Hearing loss-linked drug made safer
A safer version of a potent antibiotic for serious infections that often causes hearing loss has been developed by scientists.
An estimated 20% to 60% of all patients treated with aminoglycoside antibiotics - including newborn babies - experience partial or complete deafness, which is irreversible.
Now researchers have produced a modified version of one of the drugs that works effectively in mice without causing hearing loss or kidney damage, another common side effect.
Aminoglycosides, which include streptomycin and gentamicin, are widely used to treat serious infections and sepsis, a deadly condition marked by the immune system going into overdrive. They are also given to infants with life-threatening infections.
But the drugs have serious side effects, including hearing loss due to the destruction of inner ear hair cells that help turn sound vibrations into nerve signals.
Professor Anthony Ricci, from Stanford University in the US, said: "If we can eventually prevent people from going deaf from taking these antibiotics, in my mind, we will have been successful. Our goal is to replace the existing aminoglycosides with ones that aren't toxic."
Having successfully completed tests in mice, the team hopes to move onto patient trials "as soon as possible".
The scientists took four years to produce five grams of the newly patented antibiotic N1MS, which is derived from the aminoglycoside drug sisomicin.
Results published online in the Journal of Clinical Investigation showed that N1MS cured urinary tract infection in mice as effectively as sisomicin, without resulting in deafness.
The solution to the hearing loss problem lay in producing drug molecules that were unable to enter the hair cells through ion channels.
These are cell membrane pores that allow the passage of electrically charged particles.
Co-author Dr Alan Cheng, also from Stanford, said: "As a clinician-scientist, I treat kids with hearing loss.
"When a drug causes hearing loss it is devastating, and it's especially disturbing when this happens to a young child as they rely on hearing to acquire speech.
"When I came to Stanford seven years ago from the University of Washington, I was exploring the angle that maybe we could add drugs to protect the ear from toxicity. Tony brought up this new idea: Why don't we just not let the drug get in? Great idea, I thought."
Prof Ricci said scientists had searched for decades for ways to prevent aminoglycosides killing off the hair cells of the inner ear.
"So many approaches have failed," he added. "The main problem has been that if you succeeded in stopping the drug from killing hair cells, then you also stopped its antimicrobial effect. The drug just doesn't work anymore.
"We figured, well, let's not mess with that part of the drug. We targeted sites on the drug molecule that were not involved in the antimicrobial activity that kills off infection. This allowed us to reduce toxicity to the ear while retaining antimicrobial action."
The scientists tested nine different compounds derived from sisomicin. All were significantly less toxic to hair cells than the original drug and three matched sisomicin's ability to combat Escherichia coli (E. coli) bacteria.
N1MS turned out to be the most effective, and unlike the parent drug, was also non-toxic to kidneys.
Despite their side effects, aminoglycosides have remained a mainstay treatment for many infectious diseases including pneumonia, peritonitis and sepsis. They are often used when other antibiotics have failed to treat infections of unknown origin.
Their popularity is partly due to low cost, the fact that they do not need refrigerating, and their continued effectiveness at a time when bacterial resistance is on the rise.
They are frequently used in neonatal intensive care units to battle infections that threaten the lives of babies.
How many premature babies suffer hearing loss as a result of treatment with aminoglycosides is unknown, said Prof Ricci.
Dr Daria Mochly-Rosen, director of Spark, a Stanford programme that helps transfer medical discoveries from the lab bench to the bedside, said: "The toxicity of these drugs is something we accept as a necessary evil."