Info

With safety as a major concern e.g., the clinical issues of grepafloxacin, clinafloxacin and trovafloxacin (86), new fluoroquinolones, such as moxifloxicin, are being scrutinized for adverse effects (87). Thus, improved safety, as well as resistance profiles, are driving current research. The latest developments in DNA gyrase inhibitors addressing these issues has been published with a focus on the C-8 methoxy fluoroquinolones moxifloxacin and gatifloxacin and new advanced research compounds (88). Quinolones with C-8 methoxy groups have shown a lower propensity to induce resistance in S. pneumoniae (89). A full profile of moxifloxicin's microbiology, lower resistance frequency rates for S. pneumoniae and improved safety profile is available (87). The clinical effectiveness and results of postmarketing surveillance have also been published (90). A full evaluation of gatifloxacin's antibacterial activity, clinical PK and efficacy has also been reported (91). A new des-fluoro(6)-quinolone ganefloxacin (BMS-284756, H) in late stage development was reported to be safe and well tolerated in phase II studies of CAP and AECB (92,93). Multiple iv administration did not prolong the QTc interval (94), and less then 2% of patients were reported having CNS toxicity (95). No phototoxicity has been seen (96). As part of the SENTRY program, ganefloxacin was the most potent quinolone overall against Staphylococcus spp. (MIC50 < 0.03 mg/L) and Streptococcus spp. (MIC50 0.06 mg/L), but less effective against the enteric Gram-neg. bacilli when compared to ciprofloxacin, gatifloxacin and levofloxacin (97). Ganefloxacin is highly effective against antimicrobial resistant pneumonococcal isolates and S. aureus strains, but less effective against the ciprofloxacin-nonsusceptible S. aureus (98,99). It is also potent against C. pneumoniae and Legionella spp. (100,101).

A new fluoro-1,8-naphthyridinone with a unique oxime pyrrolidine moiety, gemifloxacin 12, has been in phase III studies for CARTIs. A complete profile of this quinolone has been published (102). While the in vitro activity of gemifloxacin is excellent against the majority of CARTI pathogens (103), there was some indication of phototoxicity and CNS effects in clinical trials (102). Currently in phase II clinical trials, ABT-49213 has been highly effective in pre-clinical studies showing excellent oral activity against S. pneumoniae and H. influenzae in a rat lung model and enhanced activity against Gram-positive species (104,105). ABT-492 showed excellent antibacterial activity against 300 strains of aerobic and anaerobic pathogens from sinusitis isolates, including quinolone resistant species, and 410 Legionella spp. (106,107). Pazufloxacin, an orally active quinolone, was launched in Japan in 2002 (108,109). Other late stage, orally active research compounds include WCK-919 which is efficacious against fluoroquinolone resistant S. pneumoniae in a mouse lung model (110), olamufloxacin (111), DK-507k which showed very good activity against S. pneumoniae (112), as did DW-286 14 both in vitro and in vivo (113). DW-286 was also potent against quinolone-resistant S. aureus (114). DQ-113 15 was active against PRSP and vancomycin-insensitive S. aureus in mouse models of pulmonary infection (115,116), and it's in vitro activity

13 14 15

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