3. Pharmacokinetic parameters used in
vancomycin efficacy and toxicity
assessments
The most common recommended pharmacokinetic parameters for vancomycin
TDM are trough concentration, area under the curve of total daily dose
(AUC24h) to minimum inhibitory concentration (MIC)
ratio, and steady state plasma concentration (Css) for
continuous infusion [13]. AUC refers to the total drug exposure to
the administered dose in a defined time period. It has been suggested
that AUC24h/MIC≥400, in microorganisms with minimum
inhibitory concentration (MIC) of ≤ 1 mg/L, can be an important
indicator of successful drug response [9]. Trough concentration
assessment is the simplest method of vancomycin pharmacokinetic
evaluation. It has been recommended that trough concentration of 15-20
µg/ml would be a suitable target concentration with promising drug
efficacy and safety [3]. But previous studies revealed that in many
patients, AUC24h/MIC values of ≥400 could be achieved
with lower values of trough concentrations (<15 µg/ml) and
these trough values could be associated with lower risk of
vancomycin-induced nephrotoxicity [14, 15]. So, AUC calculation can
be considered as the preferred method for vancomycin pharmacokinetic
assessments. Another advantage of AUC calculation is the simplicity of
vancomycin dosing based on AUC values according to the Eq. 1 [3].
\(Vancomycin\ dose=\frac{\text{Cl}}{\text{AUC}_{24h}}\) (Eq. 1)
Where vancomycin dose is in mg/day, Cl is drug clearance in L/h, and
AUC24h is the area under the cure of total daily dose in
mg.L/h.
Also, there are controversies regarding the intermittent or continuous
infusion of vancomycin and previous studies failed to reach a
superiority for either method. The most important advantages of
continuous infusion over intermittent infusion are less variability in
vancomycin plasma concentrations, less dependency on time and number of
prepared blood samples, and lower incidence of AKI [12]. Results of
a recent meta-analysis have demonstrated that although continuous
infusion of vancomycin was accompanied by lower incidence of
nephrotoxicity, there was no significant difference between continuous
and intermittent infusion approaches in terms of clinical efficacy and
mortality rate in the patients receiving vancomycin [16]. During
intermittent infusion, trough concentration sampling should be done just
before the next dose administration when steady state concentration
(Css) is achieved, i.e., after 4 to 6 elimination
half-lives (about 48 hours in normal kidney patients) [3] and can be
used for the purpose of vancomycin TDM during continuous infusion
approach. Upon intermittent vancomycin infusion, pharmacokinetic
parameters such as k and Vd can be calculated through
Eq. 2 and Eq. 3, using two level plasma sampling. To do so, one sample
should be the first peak concentration (one hour after the end of
infusion) and the other one can be drawn at an optional time during the
interval dosing and before the next dose infusion.
\(C_{t}={(C}_{\max})e^{-k(t-t^{{}^{\prime}})}\) (Eq. 2)
Where Ct is plasma concentration at time t in mg/L,
Cmax is the first peak concentration in mg/L, k is
elimination constant in h-1, t is the time of second
blood sampling in h, and t´ is the infusion time in h.
\(C_{\max}=\frac{K_{0}}{k\times V_{d}}(1-e^{-kt^{{}^{\prime}}})\) (Eq. 3)
Where Cmax is the first peak concentration in mg/L,
K0 is the drug infusion rate in mg/h, k is elimination
constant in h-1, Vd is volume of
distribution in L, and t´ is the infusion time in h.
Then, steady state concentrations could be calculated using the
aforementioned pharmacokinetic parameters according to Eq. 4 and Eq. 5
[3].
\(C_{\text{ss}}^{\max}=\frac{K_{0}(1-e^{-kt^{\prime}})}{k\times V_{d}(1-e^{-k\tau})}\)(Eq. 4)
\(C_{\text{ss}}^{\min}=C_{\text{ss}}^{\max}e^{-k(\tau-t^{{}^{\prime}})}\)(Eq. 5)
Where\(\text{\ C}_{\text{ss}}^{\max}\) and \(C_{\text{ss}}^{\min}\ \)are
peak and trough concentrations at steady state, respectively in mg/L,
K0 is drug infusion rate in mg/h, k is elimination
constant in h-1, Vd is the volume of
distribution in L, t´ is the infusion time in h, and τ is drug interval
in h.
During the continuous infusion of vancomycin, steady state concentration
could be calculated through the Eq. 6, in which vancomycin clearance is
estimated from creatinine clearance through the Eq. 7 [17].
