Skip to main content
PMC home page
Springer logoLink to Springer
. 2022 May 20;41(6):989–996. doi: 10.1007/s10096-022-04452-1

Antimicrobial activity of ceftazidime-avibactam and comparators against Pseudomonas aeruginosa and Enterobacterales collected in Croatia, Czech Republic, Hungary, Poland, Latvia and Lithuania: ATLAS Surveillance Program, 2019

V Adámková 1, I Mareković 2, J Szabó 3, L Pojnar 4, S Billová 5,✉, S Horvat Herceg 6, A Kuraieva 7, B Możejko-Pastewka 8
PMCID: PMC9135846  PMID: 35596097

Abstract

Antimicrobial susceptibility of clinical isolates collected from sites in central Europe in 2019 was tested by CLSI broth microdilution method and EUCAST breakpoints. Most active were amikacin, ceftazidime-avibactam and colistin; respectively, susceptibility rates among P. aeruginosa (n = 701) were 89.2%, 92.2% and 99.9%; difficult-to-treat (DTR) isolates, 62.5%, 37.5% and 100%; multidrug-resistant (MDR) isolates, 68.3%, 72.9% and 99.5%; meropenem-resistant (MEM-R), metallo-β-lactamase-negative (MBL-negative) isolates, 72.8%, 78.6% and 100%. Among Enterobacterales (n = 1639), susceptibility to ceftazidime-avibactam, colistin and tigecycline was ≥ 97.9%; MDR Enterobacterales, 96.8%, 94.4% and 100%, respectively; DTR isolates, ≥ 76.2% to ceftazidime-avibactam and colistin; MEM-R, MBL-negative isolates, ≥ 90.0% to ceftazidime-avibactam and colistin.

Keywords: Ceftazidime-avibactam, Pseudomonas aeruginosa, Enterobacterales, Antimicrobial surveillance, ATLAS, Difficult-to-treat

Introduction

Pseudomonas aeruginosa and members of the Enterobacterales are important pathogens that cause a range of infections. Their treatment can be problematic due to acquired and/or intrinsic antimicrobial resistance [1, 2]. Ceftazidime (a third-generation cephalosporin) in combination with avibactam (a diazabicyclooctane, non-β-lactam, β-lactamase inhibitor) has activity against Gram-negative organisms with Ambler class A, class C and some class D (e.g. OXA-48 type) β-lactamases, although the combination is not active against class B metallo-β-lactamases (MBLs) [3–5].

ATLAS (Antimicrobial Testing Leadership And Surveillance) is a freely accessible antimicrobial surveillance program with a searchable online database (www.atlas-surveillance.com) designed to chart the in vitro activity of antimicrobial agents against Gram-positive and Gram-negative organisms collected globally. In this analysis, we evaluate the in vitro activity of ceftazidime-avibactam and comparator agents against Pseudomonas aeruginosa and Enterobacterales isolates collected in 2019 from patients in Croatia, Czech Republic, Hungary, Poland, Latvia and Lithuania.

Materials and methods

Isolates of P. aeruginosa and Enterobacterales (N = 2340) were submitted by study centres in Croatia (n = 4), Czech Republic (n = 4), Hungary (n = 3), Poland (n = 4), Latvia (n = 1) and Lithuania (n = 2) in 2019 from patients of all ages. Acceptable sources were intra-abdominal, urinary tract, skin and skin structure, lower respiratory tract and bloodstream; only non-duplicate isolates of causative pathogens were accepted. Demographic information (specimen source, patient age and sex, and type of hospital setting) was recorded for each isolate.

Bacterial identification was confirmed at the central laboratory, International Health Management Associates, Inc. (IHMA; Schaumburg, IL, USA), using matrix-assisted laser desorption ionization-time of flight spectrometry (MALDI-TOF; Bruker Daltonics, Billerica, MA, USA). Susceptibility testing was according to the Clinical Laboratory Standards Institute (CLSI) broth microdilution methodology [6]. Ceftazidime-avibactam was tested with fixed concentration of avibactam at 4 mg/L. All minimum inhibitory concentration (MIC) values were interpreted using EUCAST breakpoints [7].

Difficult-to-treat (DTR) isolates were resistant to aztreonam, cefepime, ceftazidime, imipenem, meropenem, ciprofloxacin, levofloxacin and piperacillin-tazobactam. Multidrug-resistant (MDR) isolates were resistant to ≥ 1 agent from ≥ 3 classes: cephalosporins (ceftazidime, cefepime), monobactams (aztreonam), β-lactam/β-lactamase-inhibitor combinations (piperacillin-tazobactam), carbapenems (meropenem, imipenem), fluoroquinolones (levofloxacin, ciprofloxacin), aminoglycosides (amikacin) and polymyxins (colistin). Meropenem-resistant (MEM-R) isolates were isolates with an MIC to meropenem of ≥ 16 mg/L. Carbapenemase and metallo-β-lactamase (MBL) genes were determined using polymerase chain reaction (PCR) assays [8, 9]. Detected genes were amplified using flanking primers and sequenced, and sequences were compared against publicly available databases. Carbapenemase-positive isolates were identified as those with genes encoding a KPC, OXA-48-like, IMP, VIM, NDM, GES, GIM and/or SPM enzyme, and MBL-positive isolates were identified as those with genes encoding an NDM, IMP, VIM, GIM and/or SPM enzyme. MBL-negative isolates were defined as those that underwent testing but did not possess NDM, IMP, VIM, GIM and SPM genes.

