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Daptomycin versus linezolid for the treatment of vancomycin-resistant enterococcal bacteraemia: implications of daptomycin dose

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Original article

Daptomycin versus linezolid for the treatment of

vancomycin-resistant enterococcal bacteraemia: implications of

daptomycin dose

Y.-C. Chuang

1,2

, H.-Y. Lin

3

, P.-Y. Chen

4

, C.-Y. Lin

5

, J.-T. Wang

2,*

, S.-C. Chang

2

1)Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan 2)Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

3)Department of Economics, National Chengchi University, Taipei, Taiwan

4)Department of Internal Medicine, National Taiwan University Hospital Jin-Shan Branch, New Taipei, Taiwan 5)Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Yun-Lin, Taiwan

a r t i c l e i n f o

Article history:

Received 10 May 2016 Received in revised form 12 July 2016

Accepted 16 July 2016 Available online 27 July 2016 Editor: A. Huttner Keywords: Bacteraemia Daptomycin Linezolid Outcome Vancomycin-resistant enterococci

a b s t r a c t

Treatment options for vancomycin-resistant enterococci (VRE) bloodstream infection are limited. Studies comparing daptomycin or linezolid in treating VRE bloodstream infection have conflicting results and suggest daptomycin underdosing. The responses to different daptomycin doses have not been studied. We conducted a multicentre prospective cohort study to compare linezolid and dap-tomycin (6 mg/kg) for the treatment of VRE bloodstream infection. The primary outcome was 14-day mortality. We used multivariate logistic regression analysis for outcome analysis and a generalized additive model for dose-dependent response estimation. Two hundred twelve patients were included (daptomycin, n¼ 141; linezolid, n ¼ 71). All-cause 14-day mortality was higher in the daptomycin group (36.9% vs. 21.1%; p 0.03). After adjusting for confounders in logistic regression, mortality was lower in the linezolid group (adjusted odds ratio (aOR), 0.45; 95% confidence interval (CI), 0.21e0.96; p 0.04). The generalized additive model showed that higher-dose daptomycin (9 mg/kg) was asso-ciated with better survival than lower-dose daptomycin (6e9 mg/kg). Logistic regression showed that linezolid (aOR, 0.36; 95% CI, 0.17e0.79; p 0.01) and higher-dose daptomycin (aOR, 0.26; 95% CI, 0.09 e0.74; p 0.01) independently predicted lower mortality compared to lower-dose daptomycin. Line-zolid was not superior to higher-dose daptomycin in terms of mortality (aOR, 1.40; 95% CI, 0.45e4.37; p 0.57). Higher-dose daptomycin had lower mortality than lower-dose daptomycin. Despite higher mortality for lower-dose daptomycin than linezolid, linezolid conferred no survival benefit compared to higher-dose daptomycin. Ourfindings suggest that the recommended daptomycin dose is subop-timal for treating VRE bacteraemia. Y.-C. Chuang, CMI 2016;22:890.e1e890.e7

© 2016 Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases.

Introduction

Vancomycin-resistant enterococci (VRE) has emerged as an important pathogen causing nosocomial infections[1]after it was first described in 1986[2,3]. Vancomycin resistance is an important predictor of mortality of enterococcal bacteraemia[4]. However, treatment options are limited [5]. Linezolid is approved for VRE

infection[6]. However, because of its bacteriostatic nature, there are concerns about using linezolid for treating VRE bacteraemia[7]. Daptomycin has rapid bactericidal activity against enterococci

[7]. Although the recent study by Britt et al.[8]showed that dap-tomycin is superior to linezolid in treating VRE bacteraemia, their results differed from those of other studies[9,10]. Several important limitations of previous studies should be noted[8,11e16]. All of the previous studies were retrospective and may have been affected by recall bias. In addition, the recommended daptomycin dose was

6 mg/kg[17] and was based on the treatment of Staphylococcus

aureus bacteraemia. One case series demonstrated daptomycin-treated VRE bacteraemic patients receiving a daptomycin dose of

* Corresponding author. J.-T. Wang, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan, 7 Chung-Shan South Road, Taipei 100, Taiwan.

E-mail address:14bcr@yahoo.com.tw(J.-T. Wang).

