Meropenem

BackgroundIncreasing antimicrobial resistance among pathogens that cause complicated intraabdominal infections (cIAIs) supports the development of new antimicrobials. Eravacycline, a novel member of the fluorocycline family, is active against multidrug-resistant bacteria including extended-spectrum β-lactamase (ESBL) and carbapenem-resistant Enterobacteriaceae.MethodsIGNITE4 was a prospective, randomized, double-blind trial. Hospitalized patients with cIAI received either eravacycline 1 mg/kg every 12 hours or meropenem 1 g every 8 hours intravenously for 4-14 days. The primary objective was to demonstrate statistical noninferiority (NI) in clinical cure rates at the test-of-cure visit (25-31 days from start of therapy) in the microbiological intent-to-treat population using a NI margin of 12.5%. Microbiological outcomes and safety were also evaluated.ResultsEravacycline was noninferior to meropenem in the primary endpoint (177/195 [90.8%] vs 187/205 [91.2%]; difference, -0.5%; 95% confidence interval [CI], -6.3 to 5.3), exceeding the prespecified margin. Secondary endpoints included clinical cure rates in the modified ITT population (231/250 [92.4%] vs 228/249 [91.6%]; difference, 0.8; 95% CI, -4.1, 5.8) and the clinically evaluable population (218/225 [96.9%] vs 222/231 [96.1%]; (difference, 0.8; 95% CI -2.9, 4.5). In patients with ESBL-producing Enterobacteriaceae, clinical cure rates were 87.5% (14/16) and 84.6% (11/13) in the eravacycline and meropenem groups, respectively. Eravacycline had relatively low rates of adverse events for a drug of this class, with less than 5%, 4%, and 3% of patients experiencing nausea, vomiting, and diarrhea, respectively.ConclusionsTreatment with eravacycline was noninferior to meropenem in adult patients with cIAI, including infections caused by resistant pathogens.Clinical trials registrationNCT01844856.

Antibiotics are losing efficacy due to the rapid evolution and spread of resistance. Treatments targeting bacterial virulence factors have been considered as alternatives because they target virulence instead of pathogen viability, and should therefore exert weaker selection for resistance than conventional antibiotics. However, antivirulence treatments rarely clear infections, which compromises their clinical applications. Here, we explore the potential of combining antivirulence drugs with antibiotics against the opportunistic human pathogen Pseudomonas aeruginosa. We combined two antivirulence compounds (gallium, a siderophore quencher, and furanone C-30, a quorum sensing [QS] inhibitor) together with four clinically relevant antibiotics (ciprofloxacin, colistin, meropenem, tobramycin) in 9×9 drug concentration matrices. We found that drug-interaction patterns were concentration dependent, with promising levels of synergies occurring at intermediate drug concentrations for certain drug pairs. We then tested whether antivirulence compounds are potent adjuvants, especially when treating antibiotic resistant (AtbR) clones. We found that the addition of antivirulence compounds to antibiotics could restore growth inhibition for most AtbR clones, and even abrogate or reverse selection for resistance in five drug combination cases. Molecular analyses suggest that selection against resistant clones occurs when resistance mechanisms involve restoration of protein synthesis, but not when efflux pumps are up-regulated. Altogether, our work provides a first systematic analysis of antivirulence-antibiotic combinatorial treatments and suggests that such combinations have the potential to be both effective in treating infections and in limiting the spread of antibiotic resistance.

Vaborbactam (formerly RPX7009) is a novel inhibitor of serine β-lactamases, including Ambler class A carbapenemases, such as KPCs. The current study evaluated the in vitro activity of the combination agent meropenem-vaborbactam against a global collection of 991 isolates of KPC-positive Enterobacteriaceae collected in 2014 and 2015 using the Clinical and Laboratory Standards Institute (CLSI) standard broth microdilution method. The MIC90 of meropenem (when tested with a fixed concentration of 8 μg/ml of vaborbactam) for isolates of KPC-positive Enterobacteriaceae was 1 μg/ml, and MIC values ranged from ≤0.03 to >32 μg/ml; 99.0% (981/991) of isolates had meropenem-vaborbactam MICs of ≤4 μg/ml, the U.S. FDA-approved MIC breakpoint for susceptibility to meropenem-vaborbactam (Vabomere). Vaborbactam lowered the meropenem MIC50 from 32 to 0.06 μg/ml and the MIC90 from >32 to 1 μg/ml. There were no differences in the activity of meropenem-vaborbactam when the isolates were stratified by KPC variant type. We conclude that meropenem-vaborbactam demonstrates potent in vitro activity against a worldwide collection of clinical isolates of KPC-positive Enterobacteriaceae collected in 2014 and 2015.

Antimicrobial resistance driven by multidrug-resistant (MDR) Gram-negative pathogens poses a major global threat, contributing to substantial morbidity and mortality. Novel β-lactam/β-lactamase inhibitor combinations, particularly meropenem-vaborbactam (M/V) and ceftazidime-avibactam (C/A), have expanded therapeutic options; however, their comparative efficacy and safety remain uncertain. This meta-analysis compared M/V and C/A in adult patients with MDR Gram-negative infections. MEDLINE, Embase, and Cochrane Central were searched for studies evaluating M/V versus C/A in hospitalized adults. Outcomes included all-cause mortality, clinical cure, and microbiological recurrence; safety was assessed qualitatively. Data were synthesized using Review Manager, with trial sequential analysis (TSA) applied to minimize random error. Five retrospective cohort studies (three full articles and two conference abstracts) comprising 3,280 patients were included, of whom 577 received M/V and 2,703 received C/A. Populations predominantly consisted of older adults aged 57-70 years, with respiratory tract infections being most common. Pooled analyses demonstrated no statistically significant differences between M/V compared to C/A in all-cause mortality (Odds ratio [OR] 0.87; 95% CI 0.69-1.11; P = 0.26; I² = 16%), clinical cure (OR 1.41; 95% CI 0.66-3.03; P = 0.37; I² = 55%), and microbiological recurrence (OR 0.67; 95% CI 0.32-1.40; P = 0.29; I² = 0%). Qualitative synthesis indicated comparable tolerability. TSA for mortality demonstrated insufficient evidence for definitive conclusions. M/V showed no statistically significant difference over C/A; therefore, selection should be guided judiciously based on clinical context. Further studies are needed to define the optimal role of each agent within antimicrobial stewardship frameworks.