Prospective Randomized Double-Blind Comparison of Nephrotoxicity ...

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Nov. 1984, P. 766-769

Vol. 26, No. 5

0066-4804/84/110766-04$02.00/0 Copyright © 1984, American Society for Microbiology

NOTES Prospective Randomized Double-Blind Comparison of Nephrotoxicity and Auditory Toxicity of Tobramycin and Netilmicin JOSE M. GATELL,l* JUAN GARCIA SANMIGUEL,' VISI ARAUJO,' LAURA ZAMORA,' JUAN MANA,' MAGIN FERRER,2 MONTSERRAT BONET,' MONTSERRAT BOHE,' AND MARIA T. JIMENEZ DE ANTA4 Infectious Disease Unit' and Departments of Clinical Pharmacology,2 ORL,' and Microbiology,4 Hospital Clinic, Faculty of Medicine, 08036 Barcelona, Spain Received 20 March 1984/Accepted 7 August 1984

Netilmicin or tobramycin was administered to 197 patients in a prospective randomized double-blind trial. Of these patients, 140 recipients of nine or more doses of netilmicin or tobramycin could be evaluated for nephrotoxicity. Fifty-five patients were able to cooperate in the administration of serial audiograms. Nephrotoxicity of similar severity developed in 7 of 73 (9.6%) recipients of tobramycin and in 7 of 67 (10.4%) recipients of netilmicin (P > 0.05). Mild or slight auditory toxicity developed in 5 of 28 (17.8%) recipients of tobramycin and in 2 of 27 (7.4%) recipients of netilmicin (P > 0.05). (19, 27). Serum aminoglycoside levels before (trough levels) and 1 h after the start (peak levels) of drug administration were measured on the first and every third day during therapy, after each dosage change, and after every change in serum creatinine of >0.5 mg/liter. Determinations were performed by high-pressure liquid chromatography, using a modification of the method reported by Barends et al. (1). Subsequent maintenance doses were adjusted to maintain trough serum aminoglycoside levels below 2 mg/liter and peak levels between 5 and 12 mg/liter. Serum creatinine was measured before therapy, on the first day of therapy, and every third day until 2 days after cessation of therapy or patient death. A further follow-up was not regularly performed. Nephrotoxicity was defined as a rise in serum creatinine of 0.5 mg/100 ml or more if the initial creatinine level was 3 mg/100 ml. The rise was estimated by subtracting the creatinine level before therapy from the highest creatinine level. Patients receiving nine or more doses of tobramycin or netilmicin were evaluated for nephrotoxicity. Patients who met the criteria for nephrotoxicity but had another cause of acute renal failure were excluded because the main cause of the creatinine increase could not be determined. Audiograms were performed in a soundproof auditory test chamber with an audiometer (Amplaid 300; Amplaid Spa., Milan, Italy) at 250, 500, 1,000, 2,000, 4,000, and 8,000 Hz on day 1 or 2 and on day 7 of therapy and every 7 days if therapy continued. Slight auditory toxicity was defined as a decrease in the auditory threshold of 15 dB in at least two frequencies in the range of 250 to 8,000 Hz either unilaterally or bilaterally. Auditory toxicity was considered mild if the decrease in the auditory threshold was 20 dB or more, also in at least two frequencies. Patients who were given at least nine doses of tobramycin or netilmicin and who were unable to be moved to a soundproof room and to cooperate in the administration of serial audiograms were evaluated for auditory toxicity. Patients having any other cause of auditory toxicity and meeting the criteria of auditory toxicity were not considered to have an aminoglycoside-related auditory toxicity. In fact, no patient fell into this category. The chi-square test, with the Yates correction, and the Fisher exact test, when

