1.
Introduction
Vancomycin is a glycopeptide antibiotic that is effective against many
gram positive microorganisms [1], especially Methicillin-resistantStaphylococcus aureus (MRSA) [2-4]. It is a hydrophilic drug
with log P of -3.1, which is almost completely excreted from urine. In
patients with normal kidney function, about 80 to 90% of the vancomycin
single-dose administration would be excreted unchanged in urine within
24 hours [5, 6]. So, in cases with renal dysfunction, vancomycin
clearance could be diminished and dose reduction or interval time
enhancement is required [7]. Vancomycin has a minimal oral
absorption, so, the preferred route of administration in systemic
infections is intravenous (IV) route that results in 100% systemic
availability or absolute bioavailability [8]. The approved
indication of oral vancomycin is limited to Clostridium difficleinfection where systemic absorption is not required and vancomycin
administration, with a dosage range of 125-500 mg every 6 hours, can
induce local effects [9]. Bearing in mind the narrow therapeutic
index, therapeutic drug monitoring (TDM) is essential to avoid serious
adverse reactions related to over-dose exposure or response failure
associated with under-dose therapy [10]. Although vancomycin has
been prescribed more than 60 years, still controversies are remaining
about drug dosing, pharmacokinetics, and pharmacodynamic aspects of drug
therapy [3]. The recommended dose of vancomycin in critically ill
patients with severe infection would be a loading dose of 20-35 mg/kg
(max: 3 g), followed by the maintenance dose of 15-20 mg/kg every 8 to
12 hours, based on target plasma trough concentration of 15-20 µg/ml or
AUC24h/MIC values of 400-600 µg.h/ml [9]. It seems
that loading dose administration can enhance target trough concentration
achievement in both patients with preserved and impaired renal function.
However, the results of a reported retrospective observational study
revealed that loading dose administration in patients with normal renal
function was not associated with rapid target trough concentration
achievement prior to administration of the vancomycin third dose in
comparison to the control group who did not receive loading dose. The
most important risk factors that could delay the target trough
concentration achievement were higher serum albumin and higher GFR
values [11]. So, further larger clinical trials are warranted to
prove the efficacy and safety of loading dose administration in cases
with normal and impaired renal functions. The most important adverse
reaction related to vancomycin administration is vancomycin-associated
nephrotoxicity correlated with higher trough concentrations and a higher
area under the curve (AUC) values. As reported, AUC24h≥667 µg.h/ml and trough concentration ≥18.2 µg/ml could enhance the risk
of vancomycin nephrotoxicity up to 3 to 4 folds [12]. Other risk
factors of vancomycin associated nephrotoxicity include critically ill
conditions, obesity and morbid obesity, and patients with underlying
kidney disease. Also, simultaneous administration of vancomycin with
other nephrotoxic agents including amphotericin B, IV contrast agents,
aminoglycosides, loop diuretics such as furosemide, vasopressors,
piperacillin-tazobactam, and flucloxacillin can enhance the risk of
vancomycin associated acute kidney injury (AKI) [12]. Vancomycin
associated nephrotoxicity may aggravate the mortality rate and prolong
the hospital stay, especially in critically ill patients [2]. The
other less common adverse reaction related to vancomycin overdose, ie.,
ototoxicity is significantly associated with high vancomycin plasma peak
(Cmax) concentrations [7]. In the present review,
vancomycin TDM and pharmacokinetic data in population with altered
pharmacokinetics including patients with renal and/or hepatic failure,
critically ill ones, patients with burn injuries, intravenous (IV) drug
users, obese and morbidly obese patients, those with cancer, patients
undergoing organ transplantation, and vancomycin administration during
pregnancy and lactation are summarized as schematically depicted in Fig.
1. The main goal of this study was to assess different pharmacokinetic
parameters that can affect vancomycin TDM in special groups of patients
with altered pharmacokinetic characteristics. Also, pharmacoeconomic
aspects of vancomycin TDM in these groups of patients have been
discussed.