Distribution of levofloxacin-resistant E. coli isolates
A total of 10,840 isolates collected from four geographic regions and identified as resistant to levofloxacin were included in the analysis. Isolates were most commonly collected from UTIs (N = 3,229; 29.8%), followed by 2,564 (23.7%) from skin and skin structure infections, 2,313 (21.3%) from intra-abdominal infections, 1,482 (13.7%) from lower respiratory tract infections, and 1,204 (11.1%) from bloodstream infections, whilst 48 (0.4%) were from an unknown or other source. A similar distribution was observed among ESBL-positive and ESBL-negative isolates (data not shown).
The highest proportion of isolates were collected from Europe (N = 4,663; 43.0%). The proportion of isolates collected from Latin America (N = 2,699; 24.9%) and Asia/South Pacific (N = 2,337; 21.6%) were similar, and a minority were from Africa/Middle East (N = 1,141; 10.5%).
Analysis of regions combined against levofloxacin-resistant E. coli
Table 1 shows the in vitro activity of ceftazidime-avibactam and comparators against levofloxacin-resistant ESBL-positive and ESBL-negative E. coli when data from all regions of collection were combined. Rates of susceptibility to ceftazidime-avibactam and colistin were similar (≥ 99.0%) in both sets of isolates. Other comparator agents with high susceptibility rates against both sets of isolates were meropenem and imipenem (≥ 98.5%), and tigecycline (≥ 94.6%). A high susceptibility rate was observed to amikacin among ESBL-negative isolates (95.1%); however, a lower rate of 83.4% was observed among ESBL-positive isolates. For cefepime, ceftazidime and aztreonam relatively high rates of susceptibility were observed among ESBL-negative isolates (≥ 88.5%); however, a susceptibility rate of < 10% was seen among ESBL-positive isolates.
Table 1
Activity of ceftazidime-avibactam and comparator agents against levofloxacin-resistant E. coli; ATLAS, 2012–2018.
Antimicrobial
|
MIC50
(mg/L)
|
MIC90 (mg/L)
|
Range
(mg/L)
|
%S
|
%I
|
%R
|
ESBL-positive (N = 5749)
|
|
|
|
|
|
Ceftazidime-avibactam
|
0.12
|
0.5
|
≤ 0.015–≥256
|
99.0
|
—
|
1.0
|
Ceftazidime
|
32
|
128
|
0.12–≥256
|
5.3
|
14.8
|
79.9
|
Cefepime
|
32
|
32
|
≤ 0.12–≥64
|
3.0
|
10.0
|
86.9
|
Ampicillin
|
≥ 64
|
≥ 64
|
1–≥64
|
0.2
|
—
|
99.8
|
Amoxicillin-clavulanate
|
16
|
32
|
≤ 0.12–≥64
|
29.3
|
—
|
70.7
|
Piperacillin-tazobactam
|
8
|
64
|
≤ 0.25–≥256
|
64.8
|
15.2
|
20.0
|
Aztreonam
|
32
|
128
|
0.06–≥256
|
0.2
|
8.2
|
91.6
|
Imipenem
|
0.25
|
0.25
|
≤ 0.03–≥16
|
98.5
|
0.4
|
1.1
|
Meropenem
|
0.03
|
0.06
|
≤ 0.004–≥32
|
98.5
|
0.6
|
1.0
|
Colistin* (N = 4470)
|
0.25
|
1
|
≤ 0.06–≥16
|
99.1
|
—
|
0.9
|
Amikacin
|
4
|
16
|
0.5–≥128
|
83.4
|
—
|
16.6
|
Tigecycline
|
0.25
|
0.5
|
≤ 0.015–≥16
|
95.7
|
—
|
4.3
|
ESBL-negative (N = 5091)
|
|
|
|
|
|