Toxicity is the major limiting factor in the clinical usefulness of aminoglycosides (16, 26). In experimental animals the nephrotoxicity and ototoxicity of netilmicin are lower than those of the other aminoglycosides (3, 6, 9, 11, 18, 20, 22, 25, 36). Low rates of netilmicin toxicity have also been found in several open clinical studies (12, 21, 33, 35; W. H. Greene, R. Isturiz, A. Harmon, R. K. Root, and V. T. Andriole, Abstr. Int. Cong., Chemother. 12th, Florence, Italy, 1981; P. Leal del Rosal, V. Sama, A. Hernandez, and A. Aguirre, Prog. Abstr. Intersci. Conf. Antimicrob. Agents Chemother., 21st, Chicago, Ill., abstr. no. 545, 1981; P. Riben, T. Louie, E. Komachuck, J. Neeks, and A. Ronald, Abstr. Int. Cong. Chemother. 12th, Florence, Italy, 1981), and in a large prospective randomized trial (15) the ototoxicity of netilmicin was lower than that of tobramycin (P = 0.037). In four prospective randomized studies reported so far, however, the rates of toxicity of netilmicin, gentamicin, and amikacin have been similar (2, 4, 10, 17). Adult patients with possible or documented sepsis, urinary or biliary tract infection, or pneumonia and for whom an aminoglycoside was considered indicated by a doctor other than one of the investigators were candidates for entry into the trial. Informed consent was obtained in each case. Patients allergic to aminoglycosides or infected with an organism known to be resistant to tobramycin or netilmicin or who had received an aminoglycoside in the previous 30 days were not entered into the study. The trial was prospective and controlled. Drug assignments were random (a computer-generated table was used), and a double-blind evaluation of toxicity was performed. Serum aminoglycoside measurements and appropriate dosage changes were supervised by an nonblinded member of the investigative group. The patient and the clinical investigator (J.M.G.) responsible for the evaluation of each case did not know which aminoglycoside had been given. Antibiotic therapy other than aminoglycosides and nonantibiotic therapy were not controlled in trial protocol. The loading dose of tobramycin and netilmicin was 1.7 mg per kg of total body weight given intravenously over 20 or 30 min. Maintenance doses were initially adjusted for renal function according to a nomogram *

Corresponding author.

766

NOTES

VOL. 26, 1984 TABLE 1. Characteristics of the 73 patients givWn tobramycin and the 67 given netilmicin compared for nepirotoxicity Characteristic

Age (yr) Initial creatinine level

(mg/100 ml)" Duration of therapy (days) TFotal dose (g) Trough levels within the desired range (%) Peak levels within the desired range (%) Previous renal disease (no.) Concurrent drug (no.) Penicillins Cephalosporins Other antibioticse Furosemide Suspected type of infection (no.) Sepsis Urinary tract Pneumonia Biliary tract

Tobramycin

Netilmicin

Corrected P value'~

53 ± 21.3b 1.1 ± 0.2

58.5 ± 18.9 1.2 ± 0.5

NS NS

8.2 ± 2.9 1.9 ± 1

88.5d

8.1 ± 3.8 1.8 ± 1 79.4

NS NS NS

82.8

79.3

NS

9

6

NS

64 6 7 5

53 4 5 1

NS NS NS NS

14 29 22 8

17 20 24 6

NS NS NS NS

a NS, Not significant. Values are mean + SD. c To convert creatinine in milligrams per 100 ml to micromoles per liter, multiply by 88.4. d Number of determinations within the desired range divided by the total number of determinations and expressed as a percentage. e Clindamycin or metronidazole. b

necessary, were used to compare proportions; Student's t test was used to compare means. Of the 197 patients initially entered into the trial, 23 (13 given tobramycin and 10 given netilmicin) were excluded because they received fewer than nine doses of tobramycin or netilmicin, and 18 (13 given tobramycin and 5 given netilmicin) were excluded because they had another potential cause of acute renai failure apart from the administration

767

of aminoglycosides. The other causes of renal failure were hypotension or shock in eight patients, dehydratation in three, hepatorenal syndrome in four, and obstructive acute renal failure in two. Sixteen patients (seven given tobramycin and nine given netilmicin) were excluded for not adhering to the trial protocol. The nephrotoxicities of tobramycin and netilmicin were then compared in the remaining 140 patients, 73 given tobramycin and 67 given netilmicin. The two groups were homogeneous (Table 1). The mean increase in serum creatinine was identical in both treatment groups (0.2 and 0.3 mg/100 ml). Nephrotoxicity developed in 7 of 73 (9.6%) patients given tobramycin and in 7 of 67 (10.4%) patients given netilmicin (P > 0.05). The severity of nephrotoxicity was also similar in both treatment groups. Indeed, among the patients who developed nephrotoxicity, mean serum creatinine levels did not differ significantly (range, 0.5 to 2 mg/100 ml in the group given tobramycin versus 0.6 to 1.7 mg/100 ml in the group given netilmicin). Among the patients with nephrotoxicity one patient died in each group. In no case was hemodialysis required and nephrotoxicity was never considered to be the cause of either of the deaths. Fifty-five patients, 28 given tobramycin and 27 given netilmicin, could be evaluated for auditory toxicity. The two groups were homogeneous (Table 2). Slight or mild auditory toxicity (a decrease of .15 dB) developed in 5 of 28 (17.8%) patients given tobramycin and in 2 of 27 (7.4%) given netilmicin (P > 0.05). Mild auditory toxicity (decrease of .20 dB) developed in a 4 of 28 (14.2%) and in 1 of 27 (3.7%) patients given tobramycin and netilmicin, respectively (P > 0.05). The severity of auditory toxicity was similar in both groups and ranged from 15 to 40 dB at frequencies of 250 to 8,000 Hz. No risk factor could be identified for either nephrotoxicity or auditory toxicity. The present study was designed to compare the nephrotoxicity and auditory toxicity of netilmicin and tobramycin. The rates of nephrotoxicity of these drugs were almost identical. Furthermore, no statistically significant difference was reached in a multicentric comparative trial in which 230 patients were evaluated for nephrotoxicity (15). In this trial

