Comparative activity of meropenem and biapenem and their combinations with colistin against Gram-negative microorganisms-producers of carbapenemases from various groups

Objective.

To conduct a comparative in vitro analysis of the activity of biapenem and meropenem, as well as to evaluate the efficacy of their combinations with colistin against clinical isolates of Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa producing carbapenemases of different molecular classes.

Materials and Methods.

The study included 197 carbapenem-resistant clinical isolates of K. pneumoniae, A. baumannii and P. aeruginosa with a phenotype of multidrug (MDR) and extensively drug (XDR) resistance. Antibiotic susceptibility was determined by the broth microdilution method in Mueller-Hinton broth according to the ISO 20776-1:2019 standard. To assess the effect of antibiotic combinations, a modified method for testing the bactericidal activity of various combinations (MCBT) and the checkerboard method with calculation of the fractional inhibitory concentration index (ΣFIC) were used. Molecular genetic characterization of the isolates was performed by polymerase chain reaction (PCR). PKPD analysis was performed using Monte Carlo simulations to predict the efficacy of two dosing regimens for biapenem.

Results.

Biapenem demonstrated statistically significantly lower MIC50 and MIC90 values compared to meropenem against the majority of the studied isolates. The greatest advantage of biapenem was revealed against NDM metallo-β-lactamase-producing K. pneumoniae: MIC50 was 2 mg/L versus 32 mg/L for meropenem. 74% of K. pneumoniae isolates were susceptible to colistin (MIC50/MIC90 – 0.¹²⁵⁄₆₄ mg/L). 98% of P. aeruginosa isolates also remained susceptible to colistin (MIC50/MIC90 – 0.¹²⁵⁄₀.125 mg/L), confirming its status as a «last-resort» antibiotic. The activity of biapenem/avibactam combinations against P. aeruginosa was observed only against clinical isolates that did not produce carbapenemases. Against K. pneumoniae, the activity of the biapenem (4 mg/L) + avibactam (4 mg/L) combination was highest against producers of a single type of carbapenemase (KPC – bactericidal effect against 69.2% of isolates, OXA48 – 88.5% of isolates, NDM – 83.3% of isolates); among co-producers of two types of carbapenemases, resistance to this combination was noted for 75% of isolates. For the vast majority of tested clinical isolates of A. baumannii, P. aeruginosa, and K. pneumoniae, combinations of carbapenems with colistin demonstrated a synergistic (ΣFIC ≤ 0.5) or additive (ΣFIC > 0.5 and ≤ 1.0) effect. Combinations of both carbapenems with colistin exhibited bactericidal activity against most isolates. Quantitative analysis by the checkerboard method revealed that the biapenem + colistin combination has an advantage over the meropenem + colistin combination against NDM-producing K. pneumoniae isolates (FIC50 1 mg/L and 8 mg/L, respectively). For the dosage regimen of biapenem 1000 mg/8h administered as a 3-hour infusion, efficacy has been predicted for strains with a MIC of ≤4 mg/L.

Conclusions.

Biapenem exhibits a statistically significant higher in vitro activity than meropenem against meropenem-resistant clinical isolates of K. pneumoniae, A. baumannii, and P. aeruginosa with multidrug and extensive drug resistance, isolated in the Republic of Belarus. The combination of biapenem with colistin demonstrates high efficacy and synergy against multidrug-resistant isolates, making it a promising option for empirical and targeted therapy of severe infections caused by these pathogens, especially in regions with a high prevalence of MBL-producing isolates.