Contents lists available atScienceDirect

Clinical Microbiology and Infection

j o u r n a l h o m e p a g e : w w w . c l i n i c a l m i c r o b i o l o g y a n d i n f e c t i o n . c o m

http://dx.doi.org/10.1016/j.cmi.2016.07.018

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>6 mg/kg had a better outcome than those receiving a lower dose

[18]. The daptomycin dose has varied widely in previous studies

[19]. Because daptomycin exhibits concentration-dependent

bac-terial killing, underdosing may lead to underestimation of the ef-ficacy of daptomycin[19]. However, it is unclear whether the dose differences can explain the conflicting results. To our knowledge, the responses to different doses of daptomycin have not been

studied in patients who received daptomycin at a dose6 mg/kg.

The primary aim of this multicentre prospective cohort study

was to examine whether daptomycin at a dose6 mg/kg would be

associated with a higher survival rate compared to linezolid. Our secondary aim was to analyse whether higher daptomycin dose would result in better survival outcomes.

Methods

Hospital setting and patients

The study was conducted at the National Taiwan University Hospital (NTUH), a 2200-bed medical centre located in Taipei City and NTUH Yun-Lin Branch, a 600-bed teaching hospital in Yun-Lin county. The study was approved by the research ethics committee of the NTUH (NTUH 201011023RB). The informed consent process was waived by the ethics committee.

We used a previously collected database originally designed to follow VRE bacteraemic patients. Patients with VRE bacteraemia were enrolled prospectively from January 2010 through July 2015. Patients were identified through computer-generated daily microbiology re-ports. The patients who had blood culture reports of VRE on weekends or holidays were followed from the nearest workday. VRE bacter-aemia was defined as the growth of VRE in one or more blood culture from a patient with fever (body temperature38C). If the patient had multiple episodes of VRE bacteraemia during the study period,

only thefirst episode was included. Patients who had VRE

bacter-aemia and were prescribed parenteral daptomycin or linezolid were included. The decision about which drug to use and the dose for each patient was made by the primary care physician. There were no local guidelines for using a higher dose of daptomycin for the treatment of more severe infection. If a patient initially received daptomycin but this was later changed to linezolid, that patient was placed into the daptomycin group, and vice versa. Patients who were younger than 18 years of age, who were not admitted to hospital, who received<6 mg/ kg of daptomycin or who received daptomycin and linezolid in combination were excluded.

Microbiologic studies and antimicrobial susceptibility testing Blood cultures were processed by the clinical microbiology

laboratory. VRE was identified using the VITEK-2 identification

system (bioMerieux, Marcy l'Etoile, France). Vancomycin resistance

was defined as an enterococcus isolate with a minimum inhibitory

concentration (MIC) of vancomycin of32 mg/L. The blood isolates were preserved for subsequent microbiologic characterization. The MICs of linezolid and daptomycin against enterococci were deter-mined using the broth microdilution method and interpreted ac-cording to the Clinical and Laboratory Standards Institute[20]. Clinical data collection and definitions

We prospectively followed the patients daily by reviewing the electronic medical records and recorded the patients’ demographic data, underlying diseases and sites of infection. The sites of primary infection were identified according to the definitions of the US Centers for Disease Control and Prevention[21]. If no infectious focus of

bac-teraemia could be identified, the bacteraemia was classified as

primary bacteraemia. The Charlson comorbidity index was used to

adjust for underlying conditions [22]. Bacteraemia severity was

assessed using the Pitt bacteraemia score at the onset of bacteraemia

[23].

Bacteraemia onset was defined as the day when the VRE-positive sample for blood culture was drawn. The daptomycin dose was calculated according to the subject’s actual body weight. Use of

immunosuppressive agents was defined as the receipt of

antineo-plastic drugs, cyclophosphamide or other immunosuppressive agents within 6 weeks, or as receipt of prednisolone at a dosage of 20 mg daily for 2 weeks or 30 mg daily for 1 week before onset of bacteraemia. Thrombocytopaenia was defined as a platelet count

<80 000/

m

L. We recommended that the creatine phosphokinase

(CPK) level be measured at least once a week during daptomycin

treatment [24] and if symptomatic in either group of patients.

