Resistance Trends among Gram-Positive Cocci across the US and the Activity Profile of Tigecycline against Resistant Isolates

Background: Due to the prevalence of methicillin resistant S. aureus (MRSA); vancomycin resistant enterococci (VRE); and penicillin resistant S. pneu-moniae (PRSP), agents used to treat gram-positive infections should maintain activity against these re-sistant subpopulations. Data from The Surveillance Network (TSN) were reviewed for rates of MRSA, VRE and PRSP in the US over the past 10 years. The impact of resistance on the activity of tigecy-cline (TIG), used to treat infections where resistant gram-positives are commonly encountered, was de-termined.

Methods: Resistant rates were evaluated using data from TSN, a database of test results from >150 US hospitals. Also, recent (‘06-‘09) US clinical isolates of S. aureus (n=4,158), vancomycin susceptible E. faecalis (VSE; n=256), S. pneumoniae (n=658) and S. pyogenes (n=741) were centrally tested by broth microdilution (CLSI; M7-A8) against TIG. TSN data were used to evaluate TIG MICs for VRE.

Results: MRSA rates increased from 32-53% dur-ing ’98-‘08. VRE rates increased (E. faecium: 68-77%; E. faecalis 2.6-3.8%) over this period while PRSP rates and macrolide resistance among S. pyo-genes fluctuated between 16-22% and 8-11%, re-spectively. Regionally, there was a trend towards higher rates in the South Atlantic and Mid Atlantic regions and lower rates in the Pacific and Mountain regions. TIG had MIC50/MIC90s (g/ml) for MRSA (0.12/0.25), PRSP (0.015/0.03), and macrolide re-sistant S. pyogenes (0.03/0.06) identical or within 1 doubling dilution compared with the susceptible subpopulations. The susceptibility rate for TIG for S. aureus, S. pnuemoniae, and S. pyogenes was >99.7%. 87.9% of VSE were susceptible to TIG with an MIC90 of 0.5 g/ml. For VRE, TIG activity was similar to VSE based on MIC distributions.

Conclusion: Resistant gram-positive organisms are common, MRSA and VRE rates have increased in the US in the past 10 years and rates varied region-ally. TIG maintained its activity profile for these re-sistant subpopulations showing that current resis-tance commonly encountered among target GP has no impact on its in vitro activity.

Mohana K. Torres1, Deborah C. Draghi1, Karla Tomfohrde1, Chris M. Pillar1, Venkat Alluru1, Michael J. Dowzicky2, Daniel F. Sahm1

1Eurofins Medinet, Chantilly, VA, USA 2Wyeth Pharmaceuticals, Collegeville, PA, USA

Poster No. C2-1957

Contact Information: Chris M. Pillar, Ph.D. Eurofins Medinet 14100 Park Meadow Drive Chantilly, VA, USA 20151 Tel. 1.703.480.2500

Results Introduction Revised Abstract

Methods

Conclusions

This study was supported by a grant from Wyeth Pharmaceuticals.

Resistance among frequently encountered gram-positive pathogens continues to be an issue across the US, given the prevalence of methicillin resistant S. aureus (MRSA), penicil-lin and multi-drug resistant S. pneumoniae (PRSP, MDRSP), and vancomycin resistant enterococci (VRE). Tigecycline, a broad spectrum glycylcycline, is approved for use in the treat-ment of complicated skin and skin structure infections (cSSSIs) and community-acquired pneumoniae (CAP) and, given these indications, it is important to understand tigecy-cline activity against resistant subpopulations of gram-positive organisms likely to be encountered with cSSSIs and CAP. This study evaluates the prevalence of resistance among gram-positive cocci both across the US and regionally over the past 10 years and reports the current activity profile of tigecycline against both resistant and susceptible populations of recent clinical isolates of gram-positive cocci.

