. ID2017-2-030 and -033, and all patients provided written informed consent for use of their blood specimens although measure and estimate of VCM concentration in the blood were specifically focused on part of the routine hospital pharmacological procedure.
eGFR (mL/min/1.73m2) | Loading doses (First administration only) | Maintenance doses (/day) |
---|---|---|
≥120 | 30 mg/kg | 20 mg/kg × 2 |
90 - 119 | 25 mg/kg | 15 mg/kg × 2 |
80 - 89 | 15 mg/kg | 12.5 mg/kg × 2 |
60 - 79 | None | 20 mg/kg × 2 |
50 - 59 | 15 mg/kg × 2 | |
30 - 49 | 12.5 mg/kg × 2 | |
<30 | Not applicable | |
HD | 20 - 25 mg/kg | 7.5 - 10 mg/kg after HD |
Cases and Group | By Computer soft (Jan 2014-Aug 2016: VCM-soft) | By GL2016 (Sep 2016-Mar 2017: eGFR-nomogram) |
---|---|---|
Total(n) | a-total: 53 cases | b-total: 13 cases |
Grade 2 ≥ * (eGFR ≥ 60 mL/min/1.73 m2 | a-1: 38 cases | b-1: 5 cases |
Grade 3 < * (eGFR < 60 mL/min/1.73 m2) | a-2: 15 cases | b-2: 8 Cases |
*indicated by CKD guideline 2012 in Japan (JpnAssc. Kidney).
The clinical and demographic data that were normally distributed were subjected to analysis of variance, with Fisher’s exact test for multiple comparisons; those that were non-normally distributed were analyzed by non-parametric statistics, such as the Mann-Whitney U-rank test. When necessary, the results were further corrected using the Bonferroni method. All data were expressed as mean ± SD. A p-value below 0.05 denoted a statistically significant difference. All analyses were carried out using Stat View software (Abacus Concepts, Cary, NC, USA).
When all the subjects were compared, the mean measured trough value was 12.8 ± 4.7 μg/mL for the a-total group and 9.6 ± 4.6 μg/mL for the b-total group (
When the subjects with G3 and below were compared, the trough value range was 10 - 20 μg/mL in 54% and exceeded 20 μg/mL in 6% of the subjects in the a-2 group; in the b-2 group, 63% had a trough value range of 10 - 20 μg/mL and none had a trough value that exceeded 20 μg/mL.
The GL2016 established an initial target trough value range of 10 to 15 μg/mL as the adequate blood VCM concentration although the trough value of 15 to 20 μg/mL is also acceptable [
When all the subject groups were compared, the mean measured trough values for the b-total group were generally slightly lower compared with a-total group and the adequate blood concentration. In other words, using the GL2016 nomogram increased safety, but it may slightly reduce the clinical efficacy. However, in order to correct this issue, the GL2016 added an amendment that recommended an initial loading dose of VCM that is slightly higher than that given on the first day only in order to enhance clinical efficacy on day 1 [
According to the CKD guidelines 2012, CKD was defined as a disorder of the kidney, such as proteinuria, or a persistent eGFR of < 60 mL/min/1.73 m2 for 3 or more months; this definition had been used for the analysis of various renal functions [
However, comparison of subjects with relatively stable renal function (i.e., G2 and above) showed that the VCM blood concentration was adequate in the a-1 group but was significantly lower in the b-1 group. Masuda et al. retrospectively calculated the eGFR of patients after setting the initial VCM dosage using the VCM-soft and evaluated the efficacy and safety of the dosage recommended by the nomogram [
Safety can be assured when using the GL2016 for initial dose setting of VCM; however, there may be a slight decline in clinical efficacy among healthy adults. Although GL2016 was optimal for the patients with lower renal functions, future studies on a larger number of cases will be needed to re-examine the loading method in patients with normal renal function.
This work was supported by a Grant-in-Aid for Scientific Research (17K09623 to M.S.) from the Japanese Society for the Promotion of Science.
The authors declare no conflicts of interest regarding the publication of this paper.
Kamioka, Y., Suzuki, H., Seki, M., Ouchi, R., Kashiwagura, S., Koshika, S. and Watanabe, Y. (2018) Comparison of Measured Trough Values after Deriving the Initial Dose Setting of Vancomycin with a Conventional Computer Software and a Nomogram Based on the Revised Japanese 2016 Therapeutic Drug Monitoring Guidelines for Antimicrobial Agents. Pharmacology & Pharmacy, 9, 481-487. https://doi.org/10.4236/pp.2018.911037