Results

The majority of P. aeruginosa (n = 701) and Enterobacterales isolates (n = 1639) were collected from male patients, patients ≥ 18 years of age and non-ICU wards (Table 1). The highest proportion of P. aeruginosa isolates were from respiratory sources. Similar percentages of Enterobacterales isolates were from blood, respiratory or skin/musculoskeletal sources (Table 1).

Table 1.

Demographic data for Pseudomonas aeruginosa and Enterobacterales isolates, collected from Croatia, Czech Republic, Hungary, Poland, Latvia and Lithuania, 2019

Pseudomonas aeruginosa Enterobacterales
N = 701 N = 1639
n % n %
Age groups (years)
  0 to 17 85 12.1 151 9.2
  18 to 64 261 37.2 525 32.0
   ≥ 65 353 50.4 958 58.5
  Unknown 2 0.3 5 0.3
Sex
  Female 246 35.1 678 41.4
  Male 453 64.6 955 58.3
  Unknown 2 0.3 6 0.4
Patient location
  ICU 271 38.7 511 31.2
  General wards, Emergency 395 56.3 1043 63.6
  Unknown/Other 35 5.0 85 5.2
Isolates sources
  Circulatory (blood) 114 16.3 403 24.6
  Genitourinary 82 11.7 253 15.4
  Intestinal 34 4.9 213 13.0
  Respiratory 296 42.2 415 25.3
  Skin/musculoskeletal 174 24.8 355 21.7
  Unknown 1 0.1 0 0.0
Open in a new tab

Pseudomonas aeruginosa

The agents against which P. aeruginosa had the highest rates of susceptibility (using standard dosing susceptibility breakpoints) were amikacin (89.2%), ceftazidime-avibactam (92.2%) and colistin (99.9%) (Table 2). For ceftazidime alone, 74.3% of isolates were susceptible (increased exposure). A total of 5.7% (40/701) of isolates were classified as DTR and 28.4% (199/701) were MDR. Among these isolates, susceptibility to colistin was unchanged (100% and 99.5%, respectively) relative to the whole P. aeruginosa set. Susceptibility rates to amikacin and ceftazidime-avibactam were 62.5% and 37.5%, respectively, against DTR isolates and 68.3% and 72.9%, respectively, against MDR isolates (Table 2). Results against MEM-R isolates were similar to those seen against MDR isolates for the majority of agents (Table 2). Against all three resistant subsets, rates of susceptibility (increased exposure) to ceftazidime (DTR, 0.0%; MDR, 16.1%; MEM-R, 24.0%) were lower than susceptibility rates (standard dosing) reported for ceftazidime-avibactam.

Table 2.

Antimicrobial activity of ceftazidime-avibactam and comparators against Pseudomonas aeruginosa isolates collected from Croatia, Czech Republic, Hungary, Poland, Latvia and Lithuania in 2019