TABLE 2. Characteristics of the 28 patients given tobramycih and the 27 given netilmicin compared for auditory toxicity Characteristic

Age (yr) Initial creatinine level (mg/100 ml)' Duration of therapy (days) Total dose (g) Trough levels within the desired range (%) Peak levels withln the desired range (%) Previous otic disease (no.) Concurrent drug (no.) Penicillins Cephalosporins Other antibioticse Furosemide Suspected type of infection (no.) Sepsis Urinary tract Pneumonia

Biliary tract

Tobramycin

Netilmicin

Corrected P value'

49.2 ± 18.7" 1.1 ± 0.2

51.2 ± 17.6 1.2 ± 0.6

NS NS

8.3 ± 2.3 2 ±0.7

NS

96.6d

9.5 ± 4.3 2.1 ± 1 90

81.8

73.6

NS

5

9

NS

21 2 2 2

21 2 3 0

NS NS NS NS

8 12 5 3

8 8 10 1

NS NS

" NS, Not significant. b Values are mean ± SD. ' To convert creatinine in milligrams per 100 ml to micromoles per liter, multiply by 88.4. d Number of determinations within the desired range divided by the total number of determinations and expressed as a percentage. ' Clindamycin or metronidazole.

NS

NS

NS NS

768

NOTES

tobramycin was more ototoxic than netilmicin (12 versus 3%; P = 0.037) (15). Many indexes of renal damage or dysfunction have been used to define nephrotoxicity (7, 23, 28-30, 32; C. R. Smith, 0. Laskin, and P. S. Lietman, Abstr. Int. Cong. Chemother. 12th, Florence, Italy, 1981). The serum creatinine level is simple to estimate and widely available and reflects the glomercular filtration rate fairly well (13, 31). No differences in slight or mild auditory toxicity were found. However, only a relatively small group of patients was able to be moved to a soundproof room or to cooperate in the administration of serial audiograms, and only differences of 25% or greater would have been detected. Mild auditory toxicity was less in the group receiving netilmicin; however, no statistically significant difference was reached for either mild or slight auditory toxicity. From studies in different species of experimental animals, an extremely low ototoxic potential has been ascribed to netilmicin (5, 11, 22). In open and comparative clinical studies the auditory toxicity of netilmicin ranged from 0 to 23% (3, 21, 26, 33; Leal del Rosal et al., 12th ICC, 1981) depending in part on the criteria used by the investigators to define it. Any combination of unilateral or bilateral (3, 4, 10), or only bilateral (4, 14), decreases of a minimum of 5 to 20 dB (4, 17, 21) at one (3, 8) or more than one (10, 15, 24, 26) frequency has been accepted as a criterion for auditory toxicity. What is worse is that in some studies the criteria of auditory toxicity are not completely defined. In addition, testing of hearing at the bedside is not well standarized (16), and patients in poorer condition are likely to be included. For such patients, threshold values, especially of the first audiogram, may be falsely low so the detection sensitivity of auditory toxicity may be lessened. Serial evaluation of vestibular function has been difficult (16) and was not attempted in our study. In conclusion, no statistically significant differences have been found in nephrotoxicity and auditory toxicity of tobramycin and netilmicin. We believe that tobramycin and netilmicin should be selected for reasons other than nephrotoxicity or auditory toxicity unless fewer differences can be demonstrated in a similar but larger trial. This work was supported in part by grants from the Fundation Valgrande and Essex Chemie AG (Spain). L. Zamora holds research grant 341/81 from the Fondo de Investigaciones Sanitarias de la Seguridad Social. LITERATURE CITED 1. Barends, D. L., C. L. Zwaan, and A. Hulshoff. 1981. Microdetermination of tobramycin in serum by high-performance liquid

