ANTIMICROBIL AGENTS AND CHEMOTHERAPY, Apr. 1975, p. 483-485 Copyright 0 1975 American Society for Microbiology

Vol. 7, No. 4 Printed in U.S.A.

In Vitro Evaluation of a New Quinolone Antibacterial GREGORY STILWELL, KING HOLMES,

AND

MARVIN TURCK*

Department of Medicine, University of Washington, Seattle, Washington 98105 and Harborview Medical Center, Seattle, Washington 98104*

Received for publication 26 November 1974

The activity of R-802, a quinolone antibacterial agent, was studied in vitro and found to be active against Enterobacteriaceae; less than 4 ,ug of drug per ml was required to inhibit most isolates. The majority of Pseudomonas aeruginosa grew in a concentration of 256 ,g of R-802 per ml when studied in broth against an inoculum of 108 organisms per ml.

The cumulative percentage of 30 isolates each of Escherichia coli, Enterobacter, Klebsiella, indole-positive Proteus, Proteus mirabilis, and P. aeruginosa susceptible to increasing concentrations of R-802 is shown in Fig. 2 and 3, which also summarize the effects of medium and inoculum size on the antibacterial activity of this compound in agar. The results of these studies performed in agar demonstrate that R-802 was active against Enterobacteriaceae, and all 150 isolates were inhibited by 16 ,ug or less of the drug per ml in both media. In

The present studies were performed to assess the in vitro antibacterial activity of R-802, a synthetic quinolone antibacterial agent similar in structure to nalidixic and oxolinic acids (see Fig. 1)(Riker Laboratories, Inc.).

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325

(This paper was presented at the 14th Interscience Conference on Antimicrobial Agents and Chemotherapy, 11 to 13 September 1974, San Francisco, Calif.). Antibacterial activity was determined by antibiotic dilution methods performed in nutrient (Difco) and Mueller-Hinton (Difco) agar and broth. Studies in agar were performed by use of a Steers replicator device (3). The methods for performing the agar and broth dilution studies have been described previously from this laboratory (1, 2). A total of 150 isolates of Enterobacteriaceae and 30 strains of Pseudomonas aeruginosa were studied. 483

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FIG. 4. Cumulative percentage of 30 isolates each of E. coli, Enterobacter, and Klebsiella inhibited (MIC, minimal inhibitory concentration) or killed (MBC, minimal bactericidal concentration) by increasing concentrations of R-802 tested in nutrient broth medium with bacterial inocula of two different sizes.

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FIG. 6. Cumulative percentage of 30 isolates each of E. coli, Enterobacter, and Klebsiella inhibited (MIC, minimal inhibitory concentration) or killed (MBC, minimal bactericidal concentration) by increasing concentrations of R-802 tested in Mueller-Hinton broth medium with bacterial inocula of two different sizes.

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ulum sizes of bacterial cells. Against all genera, R-802 demonstrated lesser activity in broth than in agar. For example, whereas approximately 90% of 150 isolates of Enterobacteriaceae had been inhibited by 1 Mg or less of R-802 per ml when tested in agar, 16 ug/ml was needed to inhibit a comparable number of strains in broth medium. Moreover, although there was parallel activity between inhibitory and bactericidal concentrations of R-802 against most genera, isolates of P. mirabilis, indole-positive Proteus sp., and P. aeruginosa survived in high concentrations of

485

R-802. The decreased bactericidal activity was most apparent when tests were performed in Mueller-Hinton broth with the larger inoculum size of bacterial cells. For example, whereas 100% of P. aeruginosa was both inhibited and killed by 512 ,g of the drug per ml when tested in nutrient broth against 108 organisms per ml, only 75 and 25% of these isolates were inhibited and killed, respectively, in Mueller-Hinton broth. The results of these studies indicate that R-802 is active in vitro against Enterobacteriaceae. In nutrient broth with a large inoculum size of bacterial cells (108 organisms per ml), less than 4 Mg of R-802 per ml was required to inhibit most Enterobacteriaceae. Moreover, less than 1 gg/ml was necessary for inhibition when an inoculum of 106 organisms per ml was used. Although most isolates of Pseudomonas were susceptible to feasible urine levels when studied in agar, the majority of strains grew in concentrations of 256 ,g of R-802 per ml when studied in broth against the larger inoculum size of bacterial cells. Because of these encouraging in vitro results, a double-blind clinical study comparing two dosage forms of R-802 in women with bacteriuria has been initiated. This investigation was supported by a grant from Riker

Laboratories, Inc. LITERATURE CITED 1. Atala, E., H. Clark, F. Silverblatt, and M. Turck. 1969. Nalidixic acid and oxalinic acid in the treatment of chronic bacteriuria. Ann. Int. Med. 70:713-721. 2. Ronald, A., M. Turck, and R. G. Petersdorf. 1966. A critical evaluation of nalidixic acid in urinary-tract infections. N. Engl. J. Med. 275:1081-1089. 3. Steers, E., E. L. Foltz, and B. S. Graves. 1959. Inocula replicating apparatus for routine testing of bacterial susceptibility to antibiotics. Antibiot. Chemother. 9:307-311.

In vitro evaluation of a new quinolone antibacterial.

The activity of R-802, a quinolone antibacterial agent, was studied in vitro and found to be active against Enterobacteriaceae; less than 4 mug of dru...
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