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

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.

Pharmacodynamics of Doripenem Alone and in Combination with Relebactam in an In Vitro Hollow-Fiber Dynamic Model: Emergence of Resistance of Carbapenemase-Producing Klebsiella pneumoniae and the Inoculum Effect

“…However, the activity of combination 1/3 was diminished at HI and the IE was observed with both studied strains. The tendency for a greater MIC difference between SI and HI with the more susceptible K. pneumoniae strain was observed in all but one of the studied combinations (with a fixed relebactam concentration), similar to our previous study [15]. It is possible that carbapenemase enzymes are more active at increased inocula against susceptible rather than highly resistant strains.…”

“…However, during therapy the concentrations of both the inhibitor and the antibiotic are continuously changing. To account for these changes a pharmacokinetic-based (PK-based) approach to MIC determination of beta-lactam/beta-lactamase inhibitor combinations has been proposed recently [15]. The antibacterial effects of imipenem/relebactam and doripenem/relebactam combinations in time-kill experiments were accurately predicted using this approach, i.e., with MICs determined using a PK-based antibiotic-to-inhibitor concentration ratio.…”

Meropenem MICs at Standard and High Inocula and Mutant Prevention Concentration Inter-Relations: Comparative Study with Non-Carbapenemase-Producing and OXA-48-, KPC- and NDM-Producing Klebsiella pneumoniae

“…Interestingly, the higher the MIC of isolate at SI, the weaker the MIC decrease at high inocula was observed; this was seen with both carbapenemase-producing and non-carbapenemase-producing K. pneumoniae. From our previous results with imipenem and doripenem alone or in combination with the carbapenemase inhibitor relebactam, the IE was more likely when K. pneumoniae MIC was lower [33]. With highly carbapenem resistant K. pneumoniae isolates, the IE was not observed.…”