A great advancement in medication was made on October 19, 1943 in the laboratory of Selman Abraham Waksman at Rutgers University by Albert Schatz, a graduate student. Waksman and his laboratory discovered several antibiotics, including actinomycin, clavacin, streptothricin, streptomycin, grisein, neomycin, fradicin, candicidin, candidin, and others. Two of these, streptomycin and neomycin, found extensive application in the treatment of numerous infectious diseases. Streptomycin, however,  was the first antibiotic that could be used to cure the disease tuberculosis. Waksman is also credited with having coined the term antibiotics. 

The details and credit for the discovery of streptomycin were strongly contested by Albert Schatz and resulted in litigation. The contention arose because Schatz was the graduate student in charge of performing the lab work on streptomycin; however, it was argued that he was using techniques, equipment and lab space of Waksman while under Waksman’s direction. There was also debate as to whether or not Schatz should have been included in the Nobel Prize awarded in 1952 that was awarded to Wakman. However, the committee stated that the Nobel Prize was awarded not only for the discovery of streptomycin but also for the development of the methods and techniques that led up to its discovery and the discovery of many other antibiotics. The litigation ended with a settlement for Schatz and the official decision that Waksman and Schatz would be considered co-discoverers of streptomycin. 

No matter which one of them discovered the drug, streptomycin was extremely successful.  With the success of streptomycin, the development of other aminoglycosides antibiotics such as neomycin, kanamycin, gentamicin, amikacin, tobramycin, and netilmicin soon followed.

Ototoxicity

Soon after their introduction in 1944, Hinshaw and Feldman (1945) reported on the clinical efficacy of the first aminoglycoside antibiotics, informing the scientific community of their ototoxic side effects.  Over the years, subsequent studies have proved and reproved that these aminoglycoside antibiotics have ototoxic side effects.  Ototoxic means that a drug has the potential to cause toxic reactions in structures of the inner ear, including the cochlea, vestibule, semicircular canals, and otoliths.  Most audiologists know that drug-induced damage to these structures of the auditory and balance system results in a sensorineural hearing loss, tinnitus, and/or disequilibrium or dizziness.

Aminoglycoside antibiotics are the most commonly used antibiotic worldwide due to their proven effectiveness and low cost. They are often used in treating premature babies and patients with sepsis and/or pneumonia.  While aminoglycoside medications are commonly used all over the world, studies suggest that, depending upon the situation, administration, dosage and various other factors, from 20%-60% of patients treated with these drugs experience some degree of hearing loss. 

The tendency of aminoglycoside drugs to cause ototoxicity has been well established, and there are now over 100 classes of drugs associated with ototoxicity.  The list includes the usual aminoglycosides, but other antibiotics such as platinum-based antineoplastic agents, salicylates, quinine, and loop diuretics are also among the group of medications known to be ototoxic. 

New Research in Aminoglycocides

Recently a breakthrough in research into developing aminoglycosides that are not ototoxic came from the laboratories at the Stanford Initiative to Cure Hearing Loss (SICHL).  This lab has been trying to develop a versions of these valuable antibiotics that are not ototoxic for quite some time.  Part of Stanford University,  SICHL has as a mission to create biological cures for major forms of inner ear hearing impairment through a research effort that is sustained, large-industry, multidisciplinary, focused, goal-oriented, and transformational.  Its efforts stem from the belief that hearing loss is a major cause of human disability that can be conquered.  Seven years of research at  SICHL by Alan Cheng, MD and Antony Ricci, Ph.D. produced a study that demonstrates a cure with no ototoxic effects of a disorder normally treated by streptomycin. According to Cheng and Ricci, ototoxicity is a result of a drug entering the inner hair cells, which do not regenerate and are essential to the hearing process.  Their goal has long been to create a version of the medication that would enter the hair cell and not result in permanent damage to the hearing mechanism. 

