Ototoxicity of Amikacin

Transcription

1 ANTIMIcRoBIAL AGzNT8 AND CHzMarHzRAY, June 1976, p Vol. 9, No. 6 Copyright American Society for Microbiology Printed in U.S.A. Ototoxicity of Amikacin ROBERT E. BLACK, WILLIAM K. LAU, RALPH J. WEINSTEIN, LOWELL S. YOUNG,* AND WILLIAM L. HEWITT Department of Medicine, Division ofinfectious Diseases, UCLA School of Medicine, Los Angeles, California Received for publication 21 October 1975 Amikacin was used in 77 treatment courses at a dosage of.7.5 mg/kg every 8 h, and patients were monitored for ototoxicity by following serial audiograms, serum creatinine, and amikacin blood levels. Patients were leukopenic (58), were infected by gentamicin-resistant organisms (11), or had cystic fibrosis (8). Three patients developed tinnitus, but none had vertigo or nystagmus. Of 55 courses with pre- and post-treatment audiogram, 13 (24%) were associated with development of high-frequency hearing loss, which was usually bilateral. No patient had conversational hearing loss, and audiograms reverted to normal in three patients. Onset of cochlear damage occurred in one patient after therapy was stopped. The group with high-tone hearing loss, in comparison to the group without audiographic changes, received a larger mean total dose (24 versus 9.6 g), were treated for a longer duration (19 versus 9 days), and more frequently had previous aminoglycosides. Fifty-seven percent of patients with a "peak" serum level exceeding 32 Ag/ml and 55% of patients with "trough" levels exceeding 10,tg/ml developed cochlear damage. There was no difference between the groups in age, body weight, previous cochlear damage, renal disease before or during therapy, or average daily dose. Both monitoring of blood levels and limiting duration of therapy may prevent amikacin ototoxicity. Amikacin (BB-K8) is a new semisynthetic aminoglycoside antibiotic with a broad antibacterial spectrum (8). Particularly noteworthy is its effect against Pseudomonas aeruginosa and many gentamicin-resistant gram-negative bacilli (1, 11, 12). Amikacin is derived from kanamycin A and has pharmacokinetic characteristics that are similar to kanamycin (2, 3), and animal experiments suggest that it may be comparable to kanamycin with respect to ototoxicity (9). Thus, when clinical trials at this medical center began, administration of the drug was accompanied by careful surveillance for ototoxic effects. This documentation permits an estimation of the risk of eighth nerve toxicity and an analysis of the factors that contribute to it. MATERIALS AND METHODS Patient selection. The case material is from the first 77 treatment courses with amikacin at the University of California at Los Angeles Medical Center. The drug was administered as part of three concurrent clinical trials. (i) The first was a prospective controlled study comparing an amikacincarbenicillin combination with gentamicin-carbenicillin as empirical therapy of serious infection in leukopenic patients (58 courses). (ii) The second was a therapy of infections caused by gentamicinresistant bacteria or unresponsive to conventional gentamicin treatment. The former group of infections had organisms whose minimum inhibitory concentrations were.16 mg/ml of gentamicin in Mueller-Hinton broth media using techniques previously described (11). The latter group required additional aminoglycoside treatment after clinical failure of gentamicin therapy. (iii) The third was a treatment of P. aeruginosa infections in patients with cystic fibrosis (eight courses). There were 61 patients in this study; 12 patients received two courses and 2 patients received three courses for presumably separate infections. Patients with known renal impairment (serum creatinine >1.5 mg/100 mg) were excluded if an alternative antibiotic was available. Prior to treatment a history was obtained of previous ear disease, hearing loss, or previous ototoxic drugs. Auditory function. Whenever possible, pure tone audiometric tests were conducted in an auditory test chamber located in the UCLA Hearing Clinic. For nonambulatory patients, an audiogram was obtained with a portable audiometer (Beltone 10-D) in the patient's room preceding or shortly after initiation of therapy. Most patients in the first treatment category (leukopenic patients) had audiometric studies performed shortly after admission to the hospital, before the development of clinical changes necessitating antibiotic therapy. Post-treatment audiograms were obtained when not precluded by death or depressed levels of consciousness. Air conduction audiometry was conducted at frequencies of 500, 1,000, 2,000, 4,000, and 8,000 Hz. When im- 956

