Abstract
Infections due to meropenem-nonsusceptible bacterial strains (MNBSs) with meropenem minimum inhibitory concentrations (MICs) ≥ 16 mg/L have become an urgent problem. Currently, the optimal treatment strategy for these cases remains uncertain due to some limitations of currently available mono- and combination therapy regimens. Meropenem monotherapy using a high dose of 2 g every 8 h (q 8 h) and a 3-h traditional simple prolonged-infusion (TSPI) has proven to be helpful for the treatment of infections due to MNBSs with MICs of 4–8 mg/L but is limited for cases with higher MICs of ≥16 mg/L. This study demonstrated that optimized two-step-administration therapy (OTAT, i.e., a new administration model of i.v. bolus plus prolonged infusion) for meropenem, even in monotherapy, can resolve this problem and was thus an important approach of suppressing such highly resistant bacterial isolates. Herein, a pharmacokinetic (PK)/pharmacodynamic (PD) modeling with Monte Carlo simulation was performed to calculate the probabilities of target attainment (PTAs) and the cumulative fractions of response (CFRs) provided by dosage regimens and 39 OTAT regimens in five dosing models targeting eight highly resistant bacterial species with meropenem MICs ≥ 16 mg/L, including Acinetobacter baumannii, Acinetobacter spp., Enterococcus faecalis, Enterococcus faecium, Pseudomonas aeruginosa, Staphylococcus epidermidis, Staphylococcus haemolyticus, and Stenotrophomonas maltophilia, were designed and evaluated. The data indicated that meropenem monotherapy administered at a high dose of 2 g q 8 h and as an OTAT achieved a PTA of ≥90% for isolates with an MIC of up to 128 mg/L and a CFR of ≥90% for all of the targeted pathogen populations when 50% f T > MIC (50% of the dosing interval during which free drug concentrations remain above the MIC) is chosen as the PD target, with Enterococcus faecalis being the sole exception. Even though 50% f T > 5 × MIC is chosen as the PD target, the aforementioned dosage regimen still reached a PTA of ≥90% for isolates with an MIC of up to 32 mg/L and a CFR of ≥90% for Acinetobacter spp., Pseudomonas aeruginosa, and Klebsiella pneumoniae populations. In conclusion, meropenem monotherapy displays potential competency for infections due to such highly resistant bacterial isolates provided that it is administered as a reasonable OTAT but not as the currently widely recommended TSPI.
Highlights
The increasing emergence of meropenem-nonsusceptible bacterial strains (MNBSs), such as Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter spp., which are defined as any isolate displaying minimum inhibitory concentration (MIC) of 2, 4, and 4 mg/L with meropenem, imipenem, and/or doripenem, respectively [Clinical and Laboratory Standards Institute (CLSI), 2019], has become a serious global health concern (Nordmann, 2014; Iovleva and Doi, 2017; Bulens et al, 2018; Moghnieh et al, 2018; Huang et al, 2019)
Given that few attempts have been made to determine the optimal treatment for meropenem as a monotherapy against the increasing number of MNBSs with MICs ≥ 16 mg/L, this study focused on only these strains
Meropenem-specific serum PK parameters were obtained from published literature and microbiological susceptibility data for the targeted pathogens were obtained from the European Committee on Antimicrobial Susceptibility Testing (EUCAST); together with dosing parameters, such as the dose and infusion time, these data were incorporated into a PK/PD model
Summary
To the best of our knowledge, this outcome occurs because traditional simple prolonged-infusion (TSPI) leads to both a decrease in the peak concentration and a delay in the peak time, resulting in an apparent incompetency for meropenem against the isolates with MICs ≥16 mg/L For this reason, reoptimization of the method for administering meropenem in monotherapy may continue to show promise regarding the successful management of these problematic isolates, prompting us to design a theoretically optimized two-step-administration therapy (OTAT, see OTAT design in the part of Materials and Methods) for these problematic isolates. It is believed that this reoptimization will be crucial for maximizing microbiological outcomes and be important when better treatment options for these pathogens strains are absent
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