AAC Accepted Manuscript Posted Online 18 May 2015 Antimicrob. Agents Chemother. doi:10.1128/AAC.00274-15 Copyright © 2015, American Society for Microbiology. All Rights Reserved.
1
In Vitro Activity of Dalbavancin Against Drug Resistant Staphylococcus aureus from a
2
Global Surveillance Program
3 4
Sandra P. McCurdy1#, Ronald N. Jones2, Rodrigo E. Mendes2, Sailaja Puttagunta1 and Michael W. Dunne1
5 6
1
Durata Therapeutics, a subsidiary of Actavis plc, Branford, Connecticut, USA
2
JMI Laboratories, North Liberty, Iowa, USA
7 8
Running Title: Dalbavancin activity against drug-resistant S. aureus (Note)
9 10 11 12
#Corresponding Author: Mailing Address: 322 East Main Street, 3rd Floor Branford, CT 06405
13
Phone: 1-203-871-4629 E-mail: [email protected]
14
Text Word Count: 964
15 16 17 18 19 20 21 22 23 24
1
25
Abstract
26
In over a decade (2002-2012) of Staphylococcus aureus surveillance testing on 62,195 isolates,
27
dalbavancin was demonstrated to be active against isolates that were either susceptible or non-
28
susceptible to daptomycin-, linezolid- and tigecycline. Nearly all (99.8%) of multidrug-resistant
29
methicillin-resistant S. aureus were inhibited by dalbavancin at ≤0.12 µg/ml (MIC50/90, 0.06/0.06
30
µg/ml), the current United States Food and Drug Administration (USA-FDA) breakpoint.
31
Overall, only 0.35% of the monitored S. aureus had a dalbavancin MIC at either 0.25 or 0.5
32
µg/ml (non-susceptible).
33 34
Keywords: Dalbavancin, S. aureus, Resistance
35
2
36
Staphylococcus aureus is a leading cause of bacterial infections worldwide including skin and
37
soft tissue infections, bacteremia, pneumonia, endocarditis and osteomyelitis (1). Due to its
38
propensity to evolve and adapt to its host and applied treatments, S. aureus has been able to
39
acquire resistance to antimicrobial agents from penicillin in 1942 to methicillin in 1961, and in
40
more recent years to compounds such as vancomycin, linezolid and daptomycin (2,3).
41
Dalbavancin was recently approved by the USA-FDA for the treatment of acute bacterial skin
42
and skin structure infections caused by Gram-positive organisms in adults (4). Dalbavancin is a
43
semi-synthetic lipoglycopeptide structurally related to teicoplanin. Its mechanism of action
44
involves the interruption of cell wall synthesis by binding to the terminal D-alanyl-D-alanine of
45
the stem peptide in nascent cell wall peptidoglycan, thereby preventing cross-linking
46
(transpeptidation and transglycosylation) of disaccharide subunits. This disruption of the cell
47
wall results in bacterial cell death (5). To date, resistance to dalbavancin is limited to intrinsic
48
glycopeptide –resistant species and to organisms expressing the VanA phenotype of acquired
49
resistance. Dalbavancin’s potent in vitro activity has been substantiated in various animal
50
models of infection and it possesses a pharmacokinetic (PK) profile which allows once-weekly
51
intravenous (IV) dosing (4,6). The purpose of this study was to compare the in vitro activity of
52
dalbavancin against S. aureus isolates non-susceptible (NS) to three relatively recently
53
introduced antimicrobial agents (daptomycin, linezolid and tigecycline) to treat S. aureus
54
infections.
55
More than 60,000 isolates from non-duplicate clinical specimens were collected during routine
56
worldwide surveillance programs between 2002 and 2012. Isolates were collected from 104 sites
57
from the US and 66 sites in the European (Belgium, Czech Republic, France, Germany, Greece,
58
Hungary, Ireland, Italy, Netherlands, Poland, Portugal, Romania, Slovenia, Spain, Sweden, 3
59
Switzerland, Turkey, United Kingdom and Ukraine), Russian and Israeli regions. Isolates were
60
recovered from blood (9,470 isolates, 15.2%), skin and soft tissue (18,764; 30.2%), respiratory
61
tract (9,015; 14.5%), urinary tract (1,175, 1.9%) and other or undetermined infection sources
62
(23,771; 38.2%) as part of the SENTRY surveillance program (JMI Laboratories, North Liberty,
63
IA, USA).
