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Antimicrobial Agents and Chemotherapy, March 2001, p. 825-836, Vol. 45, No. 3
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.3.825-836.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

In Vitro and In Vivo Properties of Ro 63-9141, a Novel Broad-Spectrum Cephalosporin with Activity against Methicillin-Resistant Staphylococci

Paul Hebeisen,1 Ingrid Heinze-Krauss,2 Peter Angehrn,1 Peter Hohl,1 Malcolm G. P. Page,2 and Rudolf L. Then1,*

Pharmaceutical Research, F. Hoffmann-La Roche Ltd.,1 and Basilea Pharmaceutica,2 CH-4070 Basel, Switzerland

Received 26 September 2000/Returned for modification 31 October 2000/Accepted 19 December 2000

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 (MIC90) for methicillin-resistant Staphylococcus aureus (MRSA) was 4 µg/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 (MIC90 = 2 µg/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.

* Corresponding author. Mailing address: F. Hoffmann-La Roche Ltd., Biological Technologies, Bldg. 70.8, CH-4070 Basel, Switzerland. Phone: 0041-61-688 4182. Fax: 0041-61-688 2729. E-mail: rudolf.then{at}roche.com.

Antimicrobial Agents and Chemotherapy, March 2001, p. 825-836, Vol. 45, No. 3
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.3.825-836.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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