P. Hebeisen et al., In vitro and in vivo properties of Ro 63-9141, a novel broad-spectrum cephalosporin with activity against methicillin-resistant staphylococci, ANTIM AG CH, 45(3), 2001, pp. 825-836
Ro 63-9141 is a new member of the pyrrolidinone-3-ylidenemethyl cephem seri
es of cephalosporins. Its antibacterial spectrum was evaluated against sign
ificant gram-positive and gram-negative pathogens in comparison with those
of reference drugs, including cefotaxime, cefepime, meropenem, and ciproflo
xacin, Ro 63-9141 showed high antibacterial in vitro activity against gram-
positive bacteria except ampicillin-resistant enterococci, particularly van
comycin-resistant strains of Enterococcus faecium. Its MIC at which 90% of
the isolates tested were inhibited (MIC90) for methicillin-resistant Staphy
lococcus aureus (MRSA) was 4 mug/ml. Ro 63-9141 was bactericidal against MR
SA, Development of resistance to the new compound in MRSA was not observed.
Ro 63-9141 was more potent than cefotaxime against penicillin-resistant St
reptococcus pneumoniae (MIC90 = 2 mug/ml). It was active against ceftazidim
e-susceptible strains of Pseudomonas aeruginosa and against Enterobacteriac
eae except Proteus vulgaris and some isolates producing extended-spectrum b
eta -lactamases. The basis for the antibacterial spectrum of Ro 63-9141 lie
s in its affinity to essential penicillin-binding proteins, including PBP 2
' of MRSA and its stability towards p-lactamases, The in vivo findings were
in accordance with the in vitro susceptibilities of the pathogens. These d
ata suggest the potential utility of Ro 63-9141 for the therapy of infectio
ns caused by susceptible pathogens, including MRSA. Since insufficient solu
bility of Ro 63-9141 itself precludes parenteral administration in humans,
a water-soluble prodrug, Ro 65-5788, is considered for development.