Win Ratio Analyses of Piperacillin-Tazobactam Versus Meropenem for Ceftriaxone-Nonsusceptible Escherichia coli or Klebsiella pneumoniae Bloodstream Infections: Post Hoc Insights From the MERINO Trial.

BACKGROUND: Clinical trials of treatments for serious infections commonly use the primary endpoint of all-cause mortality. However, many trial participants survive their infection and this endpoint may not truly reflect important benefits and risks of therapy. The win ratio uses a hierarchical composite endpoint that can incorporate and prioritize outcome measures by relative clinical importance. METHODS: The win ratio methodology was applied post hoc to outcomes observed in the MERINO trial, which compared piperacillin-tazobactam with meropenem. We quantified the win ratio with a primary hierarchical composite endpoint, including all-cause mortality, microbiological relapse, and secondary infection. A win ratio of 1 would correspond to no difference between the 2 antibiotics, while a ratio <1 favors meropenem. Further analyses were performed to calculate the win odds and to introduce a continuous outcome variable in order to reduce ties. RESULTS: With the hierarchy of all-cause mortality, microbiological relapse, and secondary infection, the win ratio estimate was 0.40 (95% confidence interval [CI], .22-.71]; P = .002), favoring meropenem over piperacillin-tazobactam. However, 73.4% of the pairs were tied due to the small proportion of events. The win odds, a modification of the win ratio accounting for ties, was 0.79 (95% CI, .68-.92). The addition of length of stay to the primary composite greatly minimized the number of ties (4.6%) with a win ratio estimate of 0.77 (95% CI, .60-.99; P = .04). CONCLUSIONS: The application of the win ratio methodology to the MERINO trial data illustrates its utility and feasibility for use in antimicrobial trials.

Evaluation of the meropenem dosage and administration schedule in patients with bacteremia initial therapy.

BACKGROUND: The standard meropenem (MEPM) regimen allowed by insurance in Japan is 0.5 g two or three times a day. Differences in dosages and administration schedules in Japan were evaluated. METHODS: Patients with bacteremia for whom MEPM was used as the initial treatment at our institution between 2016 and 2021 were included. We retrospectively investigated patients classified into two groups: those treated according to severe infections (high-dose groupand others (low-dose group). After propensity score matching, we compared the probability of achieving free drug blood levels above the minimum inhibitory concentration (MIC) in 24 h (%fT > MIC) and outcomes. RESULTS: The probability of 100% fT > MIC was significantly higher in the high-dose group (96.4% vs 74.5%, odds ratio [OR] = 0.3, 95% confidence interval [CI] = 0.2-0.4, P = < 0.001). Regarding outcomes, the 30-day mortality rate was significantly lower in the high-dose group (1.4% vs. 11.4%, OR = 8.0, 95% CI = 1.5-43.7, P = 0.019). CONCLUSIONS: To improve outcomes in patients with bacteremia treated with MEPM, support for appropriate antimicrobial use is necessary for compliance with the dosage and administration schedule according to severe infections in initial treatment.

Anthracyclines induce DNA damage response-mediated protection against severe sepsis.

Severe sepsis remains a poorly understood systemic inflammatory condition with high mortality rates and limited therapeutic options in addition to organ support measures. Here we show that the clinically approved group of anthracyclines acts therapeutically at a low dose regimen to confer robust protection against severe sepsis in mice. This salutary effect is strictly dependent on the activation of DNA damage response and autophagy pathways in the lung, as demonstrated by deletion of the ataxia telangiectasia mutated (Atm) or the autophagy-related protein 7 (Atg7) specifically in this organ. The protective effect of anthracyclines occurs irrespectively of pathogen burden, conferring disease tolerance to severe sepsis. These findings demonstrate that DNA damage responses, including the ATM and Fanconi Anemia pathways, are important modulators of immune responses and might be exploited to confer protection to inflammation-driven conditions, including severe sepsis.