Antimicrobial MIC90 (mg/L) Range (mg/L) Susceptible, standard dosing Susceptible, increased exposure Resistant
P. aeruginosa (n = 701) n % n % n %
  Amikacin 32 0.5 – ≥ 128 625 89.2 – – 76 10.8
  Aztreonam 32 0.25 – ≥ 256 – – 586 83.6 115 16.4
  Cefepime 32 0.5 – ≥ 64 – – 539 76.9 162 23.1
  Ceftazidime 64 0.25 – ≥ 256 – – 521 74.3 180 25.7
  Ceftazidime-avibactam 8 0.12 – ≥ 256 646 92.2 – – 55 7.8
  Ciprofloxacin  ≥ 8  ≤ 0.12 – ≥ 8 – – 477 68.0 224 32.0
  Colistin 2 0.25 – ≥ 16 700 99.9 – – 1 0.1
  Gentamicin  ≥ 32  ≤ 0.12 – ≥ 32 – – – – – –
  Imipenem  ≥ 16  ≤ 0.06 – ≥ 16 – – 473 67.5 228 32.5
  Levofloxacin  ≥ 16  ≤ 0.25 – ≥ 16 – – 437 62.3 264 37.7
  Meropenem 16  ≤ 0.06 – ≥ 32 471 67.2 105 15.0 125 17.8
  Piperacillin-tazobactam  ≥ 128  ≤ 0.12 – ≥ 128 – – 501 71.5 200 28.5
  Tigecycline  ≥ 16 1 – ≥ 16 – – – – – –
DTR P. aeruginosa (n = 40)
  Amikacin 64 2 – ≥ 128 25 62.5 – – 15 37.5
  Aztreonam 64 32 – ≥ 256 – – 0 0.0 40 100
  Cefepime  ≥ 64 16 – ≥ 64 – – 0 0.0 40 100
  Ceftazidime  ≥ 256 16 – ≥ 256 – – 0 0.0 40 100
  Ceftazidime-avibactam  ≥ 256 4 – ≥ 256 15 37.5 – – 25 62.5
  Ciprofloxacin  ≥ 8 1 – ≥ 8 – – 0 0.0 40 100
  Colistin 2 0.5 – 2 40 100 – – 0 0.0
  Gentamicin  ≥ 32 0.25 – ≥ 32 – – – – – –
  Imipenem  ≥ 16 8 – ≥ 16 – – 0 0.0 40 100
  Levofloxacin  ≥ 16 4 – ≥ 16 – – 0 0.0 40 100
  Meropenem  ≥ 32 16 – ≥ 32 0 0.0 0 0.0 40 100
  Piperacillin-tazobactam  ≥ 128 32 – ≥ 128 – – 0 0.0 40 100
  Tigecycline  ≥ 16 1 – ≥ 16 – – – – – –
MDR P. aeruginosa (n = 199)
  Amikacin  ≥ 128 0.5 – ≥ 128 136 68.3 – – 63 31.7
  Aztreonam 64 4 – ≥ 256 – – 88 44.2 111 55.8
  Cefepime  ≥ 64 2 – ≥ 64 – – 45 22.6 154 77.4
  Ceftazidime  ≥ 256 2 – ≥ 256 – – 32 16.1 167 83.9
  Ceftazidime-avibactam 64 1 – ≥ 256 145 72.9 – – 54 27.1
  Ciprofloxacin  ≥ 8  ≤ 0.12 – ≥ 8 – – 51 25.6 148 74.4
  Colistin 2 0.25 – ≥ 16 198 99.5 – – 1 0.5
  Gentamicin  ≥ 32  ≤ 0.12 – ≥ 32 – – – – – –
  Imipenem  ≥ 16 0.5 – ≥ 16 – – 54 27.1 145 72.9
  Levofloxacin  ≥ 16  ≤ 0.25 – ≥ 16 – – 38 19.1 161 80.9
  Meropenem  ≥ 32  ≤ 0.06 – ≥ 32 40 20.1 46 23.1 113 56.8
  Piperacillin-tazobactam  ≥ 128 8 – ≥ 128 – – 20 10.1 179 89.9
  Tigecycline  ≥ 16 1 – ≥ 16 – – – – – –
MEM-R P. aeruginosa (n = 125)
  Amikacin  ≥ 128 1 – ≥ 128 82 65.6 – – 43 34.4
  Aztreonam 64 4 – ≥ 256 – – 68 54.4 57 45.6
  Cefepime  ≥ 64 2 – ≥ 64 – – 39 31.2 86 68.8
  Ceftazidime  ≥ 256 2 – ≥ 256 – – 30 24.0 95.0 76.0
  Ceftazidime-avibactam 64 2 – ≥ 256 82 65.6 – – 43 34.4
  Ciprofloxacin  ≥ 8  ≤ 0.12 – ≥ 8 – – 23 18.4 102 81.6
  Colistin 2 0.25 – 2 125 100 – – 0 0.0
  Gentamicin  ≥ 32 0.25 – ≥ 32 – – – – – –
  Imipenem  ≥ 16 1 – ≥ 16 – – 2 1.6 123 98.4
  Levofloxacin  ≥ 16 0.5 – ≥ 16 – – 11 8.8 114 91.2
  Piperacillin-tazobactam  ≥ 128 4 – ≥ 128 – – 23 18.4 102 81.6
  Tigecycline  ≥ 16 1 – ≥ 16 – – – – – –
MEM-R, MBL-negative P. aeruginosa (n = 103)
  Amikacin 64 1 – ≥ 128 75 72.8 – – 28 27.2
  Aztreonam 64 4 – ≥ 256 – – 55 53.4 48 46.6
  Cefepime 32 2 – ≥ 64 – – 37 35.9 66 64.1
  Ceftazidime 128 2 – ≥ 256 – – 30 29.1 73 70.9
  Ceftazidime-avibactam 16 2 – ≥ 256 81 78.6 – – 22 21.4
  Ciprofloxacin  ≥ 8  ≤ 0.12 – ≥ 8 – – 18 17.5 85 82.5
  Colistin 2 0.25 – 2 103 100 – – 0 0.0
  Gentamicin  ≥ 32 0.25 – ≥ 32 – – – – –  –
  Imipenem  ≥ 16 1 – ≥ 16 – – 2 1.9 101 98.1
  Levofloxacin  ≥ 16 0.5 – ≥ 16 – – 8 7.8 95 92.2
  Piperacillin-tazobactam  ≥ 128 4 – ≥ 128 – – 22 21.4 81 78.6
  Tigecycline  ≥ 16 1 – ≥ 16 – – – – – –
Open in a new tab

