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

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.

• Authors: P Hebeisen, I Heinze-Krauss, P Angehrn, P Hohl, M G Page, R L Then
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 45 Issue 3 Pg. 825-36 (Mar 2001) ISSN: 0066-4804 [Print] United States
• PMID: 11181368 (Publication Type: Journal Article)

Chemical References

• Bacterial Proteins
• Carrier Proteins
• Cephalosporins
• Penicillin-Binding Proteins
• Ro 63-9141
• Peptidyl Transferases
• Hexosyltransferases
• Muramoylpentapeptide Carboxypeptidase
• beta-Lactamases

Topics

• Abscess (drug therapy)
• Animals
• Bacterial Proteins
• Carrier Proteins (antagonists & inhibitors)
• Cephalosporins (metabolism, pharmacology, therapeutic use)
• Disease Models, Animal
• Enzyme Stability
• Hexosyltransferases
• Methicillin Resistance (physiology)
• Mice
• Microbial Sensitivity Tests
• Muramoylpentapeptide Carboxypeptidase (antagonists & inhibitors)
• Penicillin-Binding Proteins
• Peptidyl Transferases
• Sepsis (drug therapy)
• Staphylococcus aureus (drug effects, enzymology, metabolism)
• Substrate Specificity
• beta-Lactamases (metabolism)