Pharmacokinetics of Ro 23-9424, a dual-action cephalosporin, in animals

Christenson, James G.; Chan, Ka-Kong; Cleeland, Roy; Dix-Holzknecht, B; Farrish, Herbert H.; Patel, Indravadan H.; Specian, Anthony

doi:10.1128/aac.34.10.1895

Cited by 20 publications

(10 citation statements)

References 18 publications

(23 reference statements)

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“…Ro 23-9424 was ob tained from Hoffmann-La Roche Inc., Nutley, N.J., USA. A breakpoint of -¿8.0 mg/l indicated susceptibil ity to Ro 23-9424 [9]. Other interpretations were those reported elsewhere [7,8].…”

Section: Methodssupporting

confidence: 47%

“…One of our strains was resistant to both fleroxacin and ci profloxacin, with an MIC of > 8.0 mg/l [10], The parent strain of this organism was suscep tible to both the fluoroquinolones with an MIC of 0.06-2.0 mg/l. However, while the pa tient was on ciprofloxacin therapy, it devel oped resistance to this fluoroquinolone and cross-resistance to all other fluoroquinolones [9], This strain was inhibited by 4.0 mg/l of Ro 23-9424. All the 126 strains, including the fluoroquinolone-resistant isolate, were sus ceptible to the conventional drugs tested, with an MIC range of 0.06-2.0 mg/l.…”

Section: Resultsmentioning

confidence: 99%

“…Previously it has been shown that the ester bond could be hydrolyzed in animals to yield the parent drugs, thereby acting both as a ce phalosporin and a fluoroquinolone [11,12]. This dual action appears to confer excellent activity against a wide variety of significant bacteria [6,[13][14][15][16].…”

Section: Discussionmentioning

confidence: 99%

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Anti-<i>Brucella</i> Activity of Ro 23-9424, a Dual-Action Antibacterial

Qadri¹,

Ueno²,

Ayub³

1993

Chemotherapy

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The in vitro activity of dual-acting antibacterial Ro 23-9424 was determined by the agar dilution method against 126 clinical isolates of Brucella melitensis. It was compared with fleroxacin, ciprofloxacin and five conventional drugs. MIC₅₀ and MIC₉₀ for Ro 23-9424 were 1.0 and 4.0 mg/l, respectively, as compared with 0.25 and 0.5 mg/l for fleroxacin and ciprofloxacin. One strain which was resistant to other fluoroquinolones, with an MIC of > 8.0 mg/l, did not show cross-resistance to Ro 23-9424 and had an MIC of 4.0 mg/l. All the strains were susceptible to conventional drugs like gentamicin, streptomycin rifampicin, tetracycline and trimethoprim-sulfamethoxazole, with MICs ranging between 0.12 and 2.0 mg/l. Ro 23-9424 did not exhibit in vitro synergy with any of the conventional drugs.

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Section: Methodssupporting

confidence: 47%

Section: Resultsmentioning

confidence: 99%

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Anti-<i>Brucella</i> Activity of Ro 23-9424, a Dual-Action Antibacterial

Qadri¹,

Ueno²,

Ayub³

1993

Chemotherapy

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“…The compound has been shown to be extremely active in experimental infections in animal models. Results of pharmacokinetic studies in animals suggest that Ro 23-9424 is eliminated primarily in the urine by excretion of the intact molecule, rather than by hydrolysis to fleroxacin and desacetylcefotaxime (4). This pattern of elimination is typical of cephalosporins.…”

mentioning

confidence: 83%

In vitro activity of Ro 23-9424, a dual-action antibacterial agent, against bacterial isolates from cancer patients compared with those of other agents