64
Resistance phenotypes (non-susceptible or resistant) for daptomycin and linezolid were based
65
upon Clinical and Laboratory Standards Institute (CLSI) breakpoints (7), while USA-FDA
66
breakpoints were applied for dalbavancin (3 drug classes (10).
74
Table 1 shows the activity of dalbavancin and comparator agents tested against the daptomycin-
75
NS, linezolid-R and tigecycline-NS isolates. Dalbavancin was active when tested against the
76
daptomycin-NS isolates with MIC50/90 values of 0.06/0.12 µg/mL. By comparison, the MIC50/90
77
for vancomycin against these isolates was 2/2 µg/mL, i.e. 16 to 32- fold higher. At the current
78
USA-FDA breakpoint, 91.9% of isolates with a daptomycin-NS phenotype would be categorized
79
as susceptible to dalbavancin. However, against daptomycin-NS/vancomycin susceptible
80
isolates, the susceptibility would increase to 97.1% (data not shown). The MIC50/90 for
81
dalbavancin against linezolid-R S. aureus was 0.06/0.12 µg/mL, and for vancomycin the 4
82
MIC50/90 was 1/2 µg/mL, again 16-fold higher. Against tigecycline-NS isolates, the MIC50/90 for
83
dalbavancin was 0.06/0.06 µg/mL, and for vancomycin the MIC50/90 was 1/2 µg/mL.
84
Dalbavancin, daptomycin, linezolid and vancomycin exhibited 100.0% susceptibility rates
85
against these isolates, while 26.3% showed susceptibility to clindamycin.
86
Dalbavancin and selected comparators tested against a more recent collection of MRSA isolates
87
with an MDR phenotype (surveillance years 2010-2012) (Table 1), demonstrated dalbavancin
88
activity (MIC50/90, 0.06/0.06 µg/ml) and a 99.8% overall susceptibility rate. This activity was
89
comparable to that observed for daptomycin, linezolid, tigecycline, and vancomycin (99.8-
90
100.0%).
91
In the present study, dalbavancin demonstrated potent activity against S. aureus isolates
92
characterized as daptomycin-NS, linezolid-R and tigecycline-NS when applying current CSLI
93
and USA-FDA breakpoints (4,7,8). Dalbavancin demonstrated activity that was similar to
94
comparator agents against 1,484 MRSA isolates with MDR phenotype. In the recently
95
completed dalbavancin clinical trials (DISCOVER 1 and DISCOVER 2), there were no S. aureus
96
isolates that had a dalbavancin MIC results at >0.25 µg/mL and only two isolates that had an
97
MIC of 0.25 µg/mL out of 511 isolates tested (6). One patient with an S. aureus isolate with a
98
dalbavancin MIC of 0.25 µg/mL was treated successfully with that drug. More clinical data
99
from patients with S. aureus isolates at this MIC level would be informative, but may be
100
challenging to generate given the scarcity of this phenotype in clinical practice. In over ten years
101
of dalbavancin surveillance testing, only 0.35% of S. aureus isolates were encountered that
102
exceeded the current USA-FDA susceptible breakpoint of 2
≤0.03-0.5 1-4 0.5-4 ≤0.03-0.25 ≤0.06->2
91.9 94.6 100.0 100.0 43.2
Linezolid-R (19)
Dalbavancin Vancomycin
0.06 1
0.12 2
≤0.03-0.12 0.5-2
100.0 100.0
9
MIC (µg/ml) 90% Range 0.06 2
≤0.03-0.12 0.5-2 0.25-0.5 1-2 2
100.0 100.0 100.0 100.0 26.3
MRSA (5,167)d MDR (1,484)
Dalbavancin Dalbavancin Vancomycin Daptomycin Linezolid Tigecyclinee
0.06 0.06 1 0.25 1 0.12
0.06 0.06 1 0.5 1 0.25
≤0.03-0.25 ≤0.03-0.25
1
In Vitro Activity of Dalbavancin Against Drug Resistant Staphylococcus aureus from a
2
Global Surveillance Program
3 4
Sandra P. McCurdy1#, Ronald N. Jones2, Rodrigo E. Mendes2, Sailaja Puttagunta1 and Michael W. Dunne1
5 6
1
Durata Therapeutics, a subsidiary of Actavis plc, Branford, Connecticut, USA
