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

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.


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][4][5].
ATLAS (Antimicrobial Testing Leadership And Surveillance) is a freely accessible antimicrobial surveillance program with a searchable online database (www. atlas-surve illan ce. 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].

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).

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.
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 ceftazidimeavibactam 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][15][16][17] and does not require therapeutic drug monitoring.