Trends in Susceptibility of Vancomycin-resistant...

Trends in Susceptibility of Vancomycin-resistant Enterococcus 1

faecium to Tigecycline, Daptomycin, and Linezolid and 2

Molecular Epidemiology of the Isolates: Results from the 3

Tigecycline In Vitro Surveillance in Taiwan (TIST) Study, 4

2006-2010 5

6

7

Hsih-Yeh Tsai1, Chun-Hsing Liao1, Yen-Hsu Chen2, Po-Liang Lu2, Cheng-Hua 8

Huang3, Chin-Te Lu4, Yin-Ching Chuang5, Shih-Ming Tsao6, Yao-Shen Chen7, 9

Yung-Ching Liu7, Wei-Yu Chen8, Tsrang-Neng Jang8, Hsiu-Chen Lin9, Chih-Ming 10

Chen10, Zhi-Yuan Shi11, Sung-Ching Pan12, Jia-Ling Yang12, Hsiang-Chi Kung12, 11

Chun-Eng Liu13,Yu-Jen Cheng13, Jien-Wei Liu14, Wu Sun15, Lih-Shinn Wang16, 12

Wen-Chien Ko17, Kwok-Woon Yu18, Ping-Cherng Chiang19, Ming-Hsun Lee19, 13

Chun-Ming Lee20, Gwo-Jong Hsu21, Po-Ren Hsueh1, 22* 14

15

1Section of Infectious Diseases, Department of Internal Medicine, Far Eastern 16

Memorial Hospital, Taiwan; 2Division of Infectious Diseases, Department of Internal 17

Medicine, Kaohsiung Medical University Hospital; Graduate Institute of Medicine, 18

College of Medicine, Kaohsiung Medical University, Taiwan; 3Division of Infectious 19

Diseases, Department of Internal Medicine, Cathay General Hospital, Taiwan 20

4Section of Infectious Diseases, Department of Internal Medicine, Lotung Poh-Ai 21

Hospital, Taiwan; 5Department of Internal Medicine, Chi-Mei Medical Center, 22

Taiwan; 6Infectious Section, Internal Medicine Department, Institute Microbiology 23

and Immunology, Chung Shan Medical University, and University Hospital, Taiwan 24

7Section of Infectious Diseases, Shuang Ho Hospital, Taipei Medical University and 25

Copyright © 2012, American Society for Microbiology. All Rights Reserved.Antimicrob. Agents Chemother. doi:10.1128/AAC.00533-12 AAC Accepts, published online ahead of print on 9 April 2012

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School of Medicine, Taipei Medical University, Taipei; and Section of Infectious 26

Diseases, Department of Internal Medicine, Kaohsiung Veterans General Hospital, 27

Kaohsiung, Taiwan; 8Section of Infectious Diseases, Department of Internal Medicine, 28

Shin Kong Wu Ho-Su Memorial Hospital, Taiwan; 9Department of Pediatrics, School 29

of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; 30

10Section of Infectious Diseases, Department of Internal Medicine, Tungs' Taichung 31

MetroHarbor Hospital, Taiwan; 11Section of Infectious Diseases, Department of 32

Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; 33

12Department of Internal Medicine, National Taiwan University Hospital, Taipei, 34

Taiwan; 13Section of Infectious Diseases, Department of Internal Medicine, 35

Changhua Christian Hospital, Taiwan; 14Division of Infectious Diseases, Department 36

of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung 37

University Medical College, Taiwan; 15Department of Infection Control, Pao-Chien 38

Hospital, Taiwan; 16Section of Infectious Diseases, Department of Internal Medicine, 39

Buddhist Tzu Chi General Hospital, Taiwan; 40

17Department of Medicine, National Cheng Kung University Medical College and 41

Hospital, Taiwan; 18Division of Infectious Diseases, Department of Internal Medicine, 42

Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taiwan; 43

19Division of Infectious Diseases, Department of Internal Medicine, Chang Gung 44

Medical Foundation Linkou Branch, Taiwan; 20Section of Infectious Diseases, 45

Department of Internal Medicine, Mackay Memorial Hospital 46

21Division of Infectious Diseases, Department of Internal Medicine, Ditmanson 47

Medical Foundation Chiayi Christian Hospital, Taiwan; 22Departments of Laboratory 48

