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49th ICAAC Meeting
San Francisco, CA
September 12-15, 2009
In-Vitro Potency of a Siderophore Monobactam BAL30072 (BAL) Against
Gram-negative Bacilli (GNB) with Defined β-lactamase Enzymes
Amended Abstract
1
Materials and Methods
Table 1 showing the range, MIC50, MIC90, % susceptible and % with MIC ≤4 mg/L
Background: BAL 30072 is a new siderophore monobactam with in-vitro
activity against many multi-resistant aerobic Gram-negative bacilli including Pseudomonas aeruginosa and Acinetobacter spp. We studied the
potency of BAL and comparators against 91 GNBs with characterized
β-lactamases.
Strains
91 strains with known resistance mechanisms from the collection held
at the Microbiology Department at Bristol University were tested; Acinetobacter spp. (n=7), E. coli (n=36), K. pneumoniae (n=8), P. aeruginosa
(n=33) and S. marcescens (n=7).
Methods: 91 GNB isolates were categorized by enzyme production into
11 groups. Five antimicrobials were tested, BAL; meropenem (MEM); ceftazidime (CAZ); piperacillin-tazobactam (P/T); cefepime (CPM). MICs
were determined by CLSI agar dilution methodology. Muller-Hinton agar
was supplemented with 2.2’-dipyridyl for BAL to induce iron transport.
Strains of P. aeruginosa, Acinetobacter spp., E. coli, K. pneumoniae,
and S. marcescens with CMY-2 (n=7) CTX-M (n=11), IMP-1 (n=10), IMP-4
(n=10), IMP-13 or 16 (n=5), VIM-1 (n=10), VIM-2 (n=5), VIM-4 (n=12), GIM-1
(n=3), SPM-1 (n=5) or multiple enzyme combinations (SHV, OXA, CTX,
CMY, TEM n=13) were used.
Antimicrobials
The following antimicrobials were utilised; BAL30072 (Fig. 1) and cefepime were supplied by Basilea Pharmaceutica AG, Basle, Switzerland;
meropenem supplied by Astra Zeneca, Luton, Bedfordshire UK, ceftazidime supplied by Eli Lilly, Basingstoke Hampshire, UK; and piperacillin/
tazobactam supplied by Wyeth Pharmaceuticals, Maidenhead, Berkshire.UK.
Results: BAL was the most potent agent against strains containing IMP
and SPM-1 VIM, and GIM enzymes, MIC50 0.06-4mg/L; MIC90s 2-8mg/L.
MEM was the most potent comparator MIC50s 0.03->64mg/L, MIC90s
0.06->64mg/L. BAL was less potent against CTX-M and multiple enzyme
producing strains, MIC50/90 64mg/L,16mg/L and 64mg/L respectively (MER
MIC50s/90s 0.03/0.06mg/L). Against VIM containing GNB BAL MIC50 was 1-2
mg/L, comparators MIC50s 8- ≥ 64 mg/L. Except for CPM against CMY-2
(MIC50 0.25mg/L), CAZ, P/T and CPM showed little activity against all
strains MIC50s 8->64mg/L.
Conclusions: BAL was the most potent agent against IMP-1, IMP-4,
IMP-13/16, VIM-1, VIM-2, VIM-4, GIM-1 and SPM-1 producers. MEM was
more potent than BAL against CMY-2, CTX-M and multiple enzyme
producers.
MICs
MICs were determined using the CLSI M7-A6 agar dilution method,
using cation adjusted Mueller Hinton agar. Mueller Hinton agar supplemented with 16mg/L 2,2’ Bipyridyl to induce ion transport was used
for BAL30072 .
E. coli ATCC 25922 and P.aeruginosa ATCC 27853 were used as control
strains. An inoculum of 104 cfu per spot was used. Plates were incubated
in air at 36°C for 18h.
Interpretation of % susceptible strains was determined using CLSI document M100-S19 Vol. 29 No3. The percentage of strains with MICs ≤4mg/L
was used as a comparison (Table 1)
Fig. 1 BAL30072
O
OH
Introduction
BAL30072 is a new siderophore monobactam with in-vitro activity against
many multi-resistant Gram negative bacteria including Acinetobacter
spp. and Pseudomonas aeruginosa.
Previous data has shown that BAL30072 has good activity against
clinical strains of Enterobacter spp. and ESBL producing E.coli and
E.aerogenes.1
In this study we evaluated the activity of BAL30072, and a range of
comparators against a selection of Acinetobacter, P. aeruginosa and
Enterobacteriaceae with defined resistant mechanisms.
Corresponding author:
Karen Bowker
[[email protected]]
North Bristol NHS Trust
Dept of Microbiology
Southmead Hospital
Bristol, BS10 5NB, U. K.
