This study evaluated the in vitro activity of tigecycline and other antibiotics against Enterobacteriaceae isolates exhibiting common resistance mechanisms in the US from 2006-2009. It found that 12.4% of isolates were multi-drug resistant, and 5-8% exhibited extended-spectrum beta-lactamase or AmpC production. In contrast to other agents, tigecycline maintained high activity against resistant subsets, with consistent MICs and >96% susceptibility regardless of phenotype. Against the rare imipenem-resistant isolates, tigecycline also retained potent activity at 100% susceptibility. The results support tigecycline as an important treatment option for infections involving resistant Enterobacteriaceae.

1. Activity Profile of Tigecycline against Resistant Gram-Negative Enterobacteriaceae in the United States
Background: The therapy of Enterobacteriaceae (EN) in-
fections has been complicated by extended spectrum -
lactamase (ESBL) production; AmpC mediated resistance,
the emergence of carbapenem resistance, and multi-drug
resistance (MDR). Tigecycline (TIG) is a broad-spectrum
glycylcycline used for the treatment of challenging gram-
negative infections. To determine the impact of resistance
among EN on TIG in vitro activity, isolates with ESBL,
AmpC, and MDR phenotypes were evaluated.
Methods: 3,985 EN were collected from the US in ‘06-
‘09 and were centrally tested against TIG by broth mi-
crodilution according to CLSI guidelines. Results were
analyzed according to resistant phenotypes. MDR was de-
fined as R to ≥3 agents (ampicillin, cefepime, ceftriaxone,
ciprofloxacin, gentamicin, imipenem, minocycline, and
piperacillin-tazobactam). ESBL isolates were identified
by CLSI criteria. Derepressed AmpC isolates were identi-
fied based on R to cefoxitin, ceftazidime, and cefotaxime,
no impact of clavulanic acid on ceftazidime/cefotaxime
MICs and susceptible to cefepime and carbapenem.
Results:
There were 13 K. pneumoniae resistant to imipenem iso-
lated from ‘04-‘09 (11 from the Mid Atlantic region) for
which TIG MICs were 0.25-2 g/ml.
Conclusions: The activity profile of TIG was not notably
affected by commonly encountered resistance among EN,
with consistent MIC50/90s across resistant subpopulations
compared to susceptible subpopulations, and no notable
decreases in %S based on resistant phenotype.
Mohana K. Torres1
, Deborah C. Draghi1
, Karla Tomfohrde1
, Chris M. Pillar1
, Venkat Alluru1
, Michael J. Dowzicky2
, Daniel F. Sahm1
1
Eurofins Medinet, Chantilly, VA, USA
2
Wyeth Pharmaceuticals, Collegeville, PA, USA
Poster No. C2-1956
Contact Information:
Chris M. Pillar, Ph.D.
Eurofins Medinet
14100 Park Meadow Drive
Chantilly, VA, USA 20151
Tel. 1.703.480.2500
ResultsIntroductionRevised Abstract
Methods
Conclusions
This study was supported by a grant from Wyeth Pharmaceuticals.
The emergence and spread of drug resistance among
Enterobacteriaceae has complicated the selection and
use of gram-negative therapeutics. The acquisition
of beta-lactamases (extended spectrum beta-
lactamases [ESBLs], AmpCs, and more recently car-
bapenemases [KPCs]) and the potential for multi-
drug resistance (MDR; resistance to > 3 classes of
agents) among these organisms is of concern. Using
data from recent surveillance, the prevalence of resis-
tance and the impact of resistance on the activity pro-
files of current agents can be evaluated. This study
evaluates resistance among Enterobacteriaceae in the
US and the activity of tigecycline, a broad-spectrum
glycylcycline used to treat challenging gram-
negative infections, and other anti-gram negative
therapeutics against Enterobacteriaceae, including re-
sistant subpopulations.
