BRL 17421 is a new semisynthetic beta-lactam antibiotic with an unusual spectrum of antibacterial activity. The compound exhibits exceptional stability to a wide range of bacterial beta-lactamases and is active against the majority of Enterobacteriaceae, including strains highly resistant to many of the penicillins and cephalosporins currently available. Among the clinical isolates of Enterobacteriaceae tested, the frequency of strains resistant to BRL 17421 was found to be low, and there was a slow rate of emergence of resistance during in vitro studies. BRL 17421 was highly active against Haemophilus influenzae and Neisseria gonorrhoeae, including beta-lactamase-producing strains. The compound was markedly less active against Pseudomonas aeruginosa and Bacteroides fragilis than against the Enterobacteriaceae. Against the gram-positive bacteria, BRL 17421 showed a very low level of activity. BRL 17421 was found to be 85% bound to human serum, and the antibacterial activity was diminished two- to fourfold in the presence of human serum. Against experimental infections in mice, the activity of BRL 17421 reflected the properties observed in vitro. Studies in human volunteers showed unusually high and prolonged serum concentrations of the compound after parenteral dosage, with a serum half-life of about 5 h, and approximately 85% of the dose was recovered unchanged in the urine. BRL 17421 was poorly absorbed after oral administration. The compound was well tolerated after intramuscular and intravenous administration in volunteers, with no adverse side effects.

The acid and base catalysed rearrangement products of pseudomonic acid A ( l a ) , derived from ( l a ) by intramolecular opening of the epoxide ring, have been shown to possess the trans-fused bicyclic structures (2a) and (3a). Structural assignments were made on the basis of the spectroscopic and chemical properties of (2a) and (3a) and their derivatives and confirmed by X-ray analysis. In strongly basic solution intramolecular rearrangement of (1 a) was accompanied by the loss of the nonanoate ester side chain and formation of (1 2a) and (1 3a).

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The phthalidyl ester (BRL.8988, talampicillin) of ampicillin gave serum levels in man two and a half times those obtained with ampicillin itself.Ampicillin, D-a-aminobenzylpenicillin (Ia, Fig. 1 To determine the susceptibility of BRL.8988 to hydrolysis, rates were measured over a period of 25 min in aqueous solution and human tissue homogenates as outlined in Table 1. Pivampicillin was included for comparison. It will be observed that, in buffer at pH 7.4, both BRL.8988 and pivampicillin hydrolyzed slowly to ampicillin, the rate for BRL.8988 being slightly faster. At pH 2.0 both compounds were stable to hydrolysis. In human small intestine homogenate both compounds were completely hydrolyzed after 15 min to ampicillin and this was also the case in human whole blood. However, in 2% human blood and in human liver homogenate, BRL.8988 was hydrolyzed at an appreciably faster rate than pivampicillin. Likewise in 90% human serum, BRL.8988 was 80% hydrolyzed to ampicillin after 3 min compared with less than 10% hydrolysis of pivampicillin.A 371-mg amount of BRL.8988 as its hydrochloride, equivalent to 250 mg of ampicillin,

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