Rolston

Nguyen

et al. 1992

Antimicrob Agents Chemother

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The in vitro activity of Ro 23-9424 against bacterial isolates from patients with cancer was compared with those of fleroxacin, ciprofloxacin, cefoperazone, and ceftazidime. Ro 23-9424 inhibited the majority of the members of the family Enterobacteriaceae and all Aeromonas isolates at a concentration of 1.0 ,ug/ml. It was also active against Acinetobacter spp. and Haemophilus influenzae, including f-lactamase-producing strains.The MIC for 90%o of isolates (MIC90) of Pseudomonas aeruginosa was 16.0 ,ug/ml. All group A and B streptococci were inhibited by <0.25 ,g/ml, and 90% of group G streptococci and Streptococcus pneumoniae were inhibited by 1.0 ,g/ml. All (8,13,14). Since 1980, a number of new quinolone-carboxylic acid compounds have been synthesized, and some of these have been evaluated for prophylaxis and therapy of infections in cancer patients (5,10,11,15,16). Ro 23-9424 is a novel antibacterial agent in which the microbiologically active metabolite of cefotaxime, desacetylcefotaxime, has been linked by an ester bond at the C-3 position to the carboxy group of the long-acting quinolone fleroxacin (6). We determined the activity of Ro 23-9424 against clinical isolates obtained from cancer patients and compared its activity with those of cefoperazone and ceftazidime, the most commonly used extended-spectrum cephalosporins at our institution. Fleroxacin and ciprofloxacin were also used for comparison.All

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“…The drug is hydrolyzed to a limited extent in vivo and in vitro, with release of free fleroxacin (2,8). Ro 23-9424 is broadly active against both gram-positive and some gramnegative bacteria (1, 9).…”

mentioning

confidence: 99%

In vitro activity of Ro 23-9424 against clinical isolates of Legionella species

Edelstein

1992

Antimicrob Agents Chemother

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Agar and broth microdilution MICs of Ro 23-9424 that inhibited 90% of 22 LegioneUla clinical isolates tested were 0.64 and 0.08 ,ug/ml, respectively; respective erythromycin values were 1.0 and 0.12 jglml. Ro (1 jg/ml) was slightly more active than the same erythromycin concentration in a macrophage system, for both Legionela pneumophila strains studied.Ro 23-9424 is a dual-action antibacterial agent in which desacetyl cefotaxime is covalently linked to fleroxacin (8). The drug is hydrolyzed to a limited extent in vivo and in vitro, with release of free fleroxacin (2,8). Ro 23-9424 is broadly active against both gram-positive and some gramnegative bacteria (1, 9). It is unknown whether Ro 23-9424 is concentrated in cells. Fleroxacin, but not cefotaxime, is active for intracellular Legionella pneumophila and in a guinea pig model of L. pneumophila pneumonia (6,13,14). We tested Legionella spp. with Ro 23-9424 by using a variety of susceptibility testing methods, designed to determine whether the drug is active for intracellular and extracellular Legionella spp. Two different extracellular susceptibility testing methods were used to allow comparison of results with those previously published by us and others using the two different methods (5-7, 10-13).All legionellae studied were clinical isolates. These strains were identical to those used in prior studies and were composed of two strains each of L. dumoJfii, L. 105 CFU/ml (3). Otherwise, the microdilution method was performed exactly as described previously for a macrodilution method (5). All testing was done in duplicate, and results were expressed as geometric means. A MIC found to be less than or equal to the lowest antimicrobial agent concentration tested was arbitrarily defined to be the lowest concentration tested. Erythromycin was included as a control; data for the activity of this drug for the Legionella strains we tested, as measured by agar dilution susceptibility testing, have been presented previously (5).Guinea pig pulmonary alveolar macrophages were harvested and purified as described previously (5). The final concentration of macrophages was approximately 105 cells per well. Antimicrobial susceptibility testing of intracellular L. pneumophila was performed as described previously (5). Briefly, 104 CFU of washed BCYEa plate-grown L. pneumophila was added to the purified alveolar macrophages. The bacteria and macrophages were incubated for 1 day after 1 h of incubation with shaking. Antimicrobial agents were added to the respective wells, after the wells had been washed three times to remove nonadherent bacteria. Sonic extracts of two replicate, non-antimicrobial agent-containing wells were quantitatively cultured for use as the day 1 bacterial count. Non-antimicrobial agent-containing wells were used as growth controls. After 2 more days of incubation, the supernatants were sampled and quantitatively cultured; all wells were then washed to remove antimicrobial agents. Bacterial counts in the supematant of each well were determined for another 4 ...

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Pharmacokinetics of Ro 23-9424, a dual-action cephalosporin, in animals

Cited by 20 publications

References 18 publications

Anti-<i>Brucella</i> Activity of Ro 23-9424, a Dual-Action Antibacterial

Anti-<i>Brucella</i> Activity of Ro 23-9424, a Dual-Action Antibacterial

In vitro activity of Ro 23-9424, a dual-action antibacterial agent, against bacterial isolates from cancer patients compared with those of other agents

In vitro activity of Ro 23-9424 against clinical isolates of Legionella species

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