Elevated CPK was defined as CPK higher than the upper limit of

normal. High elevation of CPK was defined as CPK more than tenfold the upper limit of normal. Creatinine clearance was estimated using Cockcroft-Gault equation[25,26]. Augmented renal clearance (ARC) was defined as creatinine clearance 130 (mL/min/1.73 m2)[26]. The primary outcome was all-cause in-hospital 14-day mortality after the onset of VRE bacteraemia. Secondary outcomes included infection-related mortality, adverse events such as thrombocyto-paenia and elevated CPK. Infection-related mortality was defined as death within 14 days after onset of VRE bacteraemia without another explanation and without resolution of infection symptoms or signs, or persistent VRE bacteraemia before death.

Statistical analysis

The mean and SD were calculated for continuous variables and percentages for categorical variables. Student's t test and Fisher's exact test were used to compare continuous and categorical vari-ables, respectively, between two groups. Multivariate logistic regression was used for outcome analysis. Variables with p0.2 in the univariate regression were included in the multivariate analysis. Multivariable models were developed by backward stepwise mini-mizing Akaike's information criterion (AIC)[27]. After stepwise AIC selection, only variables with p0.05 were considered significant

and were retained in thefinal multivariate prediction model. The

doseeresponse relationship between the daptomycin dose and

mortality was estimated using the generalized additive model (GAM)

[28]. Propensity scoreematched analyses were performed as sensi-tivity analysis[29]. Stata 14 (StataCorp, College Station, TX, USA) was used. Two-sided p values of0.05 were considered significant. Results

Two hundred twelve patients were enrolled in 2010e2015

(Fig. 1). All patients had vancomycin-resistant Enterococcus faecium infection, and three had vancomycin-resistant Enterococcus faecalis coinfection. The mean (SD) age of the study cohort was 65.1 (17.1) years, and Pitt bacteraemia score was 3.7 (2.8) points. One hundred twenty-three patients (58%) were men, and 89 (42.0%) used an

immunosuppressive agent (Table 1). Linezolid and daptomycin

MICs were available in 177 VRE isolates. No linezolid resistance was found in VRE isolated from patients receiving linezolid treatment, but two VRE isolates from patients receiving daptomycin showed daptomycin resistance.

Five of the 141 daptomycin-treated patients had changed to linezolid treatment because of a lack of improvement (five patients had microbiology-documented failure and persistent VRE bacter-aemia under daptomycin treatment). Seven of the 71 linezolid-treated patients had changed to daptomycin treatment (four due to thrombocytopaenia, one due to suspicious linezolid-related

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abnormal liver function and two due to clinical suspected poor response).

The patients' baseline characteristics differed between the daptomycin and linezolid groups (Table 1). Although the Pitt bac-teraemia score, the Charlson score and the time to effective anti-microbial therapy did not differ between the daptomycin and linezolid groups, the daptomycin group had a higher all-cause 14-day mortality (36.9% vs. 21.1%; p 0.03) and infection-related mor-tality (38.3% vs. 21.1%; p 0.01). The daptomycin group also had a trend towards higher all-cause 28-day mortality and all-cause in-hospital mortality (p 0.15 and p 0.18, respectively). There was no significant elevation of CPK or thrombocytopaenia differences be-tween the daptomycin and linezolid groups (p 0.78 and p 0.30, respectively) (Table 1). One patient in the linezolid group had elevated CPK after antimicrobial therapy was changed to dapto-mycin. Only one patient, who was in the lower-dose daptomycin group, had high CPK elevation.

Mortality analysis

In the univariate analysis, significant variables associated with all-cause 14-day mortality were daptomycin use, bacteraemia severity (indicated by the Pitt bacteraemia score and thrombocy-topaenia), catheter-related infection and steroid use. After consid-ering the above covariates as well as those variables in the univariate analysis with p<0.2 in the multivariate stepwise logistic regression analysis, linezolid use predicted lower all-cause 14-day mortality compared to daptomycin (adjusted odds ratio (aOR), 0.45; 95% confidence interval (CI), 0.21e0.96; p 0.04) (Table 2). Linezolid use also predicted lower infection-related mortality

compared to daptomycin (aOR, 0.46; 95% CI, 0.22e0.96; p 0.04).

