3 η "D Vnnfft. G.R. Voogt Department Otorhinolaryngology Η S . S c h o e m a n Department Mathematics and Statistics Medical University of Southern Africa 9 2 TB patients (7-7 years °>> α χ 5 0 0 audwmeter At the^a ^ ^ s i a r l d a r d ^ti-Wdrug'o ^ and after treatment, usmga i c > streptomycin very shghUy ο d r u g s were gender specific. • dddel, soos hoorbare OPSOMMIS G wmsmsms^-1 hierdie middels geslagspesifiek is nut. Κ ϋ ϊ , ototoxicity c; INTRODUCTION tuberculosis mycobactenû and here a g ^ Hon cases of active ^ ^ ^ ^ ' r ^ e n d i n e l l i , 1988). lion new cases annually (Fnedman ( T B ) i n re- Due to the rising incidence of tube ^ ω ^ cent years and the ^ c r e a s ng b a c t e m e n > g t e r . standard anti-tuberculosis ( a n b - T B ) ^ g 'l 1993), l i n g > Pablos-Mendez. Kilburn, C a u * e n ^ ^ ^ medical treatment has to rely on accompa- of drugs, like the a m l n o g l y c o s d e j ^ ^ ^ ^ o t o - nying adverse toxic reactions such as η Ρ t o m y c i n toxicity, etc. These aminoglycos^e mclud P ^ ^ and kanamycin. Streptomycin has a s e * c o m . the eighth cranial nerve, v e s t i b d a r d a * £ ^ ^ moner than auditory damage. Kanamyc 1 9 g 9 ) toxic, causing mainly cochlear damage ( C o l ^ Aminoglycosides L r cells in cristae or maculae of the ear. u n c & K a m e r e r > these receptors never regener^ . - 0 f having 1985). This places the P h f l c l S v ^ c o u l d result from to weigh the possibility of morbid**^hat coul ^ aminoglycoside administrftion against the ρ effects of the infection being treated. ofthe organ ofCorti,that partofthecoch ^ Jo detect the highest systemati- hear. This damagmg process y ( S c h u k n e c h t , cally progresses S e c t becomes visible 1974). By the time this dama^ng e " H z ω ^ on a conventional has been lost Hz), valuable time for P " ™ ^ 1 ^ to the high fre- and permanent d a - a g e has been ^ d b y quency region in the cochlea. * m Q H z ) hear- regularly monitoring the high J t r e a t e d w i t h ing sensitivity of J ^ v J a n > 1 9 8 4 ) . aminoglycoside drugs (Jonndort ^ ^ a t Aminoglycoside drugs are admin d e t e r m i n e d b y so-called "ototox^ally safe doBages to ^ ^ standard audiometryganging ftt frequencies Hz, while the real and e a r i y ^ m a g ^ ^ ^ g e n e r a . higher than 8000 Hz. W i t h t h e a d v e 2 Q ^ Uon audiometers ^ 6 5 ) and with very good test-rete^t re h e a r i n g a C u i t y of it has become possible to momw o f o t o t o x - t h e s e i n d i v i d u a l s t o d e t e c t ^ v e r y e a r J ^ icity, long before J ^ ^ ^ g ^ ^ U v e actions taken to halt It has also been demon- , , „ Kdskrifvir Kommunikasieafwykings, Vol. 43, 1996 Die SuidAfrikaanse Tydskrif vir Λ R ep ro du ce d by S ab in et G at ew ay u nd er li ce nc e gr an te d by th e P ub lis he r (d at ed 2 01 2) 4 G.R. Voogt & H.S. Schoem. strated that cochlear toxicity is reversible in more than half of all cases, if detected early enough and appropriate steps taken (Fee, 1980). Recently many researchers have done further studies on high frequency hearing and thresholds, with the main aim of eliminating some of the differences that existed amongst the findings of previous researchers. Okstad, Laukli & Mair (1988) compared high frequency air con- duction (AC) and electric bone conduction (EBC) thresh- olds in adults; Schechter, Fausti, Rappaport & Frey (1986) and Stelmachowicz, Beauchaine, Kalberer & Jesteadt (1989) worked on age-related high frequency AC thresh- olds; Frank (1990) examined high frequency AC thresh- olds in adults; and Frank & Dreisbach (1991) tested for repeatability of high frequency AC thresholds in adults. The vast range of differences between testing equipment, subjects and methodology resulted in considerable diffi- culties when an attempt at direct comparison of their re- sults was made. There was, however, found to be reason- able agreement on high frequency AC thresholds and norms, but less on bone conduction (BC). Therefore it would appear that many questions still need to be an- swered with regard to the exact stimulus pathways and precise components of the EBC