\(C_{\text{ss}}=\frac{K_{0}}{\text{Cl}}\) (Eq. 6)
\(Cl=0.04\left(\text{Cl}_{\text{cr}}\right)+0.22\) (Eq. 7)
Where \(C_{\text{ss}}\)steady state plasma concentration is in mg/L,
K0 is infusion rate in mg/h, Cl is vancomycin clearance
in L/h, and Clcr is creatinine clearance that is equal
to the estimated glomerular filtration rate (eGFR) in L/h.
According to these formulas, target \(C_{\text{ss}}\) values of 20-30
µg/ml and AUC24h values of 400-700 mg.h/L can be
achieved. In continuous infusion regimen, loading dose of 20 mg/kg
accelerates the steady state concentration achievement. Afterwards,
continuous infusion should be immediately initiated upon loading dose
administration. According to Eq. 8, it was suggested that in continuous
infusion approach, AUC24h could be calculated by one
sample after steady state achievement [3].
\(\text{AUC}_{24h}=C_{\text{ss}}\times 24\) (Eq. 8)
Where AUC24h is the area under the curve of total daily
dose and Css is the steady state vancomycin plasma
concentration.
3.1. Trough
concentration
Since many years ago, monitoring of the vancomycin trough concentration
has been considered as an accurate, practical, and simple approach for
vancomycin TDM purposes. Pros and cons of the trough-only vancomycin
monitoring approach are summarized in Table 1. Sample preparation for
trough concentration assessment should be done after steady-state
concentration achievement. The suitable sampling time in patients with
normal renal function can be scheduled after 48 hours of drug
administration or before the forth dose. The exact time of sampling
should be just before the next dose or up to 30 minutes prior to the
next dose. Target trough concentration of 15-20 µg/ml was recommended in
critically ill patients with severe Gram-positive infections [11].
Previous studies on vancomycin pharmacokinetics claimed that vancomycin
trough concentration had a good correlation with AUC values, especially
in adult patients with GFR≥100 ml/min. Also, it was maintained that in
such patients, trough concentration of 15-20 µg/ml may result in AUC/MIC
values of ≥400 µg.h/ml in microorganisms with MIC≤1 µg/ml [14].
Higher vancomycin trough concentrations (>20 µg/ml) are
associated with vancomycin-induced nephrotoxicity. But not all patients
with trough concentration of >20 µg/ml proceeded to
nephrotoxicity. Nephrotoxicity occurred in about 25-40% of the patients
with trough concentration of >20 µg/ml [14]. Although
the target trough concentration of 15-20 µg/ml was suggested as an
optimum concentration in vancomycin TDM assessments, it was reported
that trough concentration of >12.1 µg/ml was significantly
associated with an enhanced risk of nephrotoxicity occurrence [18].
Results of a population pharmacokinetic and vancomycin dose simulation
study revealed that trough concentrations were highly varied among
participating patients with different and/or same renal functions. So,
it seems that in order to achieve a suitable clinical response and
acceptable vancomycin efficacy with AUC values of 400 to 700 µg.h/ml,
trough concentration of >15 µg/ml is not necessary in many
patients and can induce nephrotoxicity with no further superior
efficacy. Up to 60% of adult patients with trough concentration of
<15 µg/ml could achieve target AUC24h/MIC
target values of ≥400 µg.h/ml [19]. We can conclude that the
preferred approach to vancomycin TDM and pharmacokinetic assessments
could be AUC of intervals (AUCτ) calculation rather than trough-only
monitoring approach [14]. As per the recent 2020 vancomycin
guideline, AUC24h/MIC values of 400-600 µg.h/ml for
severe MRSA infections would be a better alternative target to trough
concentration of 15-20 µg/ml for vancomycin TDM purposes [19]. It
was reported that AUC24h/MIC values of ≥400 µg.h/ml was
associated with better clinical outcomes in septic patients and
AUC24h/MIC values of ≤650 µg.h/ml was associated with
lower risk of vancomycin induced AKI [19, 20]. Another drawback in
trough-only monitoring approach could be the possible errors in sampling
time. Results of a recent prospective study have revealed that fewer
than half of the collected samples were within the normal range of
trough concentration sampling times (10-12 hours post-dose) [21]. In
general, trough-only monitoring approach with target concentration of
15-20 µg/ml has no longer been supported by recent infectious guidelines
due to its lack of clinical efficacy and higher rate of
vancomycin-induced nephrotoxicity [22]. According to a retrospective
cohort study on vancomycin TDM, trough concentration-based dosing was
accompanied by higher treatment failure rate and higher acute kidney
injury occurrence in comparison to AUC-based dosing approach [22].
Trough-based vancomycin dose adjustment can be achieved through the Eq.
9 [23].
