Randomised, Controlled Trial of the Comparative Efficacy, Auditory Toxicity, and Nephrotoxicity of Tobramycin and Netilmicin

Risk factors predisposing to auditory toxicity of aminoglycosides were analyzed from records of 187 patients enrolled in three prospective randomized trials comparing the toxicity of netilmicin, tobramycin, and amikacin. Patients were eligible if they received three or more days of therapy and at least two serial audiograms were available. The overall auditory toxicity rate was 9.6% (18 of 187). Auditory toxicity was detected in 4.4, 10.8, and 23.5% of patients given netilmicin, tobramycin, and amikacin, respectively (P = 0.05). In the univariate analysis, patients who developed auditory toxicity were significantly older (P = 0.01) and had a significantly higher (P = 0.04) percentage of trough levels of netilmicin or tobramycin above 2 mg/liter or amikacin above 5 mg/liter. In the final logistic regression model, only age was retained as independently influencing the development of auditory toxicity (P < 0.00001). Conversely, factors that did not add significantly to the prediction of auditory toxicity were aminoglycoside serum levels, total aminoglycoside dose, duration of therapy, sex, peak temperature, presence of bacteremia, shock, liver cirrhosis, dehydration, previous otic pathology or renal failure, and development of renal toxicity. At least in certain populations, age is the most important predisposing factor for the development of auditory toxicity in patients receiving aminoglycosides.

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See 1 more Smart Citation

Univariate and multivariate analyses of risk factors predisposing to auditory toxicity in patients receiving aminoglycosides

Gatell

Araujo

et al. 1987

“…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 (16) and was not attempted in our study.…”

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Prospective randomized double-blind comparison of nephrotoxicity and auditory toxicity of tobramycin and netilmicin

Gatell¹,

SanMiguel²,

Araujo³

et al. 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).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 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.

“…Antimicrobial therapy combining an aminocyclitol aminoglycoside with a beta-lactam antibiotic improved survival rates (7, 9-13, 17, 18). However, at least 15% of patients treated with these regimens will still fail to improve, and a substantial number will experience untoward renal, auditory, cutaneous, and gastrointestinal morbidity (3,8,13,29).…”

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Ceftazidime versus tobramycin-ticarcillin in the treatment of pneumonia and bacteremia

Cone¹,

Woodard²,

Stoltzman³

et al. 1985

A prospective, randomized study was undertaken to compare the efficacy and safety of ceftazidime with those of a combination of ticarcillin and tobramycin in the treatment of 40 nonneutropenic patients with pneumonia or bacteremia. Altogether, 93% of the patients receiving ceftazidime for pneumonia were cured, and 87% of those with bacteremia responded favorably. Of the subjects who were treated with ticarcillin and tobramycin for pneumonia, 76% were cured, as were 75% of those with bacteremia. Three patients treated with ceftazidime developed significant superinfection, and one individual treated with the aminoglycoside and carboxypenicillin developed reversible azotemia. Ceftazidime appears to be as efficacious as the ticarcillintobramycin combination and is probably safer with regard to oto-and nephrotoxicity; however, superinfections did occur more frequently in the group treated with ceftazidime.The prevention of high patient morbidity and mortality resulting from serious bacterial infection requires prompt antibiotic intervention. Empiric antimicrobial agent combinations of aminoglycosidic aminocyclitols and beta-lactams have been developed in an effort to broaden the antibacterial spectrum, take advantage of synergism, and prevent or delay the emergence of resistant organisms (4, 22, 23). They have become standard therapy before the isolation of a pathogen and the determination of its in vitro sensitivity. Favorable response rates vary from 57 to 97% depending on the infectious agent, the underlying disorder, and the immunological and hematological status of the host (7, 9-13, 17, 18, 26). With the advent of aminothiazolyl cephalosporins and other beta-lactams with enhanced beta-lactamase stability, three logical queries can now be posed. (i) Are these new drugs singly as effective as the established combination of an aminoglycoside and a beta-lactam? (ii) tDo resistant or superinfecting organisms quickly emerge with potential or actual complicating disease? (iii) Does the use of these agents result in a reduction of or change in the incidence of drug toxicity?Ceftazidime (CAZ; Glaxo) is one of six third-generation aminothiazolyl cephalosporins that contains a pyridine moiety at the 3 position and an 0-alpha dimethyl acetic acid side chain attached to the oxime. This acidic function produces an agent with enhanced activity against Pseudomonas aeruginosa, with a geometric mean MIC of 1.6 ,ug/ml, which compares favorably to aminoglycoside MICs. Its intrinsic activity is particularly high against members of the family Enterobacteriaceae, with 50% MICs below 1 g/atnl. CAZ has good activity against neisseriae, Haemophilus spp., gram-positive organisms except for Streptococcus faecalis, and methicillin-resistant strains of staphylococci (6,16,32).A study was designed to compare CAZ with the combination ticarcillin and tobramycin (TT) in the treatment of pneumonia and bacteremia in nonneutropenic hosts.