rpx7009 and Enterobacteriaceae-Infections

Complicated urinary tract infections are increasingly caused by multidrug-resistant organisms. Carbapenem-resistant Enterobacteriaceae (CRE) constitute a rising threat among uropathogens with significant morbidity and mortality. Meropenem-vaborbactam is a novel carbapenem and cyclic boronic acid-based beta-lactamase inhibitor combination with potent activity against subtypes of CRE. Areas covered: This article reviews mechanisms of carbapenem resistance, existing treatment options for CRE, and the current evidence to support the use of meropenem-vaborbactam for the treatment of infections caused by subtypes of CRE including complicated urinary tract infections. Expert commentary: Meropenem-vaborbactam is a superior treatment option for infections secondary to Klebsiella pneumoniae carbapenemase (KPC)-producing CRE. It is associated with higher rates of treatment success and lower rates of toxicity than traditional agents and demonstrates a potentially higher barrier to acquired antimicrobial resistance than ceftazidime-avibactam. At present, meropenem-vaborbactam should be regarded as a preferred treatment option for invasive infections secondary to KPC-producing CRE.

Topics: Adult; Animals; Anti-Bacterial Agents; Boronic Acids; Carbapenem-Resistant Enterobacteriaceae; Drug Combinations; Drug Resistance, Multiple, Bacterial; Enterobacteriaceae Infections; Humans; Klebsiella pneumoniae; Meropenem; Urinary Tract Infections

The increasing prevalence of infections due to multidrug-resistant (MDR) gram-negative bacteria constitutes a serious threat to global public health due to the limited treatment options available and the historically slow pace of development of new antimicrobial agents. Infections due to MDR strains are associated with increased morbidity and mortality and prolonged hospitalization, which translates to a significant burden on healthcare systems. In particular, MDR strains of Enterobacteriaceae (especially Klebsiella pneumoniae and Escherichia coli), Pseudomonas aeruginosa, and Acinetobacter baumannii have emerged as particularly serious concerns. In the United States, MDR strains of these organisms have been reported from hospitals throughout the country and are not limited to a small subset of hospitals. Factors that have contributed to the persistence and spread of MDR gram-negative bacteria include the following: overuse of existing antimicrobial agents, which has led to the development of adaptive resistance mechanisms by bacteria; a lack of good antimicrobial stewardship such that use of multiple broad-spectrum agents has helped perpetuate the cycle of increasing resistance; and a lack of good infection control practices. The rising prevalence of infections due to MDR gram-negative bacteria presents a significant dilemma in selecting empiric antimicrobial therapy in seriously ill hospitalized patients. A prudent initial strategy is to initiate treatment with a broad-spectrum regimen pending the availability of microbiological results allowing for targeted or narrowing of therapy. Empiric therapy with newer agents that exhibit good activity against MDR gram-negative bacterial strains such as tigecycline, ceftolozane-tazobactam, ceftazidime-avibactam, and others in the development pipeline offer promising alternatives to existing agents.

Topics: Acinetobacter baumannii; Anti-Bacterial Agents; Boronic Acids; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Enterobacteriaceae Infections; Escherichia coli; Heterocyclic Compounds, 1-Ring; Hospitals; Humans; Klebsiella pneumoniae; Meropenem; Pseudomonas aeruginosa; Sisomicin; Tetracyclines; Thienamycins

The review aims to review the positioning of meropenem-vaborbactam in clinical practice, taking into consideration the characteristics of other available drugs, namely ceftazidime-avibactam, plazomicin, and colistin.. The search terms 'meropenem-vaborbactam' or RX7009 for the years 2006 until 2021 were used.. Coupling of meropenem with the cyclic boronate derivative varobactam enhances considerably the in vitro intrinsic activity of meropenem against isolates producing KPC (

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Bacterial Proteins; beta-Lactamases; Boronic Acids; Carbapenem-Resistant Enterobacteriaceae; Ceftazidime; Drug Combinations; Enterobacteriaceae Infections; Humans; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests

Twenty patients with carbapenem-resistant Enterobacteriaceae infections were treated with meropenem-vaborbactam. Thirty-day clinical success and survival rates were 65% (13/20) and 90% (18/20), respectively. Thirty-five percent of patients had microbiologic failures within 90 days. One patient developed a recurrent infection due to meropenem-vaborbactam-nonsusceptible, ompK36 porin mutant Klebsiella pneumoniae.

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Boronic Acids; Carbapenem-Resistant Enterobacteriaceae; Enterobacteriaceae Infections; Humans; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests

The comparative efficacy of ceftazidime-avibactam and meropenem-vaborbactam for treatment of carbapenem-resistant

Topics: Aged; Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; Boronic Acids; Carbapenem-Resistant Enterobacteriaceae; Carbapenems; Ceftazidime; Cohort Studies; Drug Combinations; Drug Resistance, Multiple, Bacterial; Enterobacteriaceae Infections; Female; Humans; Male; Meropenem; Middle Aged; Retrospective Studies; Treatment Outcome; Urinary Tract Infections

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamase Inhibitors; beta-Lactamases; Boronic Acids; Carbapenem-Resistant Enterobacteriaceae; Drug Combinations; Drug Resistance, Bacterial; Enterobacteriaceae Infections; Humans; Meropenem; Microbial Sensitivity Tests; Tertiary Care Centers; Wisconsin

