AAC Accepts, published online ahead of print on 22 December 2014 Antimicrob. Agents Chemother. doi:10.1128/AAC.04809-14 Copyright © 2014, American Society for Microbiology. All Rights Reserved.
1
Activity of eravacycline against Enterobacteriaceae and Acinetobacter baumannii, including
2
multidrug-resistant isolates, from New York City
3
Marie Abdallaha, Olawole Olafisoyea, Christopher Cortesb, Carl Urbanb, David Landmana, John
4
Qualea#
5 6
Division of Infectious Diseases, SUNY Downstate Medical Center, Brooklyn, NY, USAa; The
7
Dr. James J. Rahal Jr. Division of Infectious Diseases, New York Hospital Queens, Flushing,
8
NY, USAb
9 10
Corresponding author: John Quale Email: [email protected]
11
Running title: Eravacycline activity against Gram negative bacilli
12 13 14 15 16 17 18 19 20 21 22 23
1
24
ABSTRACT
25
Eravacycline demonstrated in vitro activity against a contemporary collection of over 4000
26
Gram-negative pathogens from New York City hospitals, with MIC50/MIC90 values for
27
Escherichia coli of 0.12/0.5 µg/ml, Klebsiella pneumoniae of 0.25/1 µg/ml, Enterobacter
28
aerogenes of 0.25/1 µg/ml, E. cloacae 0.5/1of µg/ml, and A. baumannii of 0.5/1 µg/ml. Activity
29
was retained against multidrug-resistant isolates, including those expressing KPC and OXA
30
carbapenemases. For A. baumannii, eravacycline MICs correlated with increased expression of
31
the gene adeB.
32 33 34 35 36 37 38 39 40 41 42 43 44 45 46
2
47
Nosocomial infections with multidrug-resistant Gram-negative bacilli come with considerable
48
clinical and economic burden. Carbapenem-resistant Enterobacteriaceae and Acinetobacter
49
baumannii have become commonplace in many medical centers around the world. In the United
50
States, and particularly New York City, spread of Enterobacteriaceae possessing the
51
carbapenemase KPC and A. baumannii possessing OXA-type carbapenemases has been
52
especially problematic (1-3). Since these isolates are often also resistant to aminoglycosides and
53
fluoroquinolones, therapeutic options are very limited. Often the therapy of last resort are the
54
polymyxins; however there are lingering issues regarding dosing, susceptibility testing, and
55
resistance with these agents (4,5). As a result, the need for novel antibacterial agents with
56
activity against multidrug-resistant isolates has been voiced (6).
57
Eravacycline is a novel fluorocycline of the tetracycline class, being developed for both
58
intravenous and oral use, which has broad spectrum activity against Gram-negative and Gram-
59
positive aerobic and anaerobic pathogens (7). Like tigecycline, eravacycline is not affected by
60
many of the tetracycline-specific resistance mechanisms found in Gram-negative bacteria,
61
including acquired efflux systems and ribosomal protection proteins (7,8). In this report, we
62
determined the activity of eravacycline against Enterobacteriaceae and A. baumannii endemic to
63
medical centers in New York City.
64
For a three month period spanning November 2013 – January 2014, all single patient isolates
65
of E coli, K. pneumoniae, Enterobacter spp., and A. baumannii were collected from eleven
66
hospitals in Brooklyn and Queens, NY. Susceptibility tests were performed in a central research
67
laboratory using the broth microdilution (for tigecycline and eravacycline) or agar dilution (all
68
other agents) methods, according to CLSI standards (9). Ceftriaxone-resistant isolates were
69
tested, by PCR, for the presence of blaKPC and blaOXA-23-type and blaOXA-24-type using previously
3
70
described primers (1,10). Isolates of K. pneumoniae with blaKPC and A. baumannii with blaOXA23-
71
type underwent
72
described (2). Isolates were considered related if there was a 0-1 band difference. Finally, select
73
isolates of K. pneumoniae were also examined for mutations in genes encoding RamR and
74
ribosomal S10 proteins, using previously described primers and PCR conditions (11).
75
genetic fingerprinting by the rep-PCR method with ERIC-2 primer, as previously
To examine the mechanisms contributing to eravacycline resistance in A. baumannii,
76
susceptibility testing was performed using a collection of previously characterized isolates (12).