Association between daptomycin dose and mortality

Among daptomycin-treated patients, higher-dose daptomycin (per 1 mg/kg) was significantly associated with lower all-cause

14-day mortality (odds ratio, 0.76; 95% CI, 0.59e0.98; p 0.03). The GAM

was used to determine the doseeresponse relationship between

the daptomycin dose and mortality; it showed lower mortality in

patients who received higher-dose daptomycin (Supplementary

Fig. 1). Using the GAM results, a daptomycin dose of9 mg/kg was selected as the cutoff between the lower and higher doses (Supplementary Fig. 1).

There was no significant difference of the patients’ baseline

characteristics and disease severity between the lower-dose and higher-dose daptomycin-treated patients, except that the

lower-dose group weighed more (59.6 kg vs. 52.3 kg; p <0.001)

(Supplementary Table 1). Fifteen (21.3%) linezolid-treated patients died, eight (23.5%) of 34 higher-dose daptomycin-treated patients died and 44 (41.1%) of 107 lower-dose daptomycin-treated patients had 14-day mortality (p 0.01). In the univariate analysis, compared

to daptomycin dose 6 to 9 mg/kg, both daptomycin dose9 mg/kg

(odds ratio, 0.44; 95% CI, 0.18e1.06; p 0.07) and linezolid (odds ratio, 0.38; 95% CI, 0.19e0.76; p 0.006) were associated with lower all-cause 14-day mortality. In the multivariate logistic regression analysis, linezolid use (aOR, 0.36; 95% CI, 0.17e0.79; p 0.01) and

higher-dose daptomycin (aOR, 0.26; 95% CI, 0.09e0.74; p 0.01)

predicted lower 14-day mortality compared to lower-dose dapto-mycin. Compared to higher-dose daptomycin, linezolid conferred no survival benefit (aOR, 1.40; 95% CI, 0.45e4.37; p 0.57).

Sensitivity analysis

Multivariate logistic regression was used to identify indepen-dent variables associated with the choice of linezolid rather than daptomycin for subsequent propensity score matching analysis. Factors associated with linezolid use were underlying cerebral vascular disease (aOR, 2.28; p 0.05), heavier body weight (aOR, 1.04; p 0.007) and no leukopenia (aOR, 5.4; p 0.001). Using propensity score matching, we matched 66 pairs of patients provided linezolid or daptomycin to treat VRE bacteraemia. After matching, the po-tential prognostic factors and severity of illness did not differ

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significantly between the two groups. The propensity scores were 0.381 for daptomycin and 0.385 for linezolid (p 0.58).

Of the 66 pairs of patients included in the propensity score matching analysis, 13 (19.7%) linezolid-treated patients died, 3 (25%) of 12 higher-dose daptomycin-treated patients died, and 24 (44.4%) of 54 lower-dose daptomycin-treated patients died.

Line-zolid treatment independently predicted lower mortality

compared to daptomycin in the matched cohort (aOR, 0.39; 95% CI,

0.18e0.85; p 0.02). Linezolid use independently predicted lower

mortality compared to lower-dose daptomycin in the matched patients (aOR, 0.34; 95% CI, 0.14e0.79; p 0.01). Linezolid treatment was not significantly superior to higher-dose daptomycin in terms of mortality (aOR, 0.98; 95% CI, 0.14e7.03; p 0.99) in the matched cohort.

Discussion

We found a dose-dependent clinical response of daptomycin. Mortality was lower in patients treated with the higher dose compared to the lower dose of daptomycin. Although all

daptomycin-treated patients received6 mg/kg daptomycin, this

group experienced worse clinical outcomes than the linezolid

group. Mortality was higher in the group treated with lower-dose

daptomycin (6e9 mg/kg) than in the linezolid-treated group.

However, there was no difference in survival between the

higher-dose daptomycin-treated group (9 mg/kg) and the

linezolid-treated group. These findings suggest that the currently

recom-mended daptomycin dose might be suboptimal for the treatment of VRE bacteraemia.

