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].