77
Expression of adeB, abeM, and ompA was determined by real time RT-PCR and normalized to
78
that of A. baumannii ATCC 19606, as previously described (12). Multiple regression analysis
79
was used to determine any correlation between expression of efflux genes adeB, abeM, and porin
80
gene ompA with eravacycline MIC values. In addition, gene silencing of adeB was performed to
81
further determine the role of this efflux system in eravacycline resistance. Two previously-
82
characterized isolates of A. baumannii were selected based on their disparate expression of adeB
83
and susceptibility to kanamycin. Insertional inactivation of the adeB gene was performed by
84
amplifying a 979 bp fragment of the gene (AccuPrime Pfx DNA polymerase, Invitrogen Corp.,
85
Carlsbad, CA). The amplicon was inserted into the pCR-Blunt II-TOPO vector using the Zero
86
Blunt TOPO PCR Cloning Kit (Invitrogen Corp.). The plasmid was introduced into the clinical
87
isolates by electroporation. Transformants were selected from plates containing 250 µg/ml of
88
kanamycin. The presence of the insert in adeB was confirmed by PCR amplification and DNA
89
sequencing using an M13 forward primer and a primer (5’-TTGGGCTGATATTACAGGGG-3’)
90
located upstream to the insert.
91
A total of 2866 isolates of E. coli were gathered during the three month surveillance study.
92
Susceptibilities are given in the table; 13% were nonsusceptible to ceftriaxone and five isolates
4
93
carried blaKPC. The eravacycline MIC50 and MIC90 values for all of the isolates were 0.12 and 0.5
94
µg/ml, respectively. Of the isolates resistant to ceftriaxone, eravacycline MIC50 and MIC90
95
values were 0.25 and 0.5 µg/ml, respectively.
96
Among 944 isolates of K. pneumoniae, 33% were resistant to ceftriaxone and 124 isolates
97
carried blaKPC. For all of the isolates, the MIC50 and MIC90 values for eravacycline were 0.25 and
98
1 µg/ml, respectively, which were one dilution lower than the corresponding values for
99
tigecycline. For the tigecycline resistant isolates, eravacycline MIC50 and MIC90 values were 2
100
and 8 µg/ml, respectively. For both cephalosporin-resistant isolates and those expressing blaKPC,
101
MIC50 and MIC90 values of eravacycline were 0.5 and 1 µg/ml, respectively. Twenty-three
102
isolates with blaKPC, from 11 different hospitals, underwent fingerprinting. Eight rep-PCR types
103
were identified, including 12 isolates that belonged to one clone (data not shown).
104
Eleven isolates of K. pneumoniae with eravacycline MICs of ≥ 4 µg/ml underwent PCR
105
analysis of ramR and rpsJ (encoding the S10 ribosomal protein). For ramR, two isolates had a
106
nonamplifiable gene, five isolates had mutations leading to premature stop codons, and two
107
isolates had deletions leading to frameshift mutations. One isolate had a mutation leading to
108
Thr50→Ile50, and one isolate had no mutation. For rpsJ, four isolates had a nonamplifiable
109
gene, and only one had the previously described mutation leading to Val57→Leu57 (11).
110
There were 216 Enterobacter spp. isolates, including 90 E. aerogenes and 124 E. cloacae.
111
Three isolates of E. aerogenes and four isolates of E. cloacae harbored blaKPC. For all 216
112
Enterobacter spp., 96% were susceptible to tigecycline (MIC50 and MIC90 values of 0.5 and 2
113
µg/ml, respectively). The corresponding MIC50 and MIC90 values for eravacycline were 0.5 and
114
1 µg/ml, respectively. For both E. aerogenes and E. cloacae, eravacycline MIC90 values were
115
one dilution lower than that of tigecycline (Table). For the tigecycline resistant isolates, the
5
116
eravacycline MICs ranged from 0.5-2 µg/ml. For the three isolates of E. aerogenes with blaKPC,
117
two had eravacycline MIC values of 0.25 and one of 0.5 µg/ml. For the four isolates of E.
118
cloacae that had blaKPC, two each had eravacycline MIC values of 0.5 and 1 µg/ml.