chromatography with ultraviolet detection. J. Chromatogr. 225:417-426. 2. Barza, M., M. W. Lavermann, F. P. Tally, and S. L. Gorbach. 1980. Prospective, randomized trial of netilmicin and amikacin with emphasis on eight nerve toxicity. Antimicrob. Agents Chemother. 17:707-714. 3. Barza, M., V. Pinn, P. Tanguay, and T. Murray. 1978. Nephro-

toxicity of newer cephalosporins and aminoglycosides alone and in combination in a rat model. J. Antimicrob. Chemother. 4(Suppl. A):59-68. 4. Bock, B. V., P. H. Edelstein, and R. D. Meyer. 1980. Prospective comparative study of efficacy and toxicity of netilmicin and amikacin. Antimicrob. Agents Chemother. 17:217-225. 5. Brummett, R. E., K. E. Fox, R. T. Brown, and D. L. Himes. 1978. Comparative ototoxic lability of netilmicin and gentamicin. Arch. Otolaryngol. 104:579-584. 6. Chiu, P. J. S., G. H. Miller, A. D. Brown, J. F. Long, and J. A. Waitz. 1977. Renal pharmacology of netilmicin. Antimicrob. Agents Chemother. 11:821-825.

ANTIMICROB. AGENTS CHEMOTHER. 7. Coca, A., J. Blade, A. Martinez, F. Segura, E. Soriano, and M. Ribas Mundo. 1979. Tobramycin nephrotoxicity. A prospective clinical study. Postgrad. Med. J. 55:791-796. 8. Frimodt-Moller, N., S. Maigaard, and P. 0. Madsen. 1979. Netilmicin treatment of complicated urinary tract infection in patients with renal function impairment. Antimicrob. Agents Chemother. 16:406-410. 9. Hagstrom, G. L., F. C. Luft, M. N. Yum, R. S. Sloan, and D. R. Maxwell. 1978. Nephrotoxicity of netilmicin in combination with non-aminoglycoside antibiotics. Antimicrob. Agents Chemother. 13:490-498. 10. Herting, R. L., R. R. Lorber, N. Miller, arid N. R. Danzing. 1981. Multicenter comparative evaluation of netilmicin and gentamicin in adult patients. Arzneim. Forsch. 31:366-370. 11. Igarashi, M., J. K. Levy, and J. Jerger. 1978. Comparative toxicity of netilmicin and gentamicin in squirrel monkeys (Saimiri sciureus). J. Infect. Dis. 137:476-480. 12. Jahre, J. A., K. P. Fu, and H. C. Neu. 1979. Clinical evaluation of netilmicin therapy in serious infections. Am. J. Med. 66:6773. 13. Kassirer, J. P. 1971. Clinical evaluation of kidney-function glomerular-function. N. Engl. J. Med. 285:385-389. 14. Keaney, N. P., and J. K. Noele. 1980. Netilmicin toxicity in man. A volunteer study. Clin. Trials J. 17:346-359. 15. Lerner, A. L., N. P. Reyes, L. A. Cone, D. C. Blair, W. Jansen, G. Wright, and R. R. Lorber. 1983. Randomized, controlled trial of the comparative efficacy, auditory toxicity and nephrotoxicity of tobramycin and netilmicin. Lancet i:1123-1126. 16. Lerner, S. A., R. Seligsohn, and G. J. Matz. 1977. Comparative clinical studies of ototoxicity and nephrotoxicity of amikacin and gentamicin. Am. J. Med. 62:919-923. 17. Love, L. J., S. T. Schimpif, D. N. Hahn, V. M. Young, H. C. Standford, J. F. Bender, C. L. Forner, and P. H. Wiernick. 1979. Randomized trial of empiric antibiotic therapy with ticarcillin in combination with gentamicin, amikacin or netilmicin in febrile patients with granulocytopenia and cancer. Am. J. Med. 66:603-610. 18. Luft, F. C., R. Bloch, R. S. Sloan, M. N. Yum, R. Costello, and D. R. Maxwell. 1978. Comparative nephrotoxicity of aminoglycoside antibiotics in rats. J. Infect. Dis. 138:541-545. 19. Luft, F. C., D. R. Brannon, L. L. Stropes, R. J. Costello, R. S. Sloan, and D. R. Maxwell. 1978. Pharmacokinetics of netilmicin in patients with renal impairment and in patients on dialysis. Antimicrob. Agents Chemother. 14:403-407. 20. Luft, F. C., M. N. Young, and S. A. Kleit. 1976. Comparative nephrotoxicities of netilmicin and gentamicin in rats. Antimicrob. Agents Chemother. 10:845-849. 21. Maigaard, S., N. Frimodt-Moller, and P. 0. Madsen. 1978. Comparison of netilmicin and amikacin in treatment of complicated urinary tract infections. Antimicrob. Agents Chemother. 14:544-548. 22. Miller, G. H., G. Arcieri, M. J. Weinstein, and A. Waitz. 1976. Biological activity of netilmicin, a broad-spectrum semisynthetic aminoglycoside antibiotic. Antimicrob. Agents Chemother. 10:827-836. 23. Mondorf, A. W. 1978. Action des aminosides et des cephalosporins sur le tube proximale due rein human. Etudes comparatives. Nouv. Presse Med. 42:3835-3837. 24. Panwalker, A. P., J. B. Malow, V. M. Zimelis, and G. G. Jackson. 1978. Netilmicin: clinical efficacy, tolerance, and toxicity. Antimicrob. Agents Chemother. 13:170-176. 25. Parker, R. A., D. N. Gilbert, D. C. Houghton, G. A. Porter, and W. M. Bennett. 1980. Comparative nephrotoxicities of highdose netilmicin and tobramycin in rats. Antimicrob. Agents Chemother. 18:346-348. 26. Pollock, A. A., A. J. Stein, M. S. Simberkoff, and J. J. Rahal. 1981. Netilmicin therapy of gentamicin-sensitive and gentamicin-resistant gram-negative infections. Am. J. Med. Sci. 282:211. 27. Sarubbi, F. A., and J. H. Hull. 1978. Amikacin serum concentrations: prediction of levels and dosage guidelines. Ann. Intern. Med. 89:612-618. 28. Shentag, J. J., T. J. Cumbo, W. J. Jusko, and M. E. Plaut. 1978.