MIC, minimum inhibitory concentration; DTR, difficult to treat; MDR, multidrug resistant; MEM-R, meropenem resistant; MBL, metallo-β-lactamase

Among the MEM-R P. aeruginosa, 82.4% (103/125) were identified as MBL-negative. All MBL-negative isolates were susceptible to colistin (Table 2), 78.6% to ceftazidime-avibactam and 72.8% to amikacin. A total of 29.1% of MBL-negative isolates were susceptible (increased exposure) to ceftazidime alone.

Among the 125 MEM-R isolates, 22 (17.6%) were MBL-positive and 29 (23.2%) were carbapenemase-positive. Colistin was the only agent active against the MBL-positive isolates (100% susceptible, data not shown).

Enterobacterales

Susceptibility to amikacin, ceftazidime-avibactam, colistin and meropenem against Enterobacterales was ≥ 96.1%, and to ceftazidime alone, 69.5% (Table 3). Susceptibility to tigecycline was 99.8% (E. coli and C. koseri, only).

Table 3.

Antimicrobial activity of ceftazidime-avibactam and comparators against Enterobacterales isolates collected from Croatia, Czech Republic, Hungary, Poland, Latvia and Lithuania in 2019

Antimicrobial MIC90 (mg/L) MIC range (mg/L) Susceptible, standard dosing Susceptible, increased exposure Resistant
Enterobacterales (n = 1639) n % n % n %
  Amikacin 8  ≤ 0.25 – ≥ 128 1575 96.1 – – 64 3.9
  Amoxicillin-clavulanate  ≥ 32  ≤ 0.12 – ≥ 32 923 56.3 – – 716 43.7
  Aztreonam 64  ≤ 0.015 – ≥ 256 1157 70.6 39 2.4 443 27.0
  Cefepime  ≥ 64  ≤ 0.12 – ≥ 64 1198 73.1 70 4.3 371 22.6
  Ceftazidime 64  ≤ 0.015 – ≥ 256 1139 69.5 52 3.2 448 27.3
  Ceftazidime-avibactam 0.5  ≤ 0.015 – ≥ 256 1626 99.2 – – 13 0.8
  Ciprofloxacin  ≥ 8  ≤ 0.12 – ≥ 8 1092 66.6 45 2.7 502 30.6
  Colistina 1  ≤ 0.06 – ≥ 16 1304 97.9 – – 28 2.1
  Gentamicin  ≥ 32  ≤ 0.12 – ≥ 32 1314 80.2 – – 325 19.8
  Imipenem 2  ≤ 0.06 – ≥ 16 1362 83.1 231 14.1 46 2.8
  Levofloxacin  ≥ 16  ≤ 0.25 – ≥ 16 1170 71.4 87 5.3 382 23.3
  Meropenem 0.12  ≤ 0.06 – ≥ 32 1587 96.8 22 1.3 30 1.8
  Piperacillin-tazobactam  ≥ 128  ≤ 0.12 – ≥ 128 1240 75.7 – – 399 24.3
  Tigecyclineb 2 0.06 – 8 472 99.8 0 0.0 1 0.2
DTR Enterobacterales (n = 21)
  Amikacin  ≥ 128 2 – ≥ 128 12 57.1 – – 9 42.9
  Amoxicillin-clavulanate  ≥ 32  ≥ 32 0 0.0 – – 21 100
  Aztreonam  ≥ 256 16 – ≥ 256 0 0.0 0 0.0 21 100
  Cefepime  ≥ 64 32 – ≥ 64 0 0.0 0 0.0 21 100
  Ceftazidime  ≥ 256 32 – ≥ 256 0 0.0 0 0.0 21 100
  Ceftazidime-avibactam  ≥ 256 0.5 – ≥ 256 16 76.2 – – 5 23.8
  Ciprofloxacin  ≥ 8 4 – ≥ 8 0 0.0 0 0.0 21 100
  Colistina 2 0.25 – ≥ 16 20 95.2 – – 1 4.8
