Evaluation of the effectiveness of dose individualisation to achieve therapeutic vancomycin concentrations

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Stellenbosch : Stellenbosch University
ENGLISH ABSTRACT: Background The glycopeptide antibiotic vancomycin is used for treatment of methicillin resistant Gram positive cocci. Adequate vancomycin plasma concentrations are related to bacterial cure. However, inter- and intra-patient variability make it difficult to achieve therapeutic vancomycin concentrations. The primary objective of this study was to determine the effectiveness of using computerised therapeutic drug monitoring (TDM) to assist in achieving therapeutic vancomycin concentrations at a tertiary hospital in South Africa. Method This was a 2-period study consisting of a retrospective 1-month observational period followed by a prospective 1-month period where computerised TDM was implemented as an intervention to assist with vancomycin dose individualisation. Prescribers were provided with guidelines on vancomycin dosing and TDM results during both study periods. During the prospective period, all vancomycin TDM results were followed by dose individualisation using computerised TDM. In addition, the area under the-concentration-time curve over minimum inhibitory concentration (AUC/MIC) was calculated to ensure a ratio of ≥400. Results The retrospective study included 77 patients with 292 vancomycin concentrations: 69% (53/77) adult and 31% (24/77) paediatric patients. The prospective study included 80 patients with 217 vancomycin concentrations measured: 69% (55/80) adult and 31% (25/80) paediatric patients. Less vancomycin TDM data were requested during the prospective period with a median (interquartile range) of 2 (1-3) samples per patient compared with 3 (1- 5) during the retrospective period. The odds ratio of achieving therapeutic trough concentrations was 3.63 (95% confidence interval (CI): 1.81 - 7.3) in the prospective period when TDM-adjusted vancomycin dosing and correct TDM procedures were applied. The use of computerised TDM in patients on continuous infusion resulted in 26% improvement in achieving therapeutic vancomycin concentrations in the prospective period (odds ratio 2.96; 95% CI: 1.19 - 7.36). In the prospective period, AUC0-24 was 400 mg·h/L or above in 71% of occasions. Conclusion The correct use of computerised TDM results in a higher frequency of therapeutic vancomycin concentrations in a middle income setting. Trough vancomycin concentrations alone correlate poorly with AUC0-24. Achieving therapeutic vancomycin concentration may strengthen antibiotic stewardship and save on TDM resources.
AFRIKAANS OPSOMMING: Vancomycin, a glycopeptide antibiotic discovered nearly 60 years ago, is widely used as alternative to penicillin in treatment of severe infections caused by methicillin resistant Staphylococcus aureus (MRSA)[1–4]. Vancomycin is used for a variety of infections including cellulitis, pneumonia, sepsis, and endocarditis[1,2,5]. Since the 1980s there has been a steady rise in the number of MRSA infections and a subsequent increase in the use of vancomycin[1,4]. Vancomycin demonstrates concentration-independent killing and efficacy is associated with the area under the-concentration-time curve over minimum inhibitory concentration (AUC/MIC)[1,6–10]. Clinical efficacy is more likely to be achieved when vancomycin dosing achieves an AUC/MIC ≥400[1,6,7,11,12]. However, because of the difficulty in the clinical setting of repeated sampling to calculate AUC/MIC, trough vancomycin concentration monitoring with a target range of 10-20 mg/L is recommended as a surrogate marker for AUC0-24[1,6]. Supra-therapeutic trough concentrations (>20 mg/L) may result in nephrotoxicity and rarely ototoxicity[6], while sub-therapeutic trough concentrations ( 1 mg/L are high[13,14], as AUC/MIC ≥ 400 may not be attained despite achieving target trough concentrations. S 6 During a 3-month audit of vancomycin TDM at the tertiary academic institution, Tygerberg Hospital, Cape Town, South Africa, it was found that >60% of trough concentrations were outside the therapeutic range, which might be due to difficulty in dose adjusting vancomycin appropriately in response to TDM which required urgent intervention. Computerised TDM uses population pharmacokinetic (PK) modelling to account for inter- and intra-patient variability to predict dosing required to achieve therapeutic concentrations[15– 20]. Computerised TDM allows dose individualisation based on each patient’s unique vancomycin PK parameter values[15,20,21]. In addition, computerised TDM can be used to estimate AUC0-24 based on trough samples. However, to our knowledge there is no data on the application of computerised TDM in lowand middle-income settings to aid attaining therapeutic vancomycin targets. The primary objective of this study was to determine the effectiveness of using computerised TDM to assist in achieving therapeutic vancomycin trough concentrations at a tertiary academic hospital in South Africa.
Thesis (MMed)--Stellenbosch University, 2017.