3-O-Demethylfortimicin A

3-O-demethylfortimicin A disulfate (ODMF), a novel aminocyclitol antibiotic, was administered subcutaneously for three months to groups of male and female cats at 15, 30 or 60 mg base/kg/day. Gentamicin sulfate (GS) at doses of 6 and 13 mg base/kg/day served as a reference compound. Signs of vestibular toxicity were considered to include persistent unsteady gait and stance, impaired righting reflex and abnormally diminished postrotatory vestibular nystagmus. Renal toxicities produced by ODMF and GS were also determined and compared. ODMF at 15 and 30 mg base/kg/day produced no signs of vestibular toxicity, while a dosage of 60 mg base/kg/day of ODMF produced vestibular toxicity in 7/10 cats. Three affected male cats died or were killed in moribund condition between study days 49 and 64. Vestibular toxicity was observed in 10/10 cats treated with GS at 13 mg base/kg/day and in 3/10 cats at 6 mg base/kg/day. All ten cats treated with GS at 13 mg base/kg/day died or were killed in moribund condition between study days 30 and 81. The deaths and moribundity in cats treated with ODMF or GS were attributed to renal toxicity. The vestibular toxicity and nephrotoxicity produced by ODMF and GS were more severe in male cats than in females. In conclusion, ODMF given at doses up to 60 mg base/kg/day for three months induced comparatively less vestibular toxicity and renal pathology than did GS at a dose of 13 mg base/kg/day.

O-demethyl-fortimicin-A-sulfate (ODMF) is a semisynthetic derivative of fortimicin-A with increased in vitro activity especially against Pseudomonas aeruginosa. This study was designed to determine the efficacy of ODMF in the treatment of UTI and to evaluate the in vitro susceptibility of bacteria isolated from the urine of patients to ODMF as compared to tobramycin (To), gentamicin (Ge) and amikacin (Ak). In 28 hospitalized patients with acute UTI, ODMF (free base) in a dose of 2 to 5 mg/kg was administered during 7 to 14 days. Every 2 days and at least 5 times during therapy, ODMF serum levels were determined (peak and trough levels) for dosage adjustment. Urine cultures were performed on day 0 and between days 2 and 4, and susceptibility of the organisms was determined. Patients were monitored for oto and nephrotoxicity. The treatment was successful in 53.5% of patients. 35.5% of patients relapsed due to severe underlying disease. ODMF was discontinued or given in reduced dosages in 10.7% of cases because of an increase in serum creatinine during therapy. Among the 37 significant strains recovered from urine, there were 54% E. coli, 10.8% Enterobacter sp., 10.8% Proteus sp., and 10.8% Pseudomonas sp. Resistance to ODMF was demonstrated in only 5.8% of strains, against 14.7% for Ge and 11.7% for To. Susceptibility of the strains was very similar for ODMF and Ak. On the whole, clinical and bacteriological results were satisfactory and did not differ from those usually obtained with aminoglycosides in the treatment of UTI due to Gram negative bacilli.

The pharmacokinetics of 3-O-demethylfortimicin A were evaluated in 16 healthy adult male volunteers after bolus intramuscular (i.m.) and 30-min intravenous (i.v.) infusion administration of doses ranging from 0.25 to 16 mg/kg. Mean calculated peak levels of the drug in plasma after the 0.25-, 0.5-, 1-, 2-, 4-, 8-, and 16-mg/kg i.m. doses were 1.1, 1.9, 3.5, 4.9, 11.0, 21.8, and 41.3 micrograms/ml, respectively, occurring about 60 min after dosing. The biphasic decline in levels of the drug in plasma after i.v. administration was not apparent after i.m. dosing, presumably because absorption of the drug from the injection site obscured the alpha elimination phase. Mean calculated peak levels for the 1-, 2-, 4-, 8-, and 16-mg/kg 30-min i.v. infusions were 5.9, 12.2, 20.1, 36.7, and 66.4 micrograms/ml, respectively. A statistically significant trend of increasing apparent volume of distribution with increasing dose size was noted for the i.m. dose group only. Plasma drug clearance was dose level and route independent, with an excellent linear relationship between the area under the plasma drug level curve and the dose. The mean 0- to 48-h urinary recoveries of 3-O-demethylfortimicin A after the i.m. injections and i.v. infusions were 90 and 102%, respectively. After the i.m. dosings, the half-life of the drug in plasma averaged 2.0 h, and after the i.v. dosings it averaged 2.7 h. The results of the study indicated that most of the drug was cleared by renal mechanisms.