  Gentamicin  ≥ 32 0.5 – ≥ 32 8 38.1 – – 13 61.9
  Imipenem  ≥ 16  ≥ 16 0 0.0 0 0.0 21 100
  Levofloxacin  ≥ 16 2 – ≥ 16 0 0.0 0 0.0 21 100
  Meropenem  ≥ 32  ≥ 32 0 0.0 0 0.0 21 100
  Piperacillin-tazobactam  ≥ 128  ≥ 128 0 0.0 – – 21 100
  Tigecyclineb 2 0.25 – 4 – – – – – –
MDR Enterobacterales (n = 410)
  Amikacin 16 0.5 – ≥ 128 366 89.3 – – 44 10.7
  Amoxicillin-clavulanate  ≥ 32 2 – ≥ 32 108 26.3 – – 302 73.7
  Aztreonam  ≥ 256 0.03 – ≥ 256 5 1.2 6 1.5 399 97.3
  Cefepime  ≥ 64  ≤ 0.12 – ≥ 64 35 8.5 39 9.5 336 82.0
  Ceftazidime  ≥ 256 0.25 – ≥ 256 5 1.2 12 2.9 393 95.9
  Ceftazidime-avibactam 2 0.06 – ≥ 256 397 96.8 – – 13 3.2
  Ciprofloxacin  ≥ 8  ≤ 0.12 – ≥ 8 69 16.8 9 2.2 332 81.0
  Colistina 1 0.12 – ≥ 16 371 94.4 – – 22 5.6
  Gentamicin  ≥ 32  ≤ 0.12 – ≥ 32 180 43.9 – – 230 56.1
  Imipenem 4 0.12 – ≥ 16 347 84.6 26 6.3 37 9.0
  Levofloxacin  ≥ 16  ≤ 0.25 – ≥ 16 120 29.3 45 11.0 245 59.8
  Meropenem 4  ≤ 0.06 – ≥ 32 358 87.3 22 5.4 30 7.3
  Piperacillin-tazobactam  ≥ 128 0.5 – ≥ 128 81 19.8 – – 329 80.2
  Tigecyclineb 2 0.06 – 8 53 100 0 0.0 0 0.0
MEM-R Enterobacterales (n = 30)
  Amikacin  ≥ 128 0.5 – ≥ 128 20 66.7 – – 10 33.3
  Amoxicillin-clavulanate  ≥ 32 16 – ≥ 32 0 0.0 – – 30 100
  Aztreonam  ≥ 256 0.25 – ≥ 256 2 6.7 0 0.0 28 93.3
  Cefepime  ≥ 64 2 – ≥ 64 0 0.0 1 3.3 29 96.7
  Ceftazidime  ≥ 256 0.5 – ≥ 256 1 3.3 0 0.0 29 96.7
  Ceftazidime-avibactam  ≥ 256 0.12 – ≥ 256 21 70.0 – – 9 30.0
  Ciprofloxacin  ≥ 8  ≤ 0.12 – ≥ 8 1 3.3 0 0.0 29 96.7
  Colistina 2 0.25 – ≥ 16 28 93.3 – – 2 6.7
  Gentamicin  ≥ 32 0.25 – ≥ 32 13 43.3 – – 17 56.7
  Imipenem  ≥ 16 2 – ≥ 16 2 6.7 2 6.7 26 86.7
  Levofloxacin  ≥ 16 0.5 – ≥ 16 1 3.3 3 10.0 26 86.7
  Piperacillin-tazobactam  ≥ 128 64 – ≥ 128 0 0.0 – – 30 100
  Tigecyclineb 2 0.25 – 4 – – – – – –
MEM-R, MBL-negative Enterobacterales (n = 20)
  Amikacin  ≥ 128 0.5– ≥ 128 11 55.0 – – 9 45.0
  Amoxicillin-clavulanate  ≥ 32 16– ≥ 32 0 0.0 – – 20 100
  Aztreonam  ≥ 256 0.25– ≥ 256 1 5.0 0 0.0 19 95.0
  Cefepime  ≥ 64 2– ≥ 64 0 0.0 1 5.0 19 95.0
  Ceftazidime  ≥ 256 0.5– ≥ 256 1 5.0 0 0.0 19 95.0
  Ceftazidime-avibactam 4 0.12– ≥ 256 19 95.0 – – 1 5.0
  Ciprofloxacin  ≥ 8 4– ≥ 8 0 0.0 0 0.0 20 100
  Colistina 2 0.25– ≥ 16 18 90.0 – – 2 10.0
  Gentamicin  ≥ 32 0.25– ≥ 32 7 35.0 – – 13 65.0
  Imipenem  ≥ 16 2– ≥ 16 2 10.0 2 10.0 16 80.0
  Levofloxacin  ≥ 16 1– ≥ 16 0 0.0 1 5.0 19 95.0
  Piperacillin-tazobactam  ≥ 128 64– ≥ 128 0 0.0 – – 20 100
  Tigecyclineb 2 0.25–4 – – – – – –
Open in a new tab

