PC-904, sodium 6-{ d (−)-α-(4-hydroxy-1,5-naphthyridine-3-carboxamido) phenylacetamido}-penicillanate, is a novel semisynthetic penicillin derivative that possesses a broad spectrum of in vitro and in vivo antibacterial activities. In low concentrations, PC-904 inhibits growth against large proportions of the gram-positive and gram-negative organisms susceptible to carbenicillin and gentamicin. In addition, PC-904 is several times more potent than carbenicillin against organisms such as Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Proteus vulgaris, Shigella, Salmonella, Neisseria gonorrhoeae , and Bacteroides fragilis . Most striking are the inhibitory effects of PC-904 against P. aeruginosa and K. pneumoniae . Against these two clinical isolates, PC-904 is, respectively, 35 and 100 times more active than carbenicillin. The minimum inhibitory concentrations of PC-904 against P. aeruginosa are comparable to those of gentamicin. PC-904 acts bactericidally. The effect of inoculum size on the antibacterial activity is often small and generally comparable to carbenicillin. The rate of binding to serum protein is high (88 to 98%), but the effect of the addition of serum on the drug's activity is not marked, because such binding is reversible. It is confirmed that PC-904 has a very potent in vivo antibacterial activity against gram-negative and gram-positive organisms. Against systemic infections with P. aeruginosa, K. pneumoniae , and E. coli in mice, PC-904 is 7 to 10 times, over 8 times, and 2 to 15 times more active than carbenicillin, respectively.

The chemotherapeutic properties of miloxacin (5,8-dihydro-5-methoxy-8-oxo-2H-1,3-dioxolo-[4,5-g] As shown in Fig. 1, miloxacin [5,8-dihydro-5-methoxy-8-oxo-2H-1,3-dioxolo-[4,5-g]quinoline-7-carboxylic acid], synthesized in our laboratories (1), is a quinoline derivative closely related structurally to oxolinic acid (4) and reported to be much more active against gram-negative bacteria in vitro and in vivo than nalidixic acid.This report compares the in vitro and in vivo activities of miloxacin against various organisms with the activities of oxolinic acid and nalidixic acid. MATERIALS AND METHODSAntimicrobial agents. Miloxacin and oxolinic acid were synthesized in our laboratories. Nalidixic acid was extracted with chloroform from commercial tablets and washed with ethanol; its melting point was 225 to 231°C. Each drug was dissolved in 1% sodium carbonate solution in a concentration of 5 mg/ml. These stock solutions were diluted with M/15 phosphate buffer (pH 7.4) before use.Strains. Of the strains examined in this study, the clinical isolates were obtained from patients in Osaka National Hospital and practicing doctors in Kyoto. All standard strains were maintained in our laboratories.Susceptibility test. The antibacterial activities of miloxacin, oxolinic acid, and nalidixic acid were evaluated by a routine agar plate dilution method. The clinical strains in Table 1 except for Haemophilus influenzae and the laboratory standard strains of Enterobacteriaceae, streptococci, bacilli, and corynebacteria in Table 2 were grown overnight at 37°C in tryptic soy broth (Nissui) yielding a viable cell count of about 109 cells per ml. All strains of H. influenzae were grown overnight at 37°C in chocolate broth yielding about 107 viable cells per ml. All strains of anaerobes were grown overnight in GAM broth (Nissui) at 370C to yield 109 cells per ml. Strains of Neisseria were grown for 2 days on a rabbit blood agar plate, the growth being removed just before use and resuspended in tryptic soy broth so as to yield a viable cell count of 10' cells per ml. Two strains of Mycoplasma were grown for two days in PPLO broth (Difco) supplemented by 10% yeast extract and 20% horse serum yielding 106 cells per ml.A 1-jd amount of undiluted culture was transferred to the surface of the drug-containing agar by a Typing Apparatus (Mutoh Kikai Co., Ltd., Tokyo, Japan) multipoint inoculating device, yielding final inocula of 103 Mycoplasma, 104 Haemophilus and Neisseria, and 105 to 106 for all other bacteria. The media used in these measurements were Eugon blood agar for streptococci, chocolate agar for Neisseria, Arakawa agar for corynebacteria, GAM agar for anaerobes, PPLO agar for Mycoplasma, and heart infusion agar for all other bacteria. All plates were incubated overnight at 37°C in air, with the exception of the anaerobes, which were incubated in a GasPak jar (BBL Microbiology Systems), H. influenzae and Neisseria, which were incubated in a 5% CO2 incubator for 48 h, and Mycoplasma, which was incubated in moisture-saturated box for...

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