2 VOL. 9, 1976 paired hearing was observed, pure tone bone conduction thresholds at the same test frequencies were conducted to determine if hearing loss was due to middle ear or sensorneural impairment. A conservative approach to evaluating hearing loss was taken due to the illness of the patients and poor room acoustics. A loss of 15 decibels (db) or more from the pre-treatment threshold was regarded as significant. In addition, a 15-dB loss was considered significant if it occurred at one frequency while the remainder of the audiograms remained consistent from pre- to post-treatment tests. Of the 77 treatment courses, 55 (72%) could be evaluated with paired audiograms. During therapy, patients were monitored for development of tinnitus, vertigo, or conversational hearing loss. Antimicrobial dosage. Amikacin was administered at a dose of approximately 7.5 mg/kg every 8 h with a maximum dose of 1,500 mg/day. The daily dose was 20 to 25 mg/kg in 75% of the total group. Eighteen percent was given less than 20 mg/kg per day and 7% more than 25 mg/kg per day. To reduce the chance of bleeding in thrombocytopenic patients most doses were given intravenously in a 5% glucose in water infusion over 20 to 30 min; the remainder were given intramuscular injections. These doses were selected with the following considerations. (i) Total daily dose was limited to 1.5 g, as recommended for kanamycin (package insert). (ii) Infusions or injections were given every 8 h since by 8 h post-administration blood levels declined to less than 8,ug/ml, the concentration required to inhibit most gram-negative rods (11). (iii) Progressive accumulation of antibiotic, i.e., increasing "trough" levels, was infrequently observed at this dosage. The five patients receiving more than 25 mg/kg per day were pediatric patients in whom larger doses (by weight) were necessary to achieve "peak" serum levels exceeding 20 ug/ml. (iv) Severity of both underlying disease and complicating infection in all patient groups justified the use of large antibiotic doses. Laboratory studies. Serum creatinine levels were followed three times a week. Blood was drawn for amikacin blood levels on day 1 and alternate days thereafter. Levels were drawn immediately preceding (trough) and after (peak) the dose of amikacin. After an intramuscular dose of the drug, the peak was measured 1 h later, whereas the peak level following an intravenous infusion was measured 30 to 45 min after completion of the infusion. Serum levels were determined by either a microbiological assay or radioenzymatic acetylation as described previously (10). Analysis of data. Risk factors that may potentially contribute to amikacin ototoxicity that were considered included: symptoms during therapy such as tinnitus; age; body weight; audiographic evidence of hearing impairment prior to therapy; mean milligrams per kilogram of amikacin per day for the course of therapy; number of days amikacin was received for each course; total grams of amikacin received each course; previous aminoglycoside therapy; highest peak amikacin blood level for each course; highest trough amikacin blood level for each OTOTOXICITY OF AMIKACIN 957 course; and renal impairment developing while on amikacin. Statistical analysis was carried out using either a Fisher's exact test ("two-tail") or an unpaired Student's t test. RESULTS Symptoms associated with amikacin therapy. During the 77 treatment courses only three patients complained of tinnitus. At the time of initial symptoms audiograms demonstrated high-frequency hearing loss in two patients, but paired audiometric studies showed no change in the other. Therapy was discontinued and symptoms (but not hearing loss) slowly resolved. No patients complained of conversational hearing impairment or developed vertigo and nystagmus. Cochlear damage. Table 1 summarizes the incidence of cochlear damage. Of the 55 treatment courses (44 patients) for which paired audiograms were available, 13 (24%) patients developed perceptive hearing loss. (Percentage calculations were based on the number of patients with hearing loss per number of courses. No patient with hearing loss was counted twice.) The impairment was bilateral in seven patients and unilateral in six. The higher frequencies were most commonly involved. At 8,000 Hz hearing impairment was observed in 10 of 12 patients tested and at 4,000 Hz in 8 of 13 subjects. In those with hearing loss a mean reduction of threshold of 37 and 39 db was observed at 8,000 and 4,000 Hz, respectively. Hearing loss at 2,000 Hz occurred in four patients but was not sufficient to result in loss of conversational hearing ability. Subsequent audiograms demonstrated recovery to pretherapy auditory threshold in 3 of 13 patients (23%). In the remaining patients, hearing loss TABLE 1. Study populations and cochlear damage NN.t No. with No. with Ici hearingini Patients treated N paired audi- loss (-15 dence (%)a ograms Leukopenic Infected with gen b 67 tamicin-resistant bacteria With cystic fibrosis Total a Based only on the course with paired audiograms. A total of three patients with hearing loss had subsequent studies which demonstrated recovery to pre-therapy auditory threshold. b Two additional patients developed tinnitus with amikacin therapy.