MIC, minimum inhibitory concentration; ESBL, extended-spectrum β-lactamase; DTR, difficult to treat; MDR, multidrug resistant; MEM-R, meropenem resistant; MBL, metallo-β-lactamase

aFor colistin, Morganella morganii, Proteus spp., Providencia spp. and Serratia spp. were excluded from analysis because of their intrinsic resistance; therefore, number of isolates tested against colistin: Enterobacterales, n = 1332; ESBL-positive Enterobacterales, n = 297; DTR Enterobacterales, n = 21; MDR Enterobacterales, n = 393; MEM-R Enterobacterales, n = 30; MBL-negative Enterobacterales, n = 20

bFor tigecycline, susceptibility and resistance rates among the Enterobacterales were only calculated for Escherichia coli and Citrobacter koseri as EUCAST breakpoints are only approved against these species: Enterobacterales, n = 473; ESBL-positive Enterobacterales, n = 66; DTR Enterobacterales, n = 1; MDR Enterobacterales, n = 53; MEM-R Enterobacterales, n = 1; MBL-negative Enterobacterales, n = 1. Percentages not given when < 10 isolates. MIC90 and MIC range data for tigecycline are calculated for all Enterobacterales collected

Of the Enterobacterales, 1.3% (21/1639) were DTR and 25.0% (410/1639) were MDR. Among MDR isolates, susceptibility rates were highest to ceftazidime-avibactam (96.8%), colistin (94.4%) and tigecycline (100%, E. coli and C. koseri only), and among DTR isolates, ≥ 57.1% were susceptible to amikacin, ceftazidime-avibactam and colistin (Table 3). Few isolates were susceptible to ceftazidime alone (MDR, 1.2%; DTR, 0.0%).

Of the 30/1639 isolates that were MEM-R, 66.7% were susceptible to amikacin, 70% to ceftazidime-avibactam and 93.3% to colistin; however, only 3.3% were susceptible to ceftazidime alone. Of the 20 MEM-R, MBL-negative isolates, 95.0% were susceptible to ceftazidime-avibactam, 90.0% were susceptible to colistin and only one isolate was susceptible to ceftazidime alone. Ten MEM-R isolates were MBL-positive, of which 9 were amikacin-susceptible and all 10 were colistin-susceptible (data not shown). Among the 26/30 carbapenemase-positive isolates, 65.4% were susceptible to amikacin, 69.2% to ceftazidime-avibactam and 92.3% to colistin.

Discussion

Susceptibility among P. aeruginosa was highest to amikacin, ceftazidime-avibactam and colistin and among the Enterobacterales, to ceftazidime-avibactam, colistin and tigecycline (E. coli and C. koseri only), followed by meropenem and amikacin. Similar results have been reported for isolates collected in 2012–2015 across Europe [10, 11], although for colistin and tigecycline, susceptibility rates among Enterobacterales were lower than in our study [11]. This is likely due to inclusion of a broader range of species of Enterobacterales by Kazmierczak et al. [11]. Similar ATLAS data were also reported for Central Europe/Israel (2014–2018) [12], indicating that susceptibility rates to ceftazidime-avibactam, colistin and amikacin remain stable in the region. As previously reported [10, 11], susceptibility rates to ceftazidime alone were low compared with ceftazidime and avibactam combined, particularly among resistant subsets.

Among P. aeruginosa and Enterobacterales 5.7% and 1.3% were DTR, respectively. DTR is a valuable category, comprising isolates that are not susceptible to first-line, high-efficacy, low-toxicity agents [13]. The majority of DTR isolates in our study were susceptible to colistin (P. aeruginosa, 100%; Enterobacterales, 95.2%) and most DTR Enterobacterales were susceptible to ceftazidime-avibactam (76.2%); however, the rate was reduced against DTR P. aeruginosa (37.5% susceptible). Amikacin susceptibility rates against DTR isolates were 62.5% (P. aeruginosa) and 57.1% (Enterobacterales).

Most (82.4%) MEM-R P. aeruginosa were MBL-negative and, as with the other subsets in this analysis, their susceptibility was highest to ceftazidime-avibactam, amikacin and colistin. The susceptibility breakpoint for ceftazidime alone only applies at increased exposure, and susceptibility was low compared with ceftazidime-avibactam (29.1% vs. 78.6%), demonstrating the value of combining avibactam with ceftazidime. The other MEM-R isolates (17.6%) were MBL-positive, against which only colistin was active. A lower rate of Enterobacterales than P. aeruginosa were meropenem-resistant (1.8% vs. 17.8%), similar to the rates reported by Kristóf et al. [12]. Two thirds of MEM-R Enterobacterales were MBL-negative and, as reported previously [3], most were susceptible to ceftazidime-avibactam and colistin. As with P. aeruginosa, few Enterobacterales isolates were susceptible to ceftazidime alone, in line with previous reports [3], again demonstrating the value of the combination.

