Antimicrobial susceptibility to last-resort antibiotics in carbapenemase-producing bacteria from Ukrainian patients

Abstract

Since March 2022, an increase was observed in multidrug-resistant microorganisms (MDRO), associated with the hospital transfer of Ukrainian patients. The goal was to collect phenotypic susceptibility data and assess clinical implications. Carbapenemase-producing Enterobacterales (CPE, n = 96), Pseudomonas aeruginosa (CPPA, n = 20), and carbapenem-resistant Acinetobacter baumannii-calcoaceticus (CRAB, n = 6) from Ukrainian patients were obtained from March to December 2022 from the Dutch MDRO surveillance. Antimicrobial susceptibility testing was performed using broth microdilution (BMD) when available, fosfomycin agar dilution, disk diffusion (DD) for cefiderocol, and diverse gradient strips. All isolates were sequenced with Illumina next-generation sequencing. For meropenem, aminoglycosides, ceftazidime-avibactam, ceftolozane-tazobactam, and imipenem-relebactam, susceptibility rates were low (0%-30%), due to the high number of bla_NDM-positive isolates (79/122; 65%). For cefiderocol, results depended on reading with or without microcolonies, applying EUCAST or CLSI breakpoints, and whether DD or BMD was used; e.g., for Klebsiella pneumoniae, 30%-97% were susceptible. For colistin, 103/111 (93%) non-intrinsically resistant CPE/CPPA/CRAB isolates were susceptible. For most CPE, a low minimal inhibitory concentration (MIC) of <0.5 mg/L was measured for tigecycline and ceftazidime-avibactam-aztreonam. For CPPA, cefiderocol tested susceptible in 65%-100% of isolates. For CRAB, ampicillin-sulbactam MICs were ≥128 mg/L; for sulbactam-durlobactam, 1-2 mg/L. Admission in a Ukrainian hospital in the last year was a risk factor for MDRO, and majority were screening isolates (79%). There is extensive phenotypic resistance to last-resort antibiotics in MDRO from Ukrainian patients. Interpretation of cefiderocol susceptibility results depends on several variables. When treating patients recently admitted in Ukraine, suspected for Gram-negative bacterial infection, this should be taken into consideration.

Importance: Since March 2022, multidrug-resistant microorganisms associated with Ukrainian patients have been detected in national surveillance systems of several European countries. We studied the phenotypic antimicrobial susceptibility to last-resort antibiotics of multidrug-resistant microorganisms from Ukrainian patients in the Netherlands and assessed clinical implications. Our research revealed that there was extensive phenotypic resistance to last-resort antibiotics. Healthcare professionals should be aware of multidrug-resistant microorganisms when treating patients recently admitted in Ukraine, suspected for Gram-negative bacterial infection.

Keywords: Acinetobacter baumannii; Pseudomonas aeruginosa; Ukraine; War; antimicrobial susceptibility testing; carbapenemase-producing Enterobacterales; cefiderocol; ceftazidime–avibactam; ceftolozane–tazobactam; imipenem–relebactam; multidrug-resistant microorganisms.

Fig 1

wgMLST analysis of MDRO from Ukrainian patients. Each circle represents an MDRO isolate per person, and the circle size indicates the number of isolates. Genetic clusters are indicated with gray halos. A genetic cluster of K. pneumoniae, P. aeruginosa, E. coli, A. baumannii, P. mirabilis, and P. stuartii isolates is defined as ≥2 isolates that differ by ≤20, ≤15, ≤25, ≤15, ≤15, and ≤15 alleles, respectively.

Fig 2

(A–C) Susceptibility of K. pneumoniae, P. aeruginosa, and E. coli, respectively, to cefiderocol. Green is the percentage of susceptible isolates, red is the percentage of resistant isolates, according to EUCAST and CLSI interpretation, respectively. Orange indicates the area of technical uncertainty (ATU) for EUCAST (18–21 mm for Enterobacterales, 14–21 mm for P. aeruginosa; 22 mm was regarded as susceptible) and indicates “I” for CLSI. (D) Mueller Hinton agar plates with susceptibility results for cefiderocol for six different K. pneumoniae isolates: two susceptible isolates, two resistant isolates (according to EUCAST and CLSI), and two isolates for which the interpretation was dependent on whether results were read with or without microcolonies.