119
Only 31% of the 158 isolates of A. baumannii were susceptible to meropenem. Fifty-eight
120
were found to have blaOXA-23-like, two carried blaOXA-24-like, and one harbored blaKPC. For all 158
121
isolates, 66% were susceptible to tigecycline (MIC ≤ 2 µg/ml). The MIC50 and MIC90 values of
122
eravacycline were 0.5 and 1 µg/ml, which were fourfold lower than the corresponding values for
123
tigecycline. Among the tigecycline-resistant isolates, the MIC50 and MIC90 values of
124
eravacycline were 1 and 2 µg/ml, respectively. For the 58 isolates that had blaOXA-23-like, the
125
MIC90 value for eravacycline was 1 µg/ml. Eighteen isolates, from eight hospitals, with blaOXA-
126
23-like
127
belonging to a single clone (data not shown).
underwent fingerprinting. A total of 10 rep-PCR types were identified, including six
128
A collection of thirty-eight previously characterized isolates of A. baumannii, representing 10
129
different strains, were examined (12). Of the 38 isolates, 26 were resistant to meropenem. None
130
harbored blaKPC, blaOXA23-type, or blaOXA24-type carbapenemases. The eravacycline MIC values
131
ranged from 0.06-4 μg/ml, with MIC50 and MIC90 values of 0.5 and 2 µg/ml, respectively. By
132
multiple regression analysis, there was a significant correlation between the eravacycline MICs
133
and expression of adeB (P=0.002); there was no correlation with expression of abeM and ompA.
134
For five isolates with negligible adeB expression (64
87%
Meropenem
≤ 0.125
≤ 0.125
≤ 0.125 - >8
99.8%
Gentamicin
1
>8
≤ 0.25 - >8
85%
≤ 0.125
>4
≤ 0.125 - >4
69%
≤ 0.5
>4
≤ 0.5 - >4
64%
Tetracycline
4
>16
≤ 0.25 - >16
59%
Eravacycline
0.12
0.5
≤ 0.015 - 4
Ceftriaxone
≤ 0.25
>64
≤ 0.25 - >64
67%
Meropenem
≤ 0.125
4
≤ 0.125 - >8
87%
Gentamicin
0.5
>8
≤ 0.25 - >8
78%
≤ 0.125
>4
≤ 0.125 - >4
67%
≤ 0.5
>4
≤ 0.5 - >4
65%
Ciprofloxacin Trimethoprim sulfamethoxazole
K. pneumoniae (n=944)
Ciprofloxacin Trimethoprim -
11
sulfamethoxazole Tetracycline
4
>16
≤ 0.25 - >16
68%
Tigecycline
0.5
2
≤ 0.015 - 16
95%
Eravacycline
0.25
1
0.06 - 4
Ceftriaxone
≤ 0.25
32
≤ 0.25 - >64
78%
Meropenem
≤ 0.125
≤ 0.125
≤ 0.125 - >8
94%
Gentamicin
0.5
1
≤ 0.25 - >8
94%
≤ 0.125
0.5
≤ 0.125 - >4
93%
≤ 0.5
>4
≤ 0.5 - >4
91%
Tetracycline
2
>16
≤ 0.25 - >16
82%
Tigecycline
0.5
2
≤ 0.25 - >16
97%
Eravacycline
0.25
1
0.12 - 2
Ceftriaxone
≤ 0.25
2
≤ 0.25 - >64
77%
Meropenem
≤ 0.125
≤ 0.125
≤ 0.125 - >8
96%
Gentamicin
0.5
2
≤ 0.25 - >8
94%
≤ 0.125
2
≤ 0.125 - >4
89%
≤ 0.5
>4
≤ 0.5 - >4
82%
Tetracycline
2
8
≤ 0.25 - >16
79%
Tigecycline
0.5
2
≤ 0.25 - >16
96%
E. aerogenes (n=90)
Ciprofloxacin Trimethoprim sulfamethoxazole
E. cloacae (n=124)
Ciprofloxacin Trimethoprim sulfamethoxazole
12
Eravacycline
0.5
1
0.25 - 2
Ceftazidime
16
>16
≤ 0.25 - >16
33%
Meropenem
>8
>8
≤ 0.125 - >8
31%
Gentamicin
8
>8
≤ 0.25 - >8
45%
Ciprofloxacin
>4
>4
≤ 0.125 - >4
31%
Trimethoprim -
>4
>4
≤ 0.5 - >4
34%
Tetracycline
>16
>16
2 - >16
10%
Tigecycline
2
4
0.06 - 16
66%
Eravacycline
0.5
1
≤ 0.015 - 8
A. baumannii (n=158)
sulfamethoxazole
234 235 236 237
13
1
Activity of eravacycline against Enterobacteriaceae and Acinetobacter baumannii, including
2
multidrug-resistant isolates, from New York City
3
Marie Abdallaha, Olawole Olafisoyea, Christopher Cortesb, Carl Urbanb, David Landmana, John
4
Qualea#
5 6
Division of Infectious Diseases, SUNY Downstate Medical Center, Brooklyn, NY, USAa; The
7
Dr. James J. Rahal Jr. Division of Infectious Diseases, New York Hospital Queens, Flushing,
8
NY, USAb
9 10
Corresponding author: John Quale Email: [email protected]
