Due to frequent multimorbidity, polypharmacy, increased risk of adverse effects, and altered pharmacokinetics and pharmacodynamics associated with aging, pharmacotherapy in older patients is challenging[19]. For vancomycin therapy, the efficacy is dependent on appropriate dosing. Since there are no recommendations of dosing specific for the geriatric population in the current vancomycin therapeutic guidelines, the halved dose is recommended for older patients in vancomycin package insert. However, no study has been conducted on the pharmacokinetic characteristics of the halved vancomycin dose in older patients. This retrospective study aimed to investigate the pharmacokinetic characteristics and safety of older patients who were administrated with dose regimen for younger adult patients with normal kidney function (≥1.5g/day) or with a halved dosing of vancomycin (≤1g/d), to provide some suggestions for vancomycin initial dose selection and prevention of adverse reactions in this crowd of patients.
In this older population, we found a large inter-individual pharmacokinetic of vancomycin exposure between the two groups. Although the dosing for younger adult patients is not recommended for the older, most patients were still prescribed with this dose in clinical practice (84.5%). For older patients who have a certain degree of renal dysfunction, this calls for more attention. We observed more patients in group A met the target trough concentration of 10-20mg/l than in group B (55% vs. 48%), however, the proportion of supratherapeutic concentration (30.9%) was significant higher. The halved initial dose of vancomycin in group B (≤1 g/day) in older patients can still lead to higher drug concentration (20.0%). Thus, clinicians had the initial vancomycin dose adjusted of some patients according to the target concentration and therapeutic effect during the treatment (22% in group A and 33.3% in groups B). Of the patients who did not had the initial dose of vancomycin adjusted, the proportion of vancomycin trough concentration outside the range of therapeutic target was up to 56.2% (36/64) in group A and 40% (4/10) in group B, which means the actual number of patients who need to be dose-adjusted should be 54 (65.9 %) in group A and 9 (60%) in group B. These results suggest that the initial dose either in group A or group B is not appropriate for older patients considering the low incidence of target rate of vancomycin concentrations. It highlighted the fact that clinicians need to develop an understanding of the importance of vancomycin concentration monitoring and concern should be focused on how to choose the initial dose of vancomycin for older patients. Since there are no recommendations specific for the geriatric population in vancomycin guidelines by the Infectious Diseases Society of America (IDSA) [20], pharmacokinetic studies should be performed to optimize the dose regimen in these crowd of patients [21].
Several factors that may influence the pharmacokinetic and pharmacodynamic of vancomycin have been identified to be contributed to the inter-individual variability, such as sex, age, body weight, serum albumin and eGFR. Hypoalbuminemia has been proved to be associated with prolonged vancomycin half-life and higher AUC in older patients [22]. Total body weight may affect the volume of vancomycin distribution [7,23]. The present study showed that the trough concentration of vancomycin increased with age despite no significant difference was observed among age stratified, which was consistent with previous study [24]. The multivariable linear regression models found that SCr after medication (p=0.006), baseline eGFR (p=0.047) and eGFR after medication (p<0.001) were associated with vancomycin trough concentration in group A. There was no covariate associated with vancomycin trough concentration in group B, which probably owing to the small sample size included in group B have affect the generality of the study results. Nevertheless, this result illustrated that low-dose vancomycin may not cause significant changes in eGFR, so it may be more suitable for older patients.
Calculating the optimal dose in older patients is further complicated by the difficulty to accurately estimate their renal function. Glatard A et al compared the abilities of six different renal function estimation equations (Cockcroft-Gault (CG), Jelliffe (JEL), Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and modified MDRD and CKD-EPI equations) to describe vancomycin pharmacokinetics in older patients, the final analysis showed important differences in parameter distributions and AUC estimation, he concluded that each estimation equations should not be considered interchangeable for model-based estimation of vancomycin concentrations in older patients [25]. In our study, we choose Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) to estimate the creatinine clearance of older patients due to weight information of some older patients being unobtained. Besides, older patients who received the high-strength and long-term vancomycin therapy might results in unstable renal function, CKD-EPI method is more suitable since it can afford suitable dose adjustment [26].
Older patients are considered a population at high risk of nephrotoxicity when using vancomycin according to several studies[27,28]. In our study, significant correlations between vancomycin trough concentration and AKI were observed, the trough concentration in patients with AKI was significantly higher than those without (21.94±9.48mg/l vs.15.99±6.89mg/l; p=0.006). We observed that the overall incidence of AKI is lower than previous studies [29]. Meanwhile, even if the trough concentration of vancomycin in group A was significantly higher than that in group B, there was no significant difference in the incidence of AKI between the two groups, which suggest that the dose regimen of vancomycin in both groups had a mild effect on renal function and it was well tolerated for older patients. Surprisingly, the incidence of AKI in group B is a bit higher than that in group A, the probable reason was that some patients in group B had renal impairment before vancomycin administrated and lower initial dose of vancomycin was chosen for them. It is necessary to monitor vancomycin Cmin early to help older patients improve treatment efficacy and avoid AKI in the absence of further studies on appropriate initial dosage recommendation.
There are three limitations in the present study. First, due to the limited sample size, the results need to be identified in a wider population. Secord, the study was a retrospective design, the dosage of vancomycin was at physicians’ discretion, and the time of first levels collection were variable. Third, some older patients already have renal function damage before vancomycin administration, which can lead to a higher vancomycin trough concentration and higher rate of vancomycin -related adverse events.