Antibiotic Resistance

Carbapenemase-producing Enterobacteriaceae (CPE) are classified as emerging Highly Resistant Bacteria (eHRB) because they expose infected patients to the risk of treatment failure due to the strains' resistance to last-line β-lactams, carbapenems, and frequent co-resistance to other classes of antibiotics, leading to increased morbidity and mortality. Their high epidemiogenic potential has enabled their global spread. In France, the incidence of Carbapenemase-producing Enterobacteriaceae is rising sharply, both in colonization and in infections. Parallel to this increase, Escherichia coli has become the most common Carbapenemase-producing Enterobacteriaceae (35% of strains in 2024, National Research Committee data), surpassing Klebsiella pneumoniae (24%). The investigators hypothesize that the increase in the prevalence of carbapenemase-producing Echerichia coli is associated with a diversification of clones, enzymes, and their variants, and may pose a threefold threat: i) the spread of genes encoding carbapenemases within pathogenic extraintestinal Echerichia coli (ExPEC) pathogroups responsible for urinary tract infections and bacteremias, with a high risk of resistance spreading in the community, ii) the silent spread of Echerichia coli strains producing OXA-48 variants with reduced carbapenem hydrolytic activity, OXA-244 and OXA-484, which are not detected or poorly detected by conventionally used screening media and iii) the emergence of New Dehli Metallo-beta-lactamase (NDM) variants with high hydrolytic activity, such as NDM-5, within Echerichia coli clones possessing Penicillin-Binding Proteins (PLPs) with low affinity for antibiotics, leading to very high-level resistance and a therapeutic dead end in infected patients.

Multidrug-resistant (MDR) bacteria represent a significant global health challenge, particularly among immunocompromised populations such as cancer patients undergoing chemotherapy. These patients are highly susceptible to severe infections due to weakened immune defenses, often necessitating the use of broad-spectrum or combination antibiotic therapy. Combination regimens may enhance treatment efficacy through synergistic effects, helping to overcome bacterial resistance mechanisms and improve clinical outcomes. In recent years, there has been growing interest in the use of non-antibiotic drugs as adjunctive agents to enhance antimicrobial activity. These agents, often referred to as antibiotic adjuvants or resistance modifiers, may improve antibiotic effectiveness through mechanisms such as inhibition of bacterial efflux pumps, disruption of biofilm formation, or interference with resistance pathways. Verapamil, a widely used calcium channel blocker, has demonstrated potential antimicrobial and resistance-modifying properties. Experimental evidence suggests that verapamil can inhibit bacterial efflux pumps, thereby increasing intracellular concentrations of antibiotics and enhancing their activity against resistant organisms. This study aims to evaluate the in vitro synergistic antibacterial activity of verapamil in combination with selected antibiotics against MDR, extensively drug-resistant (XDR), and pandrug-resistant (PDR) bacterial isolates obtained from cancer patients. Standard microbiological methods will be used to determine antimicrobial susceptibility and minimum inhibitory concentrations, while combination effects will be assessed using established synergy testing approaches. The findings of this study may contribute to identifying novel, cost-effective strategies to combat antimicrobial resistance through drug repurposing and optimization of existing antibiotic therapies.

The FAST-MDR trial is an externally-controlled, multicentre trial with one prospective arm, evaluating the non-inferiority of the effectiveness of BPaLM in the interventional arm versus the effectiveness of the long, conventional regimen in a French historical cohort of MDR-TB patients (2006-2022). In light of recent WHO recommendations suggesting using BPaLM as a first choice for routine MDR-TB treatment and of the expected benefits of BPaLM over the standard treatment, there will be no internal comparator arm in the study.