Neutropenic Cancer Patients

Various fluoroquinolones have been used for empirical treatment of fever in neutropenic cancer patients. For ciprofloxacin, monotherapy produced less favorable results than ceftazidime alone or combination therapies 77 , whereas combination therapy gave results similar to those with standard regimes 78 . Oral regimes including ciprofloxacin also proved cheaper than parenteral combinations. Resistance among E. coli and superinfection with Gram-positive pathogens appear likely to limit such...

Skin and Soft Tissue Infections

Fluoroquinolones yield similar results to standard therapy for both Gram-positive and Gram-negative infections of the skin and soft tissues 72 , although emergence of resistance among both staphylococci notably methicillin-resistant Staphylococcus aureus (MRSA) and P aeruginosa has been observed 25 . Treatment of diabetic infections, including polymicrobial disease, with the early fluoroquinolones gave results almost as good, but persistence and resistance acquisition proved a greater problem,...

Pharmacoeconomic Aspects Of Fluoroquinolone Usage

Fluoroquinolone antibacterial agents are expensive, especially when administered intravenously. In some indications, such as Gram-negative or polymicrobial osteomyelitis (where oral fluoroquinolone therapy can replace lengthy intravenous therapy) and enteric fevers (where the excellent clinical results and low incidence of carriage states are clearly superior to standard therapy), the benefits outweigh the additional cost. Oral fluoroquinolones are also among the agents of choice for IV-oral...

Penetration into Respiratory Tissues

Fluoroquinolones produce excellent therapeutic ratios in the respiratory tract. Bronchial mucosal concentrations are 1.5 to 2 times those in serum 36-39 , although ratios between sputum bronchial secretion concentrations and those in serum after dosage within normal clinical limits range from 0.33 to 0.5 for ciprofloxacin and sparfloxacin to almost unity for pefloxacin, ofloxacin, and lomefloxacin 36 . Concentrations in alveolar lining fluid are typically two- to threefold greater than serum...

Bacterial Resistance To Fluoroquinolones

Fluoroquinolone resistance may result from chromosomal mutations coding for modifications in target subunits (primarily gyr A, but also gyr B) of bacterial topoisomerase II, alterations in expression of outer membrane proteins most importantly OmpF 8,20,21 and, in Gram-positive species, by variations in the uptake efflux processes 22 and mutations in topoisomerase IV 8,23 . Thus, resistance in the pneumococci requires mutations in both par C and gyr A configurations 23 . Plasmid-mediated...

Compounds Lacking the c6 Fluorine

The ubiquitous C-6 fluorine, held constant for nearly two decades, has been successfully removed or replaced in a few more recent chemical series. The most advanced of these is T-3811 (Figure 9), currently in phase I clinical trials. T-3811, like the other third- and fourth-generation quinolones, exhibits Gram-positive activity improved over ciprofloxacin 154 . Its activity against penicillin-resistant S. pneumoniae is improved over that of trovafloxacin. Versus the Enterobacte- figure 9...

Info

MICs for E. coli (mode) are usually < 0.1 mg liter for all agents, but resistance emergence has elevated the MIC90 to the values shown. between the fluoroquinolones, some of which have broad-spectrum activity against both Gram-negative and Gram-positive species. Others (e.g., norfloxacin and pefloxacin) are less active against Gram-positive pathogens. Ciprofloxacin retains preeminence against Gram-negative isolates, notably against P. aerugi-nosa, for which it is the drug of choice....

Elimination Pathways

The primary route of elimination of most fluoroquinolones is via the kidney 40 , the exceptions including pefloxacin, trovafloxacin, grepafloxacin, clinafloxacin, and moxifloxacin, urinary recoveries of which are 