Overall, 55 (7.8%) P. aeruginosa isolates were resistant to ceftazidime-avibactam, similar to that reported for European isolates collected in 2012–2015 [10]. Of these, 23/55 were identified as carbapenemase producers (22 MBL-positive [7 IMP, 15 VIM] and 1 carbapenemase-positive [GES] but MBL-negative). No other GES-positive isolates were identified and for the remaining 32 isolates, no carbapenemase or MBL genes were detected. In contrast, 13 (0.8%) Enterobacterales isolates were identified as resistant to ceftazidime-avibactam and 12/13 isolates were MBL-positive (4 VIM, 8 NDM-1; Citrobacter freundii [n = 1], Enterobacter cloacae [n = 8] and K. pneumoniae [n = 3]). For the remaining isolate (E. coli), no carbapenemase or MBL genes were detected. Ceftazidime-avibactam is known to be inactive against MBL-producing isolates [3].

There are limitations to this analysis; the study collected a predetermined number of isolates from each centre and so cannot be considered epidemiological. With only 1 year of data, some isolate numbers are low, particularly in the resistance subsets, meaning that some of the data should be treated with some caution.

In conclusion, rates of susceptibility to ceftazidime-avibactam were high among isolates of P. aeruginosa and Enterobacterales collected from Croatia, Czech Republic, Hungary, Poland, Latvia and Lithuania in 2019 and were similar to activity reported in previous years for isolates collected in Europe. Amikacin and colistin also continue to be active against these Gram-negative isolates, as does tigecycline against isolates of E. coli and C. koseri. Meropenem susceptibility rates were high among Enterobacterales isolates but reduced against P. aeruginosa. Ceftazidime-avibactam continues to be a good choice for the treatment of MDR Gram-negative infections, it has a safety profile consistent with that previously observed for ceftazidime alone [14–17] and does not require therapeutic drug monitoring.

Acknowledgements

The authors would like to thank the staff at International Health Management Associates (IHMA) Inc. for their co-ordination of the study and also all investigators and laboratories for their participation in the study.

Author contribution

VA, IM, JS, LP, SB, SHH, AK, BM-P participated in data interpretation, as well as drafting and reviewing the manuscript. All authors read and approved the final manuscript.

Funding

This study is funded by Pfizer. Pfizer were involved in study design and the decision to submit the work for publication. Medical writing support was provided by Wendy Hartley, PhD, at Micron Research Ltd. (Ely, UK), and was funded by Pfizer. Micron Research Ltd. also provided data management services which were funded by Pfizer.

Data availability

The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request. Data from the global ATLAS study can be accessed at https://atlas-surveillance.com.

Declarations

Conflict of interest

IM and JS have no competing interests. VA has received support for conference registration from Pfizer spol. s r.o. LP has received honoraria for poster presentation from Pfizer Polska Sp. z o.o. SB, SHH, AK and BM-P are employees of Pfizer.

