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.