Is Meropenem as a Monotherapy Truly Incompetent for Meropenem-Nonsusceptible Bacterial Strains? A Pharmacokinetic/Pharmacodynamic Modeling With Monte Carlo Simulation

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.

Competence Mining of Vancomycin (VAN) in the Management of Infections Due to Bacterial Strains With High VAN Minimum Inhibitory Concentrations (MICs): A Novel Dosing Strategy Based on Pharmacokinetic/Pharmacodynamic Modeling

“…Drawing on our previous results on meropenem against highly resistant bacteria (Song et al, 2019) and the hypothesis stated by Pea et al regarding the usefulness of continuous infusion for the treatment of borderline-susceptible pathogens (Pea and Viale, 2008), joint infusion mode with loading-rate rapid infusion (LRRI) and low-rate continuous infusion (LRCI) was speculated to be optimal and capable of yielding sufficient drug exposure for isolates with high MICs. Thus, the novel dosing strategy FIGURE 1 | Concentration-time profiles for TIII and OTSI.…”

“…If the dilemma without better options in the presence of BS H−VAN−M infections can be broken through by optimizing the administration of the available drugs which have a currently reduced competency for such infections, it must be helpful for clinicians to treat such infections. Surprisingly, studies have shown that meropenem, with administration optimization, can still achieve sufficient PK/PD exposure against highly resistant bacterial isolates (Song et al, 2019), which has aroused substantial interest in exploring the "new usage for old drugs" to improve and maximize the performance of VAN against BS H−VAN−M infections. If successful, this exploration will have important significance in clinic, especially considering the rapid progress against the MIC creep phenomenon, delays in the development of new alternatives, and lack of better treatment options.…”

Treatment options for K. pneumoniae, P. aeruginosa and A. baumannii co-resistant to carbapenems, aminoglycosides, polymyxins and tigecycline: an approach based on the mechanisms of resistance to carbapenems

“…Based on PK/PD modeling with Monte Carlo simulations, optimized prolonged infusion treatment regimens to overcome resistance have been proposed for a variety of time-dependent antimicrobials whose efficacy is best predicted by the time that the antibiotic’s concentration is above the MIC (% T > MIC, or % f T > MIC considering the free, unbound drug concentration). For example, two-step administration of meropenem (1.5 g administered intravenously over 5 min followed by a 6 h infusion of 0.5 g, repeated every 8 h) can achieve a > 90% probability of target attainment for carbapenem-resistant isolates with MIC up to 128 mg/L (considering a target 50% f T > MIC), or up to 32 mg/L (considering a higher target of 50% f T > 5 × MIC) [ 188 ]. Regarding ceftolozane/tazobactam, an extended (4–5 h) infusion may perform better compared to shorter or longer infusions, especially in patients with augmented renal clearance, and has been proposed to achieve target attainment (40% fT > MIC) for P. aeruginosa strains with MIC up to 32 mg/dl [ 189 ].…”

Treatment Options for <em>K. pneumoniae</em>, <em>P. aeruginosa</em> and <em>A. baumannii</em> Co-resistant to Carbapenems, Aminoglycosides, Colistin and Tigecycline. An Approach Based on the Mechanisms of Resistance to Carbapenems

“…The rationale of this combination is that ertapenem due to its higher affinity with the carbapenemase enzyme acts as a suicide inhibitor, allowing higher levels of the second carbapenem (typically meropenem or doripenem) [69][70][71][72]. Optimized two-step administration (intravenous bolus followed by prolonged infusion) of meropenem has also been proposed for carbapenem-resistant isolates with MIC up to 32mg/L (and potentially up to 128mg/L) [73], but clinical data are lacking.…”

“…High-dose amikacin (25-50mg/kg/day) may also be an option for CACT-resistant P. aeruginosa with borderline resistance to amikacin (MIC=16mg/dl) [114]. Optimized two-step administration of meropenem (as described above for K. pneumoniae) may also be an option but clinical data are lacking [73]. Finally, various synergistic combinations (e.g.…”