Common Drugs May Prevent Antibiotic-Induced Deafness

If clinical trials show that iron chelators work as well in humans as they do inguinea pigs, the U-M research could lead to a safe and inexpensive way toeliminate the threat of deafness to individuals treated with a common class ofbroad-spectrum antibiotics called aminoglycosides.

Discovered in the 1940s, these antibiotics---which include streptomycin,gentamicin, neomycin and others---are the most widely used antibiotics in theworld. Because they are so effective and rarely produce allergic reactions,physicians continue to prescribe them, even though they are known to causehearing loss and kidney damage in a significant percentage of individuals whotake them.

"In the United States, aminoglycosides are most often used for emergencytreatment of people with serious infections who have not responded to othertypes of antibiotics," said Jochen Schacht, a professor of biological chemistryand otolaryngology in the U-M Medical School. "Increasing levels ofantibiotic-resistant infections associated with AIDS and a worldwide resurgenceof tuberculosis, however, make it likely that their use will increase in thefuture.

"These drugs are a particularly serious problem in developing countries,especially China and Southeast Asia, where they are inexpensive and widelyavailable without a prescription," Schacht added. "Mothers take children withupper respiratory infections to their local pharmacy for an injection. As aresult, studies of deaf-mutism in southeastern China showed that two-thirds ofthe cases were caused by aminoglycosides."

The fact that aminoglycosides have toxic side-effects has been well-known sincethe 1940s, but only recently---thanks to 20 years of research by Schacht andcolleagues at the U-M and other universities---have scientists figured out howthese drugs do their damage.

In 1995, Schacht and his colleagues discovered that gentamicin is not toxicuntil it combines with iron in the bloodstream and becomes "activated." Asthese gentamicin-iron molecules form, they trigger production of freeradicals---unstable molecules that rip apart and damage cells. Thousands oftiny hair cells in the inner ear are especially vulnerable. Without functionalhair cells, the inner ear is unable to detect sounds or transmit signals toauditory neurons leading to the brain. The result is irreversible hearing loss.

"The solution was to avoid the formation of free radicals by preventing thegentamicin from binding with iron in the first place," Schacht said. "That'swhen we decided to try using iron chelators to absorb the iron and keep it fromcombining with gentamicin."

In an article published in the July 1997 issue of the Journal of Pharmacologyand Experimental Therapeutics, Schacht published the results of experimentsshowing that iron chelators did protect guinea pigs from gentamicin's ototoxiceffects. In this study, one group of guinea pigs received gentamicin byinjection. In addition to gentamicin, another group of animals also receivedinjections of two iron chelators---deferoxamine (DFO) and 2,3-dihydroxybenzoate(DHB). One group of animals also received the antioxidant mannitol. Allanimals received hearing tests before, during and after treatment. The quantityand physical condition of hair cells in the cochlea or inner ear of all animalswere examined in tests conducted at the experiment's conclusion.

While the guinea pigs receiving gentamicin alone experienced significant hearingloss with complete loss of hair cells in certain areas of the cochlea, animalsreceiving some combination of iron chelators and antioxidant therapy did muchbetter. "The most striking result was achieved with co-injection of gentamicinwith DHB and mannitol," Schacht reported. "This regimen yielded completeprotection at all measured frequencies in all animals."

Equally important, the treatment did not compromise the therapeutic effects ofgentamicin. Schacht found that iron chelators and mannitol did not lower bloodserum levels of gentamicin nor affect its ability to kill E. coli bacteria.

"We have the principle nailed down," Schacht said. "Now we must work withpharmaceutical firms to identify the most effective iron chelators andantioxidants available, determine a safe human dosage regimen, and then see ifthey will prevent hearing loss in people."

Since iron chelators and antioxidants are already approved for clinical use,Schacht said human clinical trials could start "tomorrow." He added that healready has laboratories in China and Thailand, where the problem is mostprevalent, which have agreed to conduct the trials, if Schacht can obtainfunding.

The research was funded by the National Institute on Deafness and OtherCommunication Disorders, National Institutes of Health. Co-investigators on themost recent experiment include Ben-Bo Song, U-M research fellow, and David J.Anderson, U-M professor of electrical and computer engineering. The experimentswere conducted at the U-M's Kresge Hearing Research Institute.