INTRODUCTION
Since the late 1900s, the development of many antimicrobial agents has
greatly improved human health and welfare. On the other hand, the
increase in drug-resistant bacteria due to the inappropriate use of
antimicrobials has become a problem worldwide. Recently, the
Antimicrobial Resistance Collaborators reported that in 2019, 4.95
million deaths were associated with drug-resistant bacteria, of which
1.27 million were directly attributable to drug-resistant bacteria,
strongly indicating that overcoming drug resistance is an important
global healthcare challenge (Antimicrobial Resistance Collaborators,
2022). The O’Neill Report on Drug Resistance estimates that 10 million
people will die annually from drug-resistant bacterial infections in
2050 if drug resistance increases at its current rate (O’Neill,
2016),(O’Neill, 2014). In particular, Gram-negative bacteria that have
acquired resistance by producing β-lactamases that hydrolyse β-lactam
antibiotics are positioned as a serious threat (Jacoby & Munoz-price,
2005). To treat patients with β-lactamase-producing gram-negative
bacterial infections, the combination therapy of β-lactams and
β-lactamase inhibitors, which inhibit the enzymatic inactivation of
β-lactams by β-lactamases, has been the cornerstone of treatment of
β-lactamase-producing Gram-negative bacterial infections in modern
medical care.
In the clinical use of antimicrobials, pharmacokinetic/pharmacodynamic
(PK/PD) parameters calculated using mouse infection models have
contributed to determining evidence-based clinical doses of
antimicrobials (Craig, 1998),(Andes & Craig, 2002),(Ambrose et al.,
2006). In general, it is desirable to set the PK/PD parameters using
specific minimum inhibitory concentrations (MICs) and pharmacokinetic
parameters that can directly reflect the antimicrobial drug dose to be
generalised to a wide variety of bacteria and doses. The PK/PD
parameters for most antimicrobial monotherapies in clinical use are
based on percentage of free time above MIC
(%f T>MIC) or free area under the plasma
concentration-time curve (f AUC)/MIC and free maximum
concentration (f Cmax)/MIC to set the clinical
dose (Ambrose et al., 2006). In contrast, the PK/PD parameters proposed
for β-lactam/β-lactamase inhibitors are limited tof T>CT (Coleman et al., 2014). The
CT value, meaning ’the lowest concentration of
β-lactamase inhibitor required to inhibit β-lactamase when used with a
given dose of β-lactam’ (Crass & Pai, 2019), is based on the fixed
values of factors such as MIC of the bacterial strain, β-lactam
administration method, β-lactamase genotype, gene expression levels.
This makes it impossible to analyse drug efficacy with flexibility for
bacteria with different MICs and concentrations of both drugs usingf T>CT, thus preventing comprehensive
clinical efficacy prediction. It is difficult to determine the PK/PD
parameter that reflects the instantaneous variation of MICs in the
presence of fluctuating blood concentrations of β-lactams/β-lactamase
inhibitors over time, given the interdependency in the
β-lactams/β-lactamase inhibitors drug efficacy. Therefore, PK/PD
parameters for β-lactam/β-lactamase inhibitors usingf T>CT values are not practical.
Hence, the establishment of new PK/PD parameters incorporating the
concept of MIC is desired.
We considered that using the instantaneous MIC (MICi)
for PK/PD analysis of β-lactams/β-lactamase inhibitors could overcome
this challenge. MICi is a mathematical modelling &
simulation assessment concept that depends on β-lactamase inhibitor
concentration and the sensitivity for β-lactam drugs that varies over
time. 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 MICi has
since been demonstrated for several β-lactam/β-lactamase inhibitor
combinations (Wu et al., 2018),(Abodakpi et al., 2019 a),(Abodakpi et
al., 2019 b),(Tam et al., 2021). Therefore, applying the
MICi 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. However, no
reports have demonstrated the usefulness of PK/PD analysis using
MICi.
Recently, nacubactam (OP0595), which is a DBO-type new β-lactamase
inhibitor and has antibacterial activity, is being developed as a single
drug to be co-administered with cefepime or aztreonam. This study aims
to establish a PK/PD analysis method for β-lactam/β-lactamase inhibitors
using MICi and investigate their superiority overf T>CT. For this purpose, we used
nacubactam, a novel β-lactamase inhibitor currently under development,
and aztreonam, a β-lactam drug. Furthermore, we used the PK/PD analysis
method established in this study to explore the practical PK/PD
parameters, their target values and optimal clinical doses of
aztreonam/nacubactam against β-lactamase-producing Gram-negative
bacteria.
MATERIALS and METHODS