Ceftazidime-avibactam
|
0.12
|
0.25
|
≤ 0.015–≥256
|
99.6
|
—
|
0.4
|
Ceftazidime
|
0.25
|
4
|
≤ 0.015–≥256
|
88.5
|
2.3
|
9.2
|
Cefepime
|
≤ 0.12
|
1
|
≤ 0.12–≥64
|
91.8
|
3.8
|
4.4
|
Ampicillin
|
≥ 64
|
≥ 64
|
≤ 0.5–≥64
|
17.4
|
—
|
82.6
|
Amoxicillin-clavulanate
|
8
|
32
|
≤ 0.12–≥64
|
51.4
|
—
|
48.6
|
Piperacillin-tazobactam
|
2
|
64
|
≤ 0.12–≥256
|
81.9
|
5.0
|
13.1
|
Aztreonam
|
0.12
|
4
|
≤ 0.015–≥256
|
88.9
|
2.7
|
8.3
|
Imipenem
|
0.12
|
0.25
|
≤ 0.03–≥16
|
99.1
|
0.3
|
0.6
|
Meropenem
|
0.03
|
0.06
|
≤ 0.004–≥32
|
99.3
|
0.3
|
0.4
|
Colistin* (N = 3864)
|
0.25
|
1
|
≤ 0.06–≥16
|
99.0
|
—
|
1.0
|
Amikacin
|
2
|
8
|
≤ 0.25–≥128
|
95.1
|
—
|
4.9
|
Tigecycline
|
0.25
|
0.5
|
≤ 0.015–4
|
94.6
|
—
|
5.4
|
* Colistin was included on the comparator panel from 2014 onwards |
— Indicates no breakpoint for the agent |
ESBL, extended-spectrum β-lactamase; %I, percentage of isolates susceptible, increased exposure; MIC, minimum inhibitory concentration; MIC50, MIC required to inhibit growth of 50% of isolates (mg/L); MIC90, MIC required to inhibit growth of 90% of isolates (mg/L); %R, percentage of isolates resistant; %S, percentage of isolates susceptible, standard dosing. |
Analysis by region against levofloxacin-resistant E. coli
For the regional analysis of all years pooled (2012–2018), presented in Table 2, susceptibility rates to ceftazidime-avibactam were consistently high in all regions for both ESBL-positive (97.0% in Asia/South Pacific to 99.7% in Africa/Middle East and Latin America) and ESBL-negative (99.4% in Asia/South Pacific to 100% in Latin America) levofloxacin-resistant E. coli. High susceptibility rates were also observed in each region among ESBL-positive and ESBL-negative isolates for colistin (≥ 98.5%), imipenem (≥ 96.5%), meropenem (≥ 96.5%) and tigecycline (≥ 94.1%).
Table 2
Activity of ceftazidime-avibactam and comparator agents against levofloxacin-resistant E. coli; ATLAS, by region, 2012–2018.
Antimicrobial
|
MIC50
(mg/L)
|
MIC90
(mg/L)
|
Range
(mg/L)
|
%S
|
%I
|
%R
|
Africa/Middle East, ESBL-positive (N = 609)
|
|
|
|
|
Ceftazidime-avibactam
|
0.25
|
0.5
|
≤ 0.015–≥256
|
99.7
|
—
|
0.3
|
Ceftazidime
|
32
|
128
|
0.12–≥256
|
2.8
|
13.3
|
83.9
|
Cefepime
|
32
|
≥ 64
|
0.25–≥64
|
2.5
|
7.2
|
90.3
|
Ampicillin
|
≥ 64
|
≥ 64
|
16–≥64
|
0.0
|
—
|
100
|
Amoxicillin-clavulanate
|
16
|
32
|
1–≥64
|
26.9
|
—
|
73.1
|
Piperacillin-tazobactam
|
8
|
128
|
≤ 0.25–≥256
|
61.1
|
18.2
|
20.7
|
Aztreonam
|
64
|
128
|
2–≥256
|
0.0
|
5.3
|
94.7
|
Imipenem
|
0.25
|
0.25
|
0.06–≥16
|
99.3
|
0.3
|
0.3
|
Meropenem
|
0.03
|
0.06
|
0.015–≥32
|
99.5
|
0.3
|
0.2
|
Colistin* (N = 472)
|
0.5
|
1
|
≤ 0.06–8
|
99.2
|
—
|
0.8
|
Amikacin
|
4
|
16
|
0.5–≥128
|
85.2
|
—
|
14.8
|
Tigecycline
|
0.25
|
0.5
|
0.06–4
|
96.2
|
—
|
3.8
|
Africa/Middle East, ESBL-negative (N = 532)
|
|
