Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Jun 20;10(6):1454.
doi: 10.3390/biomedicines10061454.

Klebsiella pneumoniae Susceptibility to Carbapenem/Relebactam Combinations: Influence of Inoculum Density and Carbapenem-to-Inhibitor Concentration Ratio

Maria V Golikova  1 , Kamilla N Alieva  1 , Alla V Filimonova  1 , Vladimir A Ageevets  2 , Ofeliia S Sulian  2 , Alisa A Avdeeva  2 , Sergey V Sidorenko  2   3 , Stephen H Zinner  4
Affiliations

Klebsiella pneumoniae Susceptibility to Carbapenem/Relebactam Combinations: Influence of Inoculum Density and Carbapenem-to-Inhibitor Concentration Ratio

Maria V Golikova et al. Biomedicines. .

Abstract

The inoculum effect (IE) is a well-known phenomenon with beta-lactams. At the same time, the IE has not been extensively studied with carbapenem/carbapenemase inhibitor combinations. The antibiotic-to-inhibitor concentration ratio used in susceptibility testing can influence the in vitro activity of the combination. To explore the role of these factors, imipenem/relebactam and doripenem/relebactam MICs were estimated against six Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae strains at standard inocula (SI) and high inocula (HI) by two methods: with a fixed relebactam concentration and with a fixed, pharmacokinetic-based carbapenem-to-relebactam concentration ratio. The combination MICs at HI, compared to SI, increased with most of the tested strains. However, the IE occurred with only two K. pneumoniae strains regardless of the MIC testing method. The relationship between the MICs at SI and the respective inoculum-induced MIC changes was observed when the MICs were estimated at pharmacokinetic-based carbapenem-to-relebactam concentration ratios. Thus, (1) IE was observed with both carbapenem/relebactam combinations regardless of the MIC testing method; however, IE was not observed frequently among tested K. pneumoniae strains. (2) At HI, carbapenem/relebactam combination MICs increased to levels associated with carbapenem resistance. (3) Combination MICs determined at pharmacokinetic-based carbapenem-to-inhibitor concentration ratios predict susceptibility elevations at HI in KPC-producing K. pneumoniae.

Keywords: Klebsiella pneumoniae; beta-lactamase inhibitors; beta-lactams; doripenem; imipenem; inoculum effect; relebactam.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The susceptibility of K. pneumoniae to imipenem (a,c) and doripenem (b,d) in the presence of relebactam. The interpretive criteria for susceptibility were as follows: susceptible, ≤1 mg/L; intermediate, 2 mg/L; resistant, ≥4 mg/L.
Figure 2
Figure 2
The MICs of imipenem (a) and doripenem (b) against K. pneumoniae at standard inoculum density (bars) and respective changes in the susceptibility at high inoculum density (circles). The dashed lines indicate the lower level of MIC changes associated with the inoculum effect (IE, ≥8-fold).
Figure 3
Figure 3
MIC1 (a) and MIC2 (b) values of imipenem (blue bars) and doripenem (orange bars) in the presence of relebactam against K. pneumoniae at standard inoculum density and changes in the susceptibility at high inoculum density (circles). The dashed lines indicate the lower level of MIC changes associated with the inoculum effect (IE, ≥8-fold).
See this image and copyright information in PMC

References

    1. Andrei S., Droc G., Stefan G. FDA approved antibacterial drugs: 2018–2019. Discoveries. 2019;31:e102. doi: 10.15190/d.2019.15. - DOI - PMC - PubMed
    1. Thakare R., Dasgupta A., Chopra S. Imipenem/cilastatin sodium/relebactam fixed combination to treat urinary infections and complicated intra-abdominal bacterial infections. Drugs Today. 2020;56:241–255. doi: 10.1358/dot.2020.56.4.3075796. - DOI - PubMed
    1. U.S. Food and Drug Administration. [(accessed on 21 April 2022)]; Available online: https://www.fda.gov/news-events/press-announcements/fda-approves-antibio....
    1. Galani I., Souli M., Nafplioti K., Adamou P., Karaiskos I., Giamarellou H., Antoniadou A. Study Collaborators. In vitro activity of imipenem-relebactam against non-MBL carbapenemase-producing Klebsiella pneumoniae isolated in Greek hospitals in 2015–2016. Eur. J. Clin. Microbiol. Infect. Dis. 2019;38:1143–1150. doi: 10.1007/s10096-019-03517-y. - DOI - PubMed
    1. Kurihara D., Matsumoto S., Kishi N., Ishii Y., Mori M. In vitro antibacterial activity of imipenem/relebactam against clinical isolates in Japan. Microbiol. Spectr. 2022;13:e0223521. doi: 10.1128/spectrum.02235-21. - DOI - PMC - PubMed

LinkOut - more resources