Apramycin resistance in bacteria isolated from humans, a systematic review and meta-analysis

Abstract Introduction Apramycin is an aminoglycoside antimicrobial that has been used in veterinary medicine since the 1980s but not licensed for human medicine. Because it is not impacted by common aminoglycoside resistance mechanisms, there is interest in repurposing the drug for use in humans, as a treatment of multidrug resistant Gram negative bacterial infections. Gap Statement The prevalence and factors associated with apramycin resistance in bacteria isolated from humans has received limited study but is important foundational information for considering repurposing apramycin for use in humans. Aim To systematically review and analyze data pertaining to apramycin resistance in bacteria isolated from humans and to identify knowledge gaps, to inform work evaluating the potential for re-purposing of apramycin for clinical use in humans. Methodology A systematic review was performed to evaluate apramycin resistance in bacteria isolated from humans. Results A total of 1626 references were identified during the search, with 34 studies were deemed eligible for inclusion. Pooled estimates for apramycin resistance were 6% (95% CI 1-12%) for E. coli, 1% (0-3%) for Acinetobacter spp, 2% (0-5%) for Enterobacter spp, 7% (2-15%) for Klebsiella spp, 4% (0-13%) for Pseudomonas and 0% (0-0%) for Salmonella spp. Multivariable mixed-effects meta-regression identified no effect of year ( P =0.36), bacterial species (all P >0.19), geographic region (all P >0.13) or enrollment of known carbapenem-resistant isolates ( P =0.44). The only significant variable was datasets that used known gentamicin-resistant isolates ( P =0.003). Conclusion Despite nearly 50 years of apramycin use in animals, apramycin resistance was identified in bacteria of human origin but was rare, supporting the potential value of re-purposing this drug for use in humans and suggesting that there is limited spillover of resistance from veterinary and agricultural use of apramycin.