Current resistance rates were evaluated using data from The Surveillance Network® (TSN), an electronic database of test re-sults from >150 US hospitals. Also, recent (2006-2009) US clinical isolates of S. aureus (n=4,158), vancomycin susceptible E. faecalis (n=256), S. pneumoniae (n=658) and S. pyogenes (n=741) were collected from 176 hospitals across the nine US Census Regions (table) and centrally tested at Eurofins Medi-net by broth microdilution (CLSI M7-A8; CLSI M100-S18) against tigecycline. Tigecycline activity against gram-positive cocci from surveillance studies were analyzed by relevant resis-tance phenotypes. TSN data were used to evaluate tigecycline MICs for vancomycin resistant enterococci (VRE). Multi-drug resistant S. pneumoniae (MDRSP) was defined as resistant to ≥2 of the following agents: penicillin, cefuroxime, erythromy-cin, tetracycline, and trimethoprim-sulfamethoxazole. Tigecy-cline FDA breakpoints were used to interpret data. S. aureus with MICs ≤0.5 µg/mL, S. pneumoniae ≤0.06 µg/mL, S. pyogenes ≤0.25 µg/mL, and E. faecalis (vancomycin susceptible only) ≤0.25 µg/mL were in-terpreted as susceptible.

Acknowledgments

Resistance among gram-positive cocci is common in the US with a large increase in the amount of MRSA over the past decade.

There is variation in the rates of resistance regionally with a general trend towards increased resistance in the south and south eastern US relative to other areas, with lower resistance in the western US, in par-ticular for PRSP and MRSA.

Tigecycline maintains the same activity profile against the evaluated re-sistant subpopulations of gram-positive cocci (MRSA, PRSP, VRE and macrolide-resistant S. pyogenes) relative to the respective susceptible subpopulations.

Due to its broad-spectrum of activity which includes resistant gram-positive cocci, tigecycline is a valuable therapeutic option for the treat-ment of cSSSI and CAP, infections where resistant gram-positive iso-lates are likely to be encountered.

Streptococci Resistance to penicillin among S. pnuemoniae (PRSP; based on oral penicillin breakpoints) has ranged from between 15-22% over a ten

year period in the US (Table 1). Current prevalence of PRSP vary by region from 11% in the Pacific and New England regions to 20-25% in the West South Central and South Atlantic regions (Figure 1b).

Tigecycline maintained similar activity profiles against PRSP and MDRSP (MIC50/MIC90 = 0.015/0.03 g/ml, 100%S) relative to PSSP and non-MDRSP isolates (Table 2). Similar tigecycline MIC distributions were observed between susceptible and resistant S. pneumo-niae subpopulations (Figure 2b).

Macrolide resistance among S. pyogenes was 11% in the US overall with variation in rates by region (Figure 1c). All evaluated S. pyogenes were susceptible to tigecycline, and there was no variation in activity based on macrolide resistance either by

MIC50/MIC90 (0.03/0.06 g/ml; Table 2) or MIC distribution (Figure 2c). Enterococci

Among enterococci, resistance to vancomycin was species dependent, with high resistance rates for E. faecium (77%) relative to E. fae-calis (4%) currently in the US (Table 1). These rates show an increase in resistance relative to that observed 10 years ago (68% for E. faecium, 3% for E. faecalis; Table 1).

Regionally, there tended to be higher rates of VRE in the midwest and eastern regions relative to other regions in the US, with the largest increases in resistance over the past 10 year period observed in the East South Central and South Atlantic regions (Table 1, Figure 1d).

Against vancomycin susceptible population of E. faecalis, for which tigecycline is indicated, an MIC50/MIC90 of 0.12/0.5 g/ml and 88% susceptibility rate was observed (Table 2). Results reported from TSN show that TIG has a similar MIC distri-bution against both vancomycin susceptible and resistant populations of E. faecalis and E. faecium (Figure 2d).

S. aureus Overall, the prevalence of MRSA in the US rose from 32% in 1998 to 53% in

2008 (Table 1). There was variation in MRSA rates by region, with rates <50% in the western and northeast regions of the US and higher rates (>60%) in the south and southeast regions (Figure 1a).

Tigecycline activity against S. aureus was identical by MIC50/MIC90 (0.12/0.25 g/ml; Table 2) and by MIC distribution (Figure 2a) against MRSA and MSSA subpopulations. Both MSSA and MRSA were >99.8% susceptible to tigecycline.