\(D_{2}=(\frac{C_{t2}}{C_{t1}})\times D_{1}\) (Eq. 9)
While \(D_{2}\ \)is the new dose in mg, \(C_{t2}\) is the target
steady-state trough concentration in mg/L, \(C_{t1}\) is the current
trough concentration in mg/L, and \(D_{1}\) is the previous dose in mg
resulting in plasma trough concentration of \(C_{t1}\).
3.2. Peak
concentration
Peak concentration is defined as the vancomycin plasma concentration
drawn 1 hour after the end of the 1 hour-infusion period in order to
pass the distribution phase [14]. There are controversies about the
necessity of plasma peak concentration calculation for vancomycin TDM
purposes [25]. Results of many population pharmacokinetic studies
revealed that peak concentration was not associated with either
vancomycin efficacy or vancomycin-induced nephrotoxicity [14].
However, peak concentration can be used as an essential point in AUC of
interval calculation [14]. It was reported that using both trough
and peak concentrations in AUC calculation could enhance the precision
of assessments in comparison to trough-only consideration in AUC
calculation [26]. Results of a recent Bayesian model-based
population study have revealed that AUC estimation using peak and trough
concentrations was worse than using trough-only approach. The same study
claimed that using a peak concentration that drawn just after the end of
the infusion period would be better in calculation of AUC values using
peak and trough concentrations. So, it seems that peak concentration can
be assessed just after the end of 1 hour-infusion in order to achieve
better estimation in AUC calculation, especially in one-compartment
models. Although the results of a recent pragmatic randomized controlled
trial suggested that peak-trough-based TDM approach was significantly
associated with higher therapeutic and clinical cure rate, compared to
trough-only-based TDM approach, they failed to show a significant
difference in all-cause mortality and vancomycin-induced nephrotoxicity
between these two TDM approaches [23]. Peak-trough-based vancomycin
dose adjustment could be achieved through the Eq. 10 and Eq. 11 [23]
as well as by individualized calculation of pharmacokinetic parameters,
as mentioned in the Introduction.
\(\tau=\frac{\operatorname{(ln}{C_{\text{peak}}-\ln C_{\text{trough}}})}{K_{e}}+t^{\prime}\)(Eq. 10)
\(Dose=C_{\text{peak}}\times K_{e}\times V_{d}(\frac{1-e^{-K_{e}\tau}}{1-e^{-K_{e}t^{{}^{\prime}}}})\)(Eq. 11)
Where τ is dosing interval in h, \(C_{\text{peak}}\) is steady-state
peak concentration in mg/L, \(C_{\text{trough}}\) is steady-state trough
concentration in mg/L, \(K_{e}\) is elimination constant in
h-1, \(t^{{}^{\prime}}\) is infusion time in
h,\(\text{\ \ V}_{d}\) is volume of distribution in L andDose is the new vancomycin dose in mg.
3.3.
AUC
Based on recent reports on vancomycin dosing, AUC24hcould be the preferred approach to TDM purposes [27]. Pros and cons
of the AUC-based vancomycin monitoring approach are summarized in Table
2. AUC24h calculation can be done, based on Bayesian
software programs using a trough-only sampling approach or peak-trough
sampling approach, while the latter results in higher accuracy in AUC
estimation [12]. Vancomycin dose adjustment and AUC calculation,
based on available Bayesian software programs including Adult and
Pediatric Kinetics (APK), BestDose, DoseMe, InsightRx, and Precise PK
can be considered as an alternative approach to practical uses of
clinicians and pharmacists for the purpose of vancomycin TDM and
dose-optimization. Such available soft wares are simple, flexible, and
user friendly that can be used by pharmacists and clinicians in the
field of vancomycin TDM [28]. Results of a recent review article on
the evaluation of the accuracy and efficacy of such Bayesian tools have
revealed that similar AUC estimation could be achieved through this
approach in comparison to pharmacokinetic equations using two-point
blood sampling assay for TDM purposes [29], but further larger
meta-analysis and systematic review studies are required, especially for
patients with altered pharmacokinetics to assess their accuracy and
clinical efficacy in comparison to previous approaches such as AUC
calculation using trapezoidal method and individualized pharmacokinetic
parameters calculation using at least two vancomycin plasma
concentration.
The recommended target value of ≥400 µg.h/ml with MIC value of
<1 µg/ml as well as a cut-off point of ≈600 µg.h/ml should be
considered to avoid vancomycin-induced AKI occurrence [30]. It was
reported that although there was a significant correlation between
trough concentration and AUC24h, it was moderate
(R2 of 0.51). Results of a recent population
pharmacokinetic study has revealed that AUC values could vary about
30-folds in the patients with different renal functions, lending support
to the importance of vancomycin TDM and individualized pharmacotherapy
to avoid vancomycin-induced nephrotoxicity in over-dose patients and
prevent clinical response failure in under-dose individuals. Also, the
studies indicated that trough-only monitoring approach could not be an
accurate and suitable surrogate of AUC calculation since the significant
correlation was not obvious [14, 24]. It was suggested that an
AUC24h threshold value of 700 µg.h/ml should be
considered to avoid vancomycin-induced nephrotoxicity.
