Ertapenem

Carbapenem-resistant Klebsiella pneumoniae (CRKP) poses a significant challenge in clinical settings due to limited treatment options and high mortality rates. While carbapenemase-producing CRKP has been extensively studied, the mechanisms underlying resistance in non-carbapenemase-producing CRKP remain less understood. In this study, we investigated 30 ertapenem-resistant non-carbapenemase-producing CRKP clinical isolates. Antimicrobial susceptibility testing revealed multidrug resistance in all strains. Molecular analyses showed that all isolates carried extended-spectrum β-lactamase (ESBL) and/or AmpC β-lactamase genes. Sequencing of outer membrane porin (OMP) genes revealed mutations or deletions in ompK35 and/or ompK36 in the majority of isolates. SDS-PAGE analysis confirmed reduced or absent expression of the corresponding OMP proteins in these strains. Additionally, quantitative PCR showed that several isolates exhibited overexpression of efflux pump genes. These findings indicate that the combined effects of ESBL or AmpC production, porin loss at both the genetic and protein levels, and efflux pump overactivity contribute to ertapenem resistance in non-carbapenemase-producing CRKP. Our results underscore the complexity of resistance mechanisms and highlight the importance of integrated molecular and phenotypic assessments to inform appropriate antimicrobial therapy.ImportanceThis study highlights the complex, multifactorial nature of carbapenem resistance in carbapenem-resistant Klebsiella pneumoniae (CRKP), involving enzyme-mediated resistance, reduced membrane porin expression, and overactive efflux pumps. These findings provide valuable insights into CRKP resistance mechanisms and can aid in controlling CRKP in China.

BackgoundIn recent years we have witnessed an increase in infections due to multidrug-resistant organisms in kidney transplant recipients (KTR). In our setting, we have observed a dramatic increase in infections caused by extended-spectrum betalactamase-producing (ESBL) Enterobacteriaceae in KTR. In 2014 we changed surgical prophylaxis from Cefazolin 2 g to Ertapenem 1 g.MethodsWe compared bacterial infections and their resistance phenotype during the first post-transplant month with an historical cohort collected during 2013 that had received Cefazolin.ResultsDuring the study period 110 patients received prophylaxis with Cefazolin and 113 with Ertapenem. In the Ertapenem cohort we observed a non-statistically significant decrease in the percentage of early bacterial infection from 57 to 47%, with urine being the most frequent source in both. The frequency of infections caused by Enterobacteriaceae spp. decreased from 64% in the Cefazolin cohort to 36% in the Ertapenem cohort (p = 0.005). In addition, percentage of ESBL-producing strains decreased from 21 to 8% of all Enterobacteriaceae isolated (p = 0.015). After adjusted in multivariate Cox regression analysis, male sex (HR 0.16, 95%CI: 0.03-0.75), cefazolin prophylaxis (HR 4.7, 95% CI: 1.1-22.6) and acute rejection (HR 14.5, 95% CI: 1.3-162) were associated to ESBL- producing Enterobacteriaceae infection.ConclusionsPerioperative antimicrobial prophylaxis with a single dose of Ertapenem in kidney transplant recipients reduced the incidence of early infections due to ESBL-producing Enterobacteriaceae without increasing the incidence of other multidrug-resistant microorganisms or C. difficile.