K.E. Bowker1, A.R. Noel1, T.R. Walsh2, A.P. MacGowan1,
BCARE, North Bristol NHS Trust and University of Bristol, Bristol, UK. 2University of Cardiff, Cardiff, UK
N
H2N
H
N
N
S
O
O
N
MIC50
MIC90
%≤ 4mg/L
% susceptible
1 - 64
0 .0 3 - 8
2 - >64
16 - >64
0 .0 6 - 0 .5
4
0 .0 3
>64
16
0 .2 5
-
42
42
14
0
100
42
14
57
100
1- >64
0 .0 3 - 0 .0 6
64 - >64
64 - >64
4 - >64
16
0 .0 6
>64
>64
32
>64
0 .0 6
>64
>64
>64
20
100
0
0
20
100
0
0
20
Combination of SHV,CTX,CMY,OXA,TEM enzymes (n=12, all E.coli)
B AL 30072
0.5 - >64
2
meropenem
0.015 - >64
0 .0 3
16 - >64
>64
ceftazidime
>64
16 - >64
piperacillin/tazobactam
8 - >64
32
cefepime
>64
>64
>64
>64
>64
50
83
0
0
0
83
0
0
16
IMP-1 (n=10, Acinetobacter n=5, E.coli n=4, P.aeruginosa n=1)
BAL30072
0 .2 5 - 4
1
0.12 - >64
meropenem
2
>64
4 - >64
ceftazidime
32 - >64
>64
piperacillin/tazobactam
>64
4 - >64
cefepime
1
16
>64
>64
>64
100
60
20
0
10
60
20
0
10
IMP-4 (n=10, S.marcescans n=4, K.pneumoniae n=3, P.aeruginosa n=2, E.coli n=1)
0.015 - >64
BAL30072
0.06
0.5
0.015 - >64
2
0.5
meropenem
>64
>64
1- >64
ceftazidime
>64
>64
4 - >64
piperacillin/tazobactam
0.25 - >64
8
64
cefepime
90
90
10
20
30
90
10
20
30
IMP-13/16 (n=5, all P.aeruginosa)
BAL30072
meropenem
ceftazidime
piperacillin/tazobactam
cefepime
CMY-2 enzyme (n=7, all E.coli)
BAL30072
meropenem
ceftazidime
piperacillin/tazobactam
cefepime
CTX-M enzymes (n=10, all E.coli)
BAL30072
meropenem
ceftazidime
piperacillin/tazobactam
cefepime
0 .1 2 - 2
16 - >64
>64- >64
8 - >64
>64- >64
VIM-1 (n=10, P.aeruginosa n=6, K.pneumoniae n=4)
B AL 30072
0 .1 2 - 6 4
8 - >64
meropenem
32 - >64
ceftazidime
32 - >64
piperacillin/tazobactam
16 - >64
cefepime
VIM-2 (n=5, P.aeruginosa n=3, Acinetobacter n=2)
BAL30072
0 .2 5 - 4
0.25 - >64
meropenem
16 - >64
ceftazidime
piperacillin/tazobactam
32 - 64
cefepime
16 - 32
2
>64
>64
>64
>64
-
100
0
0
20
0
0
0
20
0
1
>64
>64
>64
>64
8
>64
>64
>64
>64
80
0
0
0
0
0
0
0
0
2
8
64
32
16
VIM-4 (n=12, P.aeruginosa n=8, S.marcescans n=3, K.pneumoniae n=1)
BAL30072
1 - 32
1
8 - >64
meropenem
16
>64
32 - >64
ceftazidime
>64
8 - >64
piperacillin/tazobactam
16 - >64
64
cefepime
N
OH
O
Range
OSO3H
1. Bowker K et al. Poster P1112 In-vitro activity of a new siderophore monobactam BAL30072 against ESBL
producing Enterobacteriaceae and clinical isolates of Enterobacter cloacae. 19th ECCMID 2009. Helsinki
Finland
-
100
40
0
0
0
40
0
0
0
8
>64
>64
>64
>64
83
8
0
0
0
0
0
25
0
GIM-1 (n=3, all P.aeruginosa)
BAL30072
meropenem
ceftazidime
piperacillin/tazobactam
cefepime
1-4
>64
>64
>64
16 - 32
1
>64
>64
>64
32
-
100
0
0
0
0
0
0
0
0
SPM-1 (n=5, all P.aeruginosa )
BAL30072
meropenem
ceftazidime
piperacillin/tazobactam
cefepime
0 .5 - 4
16 - >64
16 - >64
64 - >64
32 - 64
2
>64
>64
>64
>64
-
100
0
0
0
0
0
0
0
0
Results
The range, MIC50 and MIC90 and % of strains with MICs <4mg/L are shown
in Table 1. The distribution of MICs according to resistance mechanism
is summarized in Fig. 2.
With the exception of cefepime against CMY-2 producing strains (MIC50
0.25mg/L), cefepime, ceftazidime, piperacillin/tazobactam showed little
activity against all strains MIC50s 8 - ≥64mg/L; BAL30072 MIC50 = 4mg/L.
BAL30072 was the most potent agent against strains containing IMP-1,
IMP-4, IMP-13/16, VIM-1,VIM-2, VIM-4, GIM-1 and SPM-1 enzymes, MIC50
0.06-2mg/L; MIC90 2-8mg/L.
BAL30072 was less active against CTX-M and strains with multiple enzyme
(SHV, CTX, CMY, OXA, TEM) where the MIC50 was 16/2mg/L, and MIC90
was ≥64/≥64mg/L respectively; (meropenem MIC50/90 0.03/0.06 mg/L
and 0.06/0.06 mg/L).
Against VIM containing strains BAL30072 MIC50s were 1/2 mg/L, in contrast the comparators MIC50s were 8- ≥ 64 mg/L. Similarly with GIM-1 and
SPM-1 containing strains BAL30072 was more potent; MIC50s 1/2mg/L,
comparators 32 - ≥ 64 mg/L respectively.
Fig. 2 Distribution of BAL30072 MICs according to resistance mechanism
18
SPM-1
16
GIM-1
14
VIM-4
12
n
Poster F1-1481
VIM-2
VIM-1
10
IMP13/16
8
IMP-4
IMP-1
6
MRE
4
CTX-M
2
0
CMY-2
0.008
0.03
0.12
0.5
2
8
32
>64
MIC (mg/L)
Conclusions
BAL30072 demonstrated excellent activity against carbapenemase
producing strains; BAL30072 was the most active agent against IMP,
VIM, GIM and SPM containing strains.
Meropenem was most active agent against CMY, CTX-M and multiple
enzyme producing strains.