Structural and historical background

Quinolone antibacterial research and development has enjoyed an enormous worldwide effort since the early 1960s. During this time, more than 10,000 structurally related agents have been described in many hundreds of patents and journal articles. The product of this wealth of research has been a continually improving progression of marketed quinolone antibacterial agents. From the early days of Gram-negative-selective agents limited to treatment of urinary tract infection, the field has matured...

Chemistry and Mechanism of Action of the Quinolone Antibacterials

Gootz *Department of Medicinal Chemistry and Department of Respiratory, Allergy, Immunology, Inflammation, and Infectious Diseases, Central Research Division, Pfizer, Inc., Groton, Connecticut 06340 Structural and Historical Background General Structural Features of the Quinolones First-Generation Quinolones Second-Generation Quinolones Third- and Fourth-Generation Quinolones Selectivity Activity against Mammalian Topoisomerase II and Genetic Toxicity...

Pharmacodynamics of Quinolones

Increasing attention has focused on prediction of outcomes by various pharmacodynamic (PD) parameters. These have been extensively reviewed by Wise and colleagues 37,38 . Quinolones exhibit concentration-dependent killing and both the serum peak concentration to inhibitory concentration (Cmax MIC) ratio and area under the serum inhibition curve (AUIC) can be used to model clinical and bacteriological response in community-acquired pneumonia (CAP) and acute exacerbations of chronic bronchitis...

References

D., Gruet, M. D., et al. (1962). 1,8 naphthyridine derivatives. A new class of chemotherapeutic agents. J. Med. Pharmacol. Chem. 5, 1063-1068. 2. Blum, M. D., Graham, D. J., and McCloskey, C. A. (1994). Temafloxacin syndrome Review of 95 cases. Clin. Infect. Dis. 18, 946-950. 3. Domagala, J. M. (1994). Structure-activity and structure-side-effect relationships for the quinolone antibacterials. J. Antimicrob. Chemother. 33, 685-706. 4. Crumplin, G. C., and Smith, J....

Clinical Uses Urinary Tract Infections

The fluoroquinolones are highly effective in uncomplicated urinary tract infection and are drugs of choice where bacterial resistance compromises routine P-lactam therapy (Chapter 6). Fluoroquinolone efficacy is augmented by their ability to eliminate carriage of uropathogenic E. coli in the intestine 45 . Excellent results follow standard short-course and single-dose regimens 46,47 . In complicated infections and in the elderly, these agents are as or more effective than P-lactams,...

Sexually Transmitted Diseases

All of the fluoroquinolones are effective in single-dose treatment of uncomplicated urethral, anal, and oropharyngeal gonorrhoea 51 , although such regimes are ineffective for chlamydial disease. Ofloxacin for 7 days is reliably effective in chlamydial urethritis in men, although possibly less so in women, but there are little data on genital Mycoplasma infection. Preliminary data on trovafloxacin suggest high efficacy at low single doses in gonorrhoea 52 and, after multiple dosing, for...

F

FIGURE 8 Prodrugs of quinolone agents. this nucleus. The structurally related tosufloxacin requires twice-daily dosing, however, emphasizing the contribution of trovafloxacin's azabicyclo 3.1.0 hex-ane sidechain. In keeping with the information described, trovafloxacin is judged to be a relatively lipophilic quinolone by its distribution coefficient 109 . Further support for the importance of the 8-position is the fact that C-8 halogens have also been noted to improve in vivo activity 23 ....

Metabolic and Inhibitory Interactions

The most clinically significant interaction between some fluoroquinolones and other drugs occurs with xanthine derivatives, most importantly with theophylline but also with caffeine. Inhibition of the cytochrome P450 system and resulting reduction in plasma clearance may cause nausea, vomiting, and, almost exclusively with enoxacin, convulsions during coadministration of theophylline 112 . The reduction in clearance is most pronounced with enoxacin and grepafloxacin, less so with pefloxacin and...

Third and fourthgeneration quinolones

These newer compounds are characterized by increasing structural novelty and complexity (Figure 7), which has resulted in new and useful characteristics. Increased activity against Gram-positive cocci (particularly S. pneumoniae) over that of ciprofloxacin is the criterion applied to place agents in the third generation of quinolones, while potent activity against anaerobes was used to separate a subset of these agents into a fourth generation. In some cases, enhanced potency is combined with...

Structure Activity Relationships SARs

The 1,8 naphthyridines, 4-quinolones, cinnolines. fluoroquinolones, and fluorinated naphthyridones, together with their important sidechain substituent modifications and resultant structure-activity relationships are summarized in Table I. Modifications to the nucleus converting the naphthyridine nitrogen in the 8-position to a carbon reduced adverse reactions and increased activity against Gram-positive cocci, including both streptococci and Staphylococcus aureus, whereas either piperazine or...