Since 2009, several studies have discussed the effectiveness of

daptomycin in treating VRE bacteraemia [8,11e16], although the

results are conflicting[8e10,19]. One possible explanation for the conflicting results relates to the daptomycin and linezolid doses. Daptomycin exhibits rapid concentration-dependent bactericidal activity in vitro against Gram-positive organisms, including enterococci[30]. A daptomycin dose of8 mg/kg might not induce

sustained bactericidal activity, whereas 10 mg/kg does [31]. A

previous case series noted better outcomes for patients provided daptomycin at a dose of>6 mg/kg[18]. The daptomycin dose has varied widely in previous studies (3.4e10.4 mg/kg)[13,16,32,33]. Some patients may have been underdosed. By contrast, the median daptomycin dose used in the study by Britt et al.[8]was 5.93 mg/kg (interquartile range, 5.33e6.10 mg/kg) which is more consisted to the recommended dose of 6 mg/kg. We used a minimum

Table 1

Demographics and clinical characteristics of patients with vancomycin-resistant enterococcal bacteraemia

Characteristica Daptomycin (n¼ 141) Linezolid (n¼ 71) p

Demographics

Age, y 64.4 (17.9) 66.6 (15.5) 0.40

Male 78 (55.3) 45 (63.4) 0.30

Body weight, kg 57.9 (11.2) 61.6 (14.0) 0.04

Days of prior hospitalization 33.1 (32.2) 32.0 (35.2) 0.82

Underlying condition

Charlson score 2.9 (2.5) 4.0 (2.5) 0.77

Congestive heart failure 8 (5.7) 9 (12.7) 0.10

Cerebrovascular disease 16 (11.3) 15 (21.1) 0.07

Autoimmune disease 4 (2.8) 1 (1.4) 0.67

Liver cirrhosis 25 (17.7) 19 (26.8) 0.15

Diabetes mellitus 43 (30.5) 26 (36.6) 0.44

Chronic kidney disease 43 (30/5) 25 (35.2) 0.53

Malignancy 77 (54.6) 26 (36.6) 0.01

Use of immunosuppressive agents 66 (46.8) 23 (32.4) 0.06

Steroid 22 (15.6) 10 (14.1) 0.84

Chemotherapy 51 (36.2) 14 (19.7) 0.02

Infection focus

Primary bacteraemia 95 (67.4) 38 (53.5) 0.05

Catheter-related infection 12 (8.5) 9 (12.7) 0.34

Urinary tract infection 21 (14.9) 12 (16.9) 0.69

Intra-abdominal infection 11 (7.8) 7 (9.9) 0.61

Surgical site infection 5 (3.6) 5 (7.0) 0.31

Clinical characteristic

White blood cell count (103/mL) 11.5 (13.2) 13.3 (8.7) 0.30

Leukopenia (<4000/mL) 40 (28.4) 5 (7.0) <0.001

Platelet count (103/mL) 120.1 (109.0) 163.9 (128.1) 0.01

Thrombocytopaenia (<80 000/mL) 72 (51.1) 20 (28.2) 0.002

Creatinine clearance (mL/min/1.73 m2) 34.9 (26.9) 31.5 (24.5) 0.37

Ventilator use 60 (42.6) 34 (47.9) 0.47

Pitt bacteraemia score 3.6 (3.0) 3.8 (2.5) 0.65

Pitt bacteraemia score3 76 (55.1) 47 (66.2) 0.14

Days to effective antimicrobial therapy 3.2 (1.9) 3.1 (2.5) 0.56

Antibiotics dose (mg/kg or mg every 12 hours) 7.9 (1.4) 600 Outcome

All-cause in-hospital mortality 90 (63.8) 38 (53.5) 0.18

All-cause 28 d mortality 69 (48.9) 27 (38.0) 0.15

All-cause 14 d mortality 52 (36.9) 15 (21.1) 0.03

Infection-related mortality 54 (38.3) 15 (21.1) 0.01

Switch to other group 5 (3.6) 7 (9.9) 0.11

Lack of improvement 5 (3.6) 2 (2.8) 0.99

Adverse event 0 (0) 5 (7.0) 0.004

Elevated creatinine kinase 10 (7.1) 4 (5.6) 0.78

Thrombocytopaeniab 16 (23.2) 17 (33.3) 0.30

aData are mean (SD) for continuous variables and n (%) for categorical variables, with two-tailed Student’s t test used for the former and Fisher's exact test for the latter. b Among patients who were nonthrombocytopenic before treatment.