3 958 BLACK ET AL. persisted but was not progressive after the drug was stopped. Twelve patients, after completing a course of amikacin without developing audiometric changes, were retested 2 to 6 months later (without intervening.aminoglycoside therapy). Only one patient showed development of "delayed" bilateral hearing loss, whereas two patients showed improved function (+15 db) in one ear and a comparable decrmeas in the other. Risk factors asociated with cochlear damage. The 13 patients with hearing loss ranged in age from 14 to 50. There was no significant difference between the mean age of this group and that of patients without hearing loss nor did they differ in mean body weight (Table 2). None of the patients with ototoxicity had elevated serum creatinine levels prior to therapy, but one did develop transient azotemia while on amikacin. In the nontoxic group, one patient had renal failure before and another patient experienced renal failure during therapy. Since patients with known renal insufficiency were excluded from the study, inadequate data are available to determine if renal disease increases the risk of ototoxicity. It is clear, however, that cochlear damage from amikacin occurred in patients who had normal renal function for the duration of therapy. Patients with pre-therapy audiographic evidence of high-frequency threshold depression were no more likely to develop ototoxicity while on amikacin than patients with normal pretherapy audiograms. Seven of the 13 patients with hearing loss were started on therapy with normal audiograms. There was no difference in the mean daily dose administered to the toxic or to the nontoxic patients (Table 2). However, the 13 patients with cochlear toxicity had significantly longer courses of therapy (P < 0.02) than the patients without ototoxicity. Because of the TABLz 2. Relation ofpossible risk factors to cochlear damage Course Courses without with Risk factor hearing hearn caniie (P) loss (N low = 43) = 13) Mean age (yr) >0.8 (NS)" Mean body wt (kg) <0.4 (NS) Mean daily dose >0.8 (NS) (mg/kg/day) Mean duration of <0.02 therapy (days) Mean total dose this <0.01 course (g) a NS, Not significant. ANTmzcRoB. AGENTs CHEmoTHEE. longer duration of therapy, the toxic group also had a significantly larger total dos ofamikacin (P <0.01). Therapy for greater than 10 days or with more than 15 g of aniikcin was significantly associated with hearing impairment (Table 3). Patients who were previously treated with gentamicin or amikacin were more likely to develop hearing loss (Fishei's two-tail test, P < 0.001). The incidence of this complication was 48% in those having previous aminglyco side therapy versus 6% in those not previously treated with either drug (Table 4). A similar association could also be demonstrated for gentamicin or amikacin individually. All ofthe patients treated for infection caused by gentamicin-resistant strains had previously received gentamicin, and this was the group with the highest incidence ofcochlear damage (Table 1). Only one patient who developed bilateral TABLE 3. Relationship of cochlear damage to duration of therapy and total dose NNo.wi'th Patients Teay y No. treated No.wih hearinghearing ignfcsc los() (FishYers test) (P) Duration s1o days >10 days Total Dose >15 g < Total TABLE 4. Relationship ofprevious gentamicin or amikacin therapy to cochlear damage No.h Patients taisia Therapy tno'e hear- (thfs ing hoe~n two-tail lloss os() test) (P) Previous gen <0.001 tamicin or amikacin No previous gentamicin or amikacin Previous gen <0.001 tanmicin No previous gentamicin Previous ami <0.05 kacin No previous amikacin Total

4 VOL. 9, 1976 hearing loss received another potentially ototoxic drug, furosemide, and this was given in a single dose of 20 mg. Measurement of amikacin blood levels suggested that the risk of hearing loss increased with either high peak (Table 5) or trough blood levels (Table 6). The association of ototoxicity with peak levels greater than 32 ug/ml was highly significant (Fisher's two-tail test, P < 0.01). Trough levels of greater than 10,4g/ml were also associated with ototoxicity (P < 0.05). For the compilation of these data the incidence is calculated for any patient with one or more peak or trough levels exceeding these limits. Audiometric changes in a "control" group of hospitalized patients. A control population of patients with gentamicin-resistant or unresponsive infections or patients with cystic fibrosis who were not