4. Vancomycin TDM Assessments in
Patients with Altered
Pharmacokinetics
4.1. Patients with renal
failure
Patients with renal insufficiencies have difficulties in drug
elimination and further drug accumulation, longer drug half-lives, with
nephrotoxicity occurrence being predictable. So, in such patients the
need for TDM and pharmacokinetic assessments is clear in order to
prevent the occurrence of vancomycin overdose, especially
vancomycin-associated nephrotoxicity. There is a positive correlation
between vancomycin clearance and creatinine clearance. In patients with
renal failure and reduced GFR, vancomycin clearance is diminished and
drug accumulation is predictable [36]. It was reported that the
normal half-life of vancomycin (t ½ of 4-6 hours) might be enhanced up
to 100-200 hours in patients with acute or chronic anuria [37].
Also, non-renal clearance of vancomycin was reduced in patients with
chronic renal failure which can precipitate this drug accumulation
[38]. In cases with end stage renal disease (ESRD) who require
dialysis, it was reported that vancomycin is poorly dialyzable during
low-flux hemodialysis process, given its high molecular weight of 1450
Dalton. So, the recommended dosing schedule in these ESRD patients could
be once-weekly administration. During high-flux hemodialysis, vancomycin
clearance may reach 40-130 ml/min, leading to vancomycin removal of
89.6-93.4% after a high-flux dialysis session. The recommended dosage
of vancomycin in patients undergoing hemodialysis mainly depends on the
time of vancomycin administration (intra-dialysis vs . after the
end of the dialysis session) and dialyzer permeability (high vs.low permeability), as presented in Table 3 [12]. Patient’s weight
and duration of each hemodialysis session can significantly affect the
amount of vancomycin clearance post high-flux dialysis. In patients
undergoing high-flux dialysis, vancomycin should be administered three
times a week during the last hour of the hemodialysis session or after
the end of hemodialysis [36].
It has been hypothesized that in patients with ESRD, vancomycin has
lower protein binding concentrations which resulting in higher free drug
and higher Cmax (peak concentration) values. So, lower
dose requirement in ESRD patients could also be attributed to the lower
plasma protein binding of vancomycin [36]. Results of a recent
population pharmacokinetic study indicate that vancomycin clearance and
central volume of distribution (Vc) are significantly
different between dialysis and non-dialysis patients. It was recommended
that nomogram-based vancomycin dosing in dialysis patients would be
helpful in order to achieve optimum pharmacokinetic parameters such as
trough concentration and AUC [39]. There are limited data on
vancomycin dosing in patients with chronic kidney disease (CKD), who do
not require dialysis (CKD stages of II-IV). Based on the linear positive
correlation between creatinine clearance (GFR) and vancomycin clearance
in CKD patients, vancomycin intermittent dosing can be adjusted, as
shown in Table 4 [5, 9].
In all CKD patients, the administration of a loading dose of 25-30 mg/kg
could be helpful in facilitating the achievement of target trough
concentration of >15 µg/ml. Reportedly, the recommended
dose of vancomycin empirical therapy in critically ill patients with AKI
undergoing continuous renal replacement therapy (CRRT), can be the
loading dose of 1.5 gram, followed by maintenance dose of 500 mg every 8
hours. Generally, it is emphasized that higher vancomycin doses are
required in CRRT patients than doses recommended in previous literature
in order to achieve target trough and AUC values [40]. The most
important concern about vancomycin administration in patients with renal
failure is the risk of vancomycin-associated nephrotoxicity due to
overdose exposure. Such an adverse reaction could be precipitated by
co-administration of other nephrotoxic agents in poly-pharmacy patients
[5]. . As reports suggest, vancomycin dosing based on GFR and TBW in
patients with renal failure and variable kidney function can result in
response failure or vancomycin-associated nephrotoxicity due to
under-dose and over-dose occurrence, respectively. So, vancomycin TDM
with precise monitoring of pharmacokinetic parameters seems essential to
achieve optimum individualized pharmacotherapy and better clinical
response [41]. Besides, other effective antimicrobials with MRSA
coverage such as linezolid, tigecycline, and daptomycin can be
considered due to their extra-renal elimination route. Therefore, no
dose adjustment is required for these drugs in patients with renal
failure [5].