Imipenem cilastatin sodium-associated thrombocytopenia in an older patient: A case report and literature review.

Imipenem cilastatin sodium, as a member of a new generation of ß-lactam antibiotics, has a broad spectrum of antibacterial activity and a very wide range of application. Thrombocytopenia has been reported as a rare adverse event in several studies of patients treated with imipenem cilastatin sodium. In this study, we present a case of thrombocytopenia associated with imipenem cilastatin sodium in an older patient. The 78-year-old male patient with pulmonary infection was initiated on anti-infection therapy with imipenem cilastatin sodium. On the 9th day after imipenem cilastatin sodium administration, the patient experienced a sudden and dramatic decrease in platelet count. Similarly, on the 4th day after the re-administration of imipenem cilastatin sodium for anti-infection therapy, the patient's platelet count showed a remarkable downward trend again. A time correlation between the drug therapy and the occurrence of platelet reaction was found. The patient's platelet count gradually returned to the normal level on the 6th day after the first drug withdrawal and the 13th day after the second drug withdrawal, respectively. Considering the widespread use of imipenem cilastatin sodium, healthcare providers should improve the notification of thrombocytopenia associated with imipenem cilastatin sodium.

Two cases of bacterial meningitis due to meropenem-resistant Streptococcus pneumoniae: A threat of serotype 35B, ST 558 lineage.

Although the pneumococcal conjugate vaccine (PCV) has decreased the incidence of invasive pneumococcal disease (IPD) in children, cases of IPD caused by non-PCV serotypes have been increasing. Here, we report two cases of bacterial meningitis caused by meropenem-resistant Streptococcus pneumoniae; in both the cases, 13-valent PCV (PCV13) had been administered. The isolated S. pneumoniae strains were non-PCV13 serotype 35B and resistant to penicillin G, cefotaxime, and meropenem. In addition, multilocus sequence typing (MLST) revealed the sequence type (ST) to be 558. In case 1, a 6-month-old girl recovered without sequelae after antibiotic therapy comprising cefotaxime and vancomycin, whereas in case 2, a 9-month-old boy was treated with an empirical treatment comprising ceftriaxone and vancomycin administration. However, maintaining the blood concentration of vancomycin within the effective range was difficult, due to which the antibiotics were changed to panipenem/betamipron. During the treatment, he presented with seizures, which were effectively controlled with antiepileptic drugs. The rate of incidence of penicillin-susceptible IPD has been substantially increasing after the introduction of PCV. However, an upsurge in IPD cases due to multidrug-resistant (MDR) serotype 35B has been reported in countries where PCV13 was introduced before introducing in Japan. Moreover, an increase in the proportion of MDR serotype 35B and decrease in the susceptibility to broad-spectrum antimicrobials, including meropenem, have been reported. Hence, the number of meningitis cases caused by MDR serotype 35B/ST558 may increase in the future.

Appropriate non-carbapenems are not inferior to carbapenems as initial empirical therapy for bacteremia caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae: a propensity score weighted multicenter cohort study.

The efficacy of empirical non-carbapenem antibiotics for extended-spectrum beta-lactamase-producing Enterobacteriaceae bacteremia (ESBL-B) is still inconclusive. We conducted a multicenter retrospective cohort study to evaluate the efficacy of empirical non-carbapenem antibiotics for treating ESBL-B. Electronic medical records of individuals who were diagnosed with ESBL-B were reviewed between January 2010 and December 2014 at four university hospitals in Korea. Patients were classified into non-carbapenem and carbapenem groups according to the empirical antibiotic regimen. Patients treated with appropriate empirical antibiotics and who subsequently received carbapenems as definitive therapy were included in the analysis. The inverse probability of treatment weights, a statistical method that adjusts baseline statistics by giving weights based on propensity score, was used. During the study period, 232 adequately treated patients with ESBL-B were included in the analysis: 49 patients in the non-carbapenem group and 183 in the carbapenem group. The baseline characteristics and severity of infection were similar after propensity score weighting. The 30-day mortality rates for the two groups were not statistically significantly different (non-carbapenems 6.3% and carbapenems 11.4%; P = 0.42). In a multivariate analysis, empirical treatment with non-carbapenem antibiotics was not associated with 30-day all-cause mortality (HR 1.02, 95% CI 0.99-1.06, P = 0.14). In a subgroup analysis, empirical treatment with piperacillin-tazobactam was also not associated with 30-day all-cause mortality (HR 1.21, 95% CI 0.37-4.00, P = 0.75). Appropriate non-carbapenems were not inferior to carbapenems as initial empirical therapy for ESBL-B.