Medicine and Internal Medicine, National Taiwan University Hospital, National 49

Taiwan University College of Medicine, Taipei, Taiwan 50


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*Corresponding author. Mailing address: Departments of Laboratory Medicine and 51

Internal Medicine, National Taiwan University Hospital, No.7, Chung-Shan South 52

Road, Taipei 100, Taiwan. Phone: 886-2-23123456, ext. 65355. Fax: 886-2-23224263. 53

E-mail: [email protected]. 54

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Among the 219 vancomycin-resistant Enterococcus faecium isolates collected in 56

20 Taiwanese hospitals from 2006 to 2010, all were susceptible to linezolid and 57

daptomycin, and 98.6% were susceptible to tigecycline. There was a shift 58

towards higher tigecycline MIC values (MIC90s) from 2006-2007 (0.06 μg/ml) to 59

2008-2010 (0.12 μg/ml). The MIC90s of daptomycin and linezolid remained 60

stationary. Although pulsotypes among the isolates from the 20 hospitals varied, 61

intra-hospital spreading of several clones was identified in 13 hospitals. 62

63

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65

Enterococcus species were first isolated in a patient with endocarditis in the early 66

1900s (15) and have been recognized as an important cause of nosocomial urinary 67

tract infection and bacteremia since the mid 1970s (4). Penicillin, ampicillin and 68

aminoglycosides are the drug of first-line choice of choice for the treatment of 69

enterococcal infection. Glycopeptides are effective antibiotics for the treatment of 70

infections due to beta-lactam-resistant enterococci beginning in the 1980s (7). 71

However, the rate of isolation of vancomycin-resistant enterococci (VRE) strains is on 72

the rise in North America (17), Europe (2), and Asia (4). In Taiwan, a nationwide 73

surveillance study of antimicrobial resistance in patients admitted to intensive care 74

units clearly demonstrated a significant rise in VRE among regional hospitals and 75

medical centers during the period 2003 to 2009 (5). Specifically, at the National 76

Taiwan University Hospital, rates of VRE among all enterococci species causing 77

healthcare-associated infection significantly increased from 1.7% (0.007 per 100 78

inpatient-days) in 2000 to 25.1% (0.188 per 100 inpatient-days) in 2009 (14). Clonal 79

dissemination and the presence of multiple clones of VRE have also been reported in 80

hospitals in Taiwan (8, 9). Tigecycline, daptomycin, and linezolid are now the drugs 81

of choice for the treatment of infections due to VRE. However, the in vitro 82

susceptibilities of VRE species to these agents have been shown to vary with time and 83


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between countries. Herein, we report the trends in in vitro susceptibility of 84

vancomycin-resistant E. faecium to tigecycline, daptomycin, and linezolid in Taiwan 85

during the period 2006 to 2010. 86

Clinical isolates of VRE were collected as part of the Tigecycline In Vitro 87

Surveillance in Taiwan (TIST) study, a nationwide, multi-center prospective 88

surveillance study conducted in 20 medical centers and regional hospitals throughout 89

Taiwan during the period January 2006 to December 2010 (5). Duplicate isolates from 90

the same patients were excluded (one isolate per patient). Consecutive VRE isolates 91

during a three-month period per year from each participating hospital were collected 92

with a maximal number of isolates of 10 per hospital per year. These VRE isolates 93

were identified and vancomycin resistance was determined by the disk diffusion 94

method at each hospital and reconfirmed by the central laboratory at the National 95

Taiwan University Hospital (NTUH). Minimum inhibitory concentrations (MICs) of 96

three antimicrobial agents, namely tigecycline, daptomycin, and linezolid, were 97

determined using the broth microdilution method according to the guidelines of the 98

Clinical and Laboratory Standards Institute (CLSI) (6). Susceptibility testing for the 99

three agents was performed at the same central laboratory at NTUH using same type 100

of media, Mueller-Hinton broth (BBL Microbiology Systems, Cockeysville, MD), 101

and the same protocol every year. Susceptibilities to the three agents were classified 102

based on the U.S. Food and Drug Administration (FDA), the European Committee on 103

Antimicrobial Susceptibility Testing (EUCAST-2012; www.eucast.org), and CLSI 104

2012 breakpoints (6). 105

In order to understand the genetic relatedness of vancomycin-resistant E. faecium 106

isolates, particularly those with daptomycin MICs of 4 μg/ml, pulsed-field gel 107


