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Ototoxicity
Published in John C Watkinson, Raymond W Clarke, Christopher P Aldren, Doris-Eva Bamiou, Raymond W Clarke, Richard M Irving, Haytham Kubba, Shakeel R Saeed, Paediatrics, The Ear, Skull Base, 2018
Suppressing the generation or enhancing the scavenging of ROS have therefore been proposed as potential therapeutic interventions for protecting hair cells from the lethal damage caused by aminoglycosides.120,125 However, the direct evidence that aminoglycosides trigger generation of ROS in hair cells in situ in the mature organ of Corti is limited. Nevertheless, in an experimental study the aminoglycoside apramycin, which has potent antibacterial activity and is used in veterinary medicine, was found to cause less hearing impairment and hair cell loss in vivo than other aminoglycosides and in explant cultures of the organ of Corti from neonatal mice generation of ROS was reduced in comparison with gentamicin.126 The studies with apramycin are part of a further current line of investigation: to design aminoglycoside molecules with antimicrobial activity but which do not activate cell death pathways inside hair cells.
Tobramycin
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Juan Gálvez-Acebal, Jesús Rodríguez-Baño
A newer challenge to aminoglycoside susceptibility is the spread of genes by conjugative plasmids that methylate the 30S ribosome site of activity (Doi et al., 2004). The enzymes produced by these genes are similar to the 16S rRNA methylases that protect aminoglycoside-producing actinomycetes. Spread has been observed more in the Enterobacteriaceae than in P. aeruginosa (Doi et al., 2004; Yan et al., 2004; Bogaerts et al., 2007; Ma et al., 2009; Yu et al., 2009). Several specific genes, such as armA, rmtA and rmtB, rmtC, rmtD, and npmA have been identified (Wu et al., 2009). As explained in Chapter 52, Gentamicin, this mechanism confers high-level resistance to all aminoglycosides except for neomycin, apramycin, and streptomycin (Doi and Arakawa, 2007). These methylases are frequently found in association with beta-lactamases and carbapenems (Jia et al., 2013).
In vitro and in vivo comparison of eravacycline- and tigecycline-based combination therapies for tigecycline-resistant Acinetobacter baumannii
Published in Journal of Chemotherapy, 2022
Ti Yin, Jiun-Ji Lai, Wei-Cheng Huang, Shu-Chen Kuo, Tsung-Ta Chiang, Ya-Sung Yang
The MICs of each antibiotic alone and in combination were tested in a broth microdilution checkerboard procedure [18]. A two-dimensional checkerboard with 2-fold dilutions of each antibiotic was set up for the combined treatments. Each microwell contained 100 μL of bacterial inoculum of approximately 105 CFU/mL. Synergism was determined with the fractional inhibitory concentration index (FICI) [18]. FICIs of ≤0.5, >0.5 to ≤4, and >4 were defined as synergistic, indifferent, and antagonistic, respectively [19]. The effectiveness of tigecycline- and eravacycline-based combination therapies were compared. The combined antibiotics included aminoglycosides, fluoroquinolones, broad-spectrum β-lactams, and colistin to provide the anti-pseudomonal activity that tetracyclines lack. Apramycin was also tested due to its promising effects [20], in addition to delafloxacin for its comparable effect to other fluoroquinolones and its status as a novel drug. Minocycline with colistin was used as a control due to its good in vitro and in vivo efficacies [21].
A plethora of carbapenem resistance in Acinetobacter baumannii: no end to a long insidious genetic journey
Published in Journal of Chemotherapy, 2021
Abolfazl Vahhabi, Alka Hasani, Mohammad Ahangarzadeh Rezaee, Behzad Baradaran, Akbar Hasani, Hossein Samadi Kafil, Faeze Abbaszadeh, Leila Dehghani
Apramycin is an aminoglycoside antibiotic used in veterinary medicine. Its resistance to inactivation by most aminoglycoside-modifying enzymes makes it an attractive therapeutic option against MDR Gram-negative microorganisms. The MIC50/90 values of apramycin were found to be 16/64 mg/L against carbapenem and aminoglycoside-resistant A. baumannii isolates.115,138
Carbapenemase producing Klebsiella pneumoniae: implication on future therapeutic strategies
Published in Expert Review of Anti-infective Therapy, 2022
Ilias Karaiskos, Irene Galani, Vassiliki Papoutsaki, Lamprini Galani, Helen Giamarellou
Apramycin is an aminoglycoside antibiotic that has been traditionally used in veterinary medicine. Recently, it has become a promising candidate to combat carbapenemase producing K. pneumoniae [130]. Apramycin is a monosubstituted deoxystreptamine that differs in its chemical structure from clinically relevant aminoglycosides. Apramycin exhibited significant antimicrobial activity against Enterobacterales, including carbapenemase producing strains, as well as clinical isolates of the A. baumannii complex, in comparison to aminoglycosides gentamicin and amikacin [131]. Its unique structure signalizes apramycin susceptibilities to almost all resistance determinants typically found in MDR and XDR Gram-negative bacteria. Apramycin in vitro activity against isolates with resistance mechanism, including aminoglycoside acetyltransferases (AACs), aminoglycoside phosphotransferases (APHs), aminoglycoside nucleotidyltransferases (ANTs) as well as 16s ribosomal RNA methyltransferases (RMTases) is remarkable, with the exception of production of AAC (3)-IV [131], or ApmA (a unique AAC) [132], that both inactivates apramycin. However, the superiority of apramycin to other aminoglycosides has been particularly remarkable for the presence of RMTases [131]. From a nationwide epidemiology study of 300 carbapenem resistant K. pneumoniae isolates from Greek hospitals (200 KPC, 50 NDM, 21 VIM, 14 KPC & VIM, 12 OXA-48, two NDM & OXA and one KPC & OXA-producing isolates), apramycin inhibited 86.7% of the isolates at ≤8 mg/L and was the second most active drug after plazomicin, followed by gentamicin and amikacin that were susceptible at 43% and 18%, respectively [130]. Among 84 carbapenem-resistant and hypervirulent blaKPC-2K. pneumoniae isolates, apramycin demonstrated an MIC90 of 8 mg/L, whereas the MIC90 for amikacin and gentamicin were >64 mg/L. All isolates were susceptible to ceftazidime-avibactam and genetic analysis revealed that all carbapenem-resistant and hypervirulent K. pneumoniae isolates harbored blaKPC-2, whereas 93.6% of amikacin or gentamicin-resistant strains carried the 16S rRNA methyltransferase gene rmtB [133]. Among various bacterial species tested, including CRE clinical isolates, collected between 2014 and 2017 in Europe, Asia, Africa and South America, apramycin inhibited 98% of all Enterobacterales at a concentration of 8 mg/L. Regarding K. pneumoniae it was found active in vitro against isolates producing KPC-2, OXA-181, OXA-232 and OXA-48 [131]. Notably, apramycin has also been demonstrated to be of lower toxicity than other aminoglycosides [134]. Apramycin has completed a Phase 1 clinical trial assessing the safety, tolerability, and pharmacokinetics of apramycin in healthy adults (ClinicalTrials.gov Identifier: NCT04105205).