A total of 3,985 clinical Enterobacteriaceae isolates
consisting of 1,314 E. coli, 1,328 K. pneumoniae,
538 Enterobacter spp., 538 Citrobacter spp., and 267
S. marcescens were collected from across the nine
US Census Regions from 2006 to 2009 (Table 1). All
isolates were centrally tested at Eurofins Medinet
(Chantilly, VA) against tigecycline and comparators
by broth microdilution according to CLSI guidelines
(CLSI M7-A8; CLSI M100-S18). Results were ana-
lyzed according to resistance phenotypes. MDR was
defined as resistant to ≥3 agents (ampicillin, ce-
fepime, ceftriaxone, ciprofloxacin, gentamicin,
imipenem, minocycline, and piperacillin-
tazobactam). ESBL isolates were identified by CLSI
confirmatory criteria (CLSI M100-S18). Derep-
ressed AmpC isolates were identified based on R to
cefoxitin, ceftazidime, and cefotaxime, no impact of
clavulanic acid on ceftazidime/cefotaxime MICs, and
susceptibility to cefepime and carbapenems
(Livermore et al, JAC 2001;48(S1):59-64). Due to
the infrequency of resistance to carbapenems, 7
imipenem resistant K. pneumoniae isolated prior to
2006 were also included for the analysis of the
imipenem resistant subpopulation.
Overall, 12.4% of the evaluated Enterobacteriaceae were MDR, 5.2% of E. coli
and K. pneumoniae were ESBL positive, 8.0% of Enterobacter and Citrobacter
spp. were positive for derepressed AmpC production, and 0.2% of K. pneumoniae
were imipenem resistant.
Based on overall activity (Table 2), >90% of isolates were susceptible to the evalu-
ated agents excluding ciprofloxacin (85%S). The susceptibility of isolates to tige-
cycline and imipenem exceeded 99%.
In contrast to the other agents excluding imipenem, the activity of tigecycline
against MDR isolates (MIC50/MIC90 = 0.5/2 g/ml, 96.3%S) was not notably af-
fected relative to non-MDR isolates (Table 2, Figure 1).
Similar to MDR, the activity of tigecycline was not notably impacted by ESBL
phenotype (Figure 2, Table 3; MIC50/MIC90 = 0.5/1 g/ml, 98.5%S) or derep-
ressed AmpC phenotype (Figure 3, Table 3; MIC50/MIC90 = 0.5/2 g/ml, 96.3%S).
Of the 13 imipenem resistant K. pneumoniae, 11 were isolated from the Mid-
Atlantic region (Table 4). Tigecycline maintained potent activity (MIC50/MIC90 =
0.5/2 g/ml, 100%S) against the imipenem resistant subpopulation. All were non-
susceptible to ciprofloxacin, while only 38% were susceptible to gentamicin.
Acknowledgments
Resistance among Enterobacteriaceae in the US is of concern, with multi-drug re-
sistance surpassing 10%, and ESBL and AmpC production between 5-10%.
Excluding tigecycline and imipenem, whose activity was largely unaffected against
MDR, ESBL, and AmpC isolates, large decreases in the susceptibility of these iso-
lates was noted for other gram-negative and broad-spectrum agents (cefepime,
ciprofloxacin, pip/tazo, gentamicin)
Though to date plasmid mediated carbapenem resistance has been primarily con-
fined to K. pneumoniae in one region and has been encountered at low frequency,
its emergence in other locations and other enteric species serves as a warning. In
this study, 100% of the evaluated imipenem resistant K. pneumoniae remained sus-
ceptible to tigecycline.
Tigecycline remains an important option for the treatment of challenging gram-
negative infections due to its coverage of both emerging and established resistance
among Enterobacteriaceae.
Table 4. Imipenem resistant (MIC ≥16 µg/mL) K. pneumoniae
Isolate No. Year TSN Region Source
MIC
(µg/mL)
FDA
interp
MIC
(µg/mL)
CLSI
interp
MIC
(µg/mL)
CLSI
interp
1234727 2004 Mid Atlantic Lower respiratory tract 1 S 2 I 0.25 S
1234824 2004 Mid Atlantic Urine 0.5 S >4 R >16 R
1234825 2004 Mid Atlantic Lower respiratory tract 0.5 S >4 R 16 R
1272623 2004 Mid Atlantic Lower respiratory tract 1 S 2 I 0.5 S
1272624 2004 Mid Atlantic Lower respiratory tract 1 S 2 I 0.25 S
1272885 2004 Mid Atlantic Skin/wound 0.5 S >4 R >16 R
1478485 2005 Mid Atlantic Lower respiratory tract 0.5 S >4 R 8 I
2543663 2008 Mid Atlantic Blood 0.5 S >4 R >16 R
2543667 2008 Mid Atlantic Lower respiratory tract 0.5 S >4 R 16 R
2543668 2008 Mid Atlantic Blood 0.5 S >4 R >16 R
2543821 2008 Mountian Lower respiratory tract 2 S >4 R 4 S
2545450 2009 East North Central Blood 2 S >4 R 1 S
2545647 2009 Mid Atlantic Blood 0.25 S >4 R 8 I
Tigecycline Ciprofloxacin Gentamicin
Figure 1. MIC distribution of tigecycline
against Enterobacteriaceae by MDR status
0
5
10
15
20
25
30
35
40
≤0.015 0.03 0.06 0.12 0.25 0.5 1 2 4 8 >8
MIC (g/mL)
%ofisolatesatMIC
MDR
non-MDR
Table 1. Percentage of isolates by
specimen source and US region
Source % overall
Lower respiratory tract 20.9
Urine 30.6
Blood 20.0
Skin/Wound 26.0
Other 2.5
Region
East North Central 15.5
East South Central 9.8
Mid Atlantic 12.5
Mountain 9.8
New England 7.7
Pacific 10.4
South Atlantic 12.2
West North Central 11.4
West South Central 10.7
Strain Diversity
Table 2. Antimicrobial activity of tigecycline and comparators
against Enterobacteriaceae overall and by MDR status
Organism Agent Phenotypea
Mode MIC50 MIC90 (%S) (%I) (%R)
Enterobacteriaceae Tigecycline All (n=3,985) 0.5 0.5 1 (99.3) (0.6) (0.1)
MDR (n=495) 0.25 0.5 2 (96.8) (2.6) (0.6)
non-MDR (n=3,490) 0.5 0.5 1 (99.6) (0.3) (0.1)
Cefepime All 0.03 0.06 0.5 (97.4) (0.7) (1.9)
MDR 0.06 1 >32 (79.4) (5.7) (14.9)
non-MDR 0.03 0.06 0.12 (100.0) (0.0) (0.0)
Ceftriaxone All 0.06 0.06 8 (91.0) (2.8) (6.2)
MDR >64 16 >64 (47.9) (7.7) (44.4)
non-MDR 0.06 0.06 0.5 (97.1) (2.1) (0.8)
Ciprofloxacin All ≤0.12 ≤0.12 >4 (84.9) (1.2) (13.9)
MDR >4 >4 >4 (20.6) (2.4) (77.0)
non-MDR ≤0.12 ≤0.12 0.5 (94.0) (1.1) (5.0)
Imipenem All 0.25 0.25 1 (99.6) (0.1) (0.2)
MDR 0.12 0.25 1 (98.0) (0.8) (1.2)
non-MDR 0.25 0.25 1 (99.9) (0.0) (0.1)
Gentamicin All 0.5 0.5 2 (92.0) (1.0) (7.0)
MDR >16 8 >16 (48.5) (3.6) (47.9)
non-MDR 0.5 0.5 1 (98.2) (0.6) (1.1)
Piperacillin/ Tazobactam All 2 2 16 (91.1) (3.7) (5.2)
MDR >128 16 >128 (51.1) (11.3) (37.6)
non-MDR 2 2 8 (96.8) (2.7) (0.6)
a
MDR, multi-drug resistant was defined as resistant to ≥3 of the following agents: ampicillin, cefepime, ceftriaxone, ciprofloxacin, gentamicin,
imipenem, minocycline or tetracycline, and piperacillin-tazobactam
MIC (µg/mL)
Table 3. Tigecycline activity profile against ESBL (E. coli and K. pneumoniae) and derepressed
AmpC (Citrobacter spp. and Enterobacter spp.) Enterobacteriaceae
Agent Mode MIC50 MIC90 (%S) Mode MIC50 MIC90 (%S) Mode MIC50 MIC90 (%S) Mode MIC50 MIC90 (%S)
Tigecycline 0.25 0.25 1 (99.6) 0.5 0.5 1 (98.5) 0.5 0.5 1 (99.1) 0.5 0.5 2 (96.3)
Cefepime 0.03 0.06 0.12 (99.5) >32 16 >32 (49.6) 0.03 0.06 1 (97.9) 1 2 4 (100.0)
Ceftriaxone 0.06 0.06 0.12 (98.6) >64 >64 >64 (25.2) 0.25 0.25 32 (86.4) >64 >64 >64 (3.8)
Ciprofloxacin ≤0.12 ≤0.12 >4 (85.1) >4 >4 >4 (24.4) ≤0.12 ≤0.12 1 (91.9) ≤0.12 ≤0.12 >4 (68.8)
Imipenem 0.12 0.25 0.5 (99.8) 0.25 0.25 1 (96.2) 0.5 0.5 1 (100.0) 0.5 0.5 1 (100.0)
Gentamicin 0.5 0.5 2 (93.6) >16 8 >16 (46.6) 0.5 0.5 1 (93.6) 0.25 0.5 16 (83.8)
Piperacillin/ Tazobactam 2 2 8 (96.4) >128 32 >128 (49.6) 2 2 32 (88.9) >128 128 >128 (6.3)
a
1,267 E. coli and 1,244 K. pneumoniae
b
47 E. coli and 84 K. pneumoniae
c
522 Citrobacter spp. and 474 Enterobacter spp.
d
16 Citrobacter spp. and 64 Enterobacter spp.
non-derep AmpC (n=996)
c
derep AmpC (n=80)
d
non-ESBL (n=2,511)
a
ESBL (n=131)
b
MIC (µg/mL) MIC (µg/mL) MIC (µg/mL) MIC (µg/mL)
Figure 2. MIC distribution of tigecycline
against ESBL E. coli and K. pneumoniae
non-ESBL= 1,267 E. coli and 1,244 K. pneumoniae
ESBL= 47 E. coli and 84 K. pneumoniae
0
5
10
15
20
25
30
35
40
≤0.015 0.03 0.06 0.12 0.25 0.5 1 2 4 8 >8
MIC (g/mL)
%ofisolatesatMIC
ESBL
non-ESBL
Figure 3. MIC distribution of tigecycline
against derepressed AmpC Citrobacter spp.
and Enterobacter spp.
non-derep AmpC= 522 Citrobacter spp. and 474 Enterobacter spp.
derep AmpC= 16 Citrobacter spp. and 64 Enterobacter spp.
0
5
10
15
20
25
30
35
40
45
≤0.015 0.03 0.06 0.12 0.25 0.5 1 2 4 8 >8
MIC (g/mL)
%ofisolatesatMIC
derep AmpC
non-derep AmpC
Organism Phenotype Total n
MIC50/90
(µg/mL) %S
EN Non-MDR 3,490 0.5/ 1 99.6
MDR 495 0.5/ 2 96.8
E. coli Non-ESBL 1,267 0.25/ 0.5 100
ESBL 47 0.25/ 1 100
Non-MDR 1,091 0.25/ 0.5 100
MDR 223 0.25/ 0.5 100
K. pneumoniae Non-ESBL 1,244 0.5/ 1 99.1
ESBL 84 0.5/ 2 97.6
Non-MDR 1,216 0.5/ 1 99.4
MDR 112 1/ 2 94.6
Citrobacter spp. Non-derep AmpC
a
552 0.25/ 1 100
derep AmpC 16 0.5/ 2 100
Non-MDR 484 0.25/ 1 100
MDR 54 0.5/2 100
Enterobacter spp. Non-derep AmpC 474 0.5/ 1 98.1
derep AmpC 64 1/ 2 95.3
Non-MDR 447 0.5/ 1 99.3
MDR 91 1/ 2 90.1
S. marcescens Non-MDR 252 1/ 1 98.8
MDR 15 1/ 2 93.3
a
Non-derepressed AmpC
TIG