Vancomycin plays an important role in treating methicillin-resistant
Monte Carlo simulation is useful to predict a suitable vancomycin dosing regimen because it can provide the outcome without using data from actual patients. Although previous studies have already used simulations to determine appropriate vancomycin dosing [8, 9, 10], to our knowledge, no published study has investigated appropriate vancomycin dosing for Thai patients of various ages and with varying degrees of renal function. Therefore, the aim of the present study was to predict appropriate vancomycin dosing regimens for Thai patients of various ages and with varying degrees of renal function.
After the approval from institutional review boards of Silpakorn University (approval No. 1/2558) and Chaoprayayomraj Hospital (approval No. YM 014/2558), 105 unduplicated MRSA isolates from Chaoprayayomraj Hospital, Thailand, were accumulated during 2014. The MRSA vancomycin susceptibility data were determined using an Epsilometer test or E-test (M.I.C.E; Thermo Fisher Scientific) in accordance with CLSI 2014.
A simulation was conducted using previously published population pharmacokinetic models derived from 212 Thai patients with 319 vancomycin serum concentration data to develop pharmacokinetic parameters. The 2-compartment model was the best structural model to fit the population data. Pharmacokinetic parameters were vancomycin clearance (CLv) (L/h) = 0.044 × CLcr (mL/min), the central volume of distribution (
The ratio of the 24-h area under the concentration–time curve (AUC24) and minimum inhibitory concentration (MIC) ≥400 was the marker of a good outcome of MRSA treatment with vancomycin [11]. Thus, AUC24/MIC ≥400 was used as a target value of pharmacodynamic index.
Monte Carlo simulation is a stochastic simulation method that randomly selects a parameter value from a known distribution. The process is repeated many times (usually 10,000) to generate pharmacokinetic parameters [12]. The generated pharmacokinetic parameters of each simulated patient are incorporated with the structural pharmacokinetics model, MIC distribution, and target value of the pharmacodynamic index to predict the efficacy of antibiotic dosing [13].
A total of 10,000 simulated patients were generated by Monte Carlo simulation using Oracle Crystal Ball software (Oracle Crystal Ball Faculty Classroom Edition) for each vancomycin dosing including 0.75, 1, and 1.5 g every 24 h; 1, 1.25, 1.75, and 2 g every 12 h; and 1 g every 8 h. The age and CLcr of simulated patients were specified ranging from 20 to 80 years and 20 to 100 mL/min, respectively. The mean (standard deviation) values of age and CLcr were assumed to be 50 (30) years and 60 (40) mL/min, respectively.
where the subscript
To evaluate the risk of renal toxicity, this study assessed the probability of attaining a trough concentration (
The distribution of simulated patients in various age groups, including <40, 40–60, and >60 years, was approximately 45%, 35%, and 20%, respectively, whereas that in various renal function groups, including <40, 40–60, >60–80, and >80 mL/min, was approximately 36%, 32%, 20%, and 12%, respectively (data not shown). Sources of specimens of 105 non-duplicated MRSA isolates and MIC distribution are given in
The numbers of methicillin-resistant Staphylococcus aureus (MRSA) clinical isolates according to source of specimens and minimal inhibitory concentration (MIC) distribution (n = 105)MIC (mg/L) Source of specimens Total (%) Sputum Blood 0.5 5 0 5 (4.8) 1 56 1 57 (54.3) 2 41 1 42 (40) 4 1 0 1 (1)
The probability of target attainment (PTA) of an area under the curve (AUC)/minimal inhibitory concentration (MIC) > 400 at each MIC according to age of patientsAge(years) Vancomycin dosing PTA of each MIC (%) 0.5 1 2 4 <40 0.75 g every 24 h 92.3 42.0 1.9 0.0 1 g every 24 h 100 64.6 13.8 0.0 1.5 g every 24 h 100 92.4 39.9 1.5 1 g every 12 h 100 100 62.3 14.1 1.25 g every 12 h 100 100 80.2 27.5 1 g every 8 h 100 100 92.3 41.2 1.75 g every 12 h 100 100 99.6 53.3 2 g every 12 h 100 100 100 63.9 40–60 0.75 g every 24 h 91.9 41.8 1.8 0.0 1 g every 24 h 100 60.8 13.3 0.0 1.5 g every 24 h 100 92.7 41.5 1.6 1 g every 12 h 100 100 63.5 13.9 1.25 g every 12 h 100 100 80.2 26.8 1 g every 8 h 100 100 92.6 41.1 1.75 g every 12 h 100 100 99.7 54.1 2 g every 12 h 100 100 100 65.5 >60 0.75 g every 24 h 91.3 39.9 1.2 0.0 1 g every 24 h 100 62.8 13.3 0.0 1.5 g every 24 h 100 93.2 41.6 1.3 1 g every 12 h 100 100 62.3 14.2 1.25 g every 12h 100 100 79.6 28.1 1 g every 8 h 100 100 92.3 39.8 1.75 g every 12 h 100 100 99.7 52.0 2 g every 12 h 100 100 100 64.1
