wck-771 and nadifloxacin

Nadifloxacin is a potent, broad-spectrum, quinolone agent approved for topical use in acne vulgaris and skin infections in Japan. As exposure of pathogenic and colonising bacteria to antibiotics results in drug resistance, it is not desirable to use an important, broad-spectrum antibiotic, which belongs to a class of agents widely used systemically to treat a wide variety of infections, as a topically applied preparation. On this basis, nadifloxacin is not a good option for topical treatment of acne when other effective non-antibiotic treatments are available. Nadifloxacin has potential as a topical agent for short-term treatment of skin infections. The arginine salt of its (-)-(S)-isomer is being developed as a parenteral agent based on its potency against methicillin and quinolone-resistant Staphylococcus aureus.

Topics: Acne Vulgaris; Administration, Topical; Adolescent; Adult; Animals; Anti-Infective Agents; Clinical Trials as Topic; Fluoroquinolones; Humans; Microbial Sensitivity Tests; Quinolizines; Staphylococcal Skin Infections

There is an urgent medical need for novel antibacterial agents to treat hospital infections, specially those caused by multidrug-resistant Gram-positive pathogens. The need may also be fulfilled by either exploring antibacterial agents having new mechanism of action or expanding known classes of antibacterial drugs. The paper describes a new chemical entity, compound 21, derived from hitherto little known "floxacin". The choice of the entity was made from a series of synthesized prodrugs and salts of the active chiral benzoquinolizine carboxylic acid, S-(-)-nadifloxacin. The chemistry, physicochemical characteristics, and essential bioprofile of 21 qualifies it for serious consideration as a novel drug entity against hospital infections of multi-drug-resistant Staphylococcus aureus, and its progress up to clinical phase I trials in humans is described.

Topics: Animals; Anti-Bacterial Agents; Area Under Curve; Clinical Trials, Phase I as Topic; Dogs; Drug Resistance, Multiple, Bacterial; Female; Fluoroquinolones; Half-Life; Humans; Infusions, Intravenous; Injections, Intravenous; Male; Methicillin Resistance; Mice; Microbial Sensitivity Tests; Mutation; Prodrugs; Quinolizines; Rats; Rats, Wistar; Staphylococcal Infections; Staphylococcus aureus; Stereoisomerism; Structure-Activity Relationship; Vancomycin Resistance

WCK 771, the arginine salt of S-(-)-nadifloxacin, was evaluated in animal models of staphylococcal infection and in vitro. For 302 methicillin-susceptible strains the MIC at which 50% of isolates are inhibited (MIC50) and the MIC90 of WCK 771 were 0.03 and 0.03 microg/ml, respectively, and for 198 methicillin-resistant strains the MIC50 and the MIC90 were 0.5 and 1.0 microg/ml, respectively. All methicillin-susceptible staphylococci were quinolone susceptible, and almost all methicillin-resistant staphylococci were quinolone resistant. WCK 771 was more potent than moxifloxacin, trovafloxacin, levofloxacin, and ciprofloxacin and had potency comparable to that of clinafloxacin. Only WCK 771 and clinafloxacin demonstrated strong potencies against vancomycin-intermediate Staphylococcus aureus strains (MICs = 1 microg/ml). WCK 771 is not a substrate of the NorA pump, as evident from the lack of an effect of reserpine on the MICs and similar protective doses against infections caused by efflux-positive and -negative staphylococci. WCK 771 was effective by both the oral and the subcutaneous routes in mice infected intraperitoneally with quinolone-susceptible methicillin-susceptible S. aureus (MSSA) strains. For infections caused by quinolone-resistant methicillin-resistant S. aureus (MRSA) strains, the activity of WCK 771 administered subcutaneously was superior to those of trovafloxacin and sparfloxacin, with a 50% effective dose range of 27.8 to 46.8 mg/kg of body weight. The activity of WCK 771 was superior to those of moxifloxacin, vancomycin, and linezolid in a mouse cellulitis model of infection caused by one MSSA and two MRSA strains, with effective doses of 2.5 and 5 mg/kg for the MSSA strain and 10-fold higher effective doses for MRSA strains. WCK 771, like vancomycin and linezolid, eradicated MRSA from mouse liver, spleen, kidney, and lung when it was administered subcutaneously at a dose of 50 mg/kg for four doses. These studies have demonstrated the effectiveness of WCK 771, administered orally and parenterally, for the treatment of diverse staphylococcal infections in mice, including those caused by quinolone-resistant strains.

Topics: Administration, Oral; Animals; Anti-Bacterial Agents; Area Under Curve; Bacterial Proteins; Cellulitis; Drug Resistance, Bacterial; Fluoroquinolones; Half-Life; Injections, Subcutaneous; Methicillin Resistance; Mice; Microbial Sensitivity Tests; Multidrug Resistance-Associated Proteins; Quinolizines; Sepsis; Staphylococcal Infections; Staphylococcus aureus