Endotoxemia-mediated inflammation potentiates aminoglycoside-induced ototoxicity

Abstract

The ototoxic aminoglycoside antibiotics are essential to treat severe bacterial infections, particularly in neonatal intensive care units. Using a bacterial lipopolysaccharide (LPS) experimental model of sepsis, we tested whether LPS-mediated inflammation potentiates cochlear uptake of aminoglycosides and permanent hearing loss in mice. Using confocal microscopy and enzyme-linked immunosorbent assays, we found that low-dose LPS (endotoxemia) greatly increased cochlear concentrations of aminoglycosides and resulted in vasodilation of cochlear capillaries without inducing paracellular flux across the blood-labyrinth barrier (BLB), or elevating serum concentrations of the drug. Additionally, endotoxemia increased expression of both serum and cochlear inflammatory markers. These LPS-induced changes, classically mediated by Toll-like Receptor 4 (TLR4), were attenuated in TLR4-hyporesponsive mice. Multiday dosing with aminoglycosides during chronic endotoxemia induced greater hearing threshold shifts and sensory cell loss compared to mice without endotoxemia. Thus, endotoxemia-mediated inflammation enhanced aminoglycoside trafficking across the BLB, and potentiated aminoglycoside-induced ototoxicity. These data indicate that patients with severe infections are at greater risk of aminoglycoside-induced hearing loss than previously recognized.

Otopathogenic Pseudomonas aeruginosa Enters and Survives Inside Macrophages

“…However, P. aeruginosa has been demonstrated to be resistant to a wide variety of antibiotics including β lactams (penicillins, cephalosporins, and carbapenems), fluoroquinolones (ciprofloxacin), polymyxins and macrolides (erythromycin and azithromycin) (Nordmann and Guibert, 1998; Livermore, 2002; Walsh et al, 2003; Jang and Park, 2004; Poole, 2004, 2011; Saunders J. et al, 2011; Morita et al, 2014; Mittal et al, 2015). P. aeruginosa exhibits some degree of sensitivity to aminoglycosides but this class of antibiotics has significant ototoxicity and is not recommended for the treatment of CSOM (Black et al, 2004; Jing et al, 2015; Koo et al, 2015; Leis et al, 2015). A better knowledge of the interaction of pathogens with immune cells will provide new opportunities to design effective novel therapeutic strategies against CSOM.…”

An integrated view of cisplatin-induced nephrotoxicity and ototoxicity

“…Systemic inflammation can exacerbate cochlear uptake of ototoxic drugs and potentiate cisplatin-induced ototoxicity (Koo et al, 2015; Oh et al, 2011). Thus, radiation therapy that kills commensal bacteria could inadvertently induce systemic inflammation and potentiate cisplatin-induced ototoxicity during combination anti-neoplastic therapies.…”

Identification of ion-channel modulators that protect against aminoglycoside-induced hair cell death

“…Due to their broad spectrum and rapid bactericidal activity, they are indicated as part of empirical therapy for evident or suspected sepsis and other serious infections (3,4). A major use is in pediatrics, with approximately 80% of newborns admitted to neonatal intensive care units being treated with aminoglycosides (5,6). Their use is also increasing due to emerging multidrug-resistant pathogens, e.g., in the treatment of cystic fibrosis and tuberculosis (3,7).…”