11
Running title: Eravacycline activity against Gram negative bacilli
12 13 14 15 16 17 18 19 20 21 22 23
1
24
ABSTRACT
25
Eravacycline demonstrated in vitro activity against a contemporary collection of over 4000
26
Gram-negative pathogens from New York City hospitals, with MIC50/MIC90 values for
27
Escherichia coli of 0.12/0.5 µg/ml, Klebsiella pneumoniae of 0.25/1 µg/ml, Enterobacter
28
aerogenes of 0.25/1 µg/ml, E. cloacae 0.5/1of µg/ml, and A. baumannii of 0.5/1 µg/ml. Activity
29
was retained against multidrug-resistant isolates, including those expressing KPC and OXA
30
carbapenemases. For A. baumannii, eravacycline MICs correlated with increased expression of
31
the gene adeB.
32 33 34 35 36 37 38 39 40 41 42 43 44 45 46
2
47
Nosocomial infections with multidrug-resistant Gram-negative bacilli come with considerable
48
clinical and economic burden. Carbapenem-resistant Enterobacteriaceae and Acinetobacter
49
baumannii have become commonplace in many medical centers around the world. In the United
50
States, and particularly New York City, spread of Enterobacteriaceae possessing the
51
carbapenemase KPC and A. baumannii possessing OXA-type carbapenemases has been
52
especially problematic (1-3). Since these isolates are often also resistant to aminoglycosides and
53
fluoroquinolones, therapeutic options are very limited. Often the therapy of last resort are the
54
polymyxins; however there are lingering issues regarding dosing, susceptibility testing, and
55
resistance with these agents (4,5). As a result, the need for novel antibacterial agents with
56
activity against multidrug-resistant isolates has been voiced (6).
57
Eravacycline is a novel fluorocycline of the tetracycline class, being developed for both
58
intravenous and oral use, which has broad spectrum activity against Gram-negative and Gram-
59
positive aerobic and anaerobic pathogens (7). Like tigecycline, eravacycline is not affected by
60
many of the tetracycline-specific resistance mechanisms found in Gram-negative bacteria,
61
including acquired efflux systems and ribosomal protection proteins (7,8). In this report, we
62
determined the activity of eravacycline against Enterobacteriaceae and A. baumannii endemic to
63
medical centers in New York City.
64
For a three month period spanning November 2013 – January 2014, all single patient isolates
65
of E coli, K. pneumoniae, Enterobacter spp., and A. baumannii were collected from eleven
66
hospitals in Brooklyn and Queens, NY. Susceptibility tests were performed in a central research
67
laboratory using the broth microdilution (for tigecycline and eravacycline) or agar dilution (all
68
other agents) methods, according to CLSI standards (9). Ceftriaxone-resistant isolates were
69
tested, by PCR, for the presence of blaKPC and blaOXA-23-type and blaOXA-24-type using previously
3
70
described primers (1,10). Isolates of K. pneumoniae with blaKPC and A. baumannii with blaOXA23-
71
type underwent
72
described (2). Isolates were considered related if there was a 0-1 band difference. Finally, select
73
isolates of K. pneumoniae were also examined for mutations in genes encoding RamR and
74
ribosomal S10 proteins, using previously described primers and PCR conditions (11).
75
genetic fingerprinting by the rep-PCR method with ERIC-2 primer, as previously
To examine the mechanisms contributing to eravacycline resistance in A. baumannii,
76
susceptibility testing was performed using a collection of previously characterized isolates (12).