sensation. With respect to these presently unanswered problem areas in EBC audiometry it would appear that the only truly reliable method of measuring the effect of ototoxic drugs on high frequency hearing using EBC, would be to compare each patient's post-treatment highest audible fre- quency test results with his own pre-treatment baseline results. As ototoxicity usually occurs bilaterally and given the fact that EBC cannot at the present time be effectively masked, the test results would indicate the BC hearing sensitivity of the "best" ear. This suits the purpose of this study as the only interest is determining the ototoxic ef- fect of different anti-TB drug treatments on the highest frequency the subject can hear. METHODOLOGY From patients having to undergo treatment for TB in a TB hospital, all 172 admitted to this hospital in one month were included in this study and followed up over a six month period. These included newly diagnosed TB pa- tients receiving the standard TB medication (a standard- ised four drug combination of rifampicin, isoniazid, pyrazi- namide and ethambutol), patients with resistant TB re- ceiving kanamycin (15 mg/kg/day) and patients with re- sistant TB receiving streptomycin (15mg/kg/day). This group of patients consisted of 106 males and 66 females, ranging in age from 7 to 71 years old. From the test results of the original 172 subjects, 80 were excluded because they did not have measurable hear- ing above 8 KHz, developed middle ear problems, did not show up for follow-up audiometry, absconded from the treatment regimen, had renal failure, their drug treatment was altered/stopped, or they were discharged from hospi- tal. Thus only data from 92 subjects was included in the analysis of the results. All of them had their normal hearing ( 7 8 KHz ) and their high frequency hearing ( 8 8 KHz ) tested twice in the week prior to commencement of any treatment, and thereafter once a month over a period of six months. The average thresholds of the first two of each type of audio- gram of each patient were used as the baseline audiograms for each patient against which any later changes in hear ing was compared. As no effective masking was available for the high frequency tests, the test results indicated the "best ear" high frequency hearing for each patient. Conse- quently, the results of standard audiometry of each p a . tient's left and right ears were also reworked to give a "best ear" test result, in order to be able to compare these results with those from the high frequency tests. A Maico MA-41 audiometer was used for the standard audiometry and an Audimax 500 for the high frequency tests. The Audimax audiometer works on the principle of electrostimulation. The test signal is superimposed on a modulated carrier frequency and is delivered via mylar- coated electrodes into the skin over each mastoid. Nu- merous studies have identified electrostimulation as a means of audio-transmission of electromechanical vibra- tion in the bone and tissue structures surrounding the inner ear and the cochlea. It would therefore appear that the subject's BC hearing is being tested (Sommers & Von Gierke, 1964). This audiometer tests frequencies from 200 Hz right up to 20 KHz, in 200 Hz steps. The stimulus intensities can be adjusted from 0 to 120 electrostimulation hearing threshold levels (ESHTL) in 1 ESHTL step sizes. Zero to 120 ESHTL corresponds with zero to 60 dB sound pressure level (SPL) (Voogt, 1987). Even though the full frequency range audiograms were recorded every time for the high frequency tests, for the purpose of this study only the highest frequency that the subject was able to hear at the maximum stimulus inten- sity of the Audimax audiometer, was taken into account. All test results for each patient were compared to their baseline test results to determine if any high frequency hearing loss (HFHL) had occurred. The hospital is built on a vast expanse of open field, resulting in very quiet surroundings. The hearing tests were performed in a large and unused dental examina- tion room which is situated a considerable