Developments in the pharmacokinetic

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among vancomycin-resistant E. faecium strains and linezolid consumption. ... utilize the PK/PD model and Monte Carlo simulation to evaluate the success ...
International Journal of Infectious Diseases 22 (2014) 35–40

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Developments in the pharmacokinetic/pharmacodynamic index of linezolid: a step toward dose optimization using Monte Carlo simulation in critically ill patients Haiyan Dong a, Jiao Xie a, Lihong Chen b, Taotao Wang a, Jinyue Sun a, Yingren Zhao c,*, Yalin Dong a,* a

Department of Pharmacy, The First Affiliated Hospital of Medical College, Xi’an Jiaotong University, Xi’an 710061, China Central Intensive Care Unit, The First Affiliated Hospital of Medical College, Xi’an Jiaotong University, Xi’an, 710061, China c Department of Infectious Diseases, The First Affiliated Hospital of Medical College, Xi’an Jiaotong University, Xi’an 710061, China b

A R T I C L E I N F O

S U M M A R Y

Article history: Received 12 December 2013 Received in revised form 13 January 2014 Accepted 14 January 2014

Objectives: This study evaluated the efficacy of the pharmacokinetic/pharmacodynamic (PK/PD) index for increasing the success rate of linezolid treatment based on Monte Carlo simulation, and compared differences between the calculated PK/PD breakpoints and those defined by committee for critically ill patients with linezolid treatment. Methods: A Monte Carlo simulation involving 10 000 subjects was used to analyze the pharmacokinetic parameters and microbiological data of linezolid for an effectiveness evaluation at the corresponding AUC24/MIC values (area under the serum concentration–time curve over 24 h/minimum inhibitory concentration). Results: As the PK/PD index of linezolid increased from 80 to 120, the corresponding probability of target attainment (PTA) decreased from 99.91% to 18.97%, with a MIC of 2 mg/l. Furthermore, the cumulative fraction of response (CFR) reached 90% represent an optimal regimen achieved against a population of organisms. 2.2.3. Comparison of susceptibility breakpoints PK/PD breakpoints were set at the highest MIC value with a bactericidal target attainment of 90%, as this is the accepted target attainment cutoff currently used by the CLSI when determining MIC breakpoints.17 The classified PK/PD breakpoints were then compared with those published by the CLSI (M100-S22) and EUCAST (version 3.1) for 2012 to evaluate the impact of discrepancies on the normal Gram-positive pathogen susceptibility of critically ill patients.

2. Methods 3. Results The methodology included: (1) acquisition of pharmacokinetic parameters and microbiological information, (2) Monte Carlo simulation, (3) calculation of an estimate of the PTA (defined as the probability that at least a specific value of PK/PD is achieved at a certain MIC), and (4) calculation of the cumulative fraction of response (CFR; defined as the expected population PTA for a specific drug dose and a specific population of microorganisms).14 2.1. Acquisition of pharmacokinetic parameters and microbiological information The pharmacokinetic parameters of linezolid were obtained from published studies. Pharmacokinetic studies were identified using PubMed, the National Library of Medicine search engine for the Medline database, with the following keywords linezolid, pharmacokinetics, population pharmacokinetics, critically ill patient, and ICU. Studies were included if they evaluated clinically relevant dosing regimens and provided the means for the pharmacokinetic parameters of interest with the corresponding variability. Data were obtained from the EUCAST MIC distribution website (http://www.eucast.org; last accessed April 10, 2013). 2.2. Pharmacokinetic/pharmacodynamic analyses and Monte Carlo simulation 2.2.1. Estimation of the PTA The pharmacokinetic parameters were defined as a log-normal distribution in the Monte Carlo simulation, and in the case of MIC, a

3.1. Evaluation of the PTA and CFR Table 1 gives the MIC probability distribution of selected Grampositive pathogens in critically ill patients based on EUCAST data. The distributions are based on collated data from a total of 181 634 MIC distributions from worldwide sources. The distributions include MICs from national and international studies such as resistance surveillance programs, as well as MIC distributions from published articles, the pharmaceutical industry, veterinary programs, and individual laboratories. For enterococci, 100% of the whole isolates for linezolid presented MICs of 32 mg/l, with 95.26% of the Enterococcus faecalis isolates exhibiting MICs of 2 mg/l. Nearly half of E. faecium isolates (55.41%) exhibited a high level of susceptibility to linezolid, with a MIC of 2 mg/l. Moreover, 32.22% of E. faecium isolates had a MIC of 1 mg/l. Similarly, 46.07% and 43.34% of E. faecalis isolates presented MICs of 1 and 2 mg/l for linezolid, respectively. For staphylococci, almost all of the pathogens had MICs of 2 mg/l for linezolid, among which MRSA (98.76%) and methicillin-sensitive S. aureus (MSSA; 99.47%) had a MIC of 2 mg/l. With regard to streptococci, all of the isolates presented with MICs of 8 mg/l, demonstrating a high susceptibility to linezolid. Figure 1 shows the PTA (%) calculated by PK/PD analysis and Monte Carlo simulation at MIC values in the range 0.008–64 mg/l for a linezolid dose regimen of 600 mg q12 h. With the change of MIC value in critically ill patients, the corresponding PTA value varied significantly at the targeted AUC24/MIC values of between 80 and 120. PTA values were 100% with MICs of 1 mg/l and an AUC24/MIC ranging from 80 to 120. However, for AUC24/MIC values

