4 | Discussion
This study compared the target parameters of PK/PD of vancomycin between the continuous and the intermittent methods of infusion at the same dosing regimen of 40 mg.kg-1.d-1in a pediatric population. Our study highlights the differences and advantages between the continuous and intermittent vancomycin infusions in attaining the target concentrations in critically ill children as well as the AUC/MIC ratio of vancomycin required to achieve accurate control over the target. We show that compared to the IIV, CIV results in better attainment of target levels at the same dose in critically ill pediatric patients with suspected or confirmed gram-positive infection.
Vancomycin is one of the first choices for the treatment of the severe gram-positive bacterial infection, mainly caused by MRSA and other drug-resistant bacteria in children1-4. It is a time-dependent and concentration-dependent drug16-17and many guidelines5-7 have recommended that the target trough concentration of vancomycin should be maintained between 10 to 20 mg.L-1. Several studies3,4have shown that the proportion of the conventional-dose administration reaching the recommended target valley concentration is relatively low, which is consistent with our results. This study shows that the average trough concentration of vancomycin was only 6.25 mg.L-1 in the mode of administration of the conventional intermittent intravenous infusion. Here, the average trough concentration of vancomycin was only were up to 10 mg.L-1 in 22% of 90 patients, and up to 15 mg.L-1 in 14% of patients in the trial. Especially in children, the increasing dosage of vancomycin increases the blood concentration, as well as nephrotoxicity31. To achieve the desired efficacy, safety, and long post-antibiotic effect16–17 of the pharmacodynamics characteristics of vancomycin, it is necessary to prolong the infusion time rather than increasing the dosage to increase the plasma concentration of vancomycin. S.Tafelski et al. 18 in 2015 reported that CIV reaches the therapeutic drug monitoring (TDM) of vancomycin higher than the IIV, and lowers the incidence of acute renal insufficiency. The meta analysis19 of CIV and IIV in 2016 also established that CIV could achieve higher blood concentrations and was safer than IIV. In this study, the average plateau concentration of vancomycin reached 15.22 mg.L-1 in the CIV group, 77.5% (31/40) and 55% (22/40) of patients in this group can get higher TDM of 10 mg.L-1 and 15 mg.L-1 than in the IIV group. In addition, CIV could quickly reach the steady-state blood concentration and avoided the huge fluctuation in the blood concentration between the trough and the peak caused by IIV. The pharmacokinetics and pharmacodynamics varied greatly among a special group of children with the features like rapid growth, vigorous metabolism, and immature system development. Therefore, changing the mode of administration is safer and more economical for increasing the blood concentration and reducing the incidence of drug resistance in pediatrics than by increasing the dosage of vancomycin. The in vitro pharmacodynamic studies and the animal models20-23 demonstrated that the AUC0–24h/MIC ratio of vancomycin as an optimal parameter of pharmacodynamics can predict the favorable microbiological response and clinical outcomes. However, with the higher result from the CIV group, we found that there was no significant difference in AUC0–24/MIC between the two groups when the pediatric patients aimed at the AUC/MIC ≥ 400, because of the small size of the MIC value. In clinical practice, it is difficult to calculate AUC without drawing blood several times a day and cannot be calculated merely by testing in terminal blood. In a systematic review of adult studies25,26 in which the researchers have compared the different parameters of the PK/PD of vancomycin, the minimum concentration of vancomycin correlates better with the parameters of pharmacodynamic and pharmacokinetics predominantly used in clinical medicine. The recommended trough concentration24 range is 10 to 15 mg.L-1however, it could be aimed better at the AUC/MIC ≥400. Although the pharmacokinetics model suggests that it is easier to achieve this target with a dosing regimen of 60 mg.kg-1.d-1, it is practically difficult in clinical practice because of the increased risk of renal injury31. In the American consensus guidelines and studies6 based on those guidelines, the recommended target trough range is 15–20 mg.L-1. Therefore, the index of PK/PD of vancomycin can be assessed by monitoring the blood concentration in the clinic. Under the same daily dosage of vancomycin, several studies6,7 have shown that continuous infusion (CI) can quickly reach the steady-state plateau and greatly facilitate the monitoring of the therapeutic drug concentration. The CI was recommended as a reasonable alternative to the conventional intermittent infusion (evidence level B-II) so that the drug could attain the desired therapeutic effect clinically and could subside nephrotoxicity6.
