Ototoxic Antibiotics JAMES L. SHEEHY, M.D., Los Angeles

THERE IS NO KNOWN TREATMENT for the loss of * Shortly after the introduction of streptomycin hearing that may result from the use of neomycin, and dihydrostreptomycin in the treatment of tu- berculosis, irreversible perceptive hearing losses kanamycin, dihydrostreptomycin or streptomycin. were noted as a side effect. Although hearing Frequently the loss is such that a hearing aid cannot loss became less of a problem when reduced help, and sometimes total deagness results. Losses dosage schedules were adopted, the more wide- so caused are continuing to occur, and, in the case spread use of these drugs, often in combinations with other antibiotics, in nontuberculou disease of dihydrostreptomycin, the prescribing physician has caused an increase in hearing loss in the last may not know of it, owing to the latent period of few years. Neomycin and kanamycin share this months between treatment and the onset of hearing ototoxic property. Widespread use of these drugs loss. is resulting in loss of hearing in a significant I have observed 26 cases of loss of hearing due number of cases. to these drugs (Table 1). All but three of them occurred within the last four years. Twenty were dysfunction (vertigo) becomes manifest during associated with dihydrostreptomycin therapy, four therapy with streptomycin and is reversible with with neomycin and two with kanamycin. In eight discontinuation of therapy. In the case of dihydro- of the cases associated with dihydrostreptomycin streptomycin, loss of hearing and tinnitus become therapy, the antibiotic was used in treatment of a apparent after a latent period of two to six months, cold. Two of these patients are totally deaf and are progressive and irreversible. Because of the six are helped so little by a hearing aid that they disposition of dihydrostreptomycin to cause irre- are for all practical purposes deaf. versible hearing loss and considering the latent period, it was recommended as early as 19512 that THE STREPTOMYCES ANTIBIOTICS dihydrostreptomycin not be used, either alone or The streptomyces antibiotics include streptomycin in combination with other antibiotics. Where one and its reduction product dihydrostreptomycin, of these drugs is indicated, streptomycin, which has neomycin and kanamycin. As a family, these drugs the same antibacterial spectrum, should be used. have certain properties in common: They must be Unfortunately, the combination drugs on the mar- injected to be effective systemically; they are ex- ket up until the latter part of 1959 contained creted by the kidney; they are ototoxic; and in the dihydrostreptomycin rather than, or along with, case of neomycin and kanamycin, they are nephro- streptomycin. These drugs were Bicillimycin,® toxic. The dangers of ototoxicity are obviously in- Cillimycin,® Combiotic,l Crysdimycin,® Dicrysti- creased if there is impaired renal function, and this cin,® Dihydrocillin,® Districillin,g Durycin,® S-R-D may develop during therapy with neomycin and Penicillin® and Strocillin.® Most physicians who kanamycin. used these drugs were not aware that they contained dihydrostreptomycin, or, if they were aware of it, STREPTOMYCIN AND DIHYDROSTREPTOMYCIN they were unaware of the ototoxic properties. It is true that dihydrostreptomycin has been used The ototoxicity of streptomycin and dihydrostrep- over prolonged periods in patients with tuberculosis tomycin was recognized soon after the introduction of these drugs in the treatment of tuberculosis.' TABLE 1.-CondMtion for Which Ototoxic Antibiotics Were Given Although either drug will cause loss of hearing if In 25 Cases of Resulting Deafness used in a sufficient dosage over a long enough period, Dihydro- there is a predilection for vestibular toxicity with Com- strepto- Neo- Kana- the use of streptomycin and auditory toxicity with biotic* mycin mycin mycin the use of dihydrostreptomycin (Table 2). Vestibular Urinary infection .- 1 3 3 1 Respiratory tract infection 4 4 From the Otologic Medical Group and the Department of Otolaryn- Tuberculosis .... 3 1 gology, University of Southern California School of Medicine, Los .... Angeles 33. Pneumonia 1 1 .. Sponsored by the Los Angeles Foundation of Otology. Abdominal operation .. 1 2 = Presented in part before the Southern California Chapter of the American College of Surgeons Meeting, Santa Barbara, January 7 13 4 2 16, 1960. Crystallin procaine penicillin G, sodium penicillin G, and dihy- Submitted August 4, 1960. drostreptomycin sulfate. VOL. 94, NO. 6 * JUNE 1961 363 TABLE 2.-Characteristics of OtotoxIc Actions of Streptomycin and Dlhydrostreptomycin Primary Site of Action Symptoms Onset Course Streptomycin ------Vestibular Vertigo, tinnitus During therapy Reversible Dihydrostreptomycin------Cochlear Tinnitus, hearing loss Latent period of 2 to 6 months Progressive, irreversible and loss of hearing has developed in only a small KANAMYCIN proportion of them. Recently, however, it has be- Kanamycin is a newer addition to the family of come apparent that in some patients a hearing loss streptomyces drugs. Despite the ototoxicity of this has developed after a small dose,8 presumably due drug,4 it has been recommended by the manufac- to hypersensitivity. In one case 0.5 gm. appears to turer for initial therapy in Staphylococcic infec- have caused a hearing loss.6 In others the dose was tions.i The potential seriousness of the problem, as little as 1.5 gm.,5 2 gm.,* and 7 gm.7 In some however, is manifest in the package description cases a moderate loss of hearing occurred from an (Kantrex,® Bristol) with the drug: "Patients should initial course of dihydrostreptomycin and was fol- be well hydrated during Kantrex® therapy. In lowed by a severe loss after one injection at a later patients with renal disease and impaired renal