|
|
|
Ceftazidime-avibactam
|
0.12
|
0.25
|
≤ 0.015–≥256
|
99.6
|
—
|
0.4
|
Ceftazidime
|
0.25
|
0.5
|
≤ 0.015–≥256
|
93.0
|
1.3
|
5.6
|
Cefepime
|
≤ 0.12
|
1
|
≤ 0.12–≥64
|
92.7
|
3.2
|
4.1
|
Ampicillin
|
≥ 64
|
≥ 64
|
1–≥64
|
15.0
|
—
|
85.0
|
Amoxicillin-clavulanate
|
8
|
32
|
≤ 0.12–≥64
|
56.0
|
—
|
44.0
|
Piperacillin-tazobactam
|
2
|
32
|
0.5–≥256
|
82.3
|
5.6
|
12.0
|
Aztreonam
|
0.12
|
0.5
|
≤ 0.015–≥256
|
93.0
|
1.5
|
5.5
|
Imipenem
|
0.12
|
0.25
|
0.06–≥16
|
99.1
|
0.4
|
0.6
|
Meropenem
|
0.03
|
0.06
|
0.008–16
|
99.2
|
0.2
|
0.6
|
Colistin* (N = 413)
|
0.25
|
1
|
≤ 0.06–≥16
|
98.5
|
—
|
1.5
|
Amikacin
|
2
|
8
|
0.5–≥128
|
94.4
|
—
|
5.6
|
Tigecycline
|
0.25
|
0.5
|
0.06–4
|
94.9
|
—
|
5.1
|
Asia/South Pacific, ESBL-positive (N = 1283)
|
|
|
|
|
Ceftazidime-avibactam
|
0.12
|
0.5
|
≤ 0.015–≥256
|
97.0
|
—
|
3.0
|
Ceftazidime
|
16
|
128
|
0.25–≥256
|
6.3
|
16.4
|
77.3
|
Cefepime
|
32
|
≥ 64
|
≤ 0.12–≥64
|
1.5
|
11.0
|
87.5
|
Ampicillin
|
≥ 64
|
≥ 64
|
4–≥64
|
0.2
|
—
|
99.8
|
Amoxicillin-clavulanate
|
16
|
32
|
2–≥64
|
41.6
|
—
|
58.4
|
Piperacillin-tazobactam
|
4
|
128
|
0.5–≥256
|
74.0
|
9.8
|
16.1
|
Aztreonam
|
32
|
128
|
0.06–≥256
|
0.5
|
7.9
|
91.7
|
Imipenem
|
0.25
|
0.5
|
≤ 0.03–≥16
|
96.5
|
0.3
|
3.2
|
Meropenem
|
0.03
|
0.12
|
0.008–≥32
|
96.5
|
0.5
|
3.0
|
Colistin* (N = 1012)
|
0.25
|
1
|
≤ 0.06–≥16
|
98.8
|
—
|
1.2
|
Amikacin
|
4
|
16
|
0.5–≥128
|
89.8
|
—
|
10.2
|
Tigecycline
|
0.25
|
0.5
|
0.03–≥16
|
94.3
|
—
|
5.7
|
Asia/South Pacific, ESBL-negative (N = 1054)
|
|
|
|
|
Ceftazidime-avibactam
|
0.12
|
0.25
|
≤ 0.015–≥256
|
99.4
|
—
|
0.6
|
Ceftazidime
|
0.25
|
32
|
≤ 0.015–≥256
|
77.9
|
3.1
|
19.0
|
Cefepime
|
≤ 0.12
|
1
|
≤ 0.12–≥64
|
91.4
|
3.9
|
4.7
|
Ampicillin
|
≥ 64
|
≥ 64
|
≤ 0.5–≥64
|
17.0
|
—
|
83.0
|
Amoxicillin-clavulanate
|
8
|
32
|
≤ 0.12–≥64
|
52.4
|
—
|
47.6
|
Piperacillin-tazobactam
|
2
|
32
|
0.25–≥256
|
83.5
|
4.9
|
11.6
|
Aztreonam
|
0.12
|
16
|
≤ 0.015–≥256
|
79.7
|
4.6
|
15.7
|
Imipenem
|
0.25
|
0.5
|
≤ 0.03–≥16
|
99.3
|
0.2
|
0.5
|
Meropenem
|
0.03
|
0.06
|
≤ 0.004–≥32
|
99.4
|
0.1
|
0.5
|
Colistin (N = 780)
|
0.25
|
1
|
≤ 0.06–≥16
|
99.4
|
—
|
0.6
|
Amikacin
|
2
|
8
|
≤ 0.25–≥128
|
96.5
|
—
|
3.5
|
Tigecycline
|
0.25
|
0.5
|
0.03–4
|
94.7
|
—
|
5.3
|
Europe, ESBL-positive (N = 2290)
|
|
|
|
|
|
Ceftazidime-avibactam
|
0.12
|
0.5
|
≤ 0.015–≥256
|
99.6
|
—
|
0.4
|
Ceftazidime
|
16
|
128
|
0.12–≥256
|
6.0
|
17.2
|
76.9
|
Cefepime
|
32
|
≥ 64
|
≤ 0.12–≥64
|
4.6
|
12.6
|
82.8
|
Ampicillin
|
≥ 64
|
≥ 64
|
1–≥64
|
0.3
|
—
|
99.7
|
Amoxicillin-clavulanate
|
16
|
32
|
≤ 0.12–≥64
|
25.9
|
—
|
74.1
|
Piperacillin-tazobactam
|
8
|
128
|
≤ 0.25–≥256
|
61.3
|
15.8
|
22.9
|
Aztreonam
|
32
|
128
|
0.5–≥256
|
0.3
|
10.3
|
89.4
|
Imipenem
|
0.25
|
0.25
|
≤ 0.03–≥16
|
99.0
|
0.4
|
0.6
|
Meropenem
|
0.03
|
0.06
|
≤ 0.004–≥32
|
98.9
|
0.6
