In vivo Evaluation of a Dual-Action Antibacterial, Ro 23-9424, Compared to Cefotaxime and Fleroxacin

Positron emission tomography (PET) with [18Fjfleroxacin was used to study the pharmacokinetics of fleroxacin, a new broad-spectrum fluoroquinolone, in 12 healthy volunteers (9 men and 3 women). The subjects were infused with a standard therapeutic dose of fleroxacin (400 mg) supplemented with -20 mCi of[18F]fleroxacin. Serial PET images were made and blood samples were collected for 8 h, starting at the initiation of the infusion. The subjects were then treated with unlabeled drug for 3 days (400 mg/day). On the fifth day, infusion of radiolabeled drug, PET imaging, and blood collection were repeated. In most organs, there was rapid accumulation of radiolabeled drug, with stable levels achieved within 1 h after completion of the infusion.Especially high peak concentrations (in micrograms per gram) were achieved in the kidney (>34), liver (>25), lung (>20), myocardium (>19), and spleen (>18). Peak concentrations of drug more than two times the MIC for 90% of Enterobacteriaceae strains tested (>10-fold for most organisms) were achieved in all tissues except the brain and remained above this level for more than 6 to 8 h. The plateau concentrations in tissues (2 to 8 h, in micrograms per gram ± standard error of the mean) of drug were as follows: brain, 0.

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confidence: 99%

Pharmacokinetics of [18F]fleroxacin in healthy human subjects studied by using positron emission tomography

Fischman

Livni

Babich

et al. 1993

“…Ro 23-9424 has broad and potent antibacterial activity in vitro (2,9,12) and in vivo (3). The antibacterial spectrum reflects contributions of both the cephalosporin moiety (notably, streptococci) and the quinolone moiety (notably, ,-lactamase-overproducing strains).…”

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confidence: 99%

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

Christenson

Chan

Cleeland

et al. 1990

Ro 23-9424 is a dual-action cephalosporin with an aminothiazolylmethoxyimino-type side chain at the 7 position and fleroxacin esterified at the 3' position. The new compound has broad and potent antibacterial activity in vitro and in vivo, reflecting contributions from both the , (-lactam Ro 23-9424 is a cephalosporin with an aminothiazolylmethoxyimino-type side chain at the 7 position and fleroxacin esterified at the 3' position (1). Ro 23-9424 has broad and potent antibacterial activity in vitro (2, 9, 12) and in vivo (3). The antibacterial spectrum reflects contributions of both the cephalosporin moiety (notably, streptococci) and the quinolone moiety (notably, ,-lactamase-overproducing strains). Ro 23-9424 binds to penicillin-binding proteins and inhibits replicative DNA biosynthesis (8). These observations have led to the use of the term "dual-action cephalosporins" for Ro 23-9424 and analogous compounds (1,8).It was originally proposed by O'Callaghan et al. (15) that the second "warhead" of such a cephalosporin, in this case, the fleroxacin moiety of Ro 23-9424, is released when the ,-lactam ring is opened by a bacterial enzyme, such as a P-lactamase. In the case of Ro 23-9424, active quinolone may also be released by enzymatic or nonenzymatic hydrolysis of the ester linkage. It is well known that 3'-acetoxy cephalosporins, such as cephalothin, cephapirin, and cefotaxime, are deesterified in vivo to form 3-hydroxymethylcephalosporins (4, 5, 19). These metabolites have antibacterial activity, but they are less potent than the acetylated cephalosporins. Hydrolysis of the ester bond of Ro 23-9424 presumably results in the formation of fleroxacin and the 3-hydroxymethylcephalosporin desacetylcefotaxime, both of which have antibacterial activity. The extent to which Ro 23-9424 exerts the proposed mechanism of action in vivo (wherein the quinolone is released by a bacterial process), or acts as a combination of active metabolites, is therefore determined by its pharmacokinetic properties. This study *

“…The cephalosporin 3'-quinolone ester Ro 23-9424 is a broad-spectrum antibacterial agent active both in vitro and in vivo (2,3,14). The compound is bactericidal, free of inoculum effects, and active against cephalosporin-and quinolone-resistant organisms.…”

Section: Discussionmentioning

confidence: 99%

“…Ro 23-9424 combines the antibacterial spectrum and potency of its two components (2,3,10,14). It binds to essential penicillin-binding proteins (PBPs) of Escherichia coli and Staphylococcus aureus (10).…”

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confidence: 99%

Escherichia coli resistant to cephalosporins and quinolones is still susceptible to the cephalosporin-quinolone ester Ro 23-9424

Pace

Bertasso

Georgopapadakou

1991

Ro 23-9424 is a broad-spectrum antibacterial agent consisting of a cephalosporin (desacetylcefotaxime) linked through an ester bond to a fluoroquinolone (fleroxacin). Its activity against mutants of Escherichia coli TE18 resistant to both antibacterial components was examined. E. coli TE18 overproduces the AmpC ,I-lactamase and is resistant to several cephalosporins, including desacetylcefotaxime (MIC, 50 ,ug/ml), although it is still susceptible to Ro 23-9424 (MIC, 0.2 ,ug/ml). Thirty-five spontaneous, two-step mutants of E. coli TE18 which were resistant to fleroxacin (MIC, 50 ,ig/ml) were isolated. In the mutants, replicative DNA biosynthesis (permeabilized cells) was resistant to fleroxacin, and some mutants had porin abnormalities.However, all remained susceptible to Ro 23-9424 (MIC, 0.5 ,ig/ml). Examination of ,B-lactamase activity in the parent strain revealed that it hydrolyzes desacetylcefotaxime more rapidly than it does Ro 23-9424. Thus, Ro 23-9424 may be less susceptible to the gram-negative, chromosomal ,-lactamases that hydrolyze several broad-spectrum cephalosporins and may be effective in cases in which neither of its two components is active.Ro 23-9424 is a synthetic, broad-spectrum antibacterial agent consisting of a cephalosporin (desacetylcefotaxime) linked through an ester bond to a fluoroquinolone (fleroxacin). Ro 23-9424 combines the antibacterial spectrum and potency of its two components (2,3,10,14). It binds to essential penicillin-binding proteins (PBPs) of Escherichia coli and Staphylococcus aureus (10). It also inhibits replicative DNA biosynthesis and produces filamentation in E. coli (10). However, it is unclear whether the intact molecule is responsible for the antibacterial activity. It has been suggested that Ro 23-9424 initially acts as a cephalosporin but that upon decomposition free fleroxacin is released and quinolone activity appears (10). Considering that a low level of fleroxacin is present in the sera of animals receiving Ro 23-9424, it is plausible that, in vivo, the agent acts as a quinolone prodrug (14). However, Ro 23-9424 may be more resistant to animal esterases than are esters of other cephalosporins and P-lactams (11,15,26), as it is excreted predominantly intact in the urine of primates (14). This study was undertaken to determine whether intact Ro 23-9424 can be responsible for the antibacterial effect in E. coli. To that end, fleroxacin-resistant mutants were selected from E. coli TE18. This strain is already resistant to the cephalosporin component, desacetylcefotaxime, because of AmpC P-lactamase overproduction (20) (Table 1). Therefore, the mutants selected would be resistant to both decomposition products of Ro 23-9424, and any antibacterial activity should arise from the intact molecule. The parent strain, E. coli TE18, and the mutants were subsequently examined with respect to porn expression, permeability, P-lactamase activity, PBP profile, replicative DNA biosynthesis, and antibiotic susceptibility profile. MATERIALS AND METHODS