Meropenem-vaborbactam: a carbapenem and beta-lactamase inhibitor with activity against carbapenem-resistant Enterobacteriaceae.

Meropenem-vaborbactam is a carbapenem and ß-lactamase inhibitor combination that is newly indicated for the treatment of complicated urinary tract infections (cUTI), including adult pyelonephritis. Vaborbactam was developed due to emergence of carbapenem-resistant strains of Enterobacteriaceae. In a phase I trial, patients that received meropenem-vaborbactam 2-2 g intravenously over 3 h every 8 h, Cmax was 58.2 ± 10.8 µg/mL for meropenem and 59.0 ± 8.4 µg/mL for vaborbactam. AUC0-8 was 186 ± 33.6 µg â€¢ h/mL for meropenem and 204 ± 34.6 µg â€¢ h/mL for vaborbactam. Vss = 16.3 ± 2.6 L for meropenem and 17.6 ± 2.6 L for vaborbactam. Protein binding for vaborbactam averaged 33% in humans. Plasma clearance ranged from 10.42 ± 1.85 to 14.77 ± 2.84 L/h. One phase III trial evaluated efficacy for meropenem-vaborbactam 2-2 g intravenously every 8 h versus piperacillin-tazobactam 4-0.5 g intravenously every 8 h in complicated UTI. It found non-inferiority and statistical superiority for meropenem in overall success at the end of treatment primary end point. In another phase III trial evaluating efficacy in carbapenem-resistant Enterobacteriaceae (CRE) infections, meropenem-vaborbactam 2-2 g intravenously every 8 h was associated with decreased 28-day mortality and increased clinical cure compared with a best available therapy group.

Were all carbapenemases created equal? Treatment of NDM-producing extensively drug-resistant Enterobacteriaceae: a case report and literature review.

PURPOSE: There is currently a paucity of published literature focused on the treatment of infections caused by NDM-producing organisms. METHODS: We describe a case of a bacteraemia caused by an extensively drug-resistant (XDR) New Delhi metallo-ß-lactamase (NDM)-producing Serratia marcescens and review the treatment options for XDR NDM-producing Enterobacteriaceae. RESULTS: Infections caused by New Delhi beta-lactamase (NDM)-producing Enterobacteriaceae are becoming increasingly prevalent worldwide. The presence of the enzyme results in multidrug-resistant and extensively drug-resistant phenotypes which often pose a treatment challenge. Despite this challenge, case reports and series have demonstrated good clinical outcomes with numerous treatment options in comparison to infections due to KPC-producing Enterobacteriaceae. CONCLUSIONS: Further good-quality research focused on the treatment of NDM-producing Enterobacteriaceae is warranted.

Pharmacokinetics of meropenem in septic patients on sustained low-efficiency dialysis: a population pharmacokinetic study.

