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 g/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 g/ml). It was active against ceftazidime-susceptible strains of Pseudomonas aeruginosa and against Enterobacteriaceae except Proteus vulgaris and some isolates producing extended-spectrum -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 -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.Methicillin-resistant staphylococci (MRS) have become a serious problem in many parts of the world. Although the incidence of strains of methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), and other MRS varies from country to country and from hospital to hospital (3, 5), it has been steadily increasing worldwide in the last decade (10,18,19). MRS are resistant not only to the available -lactam antibiotics, but also, in most instances, to structurally unrelated classes of antibacterials (for mainly unknown reasons) and thus represent a prime target in the current search for new antimicrobials.MRS are characterized by the expression of a special penicillin-binding protein (PBP), PBP 2Ј, that is not present in methicillin-susceptible staphylococci. This PBP is causally connected with methicillin resistance, as it functions as a transpeptidase and is not efficiently inhibited by commercially available -lactams, in contrast to the other transpeptidases in staphylococci, PBP 1, PBP 2, and PBP 3. However, the poor affinity of PBP 2Ј for -lactam antibiotics does not seem to be inherent in the -lactam structure since new carbapenems and cephalosporins that are good inhibitors of PBP 2Ј have recently been described (1,6,11,12,14,20).Ro 63-9141, the active principle of the water-soluble prodrug Ro 65-5788, is a novel parenteral cephalosporin with broad-spe...
