Comparative evaluation of the antibacterial activity and toxicity of a large panel of aminoglycoside antibiotics

There is a critical need for the development of novel antibiotics due to widespread occurrence of multidrug resistance. Despite their adverse effects, namely, nephrotoxicity and ototoxicity, the emergence of multi-drug resistant bacteria that are resistant to potent antibiotics such as the fluoroquinolones and the ß-lactams has highlighted the prominent role of aminoglycoside antibiotics (AGs).

We carried out a comprehensive comparative characterization of the antibacterial efficacy of a whole series of AGs and AG congeners against a large panel of 61 well characterized ESKAPE clinical isolates, and investigated their ototoxic and nephrotoxic potential, using the OC-k3 and HEI-OC1 otic cell lines and the kidney LLC-PK1 cell line, respectively, all under a common set of experimental conditions; additionally, a selection of these AGs was tested on murine cochlear explants; this information is not available in the literature.

Out of 26 AGs tested, eight commercial AGs and four AG congeners demonstrated strong antibacterial activity against multi-drug resistant pathogens. Eight commercial AGs (amikacin, apramycin, gentamicin, isepamicin, neomycin, paromomycin, sisomicin and tobramycin) and four AG congeners (gentamicin C1a, C2, C2a and neomycin B) demonstrated strong antibacterial activity. Amikacin and isepamicin did not exert toxicity on murine cochlear explants. In addition, amikacin was the only one that did not exert significant nephrotoxicity on the LLC-PK1 cell line. Work on cochlear explants identified neomycin B and gentamicin C1a congeners as less ototoxic than their corresponding AG mixtures, although the congeners were more nephrotoxic. Importantly, we have for the first time directly compared the antibacterial activity and toxicity of seven of the most common gentamicin congeners. We identified gentamicin congeners B1 and X2 as highly toxic, while exhibiting very low antibacterial activity.

We have demonstrated the utility of natural and semi-synthetic AGs against a large panel of multidrug-resistant clinical isolates present in our hospitals. We carried out a comparative assessment of the nephro- and ototoxicity of all these AGs and our data particularly highlighted a very high toxicity of the gentamicin congeners B1 and X2; these congeners may be present in small amounts in commercial gentamicin mixtures and their high toxicity, generally overlooked, could have serious negative implications when gentamicin formulations are applied in the clinic. Nonetheless, it must be taken into account that these studies were conducted on cell lines and, although the concentrations of AGs that are recorded in patients' plasma are variable, -depending on factors such as dosing regimens and the infectious agent-, the AG concentrations we applied to the cultures are well above these concentrations; confirmation of these results in in vivo models will thus be required.