|
0.5
|
Colistin* (N = 1754)
|
0.5
|
1
|
≤ 0.06–≥16
|
99.1
|
—
|
0.9
|
Amikacin
|
4
|
16
|
0.5–≥128
|
79.9
|
—
|
20.1
|
Tigecycline
|
0.25
|
0.5
|
≤ 0.015–4
|
96.3
|
—
|
3.7
|
Europe, ESBL-negative (N = 2373)
|
|
|
|
|
|
Ceftazidime-avibactam
|
0.12
|
0.25
|
≤ 0.015–≥256
|
99.5
|
—
|
0.5
|
Ceftazidime
|
0.25
|
1
|
0.03–≥256
|
91.0
|
2.4
|
6.7
|
Cefepime
|
≤ 0.12
|
1
|
≤ 0.12–≥64
|
91.1
|
4.3
|
4.6
|
Ampicillin
|
≥ 64
|
≥ 64
|
≤ 0.5–≥64
|
16.0
|
—
|
84.0
|
Amoxicillin-clavulanate
|
16
|
32
|
≤ 0.12–≥64
|
47.8
|
—
|
52.2
|
Piperacillin-tazobactam
|
2
|
64
|
≤ 0.12–≥256
|
79.6
|
5.1
|
15.3
|
Aztreonam
|
0.12
|
1
|
≤ 0.015–≥256
|
91.4
|
2.6
|
6.0
|
Imipenem
|
0.12
|
0.25
|
≤ 0.03–≥16
|
98.7
|
0.5
|
0.8
|
Meropenem
|
0.03
|
0.06
|
≤ 0.004–≥32
|
99.2
|
0.4
|
0.4
|
Colistin* (N = 1786)
|
0.25
|
1
|
≤ 0.06–≥16
|
98.9
|
—
|
1.1
|
Amikacin
|
2
|
8
|
0.5–≥128
|
95.0
|
—
|
5.0
|
Tigecycline
|
0.25
|
0.5
|
≤ 0.015–4
|
94.1
|
—
|
5.9
|
Latin America, ESBL-positive (N = 1567)
|
|
|
|
|
Ceftazidime-avibactam
|
0.12
|
0.5
|
≤ 0.015–≥256
|
99.7
|
—
|
0.3
|
Ceftazidime
|
32
|
128
|
0.5–≥256
|
4.3
|
10.7
|
84.9
|
Cefepime
|
32
|
32
|
≤ 0.12–≥64
|
2.3
|
6.6
|
91.1
|
Ampicillin
|
≥ 64
|
≥ 64
|
8–≥64
|
0.1
|
—
|
99.9
|
Amoxicillin-clavulanate
|
16
|
32
|
≤ 0.12–≥64
|
25.3
|
—
|
74.7
|
Piperacillin-tazobactam
|
8
|
64
|
≤ 0.25–≥256
|
63.8
|
17.7
|
18.5
|
Aztreonam
|
64
|
128
|
0.5–≥256
|
0.1
|
6.4
|
93.5
|
Imipenem
|
0.12
|
0.25
|
0.06–≥16
|
99.2
|
0.4
|
0.4
|
Meropenem
|
0.03
|
0.06
|
0.015–≥32
|
99.0
|
0.6
|
0.4
|
Colistin* (N = 1232)
|
0.25
|
1
|
≤ 0.06–8
|
99.1
|
—
|
0.9
|
Amikacin
|
4
|
16
|
0.5–≥128
|
82.6
|
—
|
17.4
|
Tigecycline
|
0.25
|
0.5
|
≤ 0.015–4
|
95.8
|
—
|
4.2
|
Latin America, ESBL-negative (N = 1132)
|
|
|
|
|
Ceftazidime-avibactam
|
0.12
|
0.25
|
≤ 0.015–4
|
100
|
—
|
0.0
|
Ceftazidime
|
0.25
|
1
|
0.03–≥256
|
91.1
|
1.7
|
7.2
|
Cefepime
|
≤ 0.12
|
1
|
≤ 0.12–≥64
|
93.3
|
3.1
|
3.6
|
Ampicillin
|
≥ 64
|
≥ 64
|
1–≥64
|
22.0
|
—
|
78.0
|
Amoxicillin-clavulanate
|
8
|
32
|
≤ 0.12–≥64
|
56.0
|
—
|
44.0
|
Piperacillin-tazobactam
|
2
|
32
|
0.25–≥256
|
84.9
|
4.4
|
10.7
|
Aztreonam
|
0.12
|
1
|
≤ 0.015–≥256
|
90.5
|
1.9
|
7.6
|
Imipenem
|
0.12
|
0.25
|
≤ 0.03–≥16
|
99.5
|
0.1
|
0.4
|
Meropenem
|
0.03
|
0.06
|
0.008–≥32
|
99.4
|
0.4
|
0.3
|
Colistin* (N = 885)
|
0.25
|
1
|
≤ 0.06–≥16
|
99.1
|
—
|
0.9
|
Amikacin
|
2
|
8
|
≤ 0.25–≥128
|
94.4
|
—
|
5.6
|
Tigecycline
|
0.25
|
0.5
|
≤ 0.015–4
|
95.5
|
—
|
4.5
|
* Colistin was included on the comparator panel from 2014 onwards |
— Indicates no breakpoint for the agent |
ESBL, extended-spectrum β-lactamase; %I, percentage of isolates susceptible, increased exposure; MIC, minimum inhibitory concentration; MIC50, MIC required to inhibit growth of 50% of isolates (mg/L); MIC90, MIC required to inhibit growth of 90% of isolates (mg/L); %R, percentage of isolates resistant; %S, percentage of isolates susceptible, standard dosing. |
