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. 2001 Mar;45(3):825-36.
doi: 10.1128/AAC.45.3.825-836.2001.

In vitro and in vivo properties of Ro 63-9141, a novel broad-spectrum cephalosporin with activity against methicillin-resistant staphylococci

P Hebeisen  1 , I Heinze-Krauss, P Angehrn, P Hohl, M G Page, R L Then
Affiliations

In vitro and in vivo properties of Ro 63-9141, a novel broad-spectrum cephalosporin with activity against methicillin-resistant staphylococci

P Hebeisen et al. Antimicrob Agents Chemother. 2001 Mar.

Abstract

Ro 63-9141 is a new member of the pyrrolidinone-3-ylidenemethyl cephem series of cephalosporins. Its antibacterial spectrum was evaluated against significant gram-positive and gram-negative pathogens in comparison with those of reference drugs, including cefotaxime, cefepime, meropenem, and ciprofloxacin. Ro 63-9141 showed high antibacterial in vitro activity against gram-positive bacteria except ampicillin-resistant enterococci, particularly vancomycin-resistant strains of Enterococcus faecium. Its MIC at which 90% of the isolates tested were inhibited (MIC(90)) for methicillin-resistant Staphylococcus aureus (MRSA) was 4 microg/ml. Ro 63-9141 was bactericidal against MRSA. Development of resistance to the new compound in MRSA was not observed. Ro 63-9141 was more potent than cefotaxime against penicillin-resistant Streptococcus pneumoniae (MIC(90) = 2 microg/ml). It was active against ceftazidime-susceptible strains of Pseudomonas aeruginosa and against Enterobacteriaceae except Proteus vulgaris and some isolates producing extended-spectrum beta-lactamases. The basis for the antibacterial spectrum of Ro 63-9141 lies in its affinity to essential penicillin-binding proteins, including PBP 2' of MRSA, and its stability towards beta-lactamases. The in vivo findings were in accordance with the in vitro susceptibilities of the pathogens. These data suggest the potential utility of Ro 63-9141 for the therapy of infections caused by susceptible pathogens, including MRSA. Since insufficient solubility of Ro 63-9141 itself precludes parenteral administration in humans, a water-soluble prodrug, Ro 65-5788, is considered for development.

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Figures

FIG. 1
FIG. 1
Chemical structures of Ro 63-9141 and its prodrug Ro 65-5788.
FIG. 2
FIG. 2
Structure of FAMP.
FIG. 3
FIG. 3
Bactericidal activity against an MSSA isolate in comparison with that of vancomycin.
FIG. 4
FIG. 4
Rapid bactericidal action against MRSA (S. aureus 42080) and gram-negative E. coli ATCC 25922.
FIG. 5
FIG. 5
Increase of MIC upon exposure to Ro 63-9141 or reference compounds in S. aureus 745 (inoculum, 2 × 108 CFU/plate).
See this image and copyright information in PMC

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