Combined antibiotic therapy is widely used for infections caused by carbapenem-resistant K. pneumoniae. The objective of this work was to identify the synergistic activity of combinations of two carbapenems against multidrug- and extensively drug-resistant K. pneumoniae strains producing various types of carbapenemases. For 60 antibiotic-resistant K. pneumoniae strains isolated in 8 cities of Belarus, the minimum inhibitory concentrations (MIC) of colistin and carbapenems were determined by subsequent broth microdilution method, and the genes of carbapenemases and phosphoethanolamine transferases were detected. The checkerboard method was used to determine the sensitivity to the combination of ertapenem and doripenem. High MIC values of carbapenems were revealed for NDM carbapenemase-producing strains (MIC50 of meropenem 64 mg/L, MIC50 of doripenem 64 mg/L). Doripenem was more active; MIC of doripenem ≤ 16 mg/L (low level of resistance) was determined in 28 (46.7%) strains, MIC of meropenem ≤ 16 mg/L - in 8 (13.3% of strains). The effect of potentiating the activity of doripenem with ertapenem at a fixed pharmacokinetic / pharmacodynamic concentration was observed for 20.0% of the strains producing KPC carbapenemase and 29.0% of the strains producing OXA-48 carbapenemase. The potentiating effect was independent of the presence of colistin resistance. Thus, the ability of ertapenem to potentiate the antimicrobial activity of doripenem and meropenem against some of the strains producing serine carbapenemases (KPC and OXA-48) was confirmed. The necessity of routine determination of the true MIC values of carbapenems was shown to optimize their dosage regimens and select the combination antibiotic therapy regimens.

Background. Combined antibiotic therapy is the main treatment for infections caused by antibiotic-resistant bacteria. The aim of this research was to identify the synergistic activity of antibiotic combinations against invasive extensively drug-resistant K. pneumoniae strains producing carbapenemases. Material and methods. For 12 invasive KPC-, OXA-48- and NDM-producing K. pneumoniae strains, the minimum inhibiting concentrations of antibiotics were determined. The susceptibility to antibiotic combinations was determined using the modified disk diffusion method. Results. The effect of potentiating the activity of colistin with aztreonam (58.3% of strains), azithromycin (33.3%), clarithromycin (41.7%), rifampicin (33.3%) as well as doxycycline (50%) was noted. High microbiological efficiency of ceftazidime/avibactam against all producers of KPC and OXA-48-carbapenemases was demonstrated. For MBLNDM-producing strains, a synergistic effect of the combination of ceftazidime/avibactam and aztreonam with restoration of susceptibility was revealed. Conclusion. The obtained findings open up perspectives for combination therapy of bloodstream infections caused by XDR-strains of K. pneumoniae.

Показана лидирующая роль антибиотикорезистентных штаммов K. pneumoniae в этиологической структуре внутрибольничных инфекций. Рассмотрены основные механизмы возникновения и распространения устойчивости K. pneumoniae к карбапенемам и полимиксинам. Показано значение карбапенемаз KPC, OXA-48 и NDM в формировании множественной и экстремальной антибиотикорезистентности. Оценена динамика распространения колистинорезистентных карбапенемазопродуцирующих госпитальных штаммов в 2016–2020 гг. Выполнены детекция генов карбапенемаз и определение чувствительности антибиотикорезистентных штаммов к комбинациям антибиотиков. Проанализированы варианты комбинированной антимикробной терапии пациентов с инфекциями, вызванными экстремально антибиотико-резистентными штаммами K. pneumoniae, отражены пути ее оптимизации. The leading role of antibiotic-resistant K. pneumoniae strains in the etiological structure of nosocomial infections has been shown. The main mechanisms of the emergence and spread of resistance of K. pneumoniae to carbapenems and polymyxins are considered. The importance of carbapenemases KPC, OXA-48 and NDM in the formation of multidrug resistance and extensively drug resistance was studied. The dynamics of the spread of colistin-resistant carbapenemase- producing hospital strains in 2016-2020 was estimated. Carbapenemase genes were detected and the sensitivity of antibiotic-resistant strains to antibiotic combinations was determined. Variants of combined antimicrobial therapy for patients with infections caused by extensively drug-resistant strains of K. pneumoniae were analyzed, ways of its optimization were indicated.