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