MC-02479

RWJ-54428 (also known as MC-02,479) is a new cephalosporin with promising activity against gram-positive bacteria. The pharmacodynamics (PDs) of RWJ-54428 against Staphylococcus aureus , Streptococcus pneumoniae , and Enterococcus faecalis were studied in a neutropenic mouse thigh infection model. The RWJ-54428 MICs ranged from 0.25 to 1 mg/liter. Mice with ca. 10 6 CFU/thigh at the initiation of therapy were treated intraperitoneally with RWJ-54428 at doses that ranged from 3 to 1,200 mg/kg of body weight/day (in 2, 3, 4, 6, or 12 divided doses) for 24 h. The maximal reductions in bacterial counts in thigh tissues at 24 h for the methicillin-resistant S. aureus , penicillin-resistant S. pneumoniae , and E. faecalis strains were −2.8, −3.8, and −1.7 log 10 CFU/thigh, respectively. The percentage of a 24-h dosing interval that the unbound serum RWJ-54428 concentrations exceeded the MIC ( fT>MIC ) was the pharmacokinetic (PK)-PD parameter that best described the efficacy of RWJ-54428. The fT>MIC s for a bacteriostatic effect (no net change in the numbers of CFU/thigh over 24 h) ranged from 14 to 20% for staphylococci and streptococci; for maximal reductions in the numbers of CFU/thigh, the fT>MIC s ranged from 22 to 36% for these strains. For E. faecalis , the ranges of fT>MIC s for static and maximal effects were 30 to 46% and 55 to 60%, respectively. These data show that treatment with RWJ-54428 results in marked antibacterial effects in vivo, with the PK-PD parameters for efficacy being comparable to those for the efficacy of penicillins and carbapenems active against staphylococci and pneumococci.

Antibiotic resistance in Streptococcus pneumoniae is not only increasing with penicillin but also with other antimicrobial classes including the macrolides, tetracyclines and sulfonamides. This trend with antibiotic resistance has highlighted the need for the further development of new anti-infectives for the treatment of pneumococcal infections, particularly against multi-drug resistant pneumococci. Several new drugs with anti-pneumococcal activity are at various stages of development and will be discussed in this review. Two new cephalosporins with activity against S. pneumoniae include ceftobiprole and RWJ-54428. Faropenem is in a new class of beta-lactam antibiotics called the penems. Structurally, the penems are a hybrid between the penicillins and cephalosporins. Sitafloxacin and garenoxacin are two new quinolones that are likely to have a role in treating pneumococcal infections. Oritavancin and dalbavancin are glycopeptides with activity against methicillin-resistant S. aureus and vancomycin-resistant Enterococcus spp. as well as multi-drug resistant pneumococci. Tigecycline is the first drug in a new class of anti-infectives called the glycycyclines that has activity against penicillin-resistant pneumococci.