apramycin and Enterobacteriaceae-Infections

Widespread antimicrobial resistance often limits the availability of therapeutic options to only a few last-resort drugs that are themselves challenged by emerging resistance and adverse side effects. Apramycin, an aminoglycoside antibiotic, has a unique chemical structure that evades almost all resistance mechanisms including the RNA methyltransferases frequently encountered in carbapenemase-producing clinical isolates. This study evaluates the in vitro activity of apramycin against multidrug-, carbapenem- and aminoglycoside-resistant Enterobacteriaceae and Acinetobacter baumannii, and provides a rationale for its superior antibacterial activity in the presence of aminoglycoside resistance determinants.. A thorough antibacterial assessment of apramycin with 1232 clinical isolates from Europe, Asia, Africa and South America was performed by standard CLSI broth microdilution testing. WGS and susceptibility testing with an engineered panel of aminoglycoside resistance-conferring determinants were used to provide a mechanistic rationale for the breadth of apramycin activity.. MIC distributions and MIC90 values demonstrated broad antibacterial activity of apramycin against Escherichia coli, Klebsiella pneumoniae, Enterobacter spp., Morganella morganii, Citrobacter freundii, Providencia spp., Proteus mirabilis, Serratia marcescens and A. baumannii. Genotypic analysis revealed the variety of aminoglycoside-modifying enzymes and rRNA methyltransferases that rendered a remarkable proportion of clinical isolates resistant to standard-of-care aminoglycosides, but not to apramycin. Screening a panel of engineered strains each with a single well-defined resistance mechanism further demonstrated a lack of cross-resistance to gentamicin, amikacin, tobramycin and plazomicin.. Its superior breadth of activity renders apramycin a promising drug candidate for the treatment of systemic Gram-negative infections that are resistant to treatment with other aminoglycoside antibiotics.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Africa; Aminoglycosides; Anti-Bacterial Agents; Asia; Carbapenems; Drug Resistance, Bacterial; Enterobacteriaceae; Enterobacteriaceae Infections; Europe; Genotype; Humans; Microbial Sensitivity Tests; Nebramycin; South America; Whole Genome Sequencing

We evaluated activity of apramycin, a non-ototoxic/non-nephrotoxic aminocyclitol against 141 clinical Enterobacteriaceae isolates, 51% of which were non-susceptible to carbapenems (CRE). Among CRE, 70.8% were apramycin susceptible, which compared favorably to aminoglycosides in current clinical use. Our data suggest that apramycin deserves further investigation as a repurposed, anti-CRE therapeutic.

Topics: Anti-Bacterial Agents; beta-Lactam Resistance; Enterobacteriaceae; Enterobacteriaceae Infections; Humans; Microbial Sensitivity Tests; Nebramycin

Apramycin is a recently developed aminoglycoside restricted to veterinary therapy. Production of a 3-aminoglycoside acetyltransferase type IV (AAC(3)-IV) conferring cross-resistance to this drug and to gentamicin was detected in 1984 in France in bacteria of bovine origin. This mechanism of resistance was apparently confined to animals. We have studied 17 strains resistant to apramycin and gentamicin isolated in 5 hospitals in Belgium. Conjugative plasmids encoding an AAC(3)IV were present in 14 isolates. Comparison of the restriction fingerprints revealed 6 different plasmid patterns: 8 plasmids belonged to 2 groups sharing extensive intragroup homology and 4 were not related to the other replicons. These results indicate dissemination of plasmids within and between hospitals, but also of the gene encoding an AAC(3)IV.

Topics: Animals; Anti-Bacterial Agents; Cattle; Cross Infection; DNA Probes; Drug Resistance, Microbial; Enterobacteriaceae; Enterobacteriaceae Infections; Humans; Nebramycin; Nucleic Acid Hybridization; R Factors; Replicon; Transfection