In vitro activity of apramycin against 16S-RMTase-producing Gram-negative isolates

Abstract

Apramycin is an aminoglycoside (AG) with a unique structure that is little affected by plasmid-mediated mechanisms of AG resistance, including most AG-modifying enzymes and 16S rRNA methyltransferases (16S-RMTases). We evaluate the activity of apramycin against a collection of 16S-RMTase-producing isolates, including Enterobacterales, non-fermenting bacteria and carbapenemase producers. In total, 164 non-duplicate 16S-RMTase-producing isolates, including 84 Enterobacterales, 53 A. baumannii and 27 P. aeruginosa isolates, were included in the study. Whole-genome sequencing (WGS) was performed on all isolates with Illumina technology. The MIC of apramycin was determined by broth microdilution with customized Sensititre plates (Thermo Fisher Scientific, Dardilly, France). We found that 95% (156/164) of the 16S-RMTase-producing isolates were susceptible to apramycin, with a MIC50 of 4 mg/L and a MIC90 of 16 mg/L, respectively. Resistance rates were higher in P. aeruginosa (11%) than in A. baumannii (4%) or Enterobacterales (4%) (p < 0.0001 for each comparison). Eight isolates were resistant to apramycin including one isolate with a MIC > 64 mg/L due to acquisition of the aac(3)-IV gene. The genetic environment of the aac(3)-IV gene was similar to that in the pAH01-4 plasmid of an E. coli isolate from chicken in China. Resistance to apramycin remains rare in 16S-RMTase-producing isolates. Apramycin may, therefore, be an interesting alternative treatment for infections caused by 16S-RMTase and carbapenemase producers.