In our study, CIV could reach the steady-state concentration quickly, attaining a better index of the PK/PD of vancomycin, and did not increase the risks of adverse reactions such as nephrotoxicity and ototoxicity. However, vancomycin did not show clinical efficacy in all the patients and the outcome worsened upon altering the mode of infusing vancomycin. Dynamic monitoring on the full blood examination such as white blood cell count, neutrophil count), CRP, PCT, and cytokines showed no significant differences in the degree of the index of inflammation between the two groups. This indirectly indicated that changing the mode of infusion of vancomycin did not affect the clinical anti-infective effect, and the low MIC value of vancomycin on those patients does not correlate with this result. Vancomycin, as a time-dependent and concentration-dependent drug16-17. The pharmacodynamic parameter related to the curative effect refers to the time that exceeds the MIC. The best bactericidal concentration is about 4–5 times the MIC of vancomycin in the previous studies3. Based on the distribution of MIC in this study, the MIC of bacteria is mostly found to be around 0.5 to 1 mg.L-1, which is similar to the data from the European Committee on Antibiotic Susceptibility Testing (EUCAST)26. So, in this trial, we found that the differences in the target concentration between the two groups do not affect the clinical efficacy because the lowest blood concentration (4.9 mg.L-1) in this group is still greater than 4 times the bacterial MIC. However, the proportion of the high MIC of MRSA in the sensitive range increases with the wide application of vancomycin. This is because of the frequent bacterial MIC drift of vancomycin2,19,20. As a result, there is an increased risk of treatment failure and subsequent vancomycin resistance. In our study, only one patient from the IIV group had longer days of medication than the others with the trough concentration being 5.60 mg/L and the AUC0-24 h/MIC < 200 (MIC = mg.L-1). Although the clinical outcome of the anti-infective therapy had benefited significantly, its duration of medication in this patient was significantly longer than the average in the same group (17 days vs 13 days). As per the latest guidelines6, the TDM of 10 mg.L-1should be considered as the lowest target concentration. The TDM of vancomycin attaining the target trough concentration would signify a more effective anti-infective effect with a reduced likelihood of drug resistance. According to the latest updated Chinese guidelines27, the pharmacokinetics of vancomycin in neonates and children recommended a TDM between 5 to 15 mg.L-1. At the same time, a high proportion of the MIC ≤ 1 and the additional nephrotoxicity associated with a higher dosage of vancomycin should be taken into consideration. Hence, it is necessary to consider bacterial resistance in future studies and clinical applications and to adjust the drug dosage on time based on the changes in the MIC.
Vancomycin is mainly metabolized by the kidney. It is necessary to monitor the renal function during the vancomycin treatment because in severe patients vancomycin often leads to multiple organ dysfunction. Some studies29 reported that there was a close correlation between the dosage of vancomycin and renal injury. An individual exposed to high-dose vancomycin treatment was more prone to renal injury, and CIV could reduce the drug-related adverse effects compared with IIV at the same dosage of vancomycin.27 Giulia DAet.al. 28 conducted a meta-analysis of the different modes of infusion of vancomycin on the patients infected with gram-positive bacteria. Although there was no significant difference in the mortality between CIV and IIV, CIV could reduce the incidence of nephrotoxicity compared to IIV. S.Tafelskiet.al. 18 in 2015 reported a clinical study in which a total of 125 patients with ICU were included. This study reported that the target blood concentration in the patients receiving CIV reached faster (39%) than in patients receiving IIV (61%). In addition, during hospitalization, there was a 35% incidence of acute kidney injury (AKI) in the IIV group and 26% in the CIV group. However, there was no significant difference in the mortality, length of stay in ICU, and duration of mechanical ventilation between the two groups, hence it could be assumed that patients with severe infection or with large changes in renal function can benefit from CIV.
Vancomycin induces nephrotoxicity by damaging the glomeruli and proximal tubules. β2-MG is a small molecular protein produced by the lymphocytes and platelets, which can be reabsorbed through the renal tubules. Hence, it has less content in the urine of normal healthy people and can be used for the detection of early renal function injury in combination with NAGL. This study revealed no difference in the rate of nephrotoxicity. CI can prevent the transient increase in the peak level of vancomycin in the serum during the intravenous injection. In this way, the target concentration is achieved without increasing the dosage of vancomycin; hence, the risk of renal injury can be theoretically reduced.
The use of vancomycin in infants and young children also demands caution against ototoxicity. In this study, no abnormality was found on monitoring the hearing at concentrations higher than 15 mg.L-1 in the blood. In the CIV group, one child had transient skin redness, which improved after controlling the speed of infusion.
There was a limitation to this study. The data within each age strata in our research were limited, and the gram-positive bacteria were isolated from only 42 (42/90, 46.7%) patients. We need to enlarge our sample size for the future studies.
Hence, we can conclude that vancomycin is effective and safe in children with a severe gram-positive bacterial infection. In this study, under the same daily dosage of vancomycin, CIV was found to reach the steady-state concentration quickly, and improve the index of pharmacokinetics without posing any risks of adverse reactions such as nephrotoxicity and ototoxicity.