H. Dong et al. / International Journal of Infectious Diseases 22 (2014) 35–40

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Table 1 Frequency distribution of the MIC of linezolid for the selected pathogens from the EUCAST MIC distribution website MIC (mg/l)

n

Enterococci Enterococcus faecalis Enterococcus faecium Staphylococci Staphylococcus aureus MRSA MSSA Staphylococcus capitis Staphylococcus coagulase-negative Staphylococcus coagulase-negative MRSE Staphylococcus epidermidis Staphylococcus epidermidis MSSE Staphylococcus haemolyticus Staphylococcus hominis Staphylococcus lugdunensis Staphylococcus saprophyticus Staphylococcus warneri Streptococci Streptococcus agalactiae Streptococcus anginosus Streptococcus bovis Streptococcus constellatus Streptococcus group C Streptococcus group G Streptococcus mitis Streptococcus oralis Streptococcus pneumoniae Streptococcus pyogenes Streptococcus sanguinis Streptococcus, viridans group

0.064

0.125

0.25

1

2

4

8

16

32

SB (mg/l)

0.18 0.17

0.43 0.52

5.24 7.15

46.07 32.22

43.34 55.41

4.57 4.35

0.07 0.15

0.04 0.02

0.06

4 4

0.01

0.18

0.29

2.60

0.04 0.25

0.01

0.002

3.55 1.02

0.06

0.56

5.16

0.15

0.17 0.15

2.95 2.54 1.75

24.47 8.74 4.17 28.58 9.52 29.87 17.19 28.07 4.93 14.86

58.72 98.76 99.47 9.93 22.98 6.63 10.98 10.71 7.43 6.28 10.53 42.96 11.49

6.22 0.25

1.77 0.13

31.92 0.74 0.53 60.28 65.34 89.02 54.26 79.76 59.16 73.24 59.65 46.48 72.30

4 4 4 4 4 4 4 N/A 4 4 4 4 4

0.06

5.47 10.14 14.62 40.54 8.05 2.08 20.40 14.39 7.67 12.32 23.96 10.60

80.57 76.81 65.38 50.00 82.55 82.20 75.62 78.42 65.33 67.22 71.88 73.51

13.53 12.32 19.23 1.35 6.71 14.24 1.99 6.83 25.93 18.06 3.13 15.10

0.19

8336 5214 62 420 404 571 282 6371 528 7270 84 1185 669 57 142 148 2084 138 130 74 149 674 201 278 60 080 23 294 96 755

0.68

0.02 0.05

1.35 2.01

0.24 0.72 0.77 6.76 0.67

0.50

1.49

0.05 1.08

0.96 1.21 1.04 0.79

0.5

1.73 0.37

0.01

0.34 0.15

0.08

0.19 0.01

0.15

0.15

5.63 0.68

1.48 0.36 0.03 0.06

0.004

2 2 2 2 2 2 2 2 2 2 2 2

MIC, minimum inhibitory concentration; EUCAST, European Committee on Antimicrobial Susceptibility Testing; SB, susceptibility breakpoint; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-susceptible Staphylococcus aureus; MRSE, methicillin-resistant Staphylococcus epidermidis; MSSE, methicillin-susceptible Staphylococcus epidermidis; N/A, not available.

of 80, 100, and 120 the PTA values were 99.91%, 83.28%, and 18.97%, respectively, at a MIC of 2 mg/l. Furthermore, the PTA value was always zero for one fixed AUC24/MIC target value ranging from 80 to 120 when presenting with a MIC >4 mg/l. Table 2 lists the data from the assessment of CFR (%) for a standard linezolid dosing regimen evaluated based on three AUC24/MIC values (80, 100, and 120). At the low AUC24/MIC value of 80, the corresponding CFRs of E. faecium, E. faecalis, and the majority of staphylococci (including MRSA and MSSA) and streptococci were higher than 95%; exceptions were S. aureus (93.68%) and Staphylococcus saprophyticus (94.33%). At the moderate AUC24/MIC value of

100, the corresponding CFRs of E. faecium (86.21%), E. faecalis (88.01%), and some staphylococci including S. aureus (83.91%), MRSA (82.99%), MSSA (83.37%), and S. saprophyticus (87.18%) were all lower than 90%; the remainder all attained optimization, with CFR values of >90%. At a high AUC24/MIC value of 120, the corresponding CFRs of E. faecium (50.58%), E. faecalis (60.14%), and several staphylococci and streptococci isolates were