4.2. Patients with liver
diseases
Non-renal clearance (Clnr) of vancomycin is reduced in
patients with hepatic failure [38]. Results of a retrospective
pharmacokinetic study in patients with liver disease revealed no
significant association between pharmacokinetic parameters and
biochemical parameters of liver function such as bilirubin,
transaminases (AST and ALT), Gamma-glutamyl transferase (GGT), alkaline
phosphatase (ALP), serum albumin, and lactate dehydrogenase (LDH). It
seems that vancomycin pharmacokinetics is not significantly influenced
in patients with hepatic failure. This study revealed that in patients
with hyperbilirubinemia, only Vd and t ½ values were
enhanced but not significantly [42]. In a recent pharmacokinetic
study, mean trough concentration and AUC/MIC values were higher in
patients with moderate to severe liver disease in comparison to the
patients with normal or mild liver disease due to the vancomycin
prolonged half-lives [43, 44]. The higher pharmacokinetic parameters
values resulted in the higher rate of AKI in patients with moderate to
severe liver disease, compared to normal or mild liver disease, but the
difference was not statistically significant [44]. An important
point in patients with hyperbilirubinemia could be laboratory error
occurrence in serum creatinine assessments which can under-estimate the
serum creatinine values. This point should be considered in conditions
developing to acute kidney injury due to vancomycin exposure and
pre-existing liver disease.
4.3. Critically ill
patients
Critically ill patients admitted to intensive care units (ICU) may have
different pharmacokinetic parameters in comparison to normal patients,
leading to different dosing recommendations [45]. Results of a
recent prospective study on vancomycin pharmacokinetics have revealed
that trough concentration should not be considered as an adequate
surrogate of AUC24h in these patients [46]. Sepsis
is a common cause of death among critically ill patients, which can
induce physiologic changes in patients such as endothelial permeability
enhancement that can result in capillary leakage syndrome (CLS),
vasodilation due to nitric oxide, pro-coagulation effects due to
cytokine release syndrome (CRS), and variations in the biosynthesis of
proteins. The physiological changes in septic patients give rise to
pharmacokinetic changes in critically ill patients [47]. Creatinine
clearance could be changed in septic patients either due to AKI or
augmented renal clearance (ARC) phenomenon. Also, serum albumin was
significantly reduced in sepsis, possibly due to CLS and CRS. Serum
albumin reduction might induce higher free dug amounts [47].
Vd and ClV enhancement are predictable
in septic patients, suggesting the need for higher dose requirement in
critically ill patients with sepsis [48]. In septic patients who
develop to multi-organ failure (MOF), vancomycin administration is not
appropriate because of low penetration to solid organs such as lung and
other effective antimicrobials with better tissue penetration should be
considered [48]. Results of a recent pharmacokinetic study reported
that in critically ill patients receiving vancomycin, the respective
clearance was significantly associated with age, creatinine clearance,
and serum creatinine [46]. Data of a previous pharmacokinetic study
in critically ill patients also emphasized that creatinine clearance
alone could not be a sufficient predictor of renal function in
critically ill patients. Higher trough and peak concentrations after
nomogram-based vancomycin dosing in critically ill patients could be
attributed to tubular damage in such septic patients, leading to the
reduced vancomycin elimination and higher plasma concentrations
[49]. Plasma trough concentration of 15 µg/ml during intermittent
vancomycin administration and steady state concentration of 20-30 µg/ml
during continuous vancomycin infusion could be optimal in critically ill
obese patients [50]. In critically ill trauma ICU patients,
vancomycin clearance was found to be higher than that in medical ICU
patients. Since vancomycin-associated AKI in critically ill patients
admitted to ICU is not completely reversible, close drug monitoring is
essential in these patients with altered pharmacokinetics in order to
avoid further morbidities and mortality associated with AKI occurrence
[12].
4.4. Patients with burn
injuries
Since MRSA is a common source of nosocomial infections among
hospitalized patients with severe burn injuries, vancomycin can serve as
an antibiotic of choice in the patients. Burn injuries can induce
pathophysiological changes in patients that can result in changes in
pharmacokinetic aspects of drugs. During the hyper metabolic phase, more
than 48 hours after burn injuries, creatinine clearance is significantly
enhanced that cause higher drug Cl values. Since vancomycin has renal
excretion, individualized pharmacotherapy and pharmacokinetic
assessments are necessary in patients with severe burn injuries in order
to obtain target trough concentrations and AUC values. Results of a case
control retrospective study on patients with burn injuries revealed that
patients with burns had significantly higher vancomycin Cl in comparison
to the controls. Yet, there are controversies about the mechanism of
this enhanced vancomycin Cl values and it is suggested that changes in
creatinine clearance, enhanced tubular secretion, and increased
glomerular filtration rate in patients with burns may be the possible
mechanisms. Results of this study revealed that the administration of
the same dose of 1 gram vancomycin every 12 hours could significantly
result in lower trough concentrations in patients with burns in
comparison to the controls. Also, it was revealed that
Vd was not significantly different between case and
control groups. So, it is emphasized that vancomycin administration in
traumatic patients admitted to ICU should be individualized, based on
actual body weight (ABW) and measured plasma concentrations [51].
