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During an open multicentric trial (17 centers), we have treated 62 septicemia by dibekacin, alone or associated with other antibacterial drugs. Taking into account the degree of severity of these patients, the results are considered satisfactory in 47 patients. 15 failures were noted (including 9 deaths). General and local tolerance were good, in spite of the duration of treatment.

Major abdominal surgery often involves severe postoperative infections with various pathogens: enterobacteriaceae, staphylococcus and anaerobic bacteria. For this reason a strong antibiotherapy can be necessary in the case of an infectious disease. Dibekacin was administered at a daily dose of 3 mg/kg to 22 patients suffering from very severe postoperative infection. In all the cases dibekacin was combined with a beta-lactamine and in some with nitro-imidazole derivative. The results were especially favourable in all of these cases and a good tolerance was observed.

Cochlear and vestibular ototoxicity of dibekacin was evaluated in 27 patients treated with aminoglycoside after surgery on head and neck cancer. The treatment was administered intramuscularly or intravenously during 13 days at the schedule of 3 mg/kg per day. Cochlear and vestibular functions were tested by audiometry and electronystagmography before the administration of the antibiotic and on the 14th, 30th day, and for certain patients on the 4th month after the start of the treatment. No cochlear ototoxicity was found after the dibekacin treatment. On the other hand, the dibekacin treatment produced minor abnormalities of ENG (irritative pattern).

The advent of strains resistant to antibiotics in some patients has led to reorientation of research in this field. Demonstration of the mechanism involved in resistance to aminosides has resulted in the development of derivatives active against these resistant strains. Dibekacin, a new aminoside, is the first semisynthetic antibiotic of this class to be developed, and represents the first application of carbohydrate chemistry to the industry. It possesses potent activity and very weak ototoxicity.

Dibekacin is a new aminoglycoside derived semi-synthetically from kanamycin B. Its in vitro antibacterial activity, evaluated by the study of 43 reference strains and 1,177 clinical isolates, was found to be very similar to that of gentamicin, tobramycin, sisomicin and netilmicin on strains sensitive to these aminoglycosides; in the case of strains carrying plasmidic resistance factors, dibekacin behaves like tobramycin; it is inactivated by the same bacterial enzymes.

The pharmacokinetics of dibekacin were studied in 23 patients with varying degrees of renal insufficiency. Creatinine clearance was between 4 and 51 ml/min. Chronic renal insufficiency did not affect maximum serum concentrations, nor the time required to reach a peak level after an intramuscular injection of 1 mg/kg of dibekacin. The maximum concentration was 4 to 5 mcg/ml and the peak obtained within the first hour. Renal insufficiency caused a very marked prolongation in the serum half-life of elimination. This rose from 6 hours in moderate renal insufficiency to 50 hours in a patient with a clearance of a few millilitres. Whatever the degree of renal insufficiency, it should be noted that urinary concentrations remained markedly higher than the MIC of organisms sensitive to the aminoglycoside. Dibekacin is highly dialysable, being virtually totally extracted during a 6 hours dialysis session using a membrane of 1 m2 surface area. An outline of dose adaptations in relation to the degree of renal insufficiency is suggested on the basis of these pharmacokinetic data.

Previous works have demonstrated that mammals are more susceptible to aminoside ototoxicity during the period of auditory development. In order to test the intrauterine ototoxicity of dibekacin, an experiment was designated in pregnant guinea pigs intoxicated during the last three weeks of gestation (100, 60 and 30 mg/kg for 8 days). Newborn guinea pigs were tested electrophysiologically by recording cochlear potentials from the round window in response to filtered clicks of various frequency. No fetal ototoxicity due to dibekacin could be detected in the 36 animals tested. This study indicates that dibekacin has a very low ototoxic effect, even during the period of increased sensitivity to antibiotics. Comparatively, kanamycin has a major ototoxic effect when it is administrated at the same dosage during the same period of time.

Various techniques useful for the precise functional and morphological evaluation of the auditory and vestibular systems in the guinea pig are described. Their application in the comparative study of the ototoxicity of three aminoglycosidic antibiotics (gentamicin, tobramycin and dibekacin) administered at doses of 90 mg/kg/day for 20 consecutive days is presented. In these conditions a severe cochlear impairment was observed with gentamicin and tobramycin while it was minimal with dibekacin. Vestibular impairment was also severe with gentamicin and definite, although less important, with dibekacin and tobramycin.

Thirty six patients in an intensive care unit with a bacterial bronchopulmonary infection were treated with intraparenteral dibekacin at a dose of 3 mg/kg/day. Mean age of the patients was 55 years and the mean duration of treatment 14 days. Biological material was obtained by fibro-aspiration or pleural tap. One or more organisms were identified in 36 cases. These were essentially staphylococci and Gram negative bacilli sensitive to dibekacin. Results showed a favourable course in 26 cases and a clinical improvement in 10. Clinical and biological tolerance was good. No clinical manifestations of cochleo-vestibular toxicity were seen.

Minimum inhibitory and bactericidal concentrations of 3 aminoglycosides (dibekacin, gentamicin, tobramycin) have been recorded with 617 hospital strains. 4 mg/l of tobramycin inhibited 82 to 84% of Enterobacteria, Pseudomonas, Acinetobacter and S. Aureus; the less sensitive species are Serratia (51%) and Citrobacter (68%). 4 mg/l concentration of gentamicin or dibekacin inhibited 80-83% of Pseudomonas and S. Aureus, 78-79% of Acinetobacter and 74% of Enterobacteria. Dibekacin shows an in vitro activity superior to that of gentamicin and inferior to that of tobramycin on Klebsiella and Proteus mirabilis, but is rather to that of gentamicin and tobramycin on all other bacteria species.

In this study, we evaluate the nephrotoxic potential of dibekacin (D) compared to gentamicin (G), tobramycin (T), amikacin (A) and netilmicin (N). The mean features of aminoglycoside nephrotoxicity are: a lysosomal membrane fragilization, a lysosomal phospholipidosis characterized by a decrease activity of sphingomyelinase, an increase lysosomal volume with both an increase of individual size and an increase number of lysosomes, a cell necrosis and renal failure. We have quantified these parameters biochemically and morphometrically. We can classify, considering doses and durations, the aminoglycosides as gentamicin greater than or equal to netilmicin greater than dibekacin = tobramycin greater than amikacin for decreasing nephrotoxic incidence.

The study of the bronchial concentration of dibekacin has shown a different degree of activity than that of gentamicin. This activity resembles that of amikacin with a three hour time lag from the appearance of the bronchial peak in relationship to the serum peak. In addition there seems to be a special passage mechanism for the antibiotic from the blood into the bronchial secretions since we observed an increase in the mucus/serum ratio through time.

In this cooperative trial, 181 patients with various urinary tract infections were treated by dibekacin, a new hemi-synthetic aminoglycoside. Clinical and bacteriological results confirm the efficacy of dibekacin in this indication. Local and systemic tolerance, and thus renal and cochleo-vestibular, were very satisfactory.

The principal pharmacokinetic parameters of dibekacin were studied in five adult subjects with normal renal function after IM and IV injection of a single dose of 1 mg/kg. The results obtained showed that the pharmacokinetics of dibekacine were independent of the dose (T1/2: 2.1 h; distribution volume: 14-161; renal clearance: congruent to 70 ml/min; urinary excretion in 24 hours congruent to 80%) and very similar to those of other aminoglycosides of the deoxystreptamine group.