Optimizing pharmacokinetics/pharmacodynamics of β-lactam/β-lactamase inhibitor combinations against high inocula of ESBL-producing bacteria

Abstract

Objectives Reduced in vitro β-lactam activity against a dense bacterial population is well recognized. It is commonly attributed to the presence of β-lactamase(s) and it is unknown whether the inoculum effect could be diminished by a β-lactamase inhibitor. We evaluated different β-lactam/β-lactamase inhibitor combinations in suppressing a high inoculum of ESBL-producing bacteria. Methods Three clinical isolates expressing representative ESBLs (CTX-M-15 and SHV-12) were examined. The impact of escalating β-lactamase inhibitor (tazobactam or avibactam) concentrations on β-lactam (piperacillin or ceftazidime) MIC reduction was characterized by an inhibitory sigmoid Emax model. The effect of various dosing regimens of β-lactam/β-lactamase inhibitor combinations was predicted using %T>MICi and selected exposures were experimentally validated in a hollow-fibre infection model over 120 h. The threshold exposure to suppress bacterial regrowth was identified using recursive partitioning. Results A concentration-dependent reduction in β-lactam MIC was observed (r2 ≥0.93). Regrowth could be suppressed in all six experiments using %T>MICi ≥73.6%, but only one out of six experiments below the threshold (P = 0.015). The exposures to suppress regrowth might be attained using the clinical dose of avibactam, but a much higher dose than the standard dose would be needed for tazobactam. Conclusions A dense population of ESBL-producing bacteria could be suppressed by an optimized dosing regimen of selected β-lactam/β-lactamase inhibitor combinations. The reversibility of enzyme inhibition could play an important role in diminishing the inoculum effect. In vivo investigations to validate these findings are warranted.

Development of an optimized and practical pharmacokinetics/pharmacodynamics analysis method for aztreonam/nacubactam against carbapenemase-producingK. pneumoniae

“…Ceftazidime/tazobactam, for example, showed decreased action at high bacterial levels, but ceftazidime/avibactam was said to be unaffected by inoculum levels. 14 The causes for this are unknown. However, the inoculum effect could be related to avibactam’s reversible inhibitory action and resistance to enzymatic hydrolysis.…”

Development of an Optimised Pharmacokinetics/Pharmacodynamics analysis method of β-lactam/nacubactam against Carbapenemase-Producing K. pneumoniae

“…Some β-lactam/β-lactamase inhibitor combinations, on the other hand, have been less influenced by the inoculum effect. Ceftazidime/tazobactam, for example, showed decreased action at high bacterial levels, but ceftazidime/avibactam was said to be unaffected by inoculum levels (Tam et al, 2021). The causes for this are unknown.…”

“…This concept was first proposed by Bhagunde et al(Bhagunde et al, 2012) in the imipenem/relebactam in vitroHollow-Fiber Infection Model. The utility of MIC i has since been demonstrated for several βlactam/β-lactamase inhibitor combinations (Wu et al, 2018), , (Abodakpi et al, 2019 b), (Tam et al, 2021). Therefore, applying the MIC i concept to PK/PD analysis in a murine infection model allows for flexible clinical dosing design, taking into account the interdependence of β-lactam/β-lactamase inhibitors.…”

The Application of Hollow Fiber Cartridge in Biomedicine

“…In the HFIM, the inhibitory effect of different β -lactam/ β -lactamase combinations on high inoculum are often evaluated in HFIM. The study showed that high-density extended-spectrum β -lactamase (ESBL)-producing bacteria can be inhibited by the optimized dose regimen β -lactam/ β -lactamase inhibitor combination [ 54 ].…”