given aminoglycosides was not available. To assess the association of audiometric changes with amikacin treatment, 11 leukopenic patients who had not received aminoglycosides both prior to and between two audiograms obtained at least 2 weeks apart were available for study. None developed significant bilateral cochlear damage. DISCUSSION In patients with pre- and post-treatment audiograms the incidence of high-frequency hearing loss associated with a course of amikacin in this study was 24% (13 patients of TABLE 5. Relationship ofpeak amikacin blood levels to cochlear damage Highest Patients pea amka-no. treated No ih cinmlevel with hearing loss hesring lo % (jhglml) c a > a Total a Statistical significance, P < One patient with hearing loss did not have a peak level measured. TABLE 6. Relationship of trough amikacin blood levels to cochlear damage Highest trough ami; kacin level (,ug/ml) No. treated No. with hearing loss with hearing loss (% '10 > a 55a Total a Statistical significance, P < OTOTOXICITY OF AMIKACIN courses). Three of the 13 patients had audiometric changes that were not subsequently confirmed on follow-up studies; whether this can be attributed to test variation or "reversibility" of cochlear damage cannot be deternined with certainty. A change of 15 db is considered significant by the UCLA Audiology Laboratory but, recognizing the precarious clinical state of some patients in this study, such a figure must be interpreted with caution. Accepting that 10 patients (18%) had irreversible high-frequency loss, this estimate must be viewed as conservative, however, as 21 patients did not have follow-up studies and most of these expired from their underlying disease. Temporally, the development of these audiometric changes was associated with amikacin therapy and not with administration of other potentially ototoxic agents such as furosemide or ethacrynic acid. It is conceivable that severity of underlying disease and use of antineoplastic chemotherapy and radiation therapy may have been factors contributing to ototoxicity. Nevertheless, a small control group (for the leukopenic patients) was available for study, and none of 11 patients with acute leukemia or aplastic anemia who had two audiometric studies but did not receive aminoglycoside antibiotics by the time ofthe second audiogram demonstrated significant bilateral changes. The doses of amikacin used in this study were large and were based not only on the need to achieve blood levels that would inhibit most clinically significant strains (11) but also on preliminary pharmnacokinetic studies, showing drug accumulation at such doses was uncommon in patients with normal renal function. The major therapeutic consideration was that severity of infection in seriously ill patients justified these dosages. It is interesting that our estimate of amikacin-associated cochlear damage is virtually identical to that reported by other investigators with paired data and similar audiologic criteria (7), though in the latter study the drug was given less frequently, was used in lower daily dosage, and was given to a different type of patient population. Another factor which must be considered in the interpretation of our data is that most of the patients in the leukopenic group, the largest "wing" of this study, had the first of at least two audiograms performed when they were clinically well before the start of therapy. Data on the ototoxicity of kanamycin, in contrast, is available mainly from retrospective analyses in which a large proportion of patients had abnormalities of renal function (4-6). None of our patients with high-frequency hearing loss had symptomatic conversational

5 960 BLACK ET AL. hearing impairment, but previous experience with kanamycin ototoxicity indicates that total deafness can occur and should be regarded as a potential risk with amikacin. It may be possible to limit the frequency and severity of ototoxicity by identifying risk factors or early warning signs. In this study five possible risk factors could be correlated with cochlear damage: (i) long duration of therapy; (ii) large total dose of amikacin; (iii) previous aminoglycoside therapy; (iv) high peak amikacin blood levels; and (v) high trough amikacin blood levels. The first three have been well established for kanamycin ototoxicity (4). It is also clear these variables are not independent. Obviously, duration of therapy and total dose are directly related. In addition, patients treated with