In Vitro Activity of Cephalosporin RWJ-54428 (MC-02479) against Multidrug-Resistant Gram-Positive Cocci

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Abstract
RWJ-54428 (MC-02479) is a novel cephalosporin that binds to penicillin-binding protein (PBP) PBP 2′ (PBP 2a) of methicillin-resistant staphylococci. Its in vitro activity was assessed against 472 gram-positive cocci, largely selected as epidemiologically unrelated isolates with multidrug resistance. The MIC at which 50% of isolates are inhibited (MIC 50 ) and MIC 90 of RWJ-54428 for methicillin-resistant Staphylococcus aureus (MRSA) were 1 and 2 μg/ml, respectively, whereas they were 0.5 and 0.5 μg/ml, respectively, for methicillin-susceptible S. aureus . The MIC 50 and MIC 90 were 1 and 4 μg/ml, respectively, for methicillin-resistant coagulase-negative staphylococci (MRCoNS), whereas they were 0.25 and 1 μg/ml, respectively, for methicillin-susceptible isolates. The highest MICs for MRSA and MRCoNS isolates were 2 and 4 μg/ml, respectively. The MIC 50 and MIC 90 of RWJ-54428 for Enterococcus faecalis were 0.5 and 1 μg/ml, respectively, but they were 4 and 8 μg/ml, respectively, for Enterococcus faecium . For penicillin-susceptible, -intermediate, and -resistant pneumococci, the MIC 90 s of RWJ-54428 were 0.03, 0.25, and 0.5 μg/ml, respectively, with the highest MIC for a pneumococcus being 1 μg/ml, recorded for a strain for which penicillin and cefotaxime MICs were 8 and 4 μg/ml. MICs for Lancefield group A, B, C, and G streptococci were ≤0.008 μg/ml; those for viridans group streptococci, including isolates not susceptible to penicillin, were from 0.015 to 0.5 μg/ml. RWJ-54428 did not select resistant mutants of MRSA or enterococci in challenge experiments and has the potential to be useful for the treatment of infections caused by gram-positive cocci.

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