77
Expression of adeB, abeM, and ompA was determined by real time RT-PCR and normalized to
78
that of A. baumannii ATCC 19606, as previously described (12). Multiple regression analysis
79
was used to determine any correlation between expression of efflux genes adeB, abeM, and porin
80
gene ompA with eravacycline MIC values. In addition, gene silencing of adeB was performed to
81
further determine the role of this efflux system in eravacycline resistance. Two previously-
82
characterized isolates of A. baumannii were selected based on their disparate expression of adeB
83
and susceptibility to kanamycin. Insertional inactivation of the adeB gene was performed by
84
amplifying a 979 bp fragment of the gene (AccuPrime Pfx DNA polymerase, Invitrogen Corp.,
85
Carlsbad, CA). The amplicon was inserted into the pCR-Blunt II-TOPO vector using the Zero
86
Blunt TOPO PCR Cloning Kit (Invitrogen Corp.). The plasmid was introduced into the clinical
87
isolates by electroporation. Transformants were selected from plates containing 250 µg/ml of
88
kanamycin. The presence of the insert in adeB was confirmed by PCR amplification and DNA
89
sequencing using an M13 forward primer and a primer (5’-TTGGGCTGATATTACAGGGG-3’)
90
located upstream to the insert.
91
A total of 2866 isolates of E. coli were gathered during the three month surveillance study.
92
Susceptibilities are given in the table; 13% were nonsusceptible to ceftriaxone and five isolates
4
93
carried blaKPC. The eravacycline MIC50 and MIC90 values for all of the isolates were 0.12 and 0.5
94
µg/ml, respectively. Of the isolates resistant to ceftriaxone, eravacycline MIC50 and MIC90
95
values were 0.25 and 0.5 µg/ml, respectively.
96
Among 944 isolates of K. pneumoniae, 33% were resistant to ceftriaxone and 124 isolates
97
carried blaKPC. For all of the isolates, the MIC50 and MIC90 values for eravacycline were 0.25 and
98
1 µg/ml, respectively, which were one dilution lower than the corresponding values for
99
tigecycline. For the tigecycline resistant isolates, eravacycline MIC50 and MIC90 values were 2
100
and 8 µg/ml, respectively. For both cephalosporin-resistant isolates and those expressing blaKPC,
101
MIC50 and MIC90 values of eravacycline were 0.5 and 1 µg/ml, respectively. Twenty-three
102
isolates with blaKPC, from 11 different hospitals, underwent fingerprinting. Eight rep-PCR types
103
were identified, including 12 isolates that belonged to one clone (data not shown).
104
Eleven isolates of K. pneumoniae with eravacycline MICs of ≥ 4 µg/ml underwent PCR
105
analysis of ramR and rpsJ (encoding the S10 ribosomal protein). For ramR, two isolates had a
106
nonamplifiable gene, five isolates had mutations leading to premature stop codons, and two
107
isolates had deletions leading to frameshift mutations. One isolate had a mutation leading to
108
Thr50→Ile50, and one isolate had no mutation. For rpsJ, four isolates had a nonamplifiable
109
gene, and only one had the previously described mutation leading to Val57→Leu57 (11).
110
There were 216 Enterobacter spp. isolates, including 90 E. aerogenes and 124 E. cloacae.
111
Three isolates of E. aerogenes and four isolates of E. cloacae harbored blaKPC. For all 216
112
Enterobacter spp., 96% were susceptible to tigecycline (MIC50 and MIC90 values of 0.5 and 2
113
µg/ml, respectively). The corresponding MIC50 and MIC90 values for eravacycline were 0.5 and
114
1 µg/ml, respectively. For both E. aerogenes and E. cloacae, eravacycline MIC90 values were
115
one dilution lower than that of tigecycline (Table). For the tigecycline resistant isolates, the
5
116
eravacycline MICs ranged from 0.5-2 µg/ml. For the three isolates of E. aerogenes with blaKPC,
117
two had eravacycline MIC values of 0.25 and one of 0.5 µg/ml. For the four isolates of E.
118
cloacae that had blaKPC, two each had eravacycline MIC values of 0.5 and 1 µg/ml.