Source % overallLower respiratory tract 15.9Upper respiratory tract 14.8Urine 5.0Blood 13.6Skin/Wound 47.3Other 3.4RegionEast North Central 17.7East Sout Central 9.5Mid Atlantic 11.7Mountain 10.4New England 6.2Pacific 11.3South Atlantic 12.2West North Central 11.4West South Central 9.6

Strain Diversity from '06-'09 Clinical Isolates

Figure 2. MIC distribution of tigecycline by resistance phenotype a. S. aureus b. S. pneumoniae

MSSA/ MRSA, methicillin susceptible/ resistant S. aureus PSSP/ PRSP, penicillin susceptible/ resistant S. pneumoniae ; MDR, multi-drug resistantc. S. pyogenes d. Enterococci from TSN database (2006-2008)

Ery S/ Ery R, erythromycin sysceptible/ resistant VSEfc/ VREfc, vancomycin susceptible/ resistant E. faecalis; VSEfm/ VREfm, vancymycin susceptible/ resistant E. faeciumFDA MIC breakpoints for vancomycin susceptible E. faecalis were used for interpretation

0

10

20

30

40

50

60

≤0.008 0.015 0.03 0.06 0.12 0.25 0.5 1 2 4

MIC (g/mL)

% o

f iso

late

s at

MIC

MSSAMRSA

S NS

0

10

20

30

40

50

60

70

80

≤0.008 0.015 0.03 0.06 0.12 0.25 0.5 1 2 4

MIC (g/mL)

% o

f iso

late

s at

MIC

Ery SEry R

S NS

0

10

20

30

40

50

60

70

80

90

100

≤0.12 0.25 0.5 1 2 4 >4

MIC (g/mL)

% o

f iso

late

s at

MIC

VSEfcVREfcVSEfmVREfm

S NS

0

10

20

30

40

50

60

70

80

90

≤0.008 0.015 0.03 0.06 0.12 0.25 0.5 1 2 4

MIC (g/mL)

% o

f iso

late

s at

MIC

PSSPPRSPnon-MDRMDR

S NS

Table 2. Tigecycline activity by resistance phenotypes (2006-2009)

Figure 1. TSN resistance rates in 2008 a. MRSA b. PRSP (in 2007*) c. EryR SPY (in 2006-2008*) d. VREfc / VREfm

MRSA, methicillin resistant S. aureus PRSP, penicillin resistant S. pneumoniae EryR SPY, erythromycin resistant S. pyogenes VREfc/ VREfm, vancomycin resistant E. faecalis / E. faecium

*Data from 2007 interpreted using oral penicillin breakpoints *Due to low reporting, resistance rates determined from 2006-2008