BACKGROUND: The aim of the study was to describe the population pharmacokinetics (PK) of meropenem in critically ill patients receiving sustained low-efficiency dialysis (SLED). METHODS: Prospective population PK study on 19 septic patients treated with meropenem and receiving SLED for acute kidney injury. Serial blood samples for determination of meropenem concentrations were taken before, during and after SLED in up to three sessions per patient. Nonparametric population PK analysis with Monte Carlo simulations were used. Pharmacodynamic (PD) targets of 40% and 100% time above the minimal inhibitory concentration (f T > MIC) were used for probability of target attainment (PTA) and fractional target attainment (FTA) against Pseudomonas aeruginosa. RESULTS: A two-compartment linear population PK model was most appropriate with residual diuresis supported as significant covariate affecting meropenem clearance. In patients without residual diuresis the PTA for both targets (40% and 100% f T > MIC) and susceptible P. aeruginosa (MIC ≤ 2 mg/L) was > 95% for a dose of 0.5 g 8-hourly. In patients with a residual diuresis of 300 mL/d 1 g 12-hourly and 2 g 8-hourly would be required to achieve a PTA of > 95% and 93% for targets of 40% f T > MIC and 100% f T > MIC, respectively. A dose of 2 g 8-hourly would be able to achieve a FTA of 97% for 100% f T > MIC in patients with residual diuresis. CONCLUSIONS: We found a relevant PK variability for meropenem in patients on SLED, which was significantly influenced by the degree of residual diuresis. As a result dosing recommendations for meropenem in patients on SLED to achieve adequate PD targets greatly vary. Therapeutic drug monitoring may help to further optimise individual dosing. TRIAL REGISTRATION: Clincialtrials.gov, NCT02287493 .

Helicobacter cinaedi-associated Carotid Arteritis.

A 65-year-old Japanese man with bilateral carotid atherosclerosis presented with right neck pain and fever. Contrast-enhanced computed tomography suggested carotid arteritis, and carotid ultrasonography showed an unstable plaque. The patient developed a cerebral embolism, causing a transient ischemic attack. Helicobacter cinaedi was detected in blood culture, and H. cinaedi-associated carotid arteritis was diagnosed. Empirical antibiotic therapy was administered for 6 weeks. After readmission for recurrent fever, he was treated another 8 weeks. Although the relationship between H. cinaedi infection and atherosclerosis development remains unclear, the atherosclerotic changes in our patient's carotid artery might have been attributable to H. cinaedi infection.

Pharmacokinetics of high-dose extended-infusion meropenem during pulmonary exacerbation in adult cystic fibrosis patients: a case series.

This case series explored the pharmacokinetic/pharmacodynamic (PK/PD) characteristics of meropenem (MEM) in adult cystic fibrosis (CF) patients hospitalized for a pulmonary exacerbation. From January 2015 to June 2016, all adult patients with cystic fibrosis (CF) and chronic pulmonary infection due to meropenem (MEM)-susceptible/intermediate Pseudomonas aeruginosa who received at least 48 h of MEM as an extended 3-hour infusion for treating a pulmonary exacerbation were enrolled. MEM plasma concentrations were determined by high-performance liquid chromatography. Six adult CF patients with a median age of 47 years were included in the study. MEM showed a high Vd (mean 45.98 L, standard deviation [SD] ±34.45). A minimal PK/PD target of 40% T > minimum inhibitory concentration (MIC) with respect to the MEM MIC of P. aeruginosa strains isolated from sputum during exacerbation was achieved in 5/6 patients (83%). MEM failed to achieve this target only in one patient, whose strain showed the highest MEM MIC in our cohort (8 mg/L). In all patients, MEM was well tolerated, and no adverse events were reported. In conclusion, high-dose, extended-infusion MEM during pulmonary exacerbation showed a high Vd in six adult CF patients with high median age, and was well tolerated.

Evaluation of Meropenem Pharmacokinetics in an Experimental Acute Respiratory Distress Syndrome (ARDS) Model during Extracorporeal Membrane Oxygenation (ECMO) by Using a PenP ß-Lactamase Biosensor.

