In vitro and in vivo evaluation of Ro 09-1428, a new parenteral cephalosporin with high antipseudomonal activity

Abstract

Ro 09-1428, a new parenteral cephalosporin with a catechol moiety attached at position 7 of the cephalosporin ring, showed high in vitro activity against Escherichia coli, Kkbsielia pneumoniae, Proteus mirabilis, Proteus vulgaris, and Streptococcus pyogenes, with MICs for 90% of strains tested (MIC9s) of c0.39 ,ug/ml.MorganeUa morganii, Providencia reftgeri, Citrobacterfreundii, Haemophilus influenzae, Staphylococcus aureus, and Streptococcus pneumoniae were inhibited with MIC90s of <3.13 ,ug/mi. Serratia marcescens was less susceptible to Ro 09-1428, with a MICg of 25 ,ug/ml. The most distinctive feature of Ro 09-1428 was its potent activity against Pseudomonas aeruginosa and Acinetobacter caloaceticus, with MIC90s of 0.39 and 6.25 ,Ig/ml, respectively. Most of the ceftazidime-resistant strains of P. aeruginosa, E. cloacae, and C. freundii were inhibited by Ro 09-1428, while those of S. marcescens were resistant at a concentration of 12.5 ,ug/ml. Ro 09-1428 was more active than ceftazidime against staphylococci. PBP 3 was the most sensitive target in E. coli and P. aeruginosa. The response to ferric iron in growth medium suggests that Ro 09-1428 may be taken up by transport mechanisms similar to those of other catechol cephalosporins. In accordance with its in vitro activity, Ro 09-1428 activity was equal to or greater than ceftazidime activity in efficacy against experimental septicemias in mice. The results indicate that Ro 09-1428 is a broad-spectrum cephalosporin with advantages over ceftazidime in its activity against P. aeruginosa, staphylococci, and ceftazidime-resistant strains of C. freundii and E. cloaceae.In spite of a considerable number of cephalosporins on the market, few compounds have useful activity against Pseudomonas aeruginosa. Although ceftazidime and cefpiramide are cephalosporins which inhibit the growth of P. aeruginosa at therapeutically attainable concentrations in blood, this activity leaves room for improvement. Recently, several cephalosporins containing catechol substituents have been reported as having superior antipseudomonal activities compared with those of other P-lactam antibiotics (1-9, 16).Ro 09-1428, (6R, (Fig. 1), is a parenteral cephalosporin that has a catechol moiety in the 7-acylamino side chain and showed high activity against gram-negative rods, particularly P. aeruginosa. Furthermore, the compound was found to be active against strains refractory to broad-spectrum cephalosporins. In this paper, we evaluated the in vitro and in vivo activities of Ro 09-1428 compared with those of ceftazidime. In addition, stability to ,-lactamases and affinity for penicillin-binding proteins (PBPs) are described.(This work was presented in part at the 29th Interscience Conference on Antimicrobial Agents and Chemotherapy, Houston, Tex., 17 to 20 September 1990.) MATERIALS AND METHODS Antibiotics. Ro 09-1428 and ceftriaxone were synthesized in the research laboratory of Nippon Pharmaceutical Devel-* Corresponding author. opment Institute, Hokkaido, Japan, and F. Hoffmann-La Roche A...

Siderophores as drug delivery agents: application of the “Trojan Horse” strategy

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Establishment of aging biofilms: possible mechanism of bacterial resistance to antimicrobial therapy

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Involvement of Fe Uptake Systems and AmpC β-Lactamase in Susceptibility to the Siderophore Monosulfactam BAL30072 in Pseudomonas aeruginosa

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