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electrophoresis (PFGE) profiles of SmaI-digested genomic DNAs of these isolates 108

were determined as previously described (9). 109

A total of 219 clinical isolates of vancomycin-resistant E. faecium were collected 110

from 20 hospitals during the five-year study period (Table 1). Numbers of clinical 111

isolates obtained from 2006 to 2010 were 13 in 2006, 15 in 2007, 41 in 2008, 78 in 112

2009, and 72 in 2010 (5). Susceptibility of vancomycin-resistant E. faecium to 113

tigecycline was 98.6% according to US FDA and EUCAST-2012 breakpoints (22). 114

The three VRE isolates that were less susceptible to tigecycline had tigecycline MICs 115

of 0.5, 0.5, and 1 μg/ml. All isolates were susceptible to daptomycin and linezolid 116

according to CLSI-2012 and EUCAST-2012 criteria (6). The MICs of daptomycin 117

were 2 μg/ml and the MICs of linezolid were 1-2 μg/ml for the three tigecycline 118

non-susceptible isolates. 119

The distributions of MIC values of the three agents against the 120

vancomycin-resistant E. faecium strains are shown in Table 2. MIC50 and MIC90 121

values of tigecycline, daptomycin, and linezolid against the clinical isolates were 122

≤0.03 μg/ml and 0.12 μg/ml (range, ≤0.03-1 μg/ml), 2 μg/ml and 2 μg/ml (range, 123

0.12-4 μg/ml), and 1 μg/ml and 2 μg/ml (range, 0.25-2 μg/ml), respectively. There 124

was a shift towards higher tigecycline MIC values from 2006-2007 (MIC90 of 0.06 125

μg/ml) to 2008-2010 (MIC90 of 0.12 μg/ml) (Figure 1A). The MIC values of 126


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daptomycin and linezolid against the isolates remained stationary during the study 127

period (Figure 1B and 1C). 128

A total of 14 vancomycin-resistant E. faecium isolates were susceptible to 129

daptomycin with MICs of 4 μg/ml (Table 3). Those isolates were also susceptible to 130

tigecycline and linezolid. All of the isolates were susceptible to tigecycline at a 131

concentration of 0.06 μg/ml, and nine of the 14 clinical isolates were susceptible to 132

linezolid at a concentration of 2 μg/ml. 133

Even though the pulsotypes of the isolates varied among the 20 hospitals, 13 134

hospitals in Taiwan showed evidence of intra-hospital spreading of VRE isolates with 135

the same pulsotypes (Table 3). Thirteen pulsotypes were found among the 14 isolates 136

of vancomycin-resistant E. faecium with daptomycin MICs of 4 μg/ml, indicating the 137

absence of inter-hospital spreading of these strains among Taiwanese hospitals (Figure 138

2). 139

Although the incidence of infection due to VRE has risen in recent years in many 140

countries (1, 15), the incidence of VRE in Taiwan remains relatively low (3-7%) (15), 141

especially compared to the incidence of hospital-acquired VRE infection in the United 142

States (28%).VRE species are recovered from colonized rather than infected patients 143

in many institutions (24), but VRE infection is associated with higher recurrence and 144

mortality (21). In addition, the treatment regimens for VRE infections are limited to 145


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tigecycline, daptomycin, and linezolid. However, only a few reports regarding the 146

antimicrobial susceptibility of VRE isolates to these antibiotics in certain hospitals in 147

Taiwan have been published (10, 11), and no nationwide surveillance studies of 148

susceptibility of VRE species to the above-mentioned antimicrobial agents have been 149

conducted. 150

In this study, we found that all clinical isolates of VRE were susceptible to 151

daptomycin and linezolid, and that almost all VRE isolates (98.6%) were susceptible 152

to tigecycline. Studies conducted in Europe and the United States demonstrated 153

similar findings (3, 18-20). Daptomycin non-susceptible enterococci may be an 154

emerging clinical problem in other countries (12), but they were not identified in our 155

study. In this study, the reason why the VRE isolates with daptomycin MICs of 4 156

μg/ml were selected for molecular typing to elucidate the possible clonal spreads 157

because there are concerns about achieving adequate concentrations of daptomycin 158

using standard doses (≤ 6 mg/kg) when the MICs of the isolates approach the upper 159

end (4 μg/ml) of the susceptible range (13). Higher doses of daptomycin may be 160

needed to treat infections caused by VRE isolates with higher MICs (3-4 μg/ml), 161

although there was no significant difference in time to microbiological cure between 162

