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.