INTRODUCTION: The use of antibiotics is mandatory in patients during extracorporeal membrane oxygenation (ECMO) support. Clinical studies have shown high variability in the antibiotic concentrations, as well as sequestration of them by the ECMO circuit, suggesting that the doses and/or interval administration used during ECMO may not be adequate. Thus, a fast response sensor to estimate antibiotic concentrations in this setting would contribute to improve dose adjustments. The biosensor PenP has been shown to have a dynamic range, sensitivity and specificity useful for pharmacokinetic (PK) tests in healthy subjects. However, the use of this biosensor in the context of a complex critical condition, such as ECMO during acute respiratory distress syndrome (ARDS), has not been tested. OBJECTIVES: To describe, by using PenP Biosensor, the pharmacokinetic of meropenem in a 24-h animal ARDS/ECMO model. METHODS: The PK of meropenem was evaluated in a swine model before and during ECMO. RESULTS: The PK parameters such as maximum concentration (Cmax), elimination rate constant (Ke), and cleareance (Cl), were not significantly altered during ECMO support. CONCLUSIONS: (a) ECMO does not affect the PK of meropenem, at least during the first 24 h; and (b) PenP has the potential to become an effective tool for making medical decisions associated with the dose model of antibiotics in a critical patient context.

Effect of Piperacillin-Tazobactam vs Meropenem on 30-Day Mortality for Patients With E coli or Klebsiella pneumoniae Bloodstream Infection and Ceftriaxone Resistance: A Randomized Clinical Trial.

Importance: Extended-spectrum ß-lactamases mediate resistance to third-generation cephalosporins (eg, ceftriaxone) in Escherichia coli and Klebsiella pneumoniae. Significant infections caused by these strains are usually treated with carbapenems, potentially selecting for carbapenem resistance. Piperacillin-tazobactam may be an effective "carbapenem-sparing" option to treat extended-spectrum ß-lactamase producers. Objectives: To determine whether definitive therapy with piperacillin-tazobactam is noninferior to meropenem (a carbapenem) in patients with bloodstream infection caused by ceftriaxone-nonsusceptible E coli or K pneumoniae. Design, Setting, and Participants: Noninferiority, parallel group, randomized clinical trial included hospitalized patients enrolled from 26 sites in 9 countries from February 2014 to July 2017. Adult patients were eligible if they had at least 1 positive blood culture with E coli or Klebsiella spp testing nonsusceptible to ceftriaxone but susceptible to piperacillin-tazobactam. Of 1646 patients screened, 391 were included in the study. Interventions: Patients were randomly assigned 1:1 to intravenous piperacillin-tazobactam, 4.5 g, every 6 hours (n = 188 participants) or meropenem, 1 g, every 8 hours (n = 191 participants) for a minimum of 4 days, up to a maximum of 14 days, with the total duration determined by the treating clinician. Main Outcomes and Measures: The primary outcome was all-cause mortality at 30 days after randomization. A noninferiority margin of 5% was used. Results: Among 379 patients (mean age, 66.5 years; 47.8% women) who were randomized appropriately, received at least 1 dose of study drug, and were included in the primary analysis population, 378 (99.7%) completed the trial and were assessed for the primary outcome. A total of 23 of 187 patients (12.3%) randomized to piperacillin-tazobactam met the primary outcome of mortality at 30 days compared with 7 of 191 (3.7%) randomized to meropenem (risk difference, 8.6% [1-sided 97.5% CI, -∞ to 14.5%]; P = .90 for noninferiority). Effects were consistent in an analysis of the per-protocol population. Nonfatal serious adverse events occurred in 5 of 188 patients (2.7%) in the piperacillin-tazobactam group and 3 of 191 (1.6%) in the meropenem group. Conclusions and relevance: Among patients with E coli or K pneumoniae bloodstream infection and ceftriaxone resistance, definitive treatment with piperacillin-tazobactam compared with meropenem did not result in a noninferior 30-day mortality. These findings do not support use of piperacillin-tazobactam in this setting. Trial Registration: anzctr.org.au Identifiers: ACTRN12613000532707 and ACTRN12615000403538 and ClinicalTrials.gov Identifier: NCT02176122.