MIC subgroups of ≤ 2 μg/ml versus >2 and ≤4 μg/ml of VRE isolates causing 163

bacteremia (13). We found that there was no marked increase in the trend of resistance 164


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to daptomycin and linezolid; however, we did find that there was an increase in 165

resistance to tigecycline during the study period relative to the trend in resistance rates 166

reported previously in Taiwan (10, 11). 167

In conclusion, tigecycline, daptomycin, and linezolid remain active against VRE 168

isolates. Nonetheless, the emerging resistance of VRE to these agents should be 169

monitored. Inter-hospital spreads of VRE among Taiwanese hospitals were not 170

evident, however, intra-hospital dissemination of several VRE clones was found in 171

several hospitals. 172

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TABLE 1. Pulsotypes of 219 isolates of vancomycin-resistant E. faecium from 20 265

hospitals in Taiwan from 2006 to 2010 266

267

Hospital

designation

No. of isolates No. of pulsotypes

identified

No. of pulsotypes with ≥2

isolates at an indicated

hospital/ no. of isolates

within the pulsotype with

≥2 isolates

H01 10 7 3/2, 2, 2

H02 31 16 4/5, 5, 3, 2

H03 12 11 2/2, 2

H04 5 4 1/2

H05 4 3 1/2

H06 30 17 6/4, 3, 3, 2, 2, 2

H07 9 8 1/2

H08 0 0 0

H09 0 0 0

H10 10 8 3/2,2, 2

H11 10 0

H12 18 14 3/2, 2, 2

H13 11 7 2/3, 2

H14 13 12 0

H15 11 9 1/2

H16 1 1 1/2

H17 10 7 0

H18 13 12 2/3, 2

H19 11 11 0

H20 10 8 0


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TABLE 2. Distribution of minimum inhibitory concentrations (MICs) of tigecycline, daptomycin, and linezolid for 219 vancomycin-resistant E. 268

faecium collected from 20 hospitals in Taiwan between 2006 and 2010. 269

270

Agent No.(cumulative %) of isolates with indicated MIC (μg/ml) MIC (μg/ml)

≤0.03 0.06 0.12 0.25 0.5 1 2 4 8 ≥16 50% 90%

Tigecycline 116 (53) 65 (83) 28 (95) 7 (99) 2 (99) 1 (100) 0 (100) 0 (100) 0 (100) 0 (100) ≤0.03 0.12

Daptomycin 0 (0) 0 (0) 2 (0.9) 2 (2) 11 (7) 32 (21) 158 (94) 14 (100) 0 (100) 0 (100) 2 2

Linezolid 0 (0) 0 (0) 0 (0) 1 (0.5) 14 (7) 108 (56) 96 (100) 0 (100) 0 (100) 0 (100) 1 2


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TABLE 3. Designations and minimum inhibitory concentrations (MICs) of 271

14 isolates of vancomycin-resistant E. faecium with daptomycin MICs of 4 μg/ml. 272

273 Isolate

(year of isolation)

Hospital Designation of

isolates

MIC (μg/ml)

Pulsotype Linezolid Tigecycline

1. (2010) H01 A 1 0.06 I

2. (2009) H03 B1 1 0.03 II

3. (2009) H03 B2 2 0.03 III

4. (2008) H06 C1 2 0.06 IV

5. (2008) H06 C2 0.5 0.06 V

6. (2009) H06 C3 2 0.03 VI

7. (2010) H06 C4 2 ≤0.03 VII

8. (2010) H10 D 2 0.06 VIII

9. (2008) H12 E 1 0.03 IX

10. (2007) H15 F1 2 0.06 X

11. (2009) H15 F2 2 0.03 XI

12. (2009) H15 F3 1 0.03 XI

13. (2010) H15 F4 2 0.03 XII

14. (2009) H20 G 2 0.03 XIII

274 275

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FIG. 1. Distribution of minimum inhibitory concentrations (MICs) of 277

vancomycin-resistant E. faecium to tigecycline (A), daptomycin (B), and linezolid (C) 278

with year from 2006 to 2010 279

280

281


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283

284


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285 FIGURE 2. Pulsed-field gel electrophoresis profiles and dendrogram of 14 isolates of 286

vancomycin-resistant E. faecium with daptomycin MICs of 4 μg/ml. 287

288 289

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