VOL. 26, 1984

29.

30.

31. 32.

Gentamicin tissue accumulation and nephrotoxic reactions. J. Am. Med. Assoc. 240:2067-2069. Shentag, J. J., F. M. Gengo, M. E. Plaut, D. Danner, A. Mangione, and W. J. Jusko. 1979. Urinary casts as an indicator of renal tubular damage in patients receiving aminoglycosides. Antimnicrob. Agents Chemother. 16:468-474. Shentag, J. J., T. A. Suftin, M. E. Plaut, and W. J. Jusko. 1978. Early detection of aminoglycoside nephrotoxicity with beta-2microglobulin. J. Med. 9:201-210. Smith, C. R., K. L. Baughman, C. Q. Edwards, J. F. Rogers, and P. S. Lietman. 1977. Controlled comparison and amikacin and gentamicin. N. Engl. J. Med. 296:349-353. Smith, C. R., J. J. Lipsky, 0. L. Laskin, D. B. Hellmann, E. D.

NOTES

769

Mellits, J. Longstreth, and P. S. Lietman. 1980. Double-blind comparison of the nephrotoxicity and auditory toxicity of gentamicin and tobramycin. N. Engl. J. Med. 302:1106-1109. 33. Syndman, D. R., F. P. Tally, S. H. Landesman, M. Barza, and S. L. Gorbach. 1979. Netilmicin in gram-negative bacterial infections. Antimicrob. Agents Chemother. 15:50-54. 34. Soberon, L., R. L. Bowman, E. Oastoriza-Munoz, and G. J. Kaloyanides. 1979. Comparative nephrotoxicities of gentamicin, netilmicin and tobramycin in the rat. J. Pharmacol. Exp. Ther. 210:334-343. 35. Trestman, I., J. Parsons, J. Santoro, G. Goodhart, and D. Kaye. 1978. Pharmacology and efficacy of netilmicin. Antimicrob. Agents Chemother. 13:832-836.