time. function, the daily dose should be reduced to avoid During the latter half of 1959, a number of hos- accumulation of drug in serum and tissues. In such pitals in the Los Angeles area removed all of the patients if therapy is expected to last seven days or above-mentioned combination drugs containing di- more, a pretreatment audiogram should be obtained hydrostreptomycin from their pharmacies. Shortly and repeated during therapy. Kantrex® therapy thereafter, the drug houses supplying these antibiotic should be stopped if tinnitus or subjective hearing combinations began withdrawing them from the loss develops or if follow-up audiograms show market, substituting a penicillin-streptomycin com- significant loss of high frequency response." bination. It should be pointed out, however, that Two cases of ototoxicity from kanamycin treat- although combinations of this type are safer, they ment have been observed. In one, a moderately se- certainly are not entirely without risk of damage vere hearing loss developed after a daily dose of 1 to the inner ear. gm. for 15 days in the treatment of pneumonia. In NEOMYCIN the other a severe hearing loss developed: Neomycin is a drug that has been used topically A 55-year-old physician was put in hospital with with great success in the control of many Gram- a urinary tract infection. He had a mild hearing negative and Gram-positive infections. Because of loss, the result of dihydrostreptomycin therapy for renal and auditory toxicity, systemic use of it has tuberculosis two years previously. He was given 6 been limited to patients in hospital with serious gm. of kanamycin over a three-day period and infections unresponsive to other antibacterial or shortly thereafter a severe (75 decibel) bilateral chemotherapeutic agents.3 Even when used in the hearing loss developed. Because of the severity of usual therapeutic dose (15 mg. per kilogram of the hearing loss, a hearing aid was useless to him. body weight per day) for more than ten days, renal and auditory dysfunction may develop.t The RECOMMENDATIONS nephrotoxic manifestations are said to be reversible, but the auditory symptoms are not. Most physicians 1. In view of the ototoxicity of dihydrostreptomy- seem to be aware of the nephrotoxic effects of this cin, and considering its latent period, this drug or drug, but many have not been aware that it may drug combinations containing dihydrostreptomycin cause serious deafness. should not be used systemically. Four cases of ototoxicity from neomycin have 2. When systemic streptomycin therapy is in- been observed (Table 1). In three of them the dicated, therapy should be stopped at the first sign patient became totally deaf. The following case is of ototoxicity (vertigo, tinnitus). If impaired renal typical of the findings in these cases: function is present, a lower dosage schedule should A 32-year-old nurse received 1 gm. of neomycin be used. daily for two weeks while in hospital for treatment 3. Kanamycin should be used only where sensi- of pyelonephritis. During treatment she noted the tivity tests indicate that this is the drug of choice. onset of tinnitus and one week after the last dose In a poorly hydrated patient, or one with impaired of neomnycin a hearing loss developed that rapidly renal function, reduced dosage should be used and progressed to total deafness. then only with the realization by physician and Case observed by the author. tKantrex Injection (Bristol Laboratories, Inc., Syracuse, New tPrinted on package by the vendor. York). Advertisement in J.A.M.A., 171, Dec. 12, 1959. 364 CALIFORNIA MEDICINE patient of the possibility of irreversible hearing loss REFERENCES as the result of treatment. In such a patient, a pre- 1. Glorig, A.: Relation of streptomycin and dihydro- treatment audiogram should be obtained and treat- streptomycin to hearing and the vestibular apparatus, J. ment stopped at the first sign- of ototoxicity as Speech & Hearing Disorders, 15:124, 1950. manifested by subjective complaints of tinnitus or 2. Glorig, A.: Effect of dihydrostreptomycin hydrochloride hearing loss or evidence by audiogram of loss of and sulfate on auditory mechanism, Ann. Otol., Rhin. & hearing in the higher frequencies. Laryng., 60:327-335, 1951. 4. The use of neomycin systemically should be 3. Greenwood, G. J.: Neomycin ototoxicity, A.M.A. Arch. limited to patients in hospital with a severe infection Otolaryng., 69:390-397, 1959. in whom no other drug is found to be effective. The 4. Hawkins, J. E.: The ototoxicity of kanamycin, Ann. benefits to be derived from treatment should be Otol., Rhin., & Laryng., 68:698-715, 1959. 5. International Correspondence Society of Ophthalmolo- weighed against the possibility of severe loss of gists and Otolaryngologists, Collected Letters-De Weese, hearing. The patient should be made aware of the D. D.: Series II, page 8, Jan. 15, 1957. possibility of hearing loss as a result of the treat- 6. International Correspondence Society of Ophthalmolo- ment and a pretreatment audiogram should be ob- gists and Otolaryngologists, Collected Letters-Shambaugh, tained. The patient should be observed carefully G. E.: Series II, page 2, Jan. 15, 1957. for tinnitus or hearing loss and for signs of impaired 7. International Correspondence Society of Ophthalmolo- gists and Otolaryngologists, Collected Letters-Williams, renal function. M. Series II, page 40, March 15, 1957. 5. As new antibiotics are introduced, the oto- L.: 8. Shambaugh, G. E., Jr., Derlacki, E. L., Harrison, W. toxicity should be questioned in the case of any H., House, H., House, W., Hildyard, V., Schuknecht, H., that are effective systemically only by injection. and Shea, J. J.: Dihydrostreptomycin deafness, J.A.M.A., 2122 West Third Street, Los Angeles 57. 170:1657-1660, Aug. 1, 1959.

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