Highly multidrug-resistant Gram-negative bacterial infections in war victims in Ukraine, 2022

23 Maggio 2023

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From 2014 to 2020, higher rates of antimicrobial resistance were reported in military hospitals than in civilian hospitals in Ukraine, indicating the challenges associated with reducing the spread of antibiotic-resistant bacteria during conflict.

 Identical clones of carbapenem-resistant isolates of the Acinetobacter baumannii complex has been described by a 2016 study in Ukrainian war victims treated in Germany, suggesting a possible spread in Ukrainian hospitals.

To monitor the prevalence of antimicrobial-resistant infections in Ukraine, we conducted sentinel testing of hospitalised war victims with hospital-associated infections between February and September, 2022. The patients included in this study were those who required emergency surgery and intensive care due to severe burns, shrapnel wounds, and fractures. Swabs were taken from the skin and soft tissue of patients when signs of infection were observed in wounds or burn surfaces. Catheter tips from central venous catheters showing signs of infection were sent to the microbiology department for culture. Additionally, tracheobronchial aspirates were collected from patients with signs of ventilator-associated pneumonia who had received respiratory support for more than 72 h.

Because of resource limitations in Ukraine, the isolates were analysed at Lund University's clinical microbiology laboratory, followed by antibiotic susceptibility testing at the European Committee on Antimicrobial Susceptibility Testing (EUCAST) development laboratory. Disc diffusion testing was performed in accordance with EUCAST guidelines,

 and for isolates that were either meropenem-resistant, or susceptible with increased exposure, broth microdilution was carried out according to the International Organization for Standardization method.

Ethical approval was obtained from the Committee on Bioethics, National Pirogov Memorial Medical University, Vinnytsya, Ukraine (protocol number 11; 10.11.2022).

Phenotypical characterisation was performed on 156 isolates retrieved from 141 patients, which included 133 adults with war injuries and eight newborn babies with ventilator-associated pneumonia . Two separate strains were isolated from nine patients, and three were isolated from three patients. Among the 154 isolates tested, 89 (58%) were resistant to meropenem , including 34 (76%) of 45 Klebsiella pneumoniae isolates, 38 (73%) of 52 A baumannii complex, 13 (57%) of 23 Pseudomonas aeruginosa isolates, and 4 (18%) of 22 Enterobacter spp isolates.

Extended antimicrobial susceptibility testing revealed that 52 (49%) of 107 strains were cefiderocol-resistant, including 35 (78%) of 45 Enterobacterales isolates, 6 (38%) of 16 P aeruginosa strains, and 11 (24%) of 46 A baumannii complex. Notably, 10 (9%) of 107 isolates were resistant to colistin, with K pneumoniae (n=9) and Providencia stuartii (n=1) being the affected species. Among 61 Enterobacterales and P aeruginosa isolates tested, 49 (80%) were resistant to ceftazidime–avibactam, 58 (95%) were resistant to ceftolozane–tazobactam, 51 (84%) were resistant to imipenem–relebactam, and 49 (80%) were resistant to meropenem–vaborbactam. Of note, nine (6%) of 156 isolates, all K pneumoniae, were resistant to all antimicrobials tested. Screening for carbapenemase genes revealed a dominance of blaNDM-group and blaOXA-48-like, and no blaMCR1/2 were detected.

TableExtended antimicrobial susceptibility testing

Enterobacterales (n=45)80%100%78%89%84%22%
Klebsiella pneumoniae (n=37)86%100%81%95%92%24%
Providencia stuartii (n=1)100%100%0100%0100%
Enterobacter spp (n=7)57%100%71%57%57%0
Pseudomonas aeruginosa (n=16)81%81%38%69%69%0
Acinetobacter baumannii complex (n=46)NANA24%NANA0

Data shown as proportion (%) of resistant isolates.* Enterobacterales screened as positive for carbapenemases with the meropenem disk diffusion test (cutoff <28 mm) and P aeruginosa, and A baumannii complex interpreted as susceptibile or resistant for meropenem were included in the extended antimicrobial susceptibility testing. Broth micro-dilution was used for all agents except for cefiderocol, because EUCAST considers disk diffusion to be more reliable than minimum inhibitory concentration determination. EUCAST=European Committee on Antimicrobial Suscptaibility Testing. *According to EUCAST clinical breakpoint tables.

† No clinical breakpoint, interpreted using cut-off corresponding to pharmacokinetic-pharmacodynamic breakpoint.

The report highlights the extensive antibiotic resistance observed in Gram-negative bacteria isolated from injured hospitalised war victims with nosocomial infections in Ukraine. The study found that 89 (58%) of 154 isolates were resistant to meropenem. Although most strains (including 90% of those resistant to meropenem) were sensitive to colistin, nine (6%) of 156 isolates were resistant to all antibiotics tested, including newer β-lactam β-lactamase inhibitor combinations.

Infectious complications following trauma and surgery are prevalent, and despite access to broad-spectrum antibiotics such as colistin, cefiderocol, and various enzyme inhibitors, hospital-associated infections can still be challenging to treat. Ukraine's health-care system is under immense pressure due to limited resources, which makes infection prevention and control measures difficult to maintain, possibly leading to the spread of resistant organisms. Resource support from neighbouring European countries, including access to antimicrobial agents and provision of care for war victims, could help alleviate some of these challenges.

KR, ON, and EM conceived the study. Project administration was provided by KR. The study design was finalised by KR, GK, and EM. Prior collection and preparation of clinical isolates was done by ON, DD, FN, and VB. Further laboratory work was performed by EM, LW, and TK. Data curation, analysis, and visualisation were performed by EM, VA, KR, and OL. The manuscript was initially drafted by OL and KR, and critically revised by GK, EM, VA, TK, ON, LW, and DD. All authors approved the final version of the manuscript. KR reports support by the Knut and Alice Wallenberg Foundation (KR; grant number 2018.0318) and OL and KR from the governmental funding of research within the clinical sciences. KR reports support from the Anna and Edwin Berger Foundation, Swedish Heart Lung Foundation, the Skåne County Council's Research and Development Foundation, and Swedish Research Council (grant number 2019–01053). We thank Amra Basic and Lucia Ortega Roco of the EUCAST Development Laboratory; Fredrike Bechmann; and Ann-Cathrine Petersson of the Department of Clinical Microbiology, Infection Control and Prevention, Lund. All other authors declare no competing interests.

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