Susceptibility rates to amikacin among ESBL-negative isolates were similar in all regions, from 94.4% in Africa/Middle East and Latin America to 96.5% in Europe. Among ESBL-positive isolates, susceptibility to amikacin was lower (79.9% in Europe to 89.8% in Asia/South Pacific). The susceptibility rates observed among ESBL-negative isolates to piperacillin-tazobactam were lowest in Europe (79.6%) and highest in Latin America (84.9%). In comparison, rates of susceptibility to piperacillin-tazobactam among ESBL-positive isolates were lower in each region (for example, 61.3% in Europe).
High rates of susceptibility were observed among ESBL-negative levofloxacin-resistant E. coli for cefepime in all regions (between 91.1% and 93.3%) and for ceftazidime in three of the four regions (91.0–93.0%). A lower susceptibility rate to ceftazidime of 77.9% was observed among ESBL-negative isolates in Asia/South Pacific. Few ESBL-positive isolates from any region were susceptible to cefepime or ceftazidime (≤ 6.3%). Susceptibility rates to ampicillin and amoxicillin-clavulanate were lower compared with all other agents in each region for ESBL-negative isolates. Among each regional set of ESBL-positive isolates, susceptibility rates to ampicillin and amoxicillin-clavulanate were ≤ 41.6%.
In vitro activity data, by year, for ceftazidime-avibactam, colistin, meropenem, imipenem, and tigecycline against ESBL-positive and ESBL-negative isolates are presented in Supplemental Tables 1–5. Over time, ceftazidime-avibactam, colistin, meropenem and imipenem showed consistently high and stable rates of susceptibility (≥ 96.7%) in Africa/Middle East, Europe and Latin America (Supplemental Tables 1–4). For ESBL-positive isolates collected in the Asia/South Pacific region, reduced susceptibility rates were observed in 2018 to ceftazidime-avibactam (91.8%, Supplemental Table 1), and to imipenem (90.4%) and meropenem (91.1%) (Supplemental Tables 3 and 4) when compared with each of the preceding years. Susceptibility to tigecycline was > 92.6% between 2013 and 2018; rates of susceptibility were lower in 2012.
Regional trend tests against levofloxacin-resistant E. coli over time
Figure 1 shows the proportion of levofloxacin-resistant E. coli isolates identified as ESBL-positive from each region and by year. Any changes in the rates of ESBL-positive, levofloxacin-resistant E. coli over time were not statistically significant in Africa/Middle East and Latin America. For isolates from Europe and Asia/Pacific there was a statistically significant increase in the rates of ESBL-positive isolates over time (p = 0.0029 and p = 0.0001, respectively) with rates in 2018 of 54.4% in Europe and 61.3% in Asia-Pacific.