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daptomycin dose of 6 mg/kg, and the linezolid group had better clinical outcomes on average. The higher-dose daptomycin group

(9 mg/kg) had a similar outcome or trend towards a better

outcome compared to linezolid treatment.

In addition, although linezolid 600 mg every 12 hours was used in our study and the study by Britt et al.[8], Cai et al.[34]showed that the inhibitory activity was lower in heavier patients (>80 kg) and recommended adjusting the dose by body weight to 10 mg/kg.

In the linezolid-treated group in our study, only five patients

weighed>80 kg. Body weight seemed to be higher in the study by Britt et al. compared to our linezolid-treated group (mean body

mass index, 25.5 and 23.3 kg/m2, respectively). Therefore, the

clinical effectiveness of linezolid might have been lower in heavier patients in the study by Britt et al.

All of the VRE bacteraemia treatment studies were retrospective cohort studies. The study by Britt et al.[8]is important because it included the largest sample size and had a relatively good design. However, the study by Britt et al. differed from the other studies. For example, the reported Charlson score was 9 in the study by Britt et al., which was higher than the scores of 4 to 5 in other studies

[15,32,35,36]. The length of hospital stay before bacteraemia was only 5 days in the study by Britt et al., which was shorter than the 18 to 30 days in other studies[13,32,36]. The large differences in pa-tient characteristics between the study by Britt et al. and other

studies might reflect heterogeneity between studies, which makes

it difficult to make direct comparisons. In addition, the study by

Britt et al. is limited by the patients enrolled being nearly all male, as the study was based in American Veterans Association medical centres and contained relatively few transplant recipients; there-fore, the result is not likely to be generalized to all medical centres

[37].

Higher-dose daptomycin is used to treat Gram-positive and enterococcal infections, and it is generally safe [38e40]. In our study, two (5.9%) of the higher-dose daptomycin-treated and eight (7.4%) of the lower-dose-treated patients exhibited an elevated CPK level (p 0.99). Although an elevated CPK level might relate more to the dosing interval rather than the peak daptomycin concentration

[41], and although a prior study also demonstrated that a higher daptomycin dose (>8 mg/kg) did not correlate with the highest

observed CPK level[40], a report has demonstrated that

higher-dose daptomycin might cause a higher percentage of patients to exhibit elevated CPK level[24]. Therefore, we suggest that higher-dose daptomycin be used in the treatment of VRE bacteraemia,

but the CPK level should be monitored closely until sufficient

experience proves that higher-dose daptomycin is as safe as the lower dose.

Daptomycin is cleared by the kidneys, and patients with ARC might eliminate certain antibiotics more quickly. However, because therapeutic drug monitoring was not performed, we do not know whether ARC affected the initial Cmaxof daptomycin and affected mortality. We analysed the creatinine clearance (mL/min/1.73 m2) and the association of all-cause 14-day mortality. The mean (SD)

Table 2

Logistic regression analysis of the associated with 14-day mortality

Characteristic Univariate Multivariatea

Crude odds ratio (95% CI) p Adjusted odds ratio (95% CI) p Demographics

Age 1.01 (0.99e1.03) 0.29

Male 1.01 (0.56e1.82) 0.97

Body weight 1.01 (0.99e1.04) 0.21

Days of prior hospitalization 1.00 (0.99e1.01) 0.97 Underlying condition

Charlson score 1.04 (0.93e1.16) 0.53

Congestive heart failure 0.64 (0.20e2.06) 0.46 Cerebrovascular disease 1.04 (0.46e2.34) 0.93

Autoimmune disease 1.46 (0.24e8.93) 0.68

Liver cirrhosis 1.01 (0.50e2.07) 0.97

Diabetes mellitus 1.02 (0.55e1.89) 0.95

Chronic kidney disease 1.16 (0.63e2.15) 0.63

Malignancy 1.04 (0.58e1.86) 0.90

Use of immunosuppressive agents 1.69 (0.94e3.03) 0.08

Steroid 4.02 (1.84e8.76) <0.001 3.43 (1.42e8.31) 0.006

Chemotherapy 1.16 (0.62e2.16) 0.64

Infection source

Primary bacteraemia 0.83 (0.46e1.50) 0.54

Catheter-related infection 2.65 (1.07e6.60) 0.04 Urinary tract infection 1.50 (0.70e3.24) 0.30 Intra-abdominal infection 0.59 (0.19e1.88) 0.38 Surgical site infection 0.53 (0.11e2.55) 0.43 Clinical characteristic