BackgroundInterest in carbapenems has been rising in the last few years due to the emergence of drug resistant tuberculosis. Ertapenem (ETP), given once a day parenteral, and faropenem (FAR), oral, have a better administration profile than meropenem (MEM), imipenem (IPM) and doripenem (DOR). The addition of amoxicillin-clavulanate (AMC) inhibits the hydrolysis by the carbapenemase present in Mycobacterium tuberculosis (MTB). The aim of this study was to determine the in vitro activity of ETP and FAR against susceptible and resistant clinical MTB strains by two widely use methodologies, the BACTEC960 MGIT and microdilution.Results19 clinical isolates with different susceptibility profiles and H37Rv were included. Minimal inhibitory concentration (MIC) testing was performed using two methods of different concentrations of ETP and FAR with and without AMC. MIC50 was 2 and 8 for FAR with and without AMC by both methods. MIC90 was > 16 and > 8 by microdilution and MGIT respectively and did not change after AMC addition. 18/20 samples were resistant to the highest concentration of ETP, with and without AMC. Half of the samples had some susceptibility to FAR; addition of AMC further reduced the MIC level in seven isolates. 10/20 isolates showed susceptibility to FAR and the addition of AMC further reduced the MIC in 7 isolates. However, most of the MICs were near the limit of effectiveness (8 μg/mL). Resistance to FAR was associated with resistance to MEM (p = 0.04) but not to resistance profiles of other drugs, including M/XDR status.ConclusionsThe lack of ETP activity may be associated with its degradation, independent of carbapenemase, during incubation. No susceptibility pattern to traditional drugs can predict susceptibility to FAR and susceptibility testing is not routinely available. PK/PD studies are needed as reaching the concentrations tested in these experiments may be challenging. This work highlighted some of the limitations of carbapenem use. More evidence is needed to clarify their true impact in TB treatment and outcome, considering the financial burden, complications and microbiota changes associated with their use.

Carbapenem resistance in non-carbapenemase producing Enterobacterales can display susceptibility discordance (e.g., ertapenem-non-susceptible, meropenem-susceptible), often in patients with prior antimicrobial use. We aim to characterize risk factors for carbapenem susceptibility discordant Enterobacterales (CSD-E) bloodstream infections in immunocompromised patients. We performed a retrospective, single-center study comparing adults with Enterobacterales BSI who developed subsequent carbapenem susceptibility concordant (CSC; meropenem and ertapenem susceptible) or CSD-E BSI with the same organism within 1 year. Patients who developed subsequent CSD-E BSI were matched to those with repeat CSC-E BSI based on organism. Logistic regression models evaluated CSD-E risk factors. Time-varying covariate Cox proportional hazards models evaluated time-dependent changes in antibiotic exposure when estimating the association between antibiotic use and CSD-E. Comparative genomics of available paired whole-genome sequencing (WGS) data was performed to assess genetic relatedness and antimicrobial resistance (AMR) gene content. Beta-lactam survival mechanisms (BLSM) were assessed via Tolerance Disk Test (TDTest) and Population Analysis Profiling (PAP). We evaluated 829 patients with Enterobacterales BSI. Repeat BSI was CSC-E in 81 patients (9.8%) and CSD-E in 14 patients (1.7%). Matching provided 43 CSC-E controls and 14 CSD-E cases. Univariate analysis revealed any ceftazidime-avibactam (CZA) exposure was associated with developing CSD-E BSI (odds ratio [OR], 7.41; P = 0.01). Time-varying covariate Cox regression identified each additional day of cefepime is associated with CSD-E BSI development (hazard ratio [HR], 1.055; P = 0.016). Genomic data suggest beta-lactamase amplification and outer membrane porin mutations may be potential CSD-E development mechanisms. CSD-E BSI risk factors in immunocompromised patients may include any CZA exposure and cumulative cefepime exposure. Further studies are warranted to validate CSD-E risk factors.ImportanceNon-carbapenemase-producing (non-CP) carbapenem-resistant Enterobacterales (CRE) are an important classification of CRE. Increasing rates of non-CP CRE that display carbapenem susceptibility discordance (CSD-E; ertapenem-resistant, meropenem susceptible) have been observed globally and at our institution. Our article aims to characterize risk factors, including cumulative antibiotic exposure, leading to carbapenem susceptibility discordant Enterobacterales (CSD-E) bloodstream infection (BSI) in immunocompromised patients with a history of Enterobacterales BSI. In addition, we analyzed paired whole-genome sequencing data to assess antimicrobial gene content for mechanistic rationales supporting our clinical findings. The risk factors for CSD-E development identified in this study require further validation in multicenter cohorts.