119
Only 31% of the 158 isolates of A. baumannii were susceptible to meropenem. Fifty-eight
120
were found to have blaOXA-23-like, two carried blaOXA-24-like, and one harbored blaKPC. For all 158
121
isolates, 66% were susceptible to tigecycline (MIC ≤ 2 µg/ml). The MIC50 and MIC90 values of
122
eravacycline were 0.5 and 1 µg/ml, which were fourfold lower than the corresponding values for
123
tigecycline. Among the tigecycline-resistant isolates, the MIC50 and MIC90 values of
124
eravacycline were 1 and 2 µg/ml, respectively. For the 58 isolates that had blaOXA-23-like, the
125
MIC90 value for eravacycline was 1 µg/ml. Eighteen isolates, from eight hospitals, with blaOXA-
126
23-like
127
belonging to a single clone (data not shown).
underwent fingerprinting. A total of 10 rep-PCR types were identified, including six
128
A collection of thirty-eight previously characterized isolates of A. baumannii, representing 10
129
different strains, were examined (12). Of the 38 isolates, 26 were resistant to meropenem. None
130
harbored blaKPC, blaOXA23-type, or blaOXA24-type carbapenemases. The eravacycline MIC values
131
ranged from 0.06-4 μg/ml, with MIC50 and MIC90 values of 0.5 and 2 µg/ml, respectively. By
132
multiple regression analysis, there was a significant correlation between the eravacycline MICs
133
and expression of adeB (P=0.002); there was no correlation with expression of abeM and ompA.
134
For five isolates with negligible adeB expression (64
87%
Meropenem
≤ 0.125
≤ 0.125
≤ 0.125 - >8
99.8%
Gentamicin
1
>8
≤ 0.25 - >8
85%
≤ 0.125
>4
≤ 0.125 - >4
69%
≤ 0.5
>4
≤ 0.5 - >4
64%
Tetracycline
4
>16
≤ 0.25 - >16
59%
Eravacycline
0.12
0.5
≤ 0.015 - 4
Ceftriaxone
≤ 0.25
>64
≤ 0.25 - >64
67%
Meropenem
≤ 0.125
4
≤ 0.125 - >8
87%
Gentamicin
0.5
>8
≤ 0.25 - >8
78%
≤ 0.125
>4
≤ 0.125 - >4
67%
≤ 0.5
>4
≤ 0.5 - >4
65%
Ciprofloxacin Trimethoprim sulfamethoxazole
K. pneumoniae (n=944)
Ciprofloxacin Trimethoprim -
11
sulfamethoxazole Tetracycline
4
>16
≤ 0.25 - >16
68%
Tigecycline
0.5
2
≤ 0.015 - 16
95%
Eravacycline
0.25
1
0.06 - 4
Ceftriaxone
≤ 0.25
32
≤ 0.25 - >64
78%
Meropenem
≤ 0.125
≤ 0.125
≤ 0.125 - >8
94%
Gentamicin
0.5
1
≤ 0.25 - >8
94%
≤ 0.125
0.5
≤ 0.125 - >4
93%
≤ 0.5
>4
≤ 0.5 - >4
91%
Tetracycline
2
>16
≤ 0.25 - >16
82%
Tigecycline
0.5
2
≤ 0.25 - >16
97%
Eravacycline
0.25
1
0.12 - 2
Ceftriaxone
≤ 0.25
2
≤ 0.25 - >64
77%
Meropenem
≤ 0.125
≤ 0.125
≤ 0.125 - >8
96%
Gentamicin
0.5
2
≤ 0.25 - >8
94%
≤ 0.125
2
≤ 0.125 - >4
89%
≤ 0.5
>4
≤ 0.5 - >4
82%
Tetracycline
2
8
≤ 0.25 - >16
79%
Tigecycline
0.5
2
≤ 0.25 - >16
96%
E. aerogenes (n=90)
Ciprofloxacin Trimethoprim sulfamethoxazole
E. cloacae (n=124)
Ciprofloxacin Trimethoprim sulfamethoxazole
12
Eravacycline
0.5
1
0.25 - 2
Ceftazidime
16
>16
≤ 0.25 - >16
33%
Meropenem
>8
>8
≤ 0.125 - >8
31%
Gentamicin
8
>8
≤ 0.25 - >8
45%
Ciprofloxacin
>4
>4
≤ 0.125 - >4
31%
Trimethoprim -
>4
>4
≤ 0.5 - >4
34%
Tetracycline
>16
>16
2 - >16
10%
Tigecycline
2
4
0.06 - 16
66%
Eravacycline
0.5
1
≤ 0.015 - 8
A. baumannii (n=158)
sulfamethoxazole
234 235 236 237
13