more than 15 g of amikacin were more likely to have had more serious infections due to severe underlying diseases such as leukemia, and such patients were more likely to have received aminoglycoside antibiotics on previous occasions. Assigning each of these "risk factors" a weight of 1, Table 7 demonstrates that the risk of toxicity increases markedly when three or more such factors are present. Prevention of ototoxicity would be simplified if warning symptoms occurred before toxicity. Tinnitus was observed in only three patients and two of these had high-tone hearing loss at the time of first symptoms. The majority of patients with cochlear damage had no symptoms during therapy and hence no warning of eighth nerve toxicity. The lack of a reliable warning signal for ototoxicity further emphasizes the need to observe certain precautions in using amikacin. The precautions that we specifically recommend are that if therapy is prolonged (dose >15 g) or the patient has previously been treated with aminoglycosides serial audiograms should be obtained on a biweekly basis. Further, the association of toxicity with elevated blood levels suggests that serial monitoring of blood levels may prevent ototoxicity by TABLE 7. Number of risk factors present and hearing loss Risk factors pres- No. treated Patients with ent hearing loss() Total ANTIMICROB. AGENTS CHEMOTHER. proper dosage adjustments. Observations in our patients suggest that in the absence of renal impairment hearing loss is not progressive after the drug is stopped. However, late onset of bilateral hearing loss (post-treatment) did occur in one patient. The clinical efficacy of amikacin is currently being evaluated in a number of institutions. Clearly, among its most appealing advantages are its activity against many gentamicinresistant organisms and the high serum levels that can be achieved, giving it a theoretical therapeutic advantage over several other available aminoglycosides (11). Our experience with ototoxicity looms as a significant potential disadvantage to the use of this compound when other agents of comparable efficacy are available, yet there will be obvious circumstances when its prolonged use is justified. With the availability of several new aminoglycosides, rigorous attempts should be made to define the ototoxicity of such compounds under the fairly simple conditions defined here so that comparative clinical data become available. ACKNOWLEDGMENTS This study was supported by Public Health Service training grant AI-309 from the National Institute of Allergy and Infectious Diseases. It was also supported by a grant from the Bristol Laboratories Division of the Bristol-Myers Company, Syracuse, N.Y. LITERATURE CITED 1. Bodey, G. P., and D. Stewart In vitro studies of BB-K8, a new aminoglycoside antibiotic. Antimicrob. Agents Chemother. 4: Bodey, G. P., M. Valdivieso, R. Feld, and V. Rodriquez Pharmacology of amikacin in humans. Antimicrob. Agents Chemother. 5: Cabana, B. E., and J. G. Taggart Comparative pharmacokinetics of BB-K8 and kanamycin in dogs and humans. Antimicrob. Agents Chemother. 3: Finegold, S. M Toxicity of kanamycin in adults. Ann. N.Y. Acad. Sci. 132: Frost, J. O., J. E. Hawkins, and J. F. Daly Kanamycin. II. Ototoxicity. Am. Rev. Respir. Dis. 82: Haapanen, J. H Untoward phenomena during antituberculosis treatment. I. Auditory toxicity of kanamycin in tuberculous patients. Ann. Med. Intern. Fenn. 52(Suppl. 42): Meyer, R. D., R. P. Lewis, E. D. Carmalt, and S. M. Finegold Amikacin therapy of serious gramnegative bacillary infections. Ann. Intern. Med. 83: Price, K. E., D. R. Chisholm, M. Misiek, F. Leitner, and Y. H. Tsai Microbiological evaluations of BB-K8, a new semisynthetic aminoglycoside. J. Antibiot. (Tokyo) 25: Reiffenstein, J. C., S. W. Holmes, G. H. Hottendorf, and M. E. Bierwagen Ototoxicity studies with BB-K8, a new semisynthetic aminoglycoside antibiotic. J. Antibiot. (Tokyo) 26:

6 VOL. 9, Stevens, P., L. S. Young, and W. L. Hewitt Radioimmunoassay, acetylating radio-enzymatic assay, and microbioassay of gentamicin: a comparative study. J. Lab. Clin. Med. 86: Young, L. S., and W. L. Hewitt Activity of five aminoglycoside antibiotics in vitro against gram- OTOTOXIC11Y OF AMIKACIN 961 negative bacilli and Staphylococcus aureus. Antimicrob. Agents Chemother. 4: Yu, P. K. W., and J. A. Washington II Comparative in vitro activity of three aminoglycoside antibiotics: BB-K8, kanamycin, and gentamicin. Antimicrob. Agents Chemother. 4: