Transcript percentage resistance

Susceptibility of Clostridium difficile to Surotomycin and Therapeutic
Comparators
P-
24th ECCMID
May 10th – May 13th,
2014
Barcelona, Spain
S. Copsey, S. Scotford*, S. Jones, C. Davis, M. Wootton, T. Morris, L. Chesnel, R.A. Howe
Introduction
Clostridium difficile has been identified as the primary
cause of nosocomial diarrhoea worldwide.
C. difficile
infection (CDI) is a significant cause of morbidity,
particularly in elderly hospitalised patients, and a major
burden on healthcare providers. CDI treatment remains
limited with metronidazole and vancomycin the mainstay
of treatment. Recent reports of reduced metronidazole
efficacy in severe CDI cases and certain ribotypes plus
increasing rates of relapse and re-infection warrants a
need for alternative therapies. Surotomycin is a novel
cyclic lipopeptide which has previously demonstrated
potent bactericidal activity against C. difficile. This study
aims to determine the susceptibilities of all C. difficile PCR
ribotypes (including most common ribotypes), to
surotomycin
and
comparator
antimicrobials.
The
antimicrobials tested include those commonly used as
treatments in UK, Europe and USA.
b
b
Results
Surotomycin
Metronidazole
Vancomycin
BP/
BP
BP
ECOFF Range MIC90
Range MIC90
Range MIC90
(CLSI)
(CLSI)
**
Ribo
All (580)
N/A 0.03-2 0.25
001
N/A
002
N/A
014
N/A
027
N/A
0.030.25
0.120.5
0.060.25
0.120.5
≥ 32
0.03-2 0.25
≥ 16 0.12-4
1
≥ 32
0.12
≥ 32
0.12-1
≥ 16
0.5-2
2
≥ 32
0.25
≥ 32
≥ 16
0.5-1
1
≥ 32
0.12
≥ 32
≥ 16
0.5-1
0.5
≥ 32
0.5
≥ 32
≥ 16
0.5-1
1
≥ 32
0.5
0.0120.25
0.25
0.030.25
0.25
0.122
2.0
Surotomycin
Metronidazole
10
9
8
7
6
5
4
3
2
1
0
001
002
014
020
027
078
106
0.03
0.06
0.125
0.25
0.5
10
9
8
7
6
5
4
3
2
1
0
1
002
014
020
078
106
0.125
0.25
0.5
2
Rifaximin
001
002
014
10
001
8
002
6
Figure 2:
Population
met
density of C.
difficile
vanc
isolates to
SUR, FDX, MET
and VAN.
0
0.015
0.03
0.06
0.12
0.25
0.5
1
2
027
4
2
078
2
106
0
0.5
N/A
0.008
N/A
0.015
N/A
1
2
078
106
0.001
8
7
001
6
002
5
014
4
020
3
027
2
078
1
106
0
0.015
0.016
0.03
0.004
0.008
0.016
0.125
10
9
8
7
6
5
4
3
2
1
0
≥8
4-8
8
≤ 0.25 0.06
8
≥8
2-8
8
≤ 0.25
0.25
≥8
1-16
16
≥8
4-8
8
0.060.12
0.06≤ 0.25
0.12
0.06
0.06
0.12
10% (58) of isolates were resistant to MOX
all belonged to the previously established resistant
ribotypes 001, 027 and 106
41% of isolates were resistant to CLI with no particular
ribotype implicated
0.9% (5) of isolates exhibited an MIC for TIG above the
ECOFF of ≤ 0.25 mg/L
2.2% (13) of isolates were resistant to RIF using the
putative breakpoint of ≥32 mg/L
Figure 3: Percentage resistance of C. difficile isolates to agents
tested
078
106
0.5
1
8
16
32
45
40
35
10
001
001
6
002
5
014
4
020
3
027
4
027
078
2
078
2
1
106
0
256
percentage resistance
027
7
4
2
1-8
020
12
2
0.5-2
≥8
014
Tigecycline
8
1
≥8
0.12
002
0.125
0.25
9
0.25
•
0.12
001
Clindamycin
Methods
•
0.25
0.015
Moxifloxacin
9
0.008
•
•
0.0080.015
0.0150.12
0.030.12
0.120.25
027
0
Fidaxomicin
4
580 C.difficile isolates representing all designated
ribotypes including multiples of common types (001, 002,
014, 020, 027, 078 and 106) were tested. MICs were
obtained using agar dilution according to CLSI guidelines
for clindamycin (CLI), moxifloxacin (MOX), metronidazole
(MET), rifaximin (RIF), tigecycline (TIG) and vancomycin
(VAN). CLSI breakpoints (BP) were used to interpret MET,
VAN, MOX & CLI. A EUCAST wild type epidemiological cut
off (ECOFF) was used for TIG. A previously published
putative BP of ≥32mg/L was used for RIF. There are no
established BPs for fidaxomycin (FDX) due to no/little
correlation between clinical BP/ECOFF and clinical efficacy.
No BP has been determined for surotomycin (SUR) at this
time.
0.008
0.008-1
Table 1: Range
and MIC90 of all
C. difficile
isolates
including
common types
020
4
suro
50
N/A
Moxifloxacin
Clindamycin
Tigecycline
BP/
BP
BP
Range MIC90
Range MIC90 ECOFF Range MIC90
(CLSI)
(CLSI)
**
0.120.06≥8
2
≥8
8
≤ 0.25 0.03-2 0.12
>32
>256
0.06≥ 8 0.12-32 32
≥8
1-256
8
≤ 0.25
0.12
0.12
014
020
100
N/A
0.008
•
12
10
6
150
0.015
027
0.03
12
350
200
<0.002>256
0.0040.008
0.0040.008
<0.0020.008
0.0080.015
Fidaxomicin
BP/
MIC90 ECOFF Range MIC90
**
001
Vancomycin
400
250
Range
Figure 1: Differential in MICs for common C. difficile ribotypes
8
300
Rifaximin
BP*
8
002
30
25
014
6
020
106
0
0.06
0.125
2
20
15
10
5
0
MOX
•
•
•
•
MIC90 and MIC ranges for the most
common ribotypes are shown in the table
1, fig 1
All isolates were susceptible to MET and
VAN
For FDX all isolates were inhibited by 1
mg/L, with an MIC90 of 0.25 mg/L
The MIC90 for SUR was 0.25 mg/L and all
isolates were inhibited by 2 mg
CLI
RIF
3
antimicrobials
Conclusions
Surotomycin displays good activity across all C. difficile
ribotypes. Due to the well documented issues with
current treatment options, it is likely that newer agents
such as surotomycin will become an important part of
CDI treatment in the future.
Anaerobe Reference Unit, Public Health Wales, Cardiff, UK
Email: [email protected]
TIG