Also, the results of a previous pharmacokinetic study on patients with
burns, IV drug users and control group indicated that burns patients had
significantly higher creatinine clearance, vancomycin clearance and
renal clearance in comparison to the other groups, that might be
attributed to the higher Clnr, higher GFR values, and
altered protein binding amounts in burns patients [52]. In general,
it seems that due to higher ClV and lower trough
concentrations, individualized pharmacotherapy and precise vancomycin
TDM are required in order to avoid antimicrobial resistance and response
failure due to under-dose vancomycin therapy in patients with burn
injuries [51]. As reported in an algorithmic study in patients with
thermal injuries, the optimum trough and AUC values could be achieved
through the empiric adjustment of the doses, as presented in Table 5
[53].
4.5. IV drug
users
Vancomycin is a commonly administered drug in IV drug users due to
Gram-positive infections including staphylococcal endocarditis [54].
The pharmacokinetics of vancomycin might be altered in these patients.
Results of a pharmacokinetic study revealed that the mean
ClV was about 31% higher in IV drug users in comparison
to that in the control group. However, the difference was not
statistically significant. Given the higher ClV values
in IV drug users, individualized pharmacotherapy and higher doses of
vancomycin are required in order to achieve target trough and AUC values
and better clinical response [52].
4.6. Pregnancy and
lactation
Vancomycin administration is recommended as an antimicrobial agent
during pregnancy to prevent the group B Streptococcal (GBS)
infection transmission from mother to fetus, as a prophylactic agent
before cesarean section, and treatment of Clostridium difficleinfection. Vancomycin can cross the placenta and reach amniotic fluid,
fetal serum, and cord blood [55], and no respective adverse
reactions such as ototoxicity and nephrotoxicity have been reported in
fetus after maternal administration of vancomycin during second and
third trimesters [56]. The pharmacokinetic parameters of vancomycin
might be changed during pregnancy while t ½ remains unchanged and
Vd and total Cl may be enhanced indicating the need for
higher dose administration, individualized pharmacotherapy, and precise
plasma concentration monitoring in pregnant women. Nevertheless, it is
also warned about the potential induction of fetal malformations due to
the administration of injectable vancomycin formulations that have
polyethylene glycol (PEG) 400 and/or N-acetyl D-alanine (NADA) as
excipients. [57].
Vancomycin administration is suggested in lactating women withClostridium difficle infections. Since vancomycin has poor oral
absorption, the amount of vancomycin that can pass through the milk is
limited and breast feeding could be acceptable during vancomycin oral
administration. Upon IV administration, vancomycin can be detected in
milk with relative infant dose (RID) of 4.8%. Since the RID value is
less than 10%, vancomycin IV administration during lactation seems to
be acceptable, but decision making on breast feeding during
pharmacotherapy should be based on risk/benefit assessments [57].
Given the vancomycin high molecular weight (MW of 1450 Dalton) and
hydrophilic nature (log P of -3.1), it has less tendency to pass into
the breast milk compartment [58].
4.7. Patients with organ
transplantation
Results of a retrospective cohort study on pre- and post-lung
transplantation in cystic fibrosis patients receiving vancomycin
revealed that pharmacokinetic parameters can be altered after solid
organ transplantation such as lung transplantation. So, it seems that
the population pharmacokinetic data used in vancomycin dosing in
pre-transplantation could not be used for post-transplant counterparts.
The most obvious post transplantation changes were significant reduction
in k and increment of t ½, that can be attributed to the decreased renal
clearance and administration of immunosuppressive drugs including
cyclosporine and tacrolimus and antimicrobial agents such as
trimethoprim/sulfamethoxazole and valganciclovir that are highly
nephrotoxic [59].
4.8. Obese
patients
Weight-based vancomycin dosing is dependent on the volume of
distribution (Vd) values. The value based on patient’s
weight was reported between 0.26–1.25 L/kg. So, the estimated
Vd values in obese patients are higher than that in
non-obese ones. The higher estimated Vd values in obese
patients could result in higher trough concentrations and further drug
toxicity incidence [3]. Another method of Vdcalculation regardless of weight is based on Eq. 12 [60].
\(V_{d}=\frac{\text{Vancomycin\ dose}}{C_{\max}-C_{\min}}\) (Eq. 12)
Where Vd is the volume of distribution in L, vancomycin
dose is in mg, Cmax is peak concentration in
mg/L, and Cmin is trough concentration
in mg/L.
According to Eq. 13 and Eq. 14, in obese patients with larger
Vd values and the same Cl, the smaller elimination
constants and longer half-life values are predictable. Therefore, obese
patients require higher doses of vancomycin with larger intervals of
administration, compared to non-obese patients [3].
\(Cl=k\times V_{d}\) (Eq. 13)
Where Cl is vancomycin clearance in L/h, k is elimination constant in
h-1, and Vd is the volume of
distribution in L.