The probability of target attainment (PTA) of an area under the curve (AUC)/minimal inhibitory concentration (MIC) >400 at each MIC according to renal function of patients CLcr, creatinine clearance calculated using the Cockcroft–Gault equationCLcr(mL/min) Vancomycin dosing 0.75 g every 24 h PTA of each MIC (%) 0.5 1 2 4 <40 0.75 g every 24 h 100 100 4.7 0.0 1 g every 24 h 100 100 38.7 0.0 1.5 g every 24 h 100 100 100 4.1 1 g every 12 h 100 100 100 40.0 1.25 g every 12 h 100 100 100 77.3 1 g every 8 h 100 100 100 100 1.75 g every 12 h 100 100 100 100 2 g every 12 h 100 100 100 100 40–60 0.75 g every 24 h 100 14.7 0.0 0.0 1 g every 24 h 100 86.3 0.0 0.0 1.5 g every 24 h 100 100 14.4 0.0 1 g every 12 h 100 100 86.3 0.0 1.25 g every 12 h 100 100 100 0.0 1 g every 8 h 100 100 100 14.6 1.75 g every 12 h 100 100 100 53.1 2 g every 12 h 100 100 100 87.0 >60–80 0.75 g every 24 h 100 0.0 0.0 0.0 1 g every 24 h 100 0.0 0.0 0.0 1.5 g every 24 h 100 100 0.0 0.0 1 g every 12 h 100 100 0.0 0.0 1.25 g every 12 h 100 100 59.6 0.0 1 g every 8 h 100 100 100 0.0 1.75 g every 12 h 100 100 100 0.0 2 g every 12 h 100 100 100 0.0 >80 0.75 g every 24 h 31.9 0.0 0.0 0.0 1 g every 24 h 100.0 0.0 0.0 0.0 1.5 g every 24 h 100.0 33.1 0.0 0.0 1 g every 12 h 100.0 100 0.0 0.0 1.25 g every 12 h 100.0 100 0.0 0.0 1 g every 8 h 100.0 100 32.5 0.0 1.75 g every 12 h 100.0 100 97.2 0.0 2 g every 12 h 100.0 100 100 0.0
Both PTA and CFR are outcomes of simulation applied to evaluate effectiveness of each vancomycin dosing regimen. The higher the trough concentration of vancomycin, the higher the risk of nephrotoxicity [14, 15]. Therefore, to evaluate the safety of vancomycin administration, percentage of achieving trough concentration for each vancomycin dosage should be taken into consideration.
Simulated patients in the present study presented with vancomycin dosages based on CLcr and age. It is not surprising that CLcr is a significant factor for CLv [6], but that an increasing
We found that a vancomycin dose of1.5 g per day can attain CFR ≥90% in all age groups. Variation in age may rarely influence the change in AUC24. However, the result is inconsistent with findings by Revilla et al. [3] who compared the estimated CFR between critically ill patients aged >65 years and younger patients with no severe renal impairment (CLcr >60 mL/min).
Both groups were given vancomycin at 1 g every 12 h. They found that CFR was inversely proportional to age. Their estimated CFR of critically ill patients aged >65 years was 65% but was 30% in younger patients. The present study found that a vancomycin dosage of 2 g daily, a usual dose for a patient with normal renal function (estimated from the recommended dose of 15–20 mg/kg every 12 h) [16], reached the CFR in only 64.3% of patients with CLcr >80 mL/min. However, this was not surprising because the usual dose suggested by clinical guidelines is recommended for patients infected with MRSA with an MIC of ≤1 mg/L. By contrast, the frequency of MRSA with an MIC of 2 mg/L in the present study was high (40%). Accordingly, Thai patients need a higher vancomycin dose for empirical treatment of MRSA infection. Vancomycin is excreted primarily by kidney [17]. Patients with good kidney function need higher vancomycin dosing than patients with poor kidney function to successfully treat MRSA infection. The present study showed that vancomycin dosing of at least 1.5, 2.5, 3, and 3.5 g per day could achieve CFR of ≥90% in patients with CLcr of <40, 40–60, >60–80, >80 mL/min, respectively. Thus, besides the data for vancomycin susceptibility of MRSA isolates, patient renal function has a strong effect on CFR for each vancomycin dosing.
Trough concentration of vancomycin of >20 mg/L is related to undesirable nephrotoxicity. A higher trough level is associated with a higher incidence of renal toxicity [18]. Therefore, trough concentration of vancomycin will need to be considered. As shown in
The present study has some limitations. First, vancomycin susceptibility data against MRSA were accumulated from a regional hospital in Thailand. Thus, the sensitivity profile of MRSA to vancomycin in the present study may not be applicable for the prediction of appropriate vancomycin doses for all Thai patients. Further studies collecting MRSA sensitivity data from several types of hospitals in various regions are required to predict the vancomycin dosage more widely. Second, despite that we could find therapeutic vancomycin doses for patients with a CLcr of <40 mL/min, vancomycin concentration in these patients may take some time to reach a steady state. The initial low concentration of vancomycin may increase the rate of mortality, and MRSA resistance to vancomycin may develop [21, 22]. Thus, a suitable loading dose may be necessary to reach a therapeutic concentration promptly.
Although vancomycin doses attained a CFR of ≥90% for effectively treating MRSA infection, these regimens may cause kidney injury. We recommend vancomycin doses of 0.75, 1.5, 1.5, and 2 g daily for patients with a CLcr of <40, 40–60, >60–80, and >80 mL/min, respectively, should be given to patients infected with MRSA with a vancomycin MIC of ≤1 mg/L because these regimens will attain a PTA of 100% and the majority of patients will attain a