Evaluation of the Impact of Ascorbic Acid in the Prevention of Vancomycin Induced Nephrotoxicity

Abstract

Background: Vancomycin is a cornerstone antibiotic for Methicillin Resistant Staphylococcus Aureus treatment in the intensive care unit. However, the common side effect-vancomycin associated nephrotoxicity (VAN)- limits its use. Oxidative stress is the anticipated mechanism of VAN, therefore, antioxidants were thought to have a nephro-protective role against VAN. Aim of work: The current study aimed to determine the incidence of VAN, its correlation with piperacillin/tazobactam co-administration and other risk factors in adult critically ill patients, and to investigate the potential nephroprotective role of ascorbic acid against VAN in this population. Patients and methods: An observational retrospective study was conducted at Cairo University Hospitals over a period of two years. Critically ill patients who took vancomycin for at least 72 hours were eligible for the study. Patients were classified into two groups according to whether VAN occurred or not. Patients’ demographics, clinical features, concurrent potential nephrotoxins and severity of illness data were collected at baseline and till the end of the treatment. The obtained data were analyzed to know the possible risk factors for VAN in critically ill patients. Afterwards, a prospective open label randomized controlled trial was conducted on critically ill patients at Cairo University hospitals. Eligible patients were assigned on random basis into one of two groups as follows: the intervention group (vancomycin IV 15-20 mg/kg plus ascorbic acid 2 gram before vancomycin administration by half an hour) and the control group (vancomycin IV 15-20 mg/kg only). Patients demographics, clinical features, concurrent potential nephrotoxins and severity of illness data were collected at baseline. The primary outcome was the vancomycin associated nephrotoxicity incidence and the change in the creatinine parameter, while the secondary outcome was to assess the impact of this nephrotoxicity on rate of mortality and length of stay (LOS). Results: Hundred seventy-two patients were collected from the electronic database of the critical care medicine department for the cohort study, where only 98 patients had sufficient data for analysis and met the inclusion and exclusion criteria. Seventy patients didn’t suffer from VAN where twenty-eight suffered from VAN. Males were 45 (45.9%) and median (IQR) age was 44 (29-59.25) years. Mean time of nephrotoxicity occurrence was 6.8 days while the mean time to resolve from nephrotoxicity was 3.9 days. Multivariate analysis revealed that piperacillin/tazobactam was identified as a significant risk factor that was associated with VAN [odds ratio (OR) 3.2, 95% CI 1.21-8.46, P-value 0.019]. Regarding the randomized controlled trial, 55 patients from the critical care medicine department at Cairo University hospitals were assessed, where only 41 patients were eligible and completed the study. Patients’ demographics, clinical features, concurrent potential nephrotoxins and severity of illness data (Acute physiological and chronic health evaluation II score) were all comparable at baseline. Vancomycin trough levels were comparable in both groups (P-value 0.948). The incidence of VAN was 1/21 (4.7%) versus 5/20 (25%) in the intervention and control groups, respectively (Relative risk (RR), 0.19; CI, 0.024–1.49; P-value = 0.093). Mean absolute difference of S.cr was significant when compared between both groups (P-value= 0.036). Mean absolute Cr.cl decline was significant when compared between both groups, P-value=0.04. Mortality was higher in the control group than the intervention group, however, it didn’t reach statistical significance (P-value = 0.141). Also, LOS didn’t differ significantly between both study groups (P-value = 0.129). Conclusion: The results of the cohort study revealed that VAN incidence was high in the critically ill patients (28.6%). Also, Piperacillin/tazobactam was found to increase the odds of VAN by 3.2 times. The randomized controlled trial proposed that ascorbic acid reduces VAN incidence by 20.3%, however, this reduction didn’t reach statistical significance level. Further prospective large multi-center randomized controlled studies are recommended to approve the obtained results.