\(t_{1/2}=\frac{0.693}{k}\) (Eq. 14)
Where t1/2 is the drug half-life in h and k is the
elimination constant in h-1.
It has been reported that total body weight (TBW)-based vancomycin
dosing in obese and over-weight pediatric patients may give rise to
higher vancomycin plasma trough concentrations and higher risk of
nephrotoxicity occurrence, compared to normal body habitus pediatrics.
So, the necessity of vancomycin TDM in these population would be obvious
[57]. Results of a retrospective cohort study revealed that
vancomycin trough concentration was negatively correlated with body mass
index (BMI) and creatinine clearance values, that is, the patients with
higher BMI (BMI≥24 kg/m2) and augmented creatinine
clearance, had lower trough concentration after administration of the
same doses of 1 gram vancomycin every 12 hours. Thus, personalized
pharmacotherapy and individualized dose adjustment are required in such
patients [61]. Administration of hydrophilic drugs such as
vancomycin to obese patients can result in higher Vdvalues and lower plasma concentrations. Low plasma trough concentration
in the patients may lead to clinical response failure. Accordingly,
precise concentration monitoring in obese patients is essential to
prevent both response failure and nephrotoxicity due to under-dose and
over-dose vancomycin administration, respectively. As reports indicate,
vancomycin administration with dosage of 1 gram every 8 hours may result
in appropriate target trough concentrations in obese patients with
BMI≥24 kg/m2, and further plasma sample assessments
are required for each patient [61]. Continuous vancomycin infusion
in obese patients can lead to lower vancomycin daily dose exposure and
improve therapeutic plasma concentration with better clinical response,
compared to non-obese patients [50]. Results of a pharmacokinetic
study based on Bayesian model revealed that both actual body weight
(ABW) and lean body weight (LBW) were independent predictors of
Vd. According to the results of this study, in these
obese patients, Vd and t ½ values were enhanced and
total Cl was diminished. Also, it was reported that initial vancomycin
dosing based on ABW could be superior to LBW, since ABW would be a
better predictor of pharmacokinetic parameters [62]. Also, reports
show that in morbidly obese patients with TBW of up to 200 kg,
administration of vancomycin with daily dose of 35 mg/kg (max 5.5 g/day)
in 2 divided doses, may result in target trough concentration of
5.7-14.6 µg/ml and AUC24h values of >400
µg.h/ml. In such obese patients, TBW could be a suitable predictor of
ClV. Enhanced Vd and ClVwere reported in these groups of patients [63], the enhanced
Vd amounts could be attributed to the higher adipose
tissue and muscle mass in obese patients. Considering the higher blood
volume and cardiac output in obese patients, increased blood flow and
increased ClV would be predictable. Obese patients may
have elevated amount of circulatory plasma proteins that can alter the
amounts of vancomycin protein binding and the percentage of free drug
available in plasma and target sites [64, 65]. Taking into account
the pharmacokinetic changes in obese and morbidly obese patients,
individualized pharmacotherapy and close plasma concentration monitoring
during vancomycin administration is strongly recommended.
4.9. Patients with
cancer
Vancomycin is a common antibiotic administered in cancer patients
complicated with pneumonia. Also, cancer can alter different
pharmacokinetic parameters in patients receiving vancomycin. Although
the results of previous studies reported no significant differences in
pharmacokinetic parameters of cancer and non-cancer patients [66],
results of a recent pharmacokinetic study have demonstrated that cancer
patients were with significantly higher Vd and Cl, in
comparison to the control group, leading to significantly lower initial
trough concentrations in this group of patients. So, in cancer patients
higher doses of vancomycin may be required to achieve target trough and
AUC values and ensure optimum clinical response. Doses up to 60
mg/kg/day may be required in cancer patients in order to achieve optimum
clinical response, given their higher Vd and
ClV values [67]. It was reported that cystatin-C
measurement before and during vancomycin therapy can serve as a good
predictor of required dose in cancer patients [68]. Also, patients
with solid malignancies had higher ClV values that
resulted in lower vancomycin plasma concentration. Therefore, precise
and early plasma concentration monitoring could be helpful to achieve
effective target concentrations with minimal unwanted adverse reactions
[69]. Results of a retrospective study in advanced cancer patients
revealed that cachexia associated with cancer can give rise to changes
in pharmacokinetic parameters during vancomycin administration.
Glomerular filtration rate did not show a significant difference between
cachectic and non-cachectic patients but systemic ClVwas significantly lower in cachectic cancer patients which resulted in
drug accumulation and higher vancomycin plasma concentrations. Also, the
rate of AKI occurrence in cachectic cancer patients during vancomycin
administration was significantly higher in comparison to that in the
control group. So, cancer cachexia could be considered as an important
independent risk factor of vancomycin-induced AKI [70].