New Drugs 2018, part 3.

This article discusses eight drugs recently approved by the FDA, including their indications and contraindications, precautions, dosage, and nursing considerations. The article also includes summary charts on 14 recently approved antineoplastic drugs and four drugs approved for rare disorders.

Successful Therapy of a Multidrug-Resistant Extended-Spectrum ß-Lactamase-Producing and Fluoroquinolone-Resistant Salmonella enterica Subspecies enterica Serovar Typhi Infection Using Combination Therapy of Meropenem and Fosfomycin.

We report a traveler who acquired a Salmonella enterica subspecies enterica serovar Typhi strain with resistance against ß-lactams, cephalosporins (extended-spectrum ß-lactamase-producing type SHV-12), and quinolones (plasmid-mediated quinolone resistance gene qnrB7). After clinical deterioration using meropenem monotherapy, treatment success was achieved after commencement of fosfomycin in conjunction with high-dose meropenem. The case illustrates clinical challenges of multidrug-resistant S. Typhi.

Comparing the Outcomes of Patients With Carbapenemase-Producing and Non-Carbapenemase-Producing Carbapenem-Resistant Enterobacteriaceae Bacteremia.

BACKGROUND: Carbapenem-resistant Enterobacteriaceae (CRE) are associated with considerable mortality. As mechanisms of carbapenem resistance are heterogeneous, it is unclear if mortality differs based on resistance mechanisms. We sought to determine whether CRE resistance mechanism determination is prognostically informative. METHODS: We conducted an observational study comparing 14-day mortality between patients with carbapenemase-producing (CP)-CRE compared with non-CP-CRE bacteremia. Clinical data were collected on all patients. A comprehensive DNA microarray-based assay was performed on all isolates to identify ß-lactamase-encoding genes. RESULTS: There were 83 unique episodes of monomicrobial CRE bacteremia during the study period: 37 (45%) CP-CRE and 46 (55%) non-CP-CRE. The majority of CP-CRE isolates were bla KPC (92%), followed by bla NDM (5%) and bla OXA-48-type (3%). CP-CRE isolates were more likely to have meropenem minimum inhibitory concentrations (MICs) ≥16 µg/mL, while non-CP-CRE isolates were more likely to have meropenem MICs ≤1 µg/mL (P value < .001). A total of 18 (22%) patients died within 14 days, including 12 (32%) in the CP-CRE group and 6 (13%) in the non-CP-CRE group. Adjusting for severity of illness on day 1 of bacteremia, underlying medical conditions, and differences in antibiotic treatment administered, the odds of dying within 14 days were more than 4 times greater for CP-CRE compared with non-CP-CRE bacteremic patients (adjusted odds ratio, 4.92; 95% confidence interval, 1.01-24.81). CONCLUSION: Our findings suggest that CP-CRE may be more virulent than non-CP-CRE and are associated with poorer outcomes. This underscores the added importance of delineating underlying resistance mechanisms of CRE to direct antibiotic treatment decisions.

mcr-1 and blaKPC-3 in Escherichia coli Sequence Type 744 after Meropenem and Colistin Therapy, Portugal.

Escherichia coli Ec36 was recovered from a patient in Portugal after treatment with meropenem and colistin. Besides an IncF plasmid with Tn1441d-blaKPC-3, already reported in clinical strains in this country, E. coli Ec36 co-harbored an IncX4::mcr-1 gene. Results highlight emerging co-resistance to carbapenems and polymyxins after therapy with drugs from both classes.

Multidrug-Resistant Pathogens in Hospitalized Syrian Children.