2
JMI Laboratories, North Liberty, Iowa, USA
7 8
Running Title: Dalbavancin activity against drug-resistant S. aureus (Note)
9 10 11 12
#Corresponding Author: Mailing Address: 322 East Main Street, 3rd Floor Branford, CT 06405
13
Phone: 1-203-871-4629 E-mail: [email protected]
14
Text Word Count: 964
15 16 17 18 19 20 21 22 23 24
1
25
Abstract
26
In over a decade (2002-2012) of Staphylococcus aureus surveillance testing on 62,195 isolates,
27
dalbavancin was demonstrated to be active against isolates that were either susceptible or non-
28
susceptible to daptomycin-, linezolid- and tigecycline. Nearly all (99.8%) of multidrug-resistant
29
methicillin-resistant S. aureus were inhibited by dalbavancin at ≤0.12 µg/ml (MIC50/90, 0.06/0.06
30
µg/ml), the current United States Food and Drug Administration (USA-FDA) breakpoint.
31
Overall, only 0.35% of the monitored S. aureus had a dalbavancin MIC at either 0.25 or 0.5
32
µg/ml (non-susceptible).
33 34
Keywords: Dalbavancin, S. aureus, Resistance
35
2
36
Staphylococcus aureus is a leading cause of bacterial infections worldwide including skin and
37
soft tissue infections, bacteremia, pneumonia, endocarditis and osteomyelitis (1). Due to its
38
propensity to evolve and adapt to its host and applied treatments, S. aureus has been able to
39
acquire resistance to antimicrobial agents from penicillin in 1942 to methicillin in 1961, and in
40
more recent years to compounds such as vancomycin, linezolid and daptomycin (2,3).
41
Dalbavancin was recently approved by the USA-FDA for the treatment of acute bacterial skin
42
and skin structure infections caused by Gram-positive organisms in adults (4). Dalbavancin is a
43
semi-synthetic lipoglycopeptide structurally related to teicoplanin. Its mechanism of action
44
involves the interruption of cell wall synthesis by binding to the terminal D-alanyl-D-alanine of
45
the stem peptide in nascent cell wall peptidoglycan, thereby preventing cross-linking
46
(transpeptidation and transglycosylation) of disaccharide subunits. This disruption of the cell
47
wall results in bacterial cell death (5). To date, resistance to dalbavancin is limited to intrinsic
48
glycopeptide –resistant species and to organisms expressing the VanA phenotype of acquired
49
resistance. Dalbavancin’s potent in vitro activity has been substantiated in various animal
50
models of infection and it possesses a pharmacokinetic (PK) profile which allows once-weekly
51
intravenous (IV) dosing (4,6). The purpose of this study was to compare the in vitro activity of
52
dalbavancin against S. aureus isolates non-susceptible (NS) to three relatively recently
53
introduced antimicrobial agents (daptomycin, linezolid and tigecycline) to treat S. aureus
54
infections.
55
More than 60,000 isolates from non-duplicate clinical specimens were collected during routine
56
worldwide surveillance programs between 2002 and 2012. Isolates were collected from 104 sites
57
from the US and 66 sites in the European (Belgium, Czech Republic, France, Germany, Greece,
58
Hungary, Ireland, Italy, Netherlands, Poland, Portugal, Romania, Slovenia, Spain, Sweden, 3
59
Switzerland, Turkey, United Kingdom and Ukraine), Russian and Israeli regions. Isolates were
60
recovered from blood (9,470 isolates, 15.2%), skin and soft tissue (18,764; 30.2%), respiratory
61
tract (9,015; 14.5%), urinary tract (1,175, 1.9%) and other or undetermined infection sources
62
(23,771; 38.2%) as part of the SENTRY surveillance program (JMI Laboratories, North Liberty,
63
IA, USA).
