Making Antibiotics Safer
for the Ear
Aminoglycosides are the most commonly used antibiotic worldwide. This group of antibiotics is most often used on newborns with fevers, on pregnant women whose water has broken prematurely, on patients who are in the ICU suffering from sepsis and cystic fibrosis patients with recurrent pneumonia, to name a few situations. Aminoglycosides are highly effective as antibiotics; unfortunately they can also damage hearing. Common names in this group include amikacin, gentamicin, kanamycin, neomycin, netilmicin, paromomycin, streptomycin, and tobramycin.
Anthony Ricci, PhD, Professor of Otolaryngology (Head and Neck Surgery) and of Molecular and Cellular Physiology and Dr. Alan G. Cheng, MD, Assistant Professor of Otolaryngology (Head and Neck Surgery) and Pediatrics have been collaborating for more than three years at Stanford University’s School of Medicine, and now as part of the Stanford Initiative to Cure Hearing Loss (SICHL) studying aminoglycosides and their effects on hearing in hope of improving on these life saving drugs and preventing the loss of hearing that they can cause as a side effect. .
Aminoglycosides are ototoxic, meaning that they can enter the inner ear and cause the sensory hair cells to die. The death of these hair cells is currently permanent and irreversible. According to Dr. Cheng, the hearing damage caused by such drugs is “an underestimated but significant problem.” Studies have shown that 15-20% of patients receiving a five to seven day course of aminoglycoside treatment experience hearing loss, and the risk can be higher for those who receive longer treatments or have a genetic mutation causing susceptibility. It is also important to note that the incidence of hearing loss due to aminoglycosides may be under reported due to the lack of standard screening in patients and tests which cannot identify a hearing loss at the highest frequencies. These frequencies are also the hardest to treat with hearing aids.
If aminoglycosides are ototoxic, why do we continue to use them? Dr. Cheng notes that, “…while newer antibiotics exist, and they have offered clinicians alternatives, they are not routinely used because they are often more expensive, and their safety profiles are not as established as aminoglycosides.” Further, in order to establish the safety of these newer drugs, they would have to be tested on pregnant women and newborns, something which is avoided whenever possible.
Why do aminoglycosides damage inner ear cells? Dr. Ricci explains that in the past scientists have studied the mechanism by which the hair cells are damaged by these drugs, but the success of these studies has been limited for many reasons. “First, these drugs are not metabolized and so stay in the hair cell indefinitely, so any treatment would need to continue throughout the patient’s lifetime. Given that the major treatment group is newborn babies who spike fevers postpartum, an indefinite treatment plan is really untenable. Second, the mechanism by which hair cells are affected is likely to be related to the antimicrobial effect of these compounds such that modification would alter the potency of the antibiotic. Third, these compounds have multiple modes of action, each of which can result in toxic effects likely requiring multiple interventions in order to alleviate ototoxicity.”
Dr. Ricci and Dr. Cheng have taken a different approach in their research. They started with the basic fact that if the aminoglycoside cannot enter the hair cell, then it cannot be toxic to the hair cell. The aim was to first understand how the drugs enter the hair cells and then to design new compounds which would not be able to enter these cells.
For Dr. Ricci, whose main area of expertise is hair cell biophysics, and Dr. Cheng, a clinician/researcher with a focus on inner ear cells-- the key to understanding how the drugs entered the inner ear cells was an ion channel novel to the sensory hair cells. This ion channel is responsible for converting sound waves into an electrical signal. They hypothesized that aminoglycosides entered inner ear cells via this ion channel rather than via a transport molecule, as was previously believed. Excitingly, Dr. Ricci and Dr. Cheng were able to prove this hypothesis and the ion channel is now widely accepted as the means by which aminoglycosides enter the ear.
Why is this ion channel important? This new understanding of the ion channel and an understanding of how aminoglycosides are antimicrobial has allowed Dr. Ricci and Dr. Cheng to design new compounds that are less likely to enter hair cells, and therefore not likely to cause hearing damage. Excitingly, in the first round of development, they have synthesized a compound which remained antimicrobial and was non-ototoxic. They are currently moving into testing this compound on animals and using this new knowledge to create a second round of compounds.
The long term goal is to create a new class of aminoglycoside antibiotics which will retain their effectiveness while no longer being ototoxic. Dr. Ricci points out that the research has led to the understanding that the ion channel makes inner ear hair cells more susceptible than others to damage from drug treatments such as aminoglycosides. As such, along with developing more non-ototoxic aminoglycoside antibiotics, both researchers hope to expand their research to include other important drug classes such as cisplatins, which are used in the treatment of some cancers.
SICHL is the collaborative effort of a team of scientists, surgeons and physicians, including Dr. Ricci and Dr. Cheng, who are making rapid progress in understanding the genetic, molecular, and cellular processes behind hearing loss and are utilizing new insights in stem cell proliferation, regenerative medicine, bioengineering, nanotechnology, and other specialties to develop ways to restore and protect hearing. For more information on the Stanford Initiative to Cure Hearing Loss, please visit hearinglosscure.stanford.edu
Editor’s note: The author, Kate Morris, is also the parent of a young daughter with hearing loss.