AUC24h values of >700 µg.h/ml were
significantly associated with higher incidence of vancomycin-induced
nephrotoxicity [14]. Results of a retrospective pharmacokinetic
study on American population revealed that patients with
AUC24h≥297 µg.h/ml had more than 2.7-fold improvement in
clinical response in comparison to those with lower
AUC24h values. Also, it was reported that patients with
AUC24h≥710 µg.h/ml had more than 7-folds higher risk of
nephrotoxicity occurrence due to vancomycin over-exposure [31]. In a
recent prospective study, among the participants, 19% had therapeutic
trough concentration while 70% of them had therapeutic AUC values.
Also, the results of this study revealed that 31% of the patients with
AUC≥400 µg.h/ml had trough concentration of <10 µg/ml with
68% of whom were with trough concentration of <15 µg/ml,
suggesting that AUC rather than the vancomycin trough concentration can
be considered as a suitable pharmacokinetic parameter, in order to
obtain enough clinical efficacy with lower incidence of nephrotoxicity.
The acceptable AUC targets can be achieved with lower plasma trough
concentrations [21]. Results of a retrospective pharmacokinetic
study in Japanese population revealed that AUC-guided vancomycin TDM
(target AUC>400 µg.h/ml), compared to trough-guided TDM
(target trough concentration of 15-20 µg/ml), could be associated with
lower risk of nephrotoxicity occurrence [32, 33]. Overall, according
to the reports, AUC-guided, Bayesian estimation dosing of vancomycin was
accompanied by lower incidence of vancomycin-induced nephrotoxicity,
shorter duration of antibiotic therapy, fewer blood samples, less
vancomycin exposure, and less over-dose occurrence with
cost-effectiveness. So, it seems reasonable to shift from
trough-only-guided dosing approach to AUC-guided dosing approach for
vancomycin TDM in referral hospitals in order to maintain the
therapeutic window [21, 34]. Besides the many advantages mentioned
about the use of AUC24h/MIC target concentration of
400-600 µg.h/ml for MRSA infections, yet there are some drawbacks that
should be taken into accounts. First, the target
AUC24h/MIC value of 400-600 µg.h/ml does not contribute
to other Gram-positive microorganisms that are less virulent than MRSA,
such as Methicillin-resistant coagulase negative Staphylococcus
aureus . Also, it seems that the recommended concentration of 400-600
µg.h/ml is suitable for sepsis, pneumonia, and endocarditis while other
severe infections such as meningitis and osteomyelitis may require
different AUC target values. Meanwhile, a recent meta-analysis has
revealed that AUC24h/MIC target concentration of
>400 µg.h/ml is not associated with reduced morbidity and
mortality in severe cases of MRSA infection [19].
3.4. Vancomycin clearance
(ClV)
Vancomycin clearance (ClV) is considered as a
pharmacokinetic parameter in the prediction of vancomycin efficacy and
toxicity. Results of a previous observational study on vancomycin
administration revealed that ClV was correlated with
creatinine clearance (calculated via Cockcroft-Gault equation), serum
creatinine, gender, age, weight, and neutropenia. There was a
correlation with R2 of 0.5 between ClVand creatinine clearance, so it seems that ClV should
not be considered as a suitable predictor in vancomycin clinical
pharmacokinetic assessments. Results of this study revealed that
creatinine clearance had a good correlation with 24h-urine creatinine
(with R2 of 0.8-0.9). It seems that creatinine
clearance calculation using 24h-urine creatinine assessment can promote
the correlation between ClV and creatinine clearance in
vancomycin TDM. In general, it can be suggested that
ClV, due to its high prediction errors, can not serve as
a suitable and practical clinical pharmacokinetic parameter for TDM
purposes [35].
3.5. Elimination constant
(k)
Elimination constant (k) is an indicator of renal function during the
administration of a hydrophilic drug such as vancomycin with almost
complete renal excretion. So, the higher the k values, the better kidney
function is predictable. While in patients who progress to AKI due to
vancomycin exposure, lower k values and higher t ½ amounts are expected.
In cases with normal renal function with t ½ of about 4-6 hours, k
values of 0.115-0.173 h-1 are acceptable and the
values lower than the mentioned values can be considered as an
alternative pharmacokinetic parameter for early detection of vancomycin
associated nephrotoxicity.