Dimercaptosuccinic acid in combination with carbapenems against isogenic strains of Escherichia coli producing or not producing a metallo-β-lactamase in vitro and in murine peritonitis

Abstract

Background Carbapenemase-producing Enterobacterales represent a major therapeutic challenge. MBLs, requiring zinc at their catalytic site, could be inhibited by meso-dimercaptosuccinic acid (DMSA), a heavy metal chelator already widely used for treating lead intoxication. Objectives To evaluate the activity of carbapenems alone or combined with DMSA against MBL-producing Escherichia coli in a severe murine peritonitis model. Methods Isogenic strains of wild-type E. coli CFT073 producing the MBLs NDM-1, VIM-2 and IMP-1, and the control serine carbapenemases OXA-48 and KPC-3 were constructed. MIC determinations and time–kill assays were performed for imipenem, meropenem and ertapenem alone or in combination with DMSA. Infected mice were treated intraperitoneally for 24 h with imipenem, DMSA or their combination. Bacterial counts in peritoneal fluid and spleen were assessed at 24 h. Results DMSA in combination with each carbapenem caused a significant decrease in the MICs for all MBL-producing strains, in a concentration-dependent manner, but did not provide benefit against non-MBL strains. In mice infected with the NDM-1-producing strain, the combination of imipenem and DMSA significantly reduced bacterial counts in peritoneal fluid (P = 0.0006) and spleen (P < 0.0001), as compared with imipenem alone, with no benefit against the KPC-3-producing and CFT073 strains. DMSA concentrations in plasma of mice were comparable to those obtained in humans with a standard oral dose. Conclusions DMSA restores the activity of carbapenems against MBL-producing strains, and its combination with carbapenems appears to be a promising strategy for the treatment of NDM-producing E. coli infections.

Therapeutic Options for Metallo-β-Lactamase-Producing Enterobacterales

“…97 One in vivo study showed that a zinc chelator (DMSA) used in combination with a carbapenem significantly reduced bacterial counts in an MBL-producing E. coli murine peritonitis model compared to carbapenems alone. 98 The clinical implications of these findings remain uncertain. While some case reports have shown mostly positive outcomes with carbapenem-based regimens for infections caused by MBL-producing Enterobacterales, 99 Falcone et al noted that among 6 patients who received meropenemcontaining combinations, 3 of them died, though none of them were receiving carbapenem monotherapy.…”

Synergistic Activity of Pep16, a Promising New Antibacterial Pseudopeptide against Multidrug-Resistant Organisms, in Combination with Colistin against Multidrug-Resistant Escherichia coli, In Vitro and in a Murine Peritonitis Model

“…We used the lethal murine intraperitoneal infection model previously developed by our group [13,[15][16][17]. Mice were inoculated by the intraperitoneal route with 250 µL of a bacterial suspension in porcine mucin 10% (Sigma-Aldrich), corresponding to a final inoculum of approximately 2.5 × 10 7 CFU/mL.…”

“…We developed a high-inoculum severe murine peritonitis model, responsible for 100% mice mortality in the absence of treatment. This model allows testing for animal survival and bacterial counts in the spleen and organ sterilization and is especially interesting to test for the efficacy of combinations of antibacterials [13,[15][16][17].…”