Since 2013, wounded and ill children from Syria have received treatment in Israel. Screening cultures indicated that multidrug-resistant (MDR) pathogens colonized 89 (83%) of 107 children. For 58% of MDR infections, the pathogen was similar to that identified during screening. MDR screening of these children is valuable for purposes of isolation and treatment.

Multicenter Evaluation of Ceftazidime-Avibactam and Ceftolozane-Tazobactam Inhibitory Activity against Meropenem-Nonsusceptible Pseudomonas aeruginosa from Blood, Respiratory Tract, and Wounds.

The recent escalation of occurrences of carbapenem-resistant Pseudomonas aeruginosa has been recognized globally and threatens to erode the widespread clinical utility of the carbapenem class of compounds for this prevalent health care-associated pathogen. Here, we compared the in vitro inhibitory activity of ceftazidime-avibactam and ceftolozane-tazobactam against 290 meropenem-nonsusceptible Pseudomonas aeruginosa nonduplicate clinical isolates from 34 U.S. hospitals using reference broth microdilution methods. Ceftazidime-avibactam and ceftolozane-tazobactam were active, with ceftolozane-tazobactam having significantly higher inhibitory activity than ceftazidime-avibactam. The heightened inhibitory activity of ceftolozane-tazobactam was sustained when the site of origin (respiratory, blood, or wound) and nonsusceptibility to other ß-lactam antimicrobials was considered. An extensive genotypic search for enzymatically driven ß-lactam resistance mechanisms revealed the exclusive presence of the VIM metallo-ß-lactamase among only 4% of the subset of isolates nonsusceptible to ceftazidime-avibactam, ceftolozane-tazobactam, or both. These findings suggest an important role for both ceftazidime-avibactam and ceftolozane-tazobactam against carbapenem-nonsusceptible Pseudomonas aeruginosa Further in vitro and in vivo studies are needed to better define the clinical utility of these novel therapies against the increasingly prevalent threat of multidrug-resistant Pseudomonas aeruginosa.

Substantial Impact of Altered Pharmacokinetics in Critically Ill Patients on the Antibacterial Effects of Meropenem Evaluated via the Dynamic Hollow-Fiber Infection Model.

Critically ill patients frequently have substantially altered pharmacokinetics compared to non-critically ill patients. We investigated the impact of pharmacokinetic alterations on bacterial killing and resistance for commonly used meropenem dosing regimens. A Pseudomonas aeruginosa isolate (MICmeropenem 0.25 mg/liter) was studied in the hollow-fiber infection model (inoculum ∼107.5 CFU/ml; 10 days). Pharmacokinetic profiles representing critically ill patients with augmented renal clearance (ARC), normal, or impaired renal function (creatinine clearances of 285, 120, or ∼10 ml/min, respectively) were generated for three meropenem regimens (2, 1, and 0.5 g administered as 8-hourly 30-min infusions), plus 1 g given 12 hourly with impaired renal function. The time course of total and less-susceptible populations and MICs were determined. Mechanism-based modeling (MBM) was performed using S-ADAPT. All dosing regimens across all renal functions produced similar initial bacterial killing (≤∼2.5 log10). For all regimens subjected to ARC, regrowth occurred after 7 h. For normal and impaired renal function, bacterial killing continued until 23 to 47 h; regrowth then occurred with 0.5- and 1-g regimens with normal renal function (fT>5×MIC = 56 and 69%, fCmin/MIC < 2); the emergence of less-susceptible populations (≥32-fold increases in MIC) accompanied all regrowth. Bacterial counts remained suppressed across 10 days with normal (2-g 8-hourly regimen) and impaired (all regimens) renal function (fT>5×MIC ≥ 82%, fCmin/MIC ≥ 2). The MBM successfully described bacterial killing and regrowth for all renal functions and regimens simultaneously. Optimized dosing regimens, including extended infusions and/or combinations, supported by MBM and Monte Carlo simulations, should be evaluated in the context of ARC to maximize bacterial killing and suppress resistance emergence.