Footnotes

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  • 1.Pang Z, Raudonis R, Glick BR, Lin T-J, Zhenyu Cheng Z. Antibiotic resistance in Pseudomonas aeruginosa: mechanisms and alternative therapeutic strategies. Biotechnol Adv. 2019;37:177–192. doi: 10.1016/j.biotechadv.2018.11.013. [DOI] [PubMed] [Google Scholar]
  • 2.De Oliveira DMP, Forde BM, Kidd TJ, Harris PNA, Schembri MA, Beatson SA, Paterson DL, Walker MJ. Antimicrobial resistance in ESKAPE pathogens. Clin Microbiol Rev. 2020;33:e00181–19. doi: 10.1128/CMR.00181-19. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.de Jonge BLM, Karlowsky JA, Kazmierczak KM, Biedenbach DJ, Sahm DF, Nichols WW. In vitro susceptibility to ceftazidime-avibactam of carbapenem-nonsusceptible Enterobacteriaceae isolates collected during the INFORM global surveillance study. Antimicrob Agents Chemother. 2016;60:3163–3169. doi: 10.1128/AAC.03042-15. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Levasseur P, Girard AM, Miossec C, Pace J, Coleman K. In vitro antibacterial activity of the ceftazidime-avibactam combination against Enterobacteriaceae, including strains with well-characterized β-lactamases. Antimicrob Agents Chemother. 2015;59:1931–1934. doi: 10.1128/AAC.04218-14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Papp-Wallace KM, Bajaksouzian S, Abdelhamed AM, Foster AN, Winkler ML, Gatta JA, Nichols WW, Testa R, Bonomo RA, Jacobs MR. Activities of ceftazidime, ceftaroline, and aztreonam alone and combined with avibactam against isogenic Escherichia coli strains expressing selected single β-lactamases. Diagn Microbiol Infect Dis. 2015;82:65–69. doi: 10.1016/j.diagmicrobio.2015.02.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Clinical and Laboratory Standards Institute (2018) Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standards. 11th ed. CLSI document M07. Wayne, PA: Clinical and Laboratory Standards Institute
  • 7.The European Committee on Antimicrobial Susceptibility Testing (2021) Breakpoint tables for interpretation of MICs and zone diameters. Version 11.0. http://www.eucast.org. Accessed 3 Aug 2021
  • 8.Lob SH, Kazmierczak KM, Badal RE, Hackel MA, Bouchillon SK, Biedenbach DJ, Sahm DF. Trends in susceptibility of Escherichia coli from intra-abdominal infections to and comparators in the United States according to data from the SMART program, 2009–2013. Antimicrob Agents Chemother. 2015;59:3606–3610. doi: 10.1128/AAC.05186-14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Nichols WW, de Jonge BLM, Kazmierczak KM, Karlowsky JA, Sahm DF. In vitro susceptibility of global surveillance isolates of Pseudomonas aeruginosa to ceftazidime-avibactam (INFORM 2012 to 2014) Antimicrob Agents Chemother. 2016;60:4743–4749. doi: 10.1128/AAC.00220-16. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Kazmierczak KM, de Jonge BLM, Stone GG, Sahm DF. In vitro activity of ceftazidime/avibactam against isolates of Pseudomonas aeruginosa collected in European countries: INFORM global surveillance 2012–15. J Antimicrob Chemother. 2018;73:2777–2781. doi: 10.1093/jac/dky267. [DOI] [PubMed] [Google Scholar]
  • 11.Kazmierczak KM, de Jonge BLM, Stone GG, Sahm DF. In vitro activity of ceftazidime/avibactam against isolates of Enterobacteriaceae collected in European countries: INFORM global surveillance 2012–15. J Antimicrob Chemother. 2018;73:2782–2788. doi: 10.1093/jac/dky266. [DOI] [PubMed] [Google Scholar]
  • 12.Kristóf K, Adámková V, Adler A, Gospodarek-Komkowska E, Rafila A, Billová S, Możejko-Pastewka B, Kiss F. In vitro activity of ceftazidime-avibactam and comparators against Enterobacterales and Pseudomonas aeruginosa isolates from Central Europe and Israel, 2014–2017 and 2018. Diagn Microbiol Infect Dis. 2021;101:115420. doi: 10.1016/j.diagmicrobio.2021.115420. [DOI] [PubMed] [Google Scholar]
  • 13.Kadri SS, Adjemian J, Lai YL, Spaulding AB, Ricotta E, Prevots DR, Palmore TN, Rhee C, Klompas M, Dekker JP, Powers 3rd JH, Suffredini AF, Hooper DC, Fridkin S, Danner RL, National Institutes of Health Antimicrobial Resistance Outcomes Research Initiative (NIH–ARORI) (2018) Difficult-to-treat resistance in Gram-negative bacteremia at 173 US hospitals: retrospective cohort analysis of prevalence, predictors, and outcome of resistance to all first-line agents. Clin Infect Dis 67:1803–1814. 10.1093/cid/ciy378 [DOI] [PMC free article] [PubMed]
  • 14.Carmeli Y, Armstrong J, Laud PJ, Newell P, Stone G, Wardman A, Gasink LB. Ceftazidime-avibactam or best available therapy in patients with ceftazidime-resistant Enterobacteriaceae and Pseudomonas aeruginosa complicated urinary tract infections or complicated intra-abdominal infections (REPRISE): a randomised, pathogen-directed, phase 3 study. Lancet Infect Dis. 2016;16:661–673. doi: 10.1016/S1473-3099(16)30004-4. [DOI] [PubMed] [Google Scholar]
  • 15.Mazuski JE, Gasink LB, Armstrong J, Broadhurst H, Stone GG, Rank D, Llorens L, Newell P, Pachl J. Efficacy and safety of ceftazidime-avibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infection: results from a randomized, controlled, double-blind, phase 3 program. Clin Infect Dis. 2016;62:1380–1389. doi: 10.1093/cid/ciw133. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Torres A, Zhong N, Pachl J, Timsit J-F, Kollef M, Chen Z, Song J, Taylor D, Laud PJ, Stone GG, Chow JW. Ceftazidime-avibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia (REPROVE): a randomised, double-blind, phase 3 non-inferiority trial. Lancet Infect Dis. 2018;18:285–295. doi: 10.1016/S1473-3099(17)30747-8. [DOI] [PubMed] [Google Scholar]
  • 17.Wagenlehner FM, Sobel JD, Newell P, Armstrong J, Huang X, Stone GG, Yates K, Gasink LB. Ceftazidime-avibactam versus doripenem for the treatment of complicated urinary tract infections, including acute pyelonephritis: RECAPTURE, a phase 3 randomized trial program. Clin Infect Dis. 2016;63:754–762. doi: 10.1093/cid/ciw378. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request. Data from the global ATLAS study can be accessed at https://atlas-surveillance.com.

Articles from European Journal of Clinical Microbiology & Infectious Diseases are provided here courtesy of Springer

RESOURCES