Recently published in the Journal of Clinical Investigation is a the study by Cheng and Ricci that found a safe version of aminoglycoside antibiotics that did not cause ototoxicity.  In his summary in Hearing Review, Ricci states that he made nine different compounds derived from sisomicin. All of these compounds were significantly less toxic than sisomicin to hair cells when tested in the laboratory. Three of the nine were comparable to sisomicin in combatting E. coli bacteria.  Of these three derivatives, however, N1MS was the most effective against the bacteria and the researchers used it to treat an E-coli-caused bladder infection in a mouse model while leaning hearing intact.  They also found that their new compound was non-toxic to the kidneys.While these data were recorded in laboratory mice, Cheng and Ricci plan to begin human clinical trials very soon.  In Ricci’s words, “the study presents a promising new approach to generating a new class of novel, nontoxic antibiotics” 

 

References:

Biology Online (2014). Streptomycin.  Retrieved January 21, 2015:  http://www.biology-online.org/articles/aminoglycoside/streptomycin.html

Frymark, T., Leech, H., Mullen, R., Schooling, T., Venediktov, R., & Wang, B (2010). Evidence-Based Systematic Review (EBSR): Drug-Induced Hearing Loss—
Aminoglycosides.  American Speech Language Hearing Association.  Retrieved January 20, 2015:  http://www.asha.org/uploadedFiles/EBSRAminoglycosides.pdf

Hinshaw, H. & Feldman, W. (1945).  Streptomycin in the treatment of clinical tuberculosis:  A preliminary report.  Proced. Staff Meeting Mayo Clinic, Vol 20, pp 313-318.  Retrieved January 20, 2015:  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC284232/?page=3

Kingston, W. (2004). Streptomycin, Schatz v. Waksman, and the balance of credit for discovery. journal of the history of medicine and allied sciences, 59, 441–462. Retrieved January 20, 2014:  http://jhmas.oxfordjournals.org/content/59/3/441.abstract

Morris, K., (2015).  New version of lifesaving drug is safer for the ear and kidneys. Retrieved January 23, 2015:   https://hearinglosscure.stanford.edu/2015/01/new-version-of-lifesaving-drug-is-safer-for-the-ear-and-kidneys/

Otologic Pharmacuetics (2014).  Hearing Loss.  Retrieved January 22, 2015:  http://otologicpharmaceutics.com/hearing-loss/

Pringle, P., (2012).  Notebooks shed light on antibiotics contested discovery.  New York times, June 11, 2012.  Retrieved January 21, 2015:  http://www.nytimes.com/2012/06/12/science/notebooks-shed-light-on-an-antibiotic-discovery-and-a-mentors-betrayal.html?pagewanted=all&_r=1&

Schatz, A.,(1993).  The true story of the discovery of streptomycin. Actinomycetes: Vol. IV, Part 2: 27-39.  Retrieved January 22, 2015:   http://www.albertschatzphd.com/?cat=articles&subcat=streptomycin&itemnum=001

Stanford University, Department of Otolaryngology-Head Neck Surgery(2015).  Revision to Antibiotic Could Eliminate Risk of Hearing Loss.  Retrieved January 23, 2015:  http://www.hearingreview.com/2015/01/revision-antibiotic-eliminate-risk-hearing-loss/

Wikipedia, (2014).  Ototoxicity.  Retrieved January 20, 2015:  http://en.wikipedia.org/wiki/Ototoxicity

Images:

Pringle, P., (2012).  Notebooks shed light on antibiotics contested discovery.  New York times, June 11, 2012.  Retrieved January 21, 2015:  http://www.nytimes.com/2012/06/12/science/notebooks-shed-light-on-an-antibiotic-discovery-and-a-mentors-betrayal.html?pagewanted=all&_r=1&

Stanford University, Department of Otolaryngology-Head Neck Surgery(2015).  Revision to Antibiotic Could Eliminate Risk of Hearing Loss.  Retrieved January 23, 2015:  http://www.hearingreview.com/2015/01/revision-antibiotic-eliminate-risk-hearing-loss/

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