64
Resistance phenotypes (non-susceptible or resistant) for daptomycin and linezolid were based
65
upon Clinical and Laboratory Standards Institute (CLSI) breakpoints (7), while USA-FDA
66
breakpoints were applied for dalbavancin (3 drug classes (10).
74
Table 1 shows the activity of dalbavancin and comparator agents tested against the daptomycin-
75
NS, linezolid-R and tigecycline-NS isolates. Dalbavancin was active when tested against the
76
daptomycin-NS isolates with MIC50/90 values of 0.06/0.12 µg/mL. By comparison, the MIC50/90
77
for vancomycin against these isolates was 2/2 µg/mL, i.e. 16 to 32- fold higher. At the current
78
USA-FDA breakpoint, 91.9% of isolates with a daptomycin-NS phenotype would be categorized
79
as susceptible to dalbavancin. However, against daptomycin-NS/vancomycin susceptible
80
isolates, the susceptibility would increase to 97.1% (data not shown). The MIC50/90 for
81
dalbavancin against linezolid-R S. aureus was 0.06/0.12 µg/mL, and for vancomycin the 4
82
MIC50/90 was 1/2 µg/mL, again 16-fold higher. Against tigecycline-NS isolates, the MIC50/90 for
83
dalbavancin was 0.06/0.06 µg/mL, and for vancomycin the MIC50/90 was 1/2 µg/mL.
84
Dalbavancin, daptomycin, linezolid and vancomycin exhibited 100.0% susceptibility rates
85
against these isolates, while 26.3% showed susceptibility to clindamycin.
86
Dalbavancin and selected comparators tested against a more recent collection of MRSA isolates
87
with an MDR phenotype (surveillance years 2010-2012) (Table 1), demonstrated dalbavancin
88
activity (MIC50/90, 0.06/0.06 µg/ml) and a 99.8% overall susceptibility rate. This activity was
89
comparable to that observed for daptomycin, linezolid, tigecycline, and vancomycin (99.8-
90
100.0%).
91
In the present study, dalbavancin demonstrated potent activity against S. aureus isolates
92
characterized as daptomycin-NS, linezolid-R and tigecycline-NS when applying current CSLI
93
and USA-FDA breakpoints (4,7,8). Dalbavancin demonstrated activity that was similar to
94
comparator agents against 1,484 MRSA isolates with MDR phenotype. In the recently
95
completed dalbavancin clinical trials (DISCOVER 1 and DISCOVER 2), there were no S. aureus
96
isolates that had a dalbavancin MIC results at >0.25 µg/mL and only two isolates that had an
97
MIC of 0.25 µg/mL out of 511 isolates tested (6). One patient with an S. aureus isolate with a
98
dalbavancin MIC of 0.25 µg/mL was treated successfully with that drug. More clinical data
99
from patients with S. aureus isolates at this MIC level would be informative, but may be
100
challenging to generate given the scarcity of this phenotype in clinical practice. In over ten years
101
of dalbavancin surveillance testing, only 0.35% of S. aureus isolates were encountered that
102
exceeded the current USA-FDA susceptible breakpoint of 2
≤0.03-0.5 1-4 0.5-4 ≤0.03-0.25 ≤0.06->2
91.9 94.6 100.0 100.0 43.2
Linezolid-R (19)
Dalbavancin Vancomycin
0.06 1
0.12 2
≤0.03-0.12 0.5-2
100.0 100.0
9
MIC (µg/ml) 90% Range 0.06 2
≤0.03-0.12 0.5-2 0.25-0.5 1-2 2
100.0 100.0 100.0 100.0 26.3
MRSA (5,167)d MDR (1,484)
Dalbavancin Dalbavancin Vancomycin Daptomycin Linezolid Tigecyclinee
0.06 0.06 1 0.25 1 0.12
0.06 0.06 1 0.5 1 0.25
≤0.03-0.25 ≤0.03-0.25