White blood cell count (103/mL) 1.02 (0.99e1.04) 0.15

Leukopenia (<4000/mL) 0.97 (0.48e1.98) 0.94

Platelet count (104/mL) 0.93 (0.90e0.97) <0.001 0.94 (0.91e0.98) 0.002

Thrombocytopaenia (<80 000/mL) 2.65 (1.46e4.80) 0.001

Ventilator use 1.22 (0.68e2.19) 0.50

Pitt bacteraemia score 1.26 (1.13e1.41) <0.001 1.27 (1.13e1.43) <0.001 Pitt bacteraemia score3 3.24 (1.67e6.29) 0.001

Days to initiate effective antimicrobial therapy 0.89 (0.77e1.03) 0.11 Linezolid vs. daptomycin

Reference: daptomycin use, dose 6e9 mg/kga 0.46 (0.24e0.89)

0.02 0.45 (0.21e0.96)b 0.04

Daptomycin use, dose9 mg/kg 0.44 (0.18e1.06) 0.07 0.26 (0.09e0.74) 0.01

Linezolid use 0.38 (0.19e0.76) 0.006 0.36 (0.17e0.79) 0.01

aMultivariate logistic regression model, with daptomycin dose considered in the model: n¼ 212, Nagelkerke/Cragg and Uhler's R2¼ 0.318, deviance goodness-of-fit (GOF)

test, p 0.33> 0.05; Hosmer and Lemeshow GOF test, p 0.12 > 0.05; estimated area under the ROC curve ¼ 0.79.

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creatinine clearance of the survival group was 36.2 (28.0) and of the mortality group was 28.7 (20.8) (p 0.05). Only one patient with ARC, who was in the lower-dose daptomycin group, did not have 14-day mortality. We therefore cannot demonstrate that ARC was associ-ated with higher 14-day mortality. Renal clearance was more likely to be an indicator of underlying morbidity; better renal clearance is associated with good clinical outcome, though this variable was not significant in our multivariate analysis.

This study has several limitations. Firstly, because there was no therapeutic drug monitoring of daptomycin, we were unable to show that a better pharmacodynamic parameter (peak/MIC or 24-hour area under the curve/MIC) is associated with better outcome. Secondly, although the multivariate regression approach and pro-pensity score matching showed consistent results, there may have been unmeasured confounders not examined in our study. Thirdly, this was an observational study, and the follow-up bacterial culture was dependent on the primary care physician; therefore, we could not evaluate differences in the microbiologic responses between daptomycin and linezolid treatment of VRE bacteraemia. Finally, the higher-dose cutoff was chosen using the statistical approach and should be validated in further clinical studies.

In conclusion, daptomycin displays a dose-dependent clinical response. Higher-dose daptomycin was associated with better survival than lower-dose daptomycin. Although the lower-dose

daptomycin group (6e9 mg/kg) had worse clinical outcome than

the linezolid group, the linezolid group had no survival benefit

compared to the higher-dose daptomycin group (9 mg/kg).

Further studies are needed to determine the adequate daptomycin dose for treating VRE bacteraemia. Larger randomized control trials with higher-dose daptomycin are needed to compare the efficacy of daptomycin and linezolid in treating VRE bacteraemia.

Acknowledgement

The authors thank the Third Core Facility, National Taiwan University Hospital, for technical assistance and facility support. Transparency Declaration

This study was partially supported by the Ministry of Science and Technology, Taiwan (002 -103 -MY3, 104-2314-B-002 -109 -MY3 and 103-2410-H-004 -014), and the National Taiwan University Hospital (NTUH.100-001739). All authors report no conflicts of interest relevant to this article.

Appendix A. Supplementary data

Supplementary data related to this article can be found athttp:// dx.doi.org/10.1016/j.cmi.2016.07.018.

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數據

Fig. 1 ). Using the GAM results, a daptomycin dose of 9 mg/kg was selected as the cutoff between the lower and higher doses ( Supplementary Fig

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