distance away from the main hospital buildings, resulting in an extremely quiet test environment. The treatment regimen for each subject was withheld from the audiologist until completion of the six month treatment period, and the information on the type of medi- cation was given only as standard, streptomycin or kan- amycin. Therefore the test results were grouped into a kanamycin group (K-group), a streptomycin group (S- group) and a standard anti-TB drug group (N-group). The test results of these groups were then statistically com- pared as were the results of males and females within each treatment group. RESULTS Using standard audiometry, it would appear that none of the subjects in these treatment groups experienced any resultant loss of hearing, as no differences could be found between their final audiograms and their baseline audio- grams. This, however, was not the case when considering their high frequency audiograms. In this case very clear resul- tant losses of hearing could be seen. Therefore, only the high frequency audiometric data was statistically analysed. Table 1 shows that the mean ages for the three groups were reasonably evenly matched, so the possible effect that age differences amongst the three groups could have had on the results, were negligible. Table 2 reflects the characteristics of HFHL between The South African Journal of Communication Disorders, Vol. 43, 1996 R ep ro du ce d by S ab in et G at ew ay u nd er li ce nc e gr an te d by th e P ub lis he r (d at ed 2 01 2) . . t v of Aminoglycoside Drugs in Tuberculosis Otot o x i c i t y o i * " the three « ^ ^ i T s e e n that in all three treatment From Table 3 it c a n ° u s i g n i f 1 C a n t differences in averageHFHLbet n o t d e r specific, a m i n o g l y c o s ^ ^ ^ ^ W s w a s comprised of a comparison Statistical analys g a n d N ) m r e s p t of of the three treatm nt g w a P i g ^ ^ d HFHL by the K x u e j ^ ^ ^ g r o u p s ( C h i - highly significant mi P a i r w i s e comparisons m i s t showedthat the mean HFHL value b y the rank sum test sh f r o m ^ m e a n s m i n the K-group d i f f e r J g cimically the means the S-group a n d N - p - o u p ^ ^ ^ ^ ^ K . g r o u p i h o w . i n the S- and N-groups dm & r e s u l t o f the medi- ever, suffered a marked tir cation they received. TABLE l : Age c h a r a c t e r i s t i c s ^ Treatment DISCUSSION An unfortunate a ^ c t <,f - o t o t o x i c i t y t o d ^ e f f e c t o r a y i t , „ f ττϊΉΙ, b e t w e e n t h e three TABLE 2: Comparison of H t H l . Deiw treatment groups. Treatment group Κ S Ν η 23 12 57 Age (Yrs) Mean 2,17 0,65 0,32 Std. dev. 1,76 0,28 0,20 Min. 0,20 0,20 0,00 Max. 7,60 1,20 0,80 hearing tested regularly ̂ τ Τ ^ ^ positive treat- and femies were almosi T A B L E * C o m p a r i s o n o l HFffl· b e . » * » « Λ » ϋ treatment groups»· lemaies w n u . » - 1 HFHL (KHz) Treatment group Male Female K-group: η Mean Std. Dev. 11 2,18 1,37 12 2,15 2,11 S-group: η Mean Std. Dev. 5 0,68 0,23 7 0,63 0,34 N-group: η Mean Std. Dev. 35 0,32 1 0,20 22 0,32 0,21 according to Teale, uoioman « — whatsoever. It is also possible that this mil ^ r e d u c t i o n which reduction of 12,8 KJiz over * j linearly with in- i s whether ^ ^ ^ t h e N . creasing age^ As t h e average ag ^ ^ & ^ ^ group was about 35 5 w h i c h a p . audible frequency of a b o u t 8 K H z b y g ^ pears to fit in well with the fact m a ^ a u d i - showing a high frequency ^ ^ ^ e t al. (1989) 0metryfromthisageonwards_ S b d m a c t o w ^ b e g i n s at found that the loss m h * h * a , ( 1 9 8 6 ) 3 0 - r s o l d · Die Suid-Afrikaanse skrifvir Kommunikasieafs, Vol. 43, 1996 R ep ro du ce d by S ab in et G at ew ay u nd er li ce nc e gr an te d by th e P ub lis he r (d at ed 2 01 2) 6 G.R. Voogt & H.S. Schoeman If this ageing factor is taken into consideration, then it can be deduced that in the S-group, the streptomycin treat- ment regimen actually had a fairly minor ototoxic effect, as the average HFHL of 0,65 KHz should then be reduced by 0,32 KHz, giving a 0,33 KHz HFHL as a result of the streptomycin treatment. This may then