TABLE 4.

Synergistic interactions with aminoglycosides.

Factor	Mechanism of synergy	Reported risk pattern†	Exposure timing
Loop diuretics	Blood–labyrinth barrier disruption; altered endolymphatic potential; reduced cochlear blood flow	High: substantially increased clinical risk reported; cochlear drug concentrations elevated 2–3-fold in animal models	Concurrent or near-concurrent administration
Vancomycin	Additive mitochondrial toxicity; competitive renal elimination; enhanced oxidative stress	Low–Moderate: association reported in neonatal cohorts; confounded by illness severity and indication; outcome often screening referral rather than confirmed permanent hearing loss	Concurrent administration
Platinum compounds	Complementary ROS generation; DNA damage amplification; shared uptake mechanisms	High: substantially increased risk reported across clinical and experimental studies	Prior or concurrent administration
Inflammation	TRP channel upregulation; potentiated ROS production; pro-inflammatory cytokine release	Moderate–High: increased risk reported; magnitude varies by cohort and outcome definition	Preceding inflammatory states or concurrent systemic illness
Noise exposure	Increased MET channel open probability; additional ROS generation; reduced cochlear blood flow	Moderate: additive injury reported in experimental models	Concurrent or peri-exposure
Hypoxia/Ischemia	ATP depletion; impaired protective responses; enhanced iron release	Moderate: additive injury reported in experimental models	Before or concurrent with aminoglycoside exposure

^†Reported risk pattern levels (Low, Moderate, High) represent approximate patterns derived from observational and experimental literature (Schacht et al., 2012; Cross et al., 2015; Rybak and Ramkumar, 2007; Rybak, 1993; Bates et al., 2002; Brummett et al., 1990; Vella-Brincat et al., 2011; Li and Steyger, 2009; Koo et al., 2015). Estimates vary by outcome definition (e.g., screening referral vs. audiometry-confirmed sensorineural hearing loss), follow-up duration, and confounding by illness severity. Values should not be interpreted as precise quantitative estimates.

^‡Exposure metrics: Risk patterns are derived from studies using variable exposure metrics and outcome definitions. Where specific studies are referenced, the exposure metric used (e.g., Cmax, trough, AUC, cumulative dose) is described in the corresponding manuscript text.

Abbreviations: AG, aminoglycoside; ATP, adenosine triphosphate; MET, mechanoelectrical transduction; ROS, reactive oxygen species.