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.

The increasing emergence of bacterial strains with high VAN MICs (BSH–VAN–M), such as Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcus bovis, results in growing concern that VAN is not effective against these isolates. Due to the limited data on VAN against BSH–VAN–M and the application limits of drugs currently considered to be effective for BSH–VAN–M, exploration of “new usages for old drugs” is reasonable to improve and maximize the efficacy of existing antibiotics. This study aimed to construct a novel dosing strategy to mine the competence of VAN in the management of BSH–VAN–M infections. Herein, we optimized the traditional intermittent i.v. infusion (TIII) method to create an optimal two-step infusion (OTSI). With pharmacokinetic (PK)/pharmacodynamic (PD) modeling at the targeted ratio of the daily area under the concentration-time curve (AUC0–24) to the minimum inhibitory concentration (MIC) (AUC0–24/MIC) of 400, we used Monte Carlo simulations to evaluate the efficacy of 25 VAN regimens (including 15 OTSI regimens and 10 TIII regimens with daily doses of up to 6 g) to treat pneumonia, meningitis, sternal osteomyelitis, mastitis, pleuritis, bacteremia, and bacterial pericarditis resulting from isolates with MICs of ≤64 mg/L and to the current E. faecalis, E. faecium, S. aureus, S. epidermidis, and S. bovis populations with a pooled MIC distribution. Our data indicated that 4 g/day VAN, with an OTSI but not a TIII, for mastitis, pleuritis, bacteremia, and bacterial pericarditis due to isolates with MICs of ≤4 mg/L or to the current E. faecalis, S. aureus, S. epidermidis, and S. bovis populations achieved the desired PK/PD exposure at the AUC0–24/MIC target of 400. This study suggests the superiority and feasibility of OTSI relative to TIII for the competence mining of VAN against BSH–VAN–M from the perspective of PK/PD and provides a new resource for understanding how PK/PD modeling shapes the performance of VAN to meet the growing challenges of BSH–VAN–M infections.

Purpose: The purpose of this study was 1) to predict the requisite vancomycin daily dose (Dvan) used in the target patients suffering from both bacterial infection and hematological malignancies and 2) to construct a vancomycin-dose-graphical tool to assist clinicians to develop vancomycin dosing regimens and further 3) to establish a programming process for vancomycin dynamic dosage adjustment to help clinicians to adjust vancomycin dosing regimens according to physiological and pathogenic factors of the target patients.Methods: The Dvan model associated with microbial susceptibility, vancomycin pharmacokinetics, and dosing parameters was established, and the Dvan was estimated based on the established Dvan model and using Monte Carlo simulations. Dvan achieving 90% of probability of target attainment (PTA) for bacterial isolate or cumulative fractions of response (CFR) for the bacterial population at a ratio of daily area under the curve (AUC24) to the minimum inhibitory concentration (MIC) [i.e., AUC24/MIC] of 400–600 was considered sufficient to treat infection occurring in the target patients. On the basis of the predicted Dvan, the physiological states of patients, and the pathogenic variables of infection, a vancomycin-dose-graphical tool for the target patients and a programming process for vancomycin dynamic dosage adjustment were constructed.Results: This study predicted the requisite Dvan used in patients suffering from both bacterial infection and hematological malignancies and constructed a vancomycin-dose-graphical tool for the target patients, at different physiological states and pathogenic variables, to formulate vancomycin dosing regimens. Also, this study established and expounded the formulation process of vancomycin dosage dynamic adjustment according to fluctuant renal function of the target patients.Conclusion: With the tools, the required Dvan or vancomycin dosing regimens for the target patients, at different physiological states and pathogenic variables, can be readily known, whether or not vancomycin dynamic dosage adjustment is required.