Infections due to Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae are associated with increased morbidity and high mortality. Meropenem-vaborbactam (MV) is a novel β-lactam/β-lactamase inhibitor combination active against KPC-producing Enterobacteriaceae. The aim of this post hoc analysis of the TANGO-II randomized controlled trial was to assess the efficacy of MV versus best available therapy (BAT) in the subgroup of patients without prior antimicrobial failure.. The primary outcome measure was clinical cure at the test of cure (TOC). Secondary outcome measures included (1) clinical cure at the end of therapy (EOT), (2) microbiological cure at TOC, (3) microbiological cure at EOT, and (4) 28-day all-cause mortality.. First-line MV was associated with a 42.9% absolute increase in clinical cure rate at TOC (95% confidence intervals [CI] 13.7-72.1) in comparison with first-line BAT. A 49.3% absolute increase in clinical cure rate at EOT (95% CI 20.8-77.7), a 42.6% absolute increase in microbiological cure rate at EOT (95% CI 13.4-71.8), and a 36.2% absolute increase in microbiologic cure rate at TOC (95% CI 5.9-66.6) were also observed, in addition to a 29.0% absolute reduction in mortality (95% CI - 54.3 to - 3.7). Overall, fewer adverse events were observed in the MV group than in the BAT group.. MV was superior to BAT in the subgroup of patients with serious carbapenem-resistant Enterobacteriaceae (CRE) infections and no prior antimicrobial failure, with very high rates of clinical success, and was well tolerated. Post approval and real-world studies remain essential to clearly define the most appropriate population for early, empirical MV coverage, in accordance with antimicrobial stewardship principles.. The Medicines Company.

Topics: Adult; Anti-Bacterial Agents; Boronic Acids; Carbapenem-Resistant Enterobacteriaceae; Dose-Response Relationship, Drug; Enterobacteriaceae Infections; Female; Humans; Male; Meropenem; Middle Aged

Vaborbactam is a novel inhibitor of serine β-lactamases, including KPCs, which predominate in China. It is being developed in combination with meropenem.. Using the broth microdilution method, the in vitro activity of meropenem/vaborbactam against 128 KPC-producing Enterobacteriaceae from China was investigated.. Meropenem alone showed no activity (MIC50 and MIC90 >64 mg/L), but the addition of vaborbactam potentiated meropenem in a dose-dependent manner with MIC90 decreasing from >64 to 0.5 mg/L in the presence of increasing concentrations of vaborbactam. MIC50 and MIC90 of meropenem with 8 mg/L vaborbactam (MV8) were reduced to 0.5 and 8 mg/L, respectively. MV8 (4 mg/L meropenem) inhibited 76.6% of Klebsiella pneumoniae and 100% of Escherichia coli isolates. Seventy-three (77.7%) of the K. pneumoniae isolates belonged to ST11; the remaining 22.3% of isolates were represented by 12 different STs. Of the ST11 and non-ST11 isolates, 71.2% and 95.2%, respectively, were inhibited by MV8 (4 mg/L meropenem). In 14 strains characterized for intrinsic resistance mechanisms, MV8 MIC was increased in isolates with defects in both OmpK35 and OmpK36. The highest MV8 MIC was observed in the strain that had both non-functional porins and increased expression of blaKPC and acrB.. Our findings suggest that meropenem/vaborbactam has good activity against KPC-producing Enterobacteriaceae from China. However, a higher percentage of K. pneumoniae isolates for which MV8 MIC was elevated compared with other geographical areas is noteworthy. This might be due to clonal dissemination of ST11 KPC-producing isolates that are defective in both major porins, OmpK35 and OmpK36.

Topics: Anti-Bacterial Agents; beta-Lactamase Inhibitors; beta-Lactamases; Boronic Acids; China; Enterobacteriaceae; Enterobacteriaceae Infections; Humans; Meropenem; Microbial Sensitivity Tests

There is urgent need for new therapeutic strategies to fight the global threat of antibiotic resistance. The focus of this Perspective is on chemical agents that target the most common mechanisms of antibiotic resistance such as enzymatic inactivation of antibiotics, changes in cell permeability, and induction/activation of efflux pumps. Here we assess the current landscape and challenges in the treatment of antibiotic resistance mechanisms at both bacterial cell and community levels. We also discuss the potential clinical application of chemical inhibitors of antibiotic resistance mechanisms as add-on treatments for serious drug-resistant infections. Enzymatic inhibitors, such as the derivatives of the β-lactamase inhibitor avibactam, are closer to the clinic than other molecules. For example, MK-7655, in combination with imipenem, is in clinical development for the treatment of infections caused by carbapenem-resistant Enterobacteriaceae and Pseudomonas aeruginosa, which are difficult to treat. In addition, other molecules targeting multidrug-resistance mechanisms, such as efflux pumps, are under development and hold promise for the treatment of multidrug resistant infections.

Topics: Azabicyclo Compounds; beta-Lactamase Inhibitors; Drug Resistance, Microbial; Enterobacteriaceae Infections; Humans; Imipenem; Pseudomonas Infections