also mean that the average high fre- quency hearing loss of 2,17 KHz that occurred in the K- group should be decreased by 0,32 KHz to 1,85 KHz, if the effect of ageing is to be taken into account. It therefore becomes clear that the kanamycin treat- ment regimen is more than three times more ototoxic than the streptomycin regimen (average HFHL of 2,17 KHz vs. 0,65 KHz). If the above-mentioned correction for the ef- fect of ageing is taken into consideration, then it means that the kanamycin regimen is almost six times more oto- toxic than the streptomycin regimen (average HFHL of 1,85 KHz vs. 0,33 KHz). CONCLUSION This study showed that high frequency audiometry is superior to standard audiometry with regard to the early detection of ototoxicity and that the use of standard audio- metry for detecting ototoxicity is really of no clinical value. Furthermore it was found that the so-called "safe" lev- els presently used in anti-TB treatment still lead to oto- toxic damage. These levels will most probably have to be revised. The kanamycin treatment regimen was found to be three times more ototoxic than that of streptomycin. Ageing was also found to have a possible effect on the HFHL measured. If a correction was made for HFHL oc- curring as a result of ageing, then kanamycin was found to be almost six times more ototoxic than streptomycin. It was also found that kanamycin and streptomycin ototoxicity were not gender specific as males and females were equally affected. Lastly it became quite clear that the specific effects of ageing on the high frequency hearing will require further long-term studies. REFERENCES Collins, T.F.B. (1989). Tuberculosis - Understanding and Managing the Disease. South African National Tuberculosis Association. de Vaal, J.B. (1994). Aspects of aminoglycoside therapy. Specialist Medicine, XVI(10), 24-60. Fee, W.E. (1980). Aminoglycoside ototoxicity in the human. Laryngoscope, 90(Suppl 24), 1-18. Fletcher, J.L. (1965). Reliability of high frequency thresholds. J. Aud. Res., 5, 133-137. Frank, T. (1990). High frequency hearing thresholds in young adults using a commercially available audiometer. Ear Hear, 11(8), 450-454. Frank, T. & Dreisbach, L.E. (1991). Repeatability of high frequency thresholds. Ear Hear, 12(4), 294-295. Frieden, T.R., Sterling, J., Pablos-Mendez, Α., Kilburn, J.O., Cauthen, G.M. & Dooley, S.W. (1993). The emergence of drug- resistant tuberculosis in New York City. N. Engl. J. Med., 328, 521-526. Friedman, H. & Bendinelli, M. (1988). Preface in: M. Bendinelli & H. Friedman (Eds.), Mycobacterium tuberculosis. New York: Plenum Press. Johnson, J.T. & Kamerer, D.B. (1985). Aminoglycoside Ototoxicity: an update, with implications for all drug therapies. Postgraduate Medicine, 77(5), 131-138. Okstad, S., Laukli, E. & Mair, I.W.S. (1988). High frequency audiometry: Comparison of electric bone-conduction and air- conduction thresholds. Audiology, 27, 17-26. Schechter, A.M., Fausti, S.A., Rappaport, B.Z. & Frey, R.H. (1986). Age categorization of high-frequency auditory threshold data. J. Acoust. Soc. Am., 79(3), 767-771. Schuknecht, H.F. (1974). Pathology of the Ear. Cambridge, Massachusets: Harvard University Press. Sommers, H.C. & Von Gierke, H.E. (1964). Hearing sensations in electric fields. Aerospace Medicine., 35, 834-839. Stelmachowicz, P.G., Beauchaine, K.A., Kalberer, A. & Jesteadt, W. (1989). Normative thresholds in the 8- to 20-KHz range as a function of age. J. Acoust. Soc. Am., 86(4), 1384-1391. Teale, C., Goldman, J.M. & Pearson, S.B. (1994). The association of age with the presentation and outcome of tuberculosis: a five- year survey. J.AR.D., 6(4), 7-10. Tbnndorf, J. & Kurman, B. (1984). High frequency audiometry. Annals of Otology, Rhinology and Laryngology, 93, 576-582. Voogt, G.R. (1987). Early detection of ototoxicity by high frequency audiometry - A case study. South African Journal of Communication Disorders, 34, 67-70. The South African Journal of Communication Disorders, Vol. 43, 1996 R ep ro du ce d by S ab in et G at ew ay u nd er li ce nc e gr an te d by th e P ub lis he r (d at ed 2 01 2)