Propranolol restores susceptibility of XDR Gram-negative pathogens to meropenem and Meropenem combination has been evaluated with either tigecycline or amikacin.

BACKGROUND: Infection with extensive-drug-resistant (XDR) carbapenem-resistant (CR) Gram-negative bacteria (GNB) are viewed as a serious threat to human health because of the limited therapeutic options. This imposes the urgent need to find agents that could be used as adjuvants or combined with carbapenems to enhance or restore the susceptibility of XDR CR- GNB. Therefore, this study aimed to examine the effect of propranolol (PR) in combination with Meropenem (MEM) on the susceptibility profile of XDR CR-GNB recovered from severely infected patients as well as to evaluate combining MEM with either tigecycline (TGC) or amikacin (AK). METHODS: A total of 59 non-duplicate CR- GNB were investigated for carbapenemase production by the major phenotypic methods. Molecular identification of five major carbapenemase-coding genes was carried out using polymerase chain reactions (PCR). Antimicrobial susceptibility tests were carried out using standard methods. Phenotypic and genotypic relatedness was carried out using the heatmap and ERIC PCR analysis. PR, 0.5 -1 mg/mL against the resulting non-clonal XDR CR-GNB pathogens were evaluated by calculating the MIC decrease factor (MDF). A combination of MEM with either AK or TGC was performed using the checkerboard assay. RESULTS: A total of 21 (35.6%) and 38 (64.4%) CR-GNB isolates were identified as enterobacterial isolates (including 16 (27.1%) Klebsiella Pneumoniae and 5 (8.5%) Escherichia coli) and non-fermentative bacilli (including, 23 (39%), Acinetobacter baumannii, and 15 (25.4%) Pseudomonas aeruginosa). The heatmap and ERIC PCR analysis resulted in non-clonal 28 XDR CR isolates. PR, at a concentration of 0.5 mg /ml, decreased MICs values of the tested XDR CR isolates (28; 100%) and restored susceptibility of only 4 (14.3%) isolates. However, PR (1 mg/mL) when combined with MEM has completely (28; 100%) restored the susceptibility of the tested XDR CR- GNB to MEM. The MEM + AK and MEM + TGC combination showed mostly additive effects (92.8% and 71.4%, respectively). CONCLUSION: PR at a concentration of 1 mg/mL restored the susceptibility of XDR CR- GNB to MEM which is considered a promising result that should be clinically investigated to reveal its suitability for clinical use in patients suffering from these life-threatening pathogens.