DC

50-59.9%

≤ 40-49.9% R

60% R

43.3%N=43,538

59.6%N=11,841

53.1%N=11,636

62.2%N=21,521

51.4%N=17,736

68.8%N=3,422

58.3%N=48,621

48.6%N=25,161

44.3%N=8,476

DC

15-19.9%

≤ 10-14.9% R

20% R

10.7%N=1,233

15.5%N=536

18.0%N=1,099

20.2%N=1,284

18.6%N=908

14.6%N=233

24.0%N=1,720

17.8%N=843

11.0%N=547

DC

10-14.9%

≤ 5-9.9% R

15% R

11.4%N=438

9.6%N=94

13.7%N=190

17.2%N=203

7.7%N=273

9.2%N=76

15.2%N=1,272

8.2%N=608

13.7%N=612

DC

VREfc: 2.5%, N=4,525VREfm: 73.4%, N=1,548

VREfc: 1.1%, N=2,884VREfm: 52.8%, N=430

VREfc: 4.0%, N=1,803VREfm: 62.2%, N=635

VREfc: 2.0%, N=3,200VREfm: 79.3%,

N=1,547

VREfc: 9.0%, N=3,730VREfm: 77.8%, N=1,530

VREfc: 2.2%, N=770VREfm: 65.5%, N=174

VREfc: 3.3%, N=6,090VREfm: 81.8%, N=3,372

VREfc: 4.5%, N=3,234VREfm: 79.8%, N=1,551

VREfc: 4.3%, N=1,288VREfm: 74.0%, N=308

Table 1. Resistance trends by year and US Census Region

US Census Region 1998 2001 2004 2008 2008-1998 1998 2001 2004 2007* 2007-1998 1998 2001 2004 2008 2008-1998 1998 2001 2004 2008 2008-1998 1998 2001 2004 2008 2008-1998Overall 32.4 42.9 52.3 52.7 20.3 16.4 22.0 15.5 17.8 1.4 9.3 7.5 10.6 11.0 1.7 2.6 2.9 3.4 3.8 1.2 67.7 71.2 70.1 76.8 9.1East North Central 34.7 41.6 49.5 51.4 16.7 13.1 18.0 16.6 18.6 5.5 3.2 5.8 6.9 7.1 3.9 4.1 6.0 7.6 9.0 4.9 73.4 80.4 82.0 77.8 4.4East South Central 46.9 48.5 62.8 68.8 21.9 19.6 27.3 13.9 14.6 -5.0 –a – 12.7 – ND 0.9 2.2 4.5 – – ND 31.0 81.7 68.8 65.5 34.5Mid Atlantic 35 41.9 45.8 48.6 13.6 13.9 18.6 12.4 17.8 3.9 – 10.3 8.8 6.9 ND 4.7 3.7 4.1 4.5 -0.2 76.1 73.4 68.6 79.8 3.7Mountain 28.9 37 51.1 59.6 30.7 16.1 15.3 10.7 15.5 -0.6 – – 1.6 – ND 1.3 1.5 2.7 1.1 -0.2 71.8 69.7 62.3 52.8 -19.0New England 21.6 38.4 43.2 44.3 22.7 7.0 30.8 9.9 11.0 4.0 – – – 18.4 ND – – 0.6 – – 4.3 ND – – 62.4 – – 74.0 NDPacific 22.6 31 46.2 43.3 20.7 16.4 17.9 14.9 10.7 -5.7 14.4 11.5 10.2 3.8 -10.6 2.1 0.6 1.6 2.5 0.4 74.9 52.0 53.1 73.4 -1.5South Atlantic 40.2 53.4 56.8 58.3 18.1 20.2 26.8 19.8 24.0 3.8 11.3 3.6 15.8 13.3 2.0 1.6 2.9 2.4 3.3 1.7 55.2 72.0 70.1 81.8 26.6West North Central 37 42.5 49.7 53.1 16.1 12.2 21.3 14.2 18.0 5.8 – 7.9 6.9 – ND 0.8 1.2 1.4 4.0 3.2 64.9 65.7 68.7 62.2 -2.7West South Central 29.3 43.1 59.4 62.2 32.9 18.4 26.7 17.1 20.2 1.8 5.5 5.2 13.6 12.1 6.6 3.4 1.5 1.1 2.0 -1.4 66.3 69.6 70.5 79.3 13.0*2008 data excluded due to reporting on non-meningitis isolates with both parenteral and oral breakpoints during that yearaSingle dashed line (–) indicates that < 50 results were reported; double dashed line (– –) indicates that <100 results were reported

ND - not determined

%RVREfmMRSA VREfcPRSP EryR SPY

Organism PhenotypeaTotal n Mode MIC5 0 MIC90 (%S) (%I) (%R)

S. aureus MSSA 1,552 0.12 0.12 0.25 (99.9) (0.0) (0.1)MRSA 2,606 0.12 0.12 0.25 (99.8) (0.0) (0.2)

S. pneumoniae PSSP* 479 0.015 0.015 0.03 (99.6) (0.0) (0.0)PRSP 56 0.015 0.015 0.03 (100.0) (0.0) (0.0)non-MDR 555 0.015 0.015 0.03 (99.6) (0.0) (0.0)MDR 103 0.015 0.015 0.03 (100.0) (0.0) (0.0)

S. pyogenes Ery S 645 0.03 0.03 0.06 (100.0) (0.0) (0.0)Ery R 96 0.03 0.03 0.06 (100.0) (0.0) (0.0)

E. faecalis VSE 256 0.12 0.12 0.5 (87.9) (0.0) (0.0)

MDR, multi-drug resistant; Ery S/ Ery R, erythromycin susceptible/ resistant; VSE, vancomycin susceptible E. faecalis*Penicillin (oral penicillin V) CLSI MIC interpretive standard used

MIC (µg/mL)

aMSSA/ MRSA, methicillin susceptible/ resistant S. aureus ; PSSP/ PRSP, penicillin susceptible/ resistant S.