URINARY ANTIBACTERIAL ACTIVITY FOLLOWING ORAL ADMINISTRATION OF NITROFURANS WITH DETAILED OBSERVATIONS ON 5-NITRO-2-FURALDEHYDE 2-(2-HYDROXYETHYL) SEMICARBAZONE

¹ Eaton Laboratories, Inc., Norwich, N. Y.

Twenty-seven nitrofurans have been administered orally to rats and the antibacterial activity of the urine determined. Thirteen of these were inactive and were not subjected to further study. Oral administration of the other fourteen, however, resulted in varying degrees of urinary antibacterial activity. The structure of those nitrofurans appearing in the urine was characterized by the presence of a semicarbazone, semioxamazone or closely related type of side chain in the 2-position of the furan ring.

The two most active compounds were substituted semicarbazones of 5-nitro-2-furaldehyde. Appropriate substitution in the 2- or 4-position of the semicarbazone chain, and perhaps also the carbonyl group, can increase urinary excretion of an orally administered nitrofuran.

One nitrofuran, 5-nitro-2-furaldehyde 2-(2-hydroxyethyl) semicarbazone, after oral administration is excreted in the urine in relatively large amounts (about 25 per cent of the dose administered). This nitrofuran was selected for further laboratory study.

Variations of pH from 5 to 8 in human urine do not alter the in vitro antibacterial effectiveness of this nitrofuran against the following organisms: S. aureus, E. coli, A. aerogenes, S. faecalis, and P. vulgaris. The concentrations necessary for in vitro effectiveness are readily attained in rats by oral ingestion of the drug in non-toxic amounts. It was not effective in vitro against a culture of Ps. aeruginosa.

Although the bacteria studied developed limited resistance to 5-nitro-2-furaldehyde 2-(2-hydroxyethyl) semicarbazone, they did not develop resistance to concentrations of approximately 40 mgm. per 100 cc. A virulent strain of E. coli freshly isolated from an acute case of pyelitis did not grow in this concentration.

Oral administration of only 7 mgm. per kgm. of this drug every four hours (42 mgm. per kgm. per day) to albino rats maintained a urinary concentration of 40 mgm. per 100 cc. This amount is only one-fourth the urinary saturation concentration of the drug. Its solubility is not affected by pH changes usually encountered in human urine. This nitrofuran is also excreted in the urine of the dog and man.

Feeding of 40 to 50 mgm. per kgm. per day of this nitrofuran to rats and dogs for periods of seven weeks to three months produced no detectable ill effects. This daily dose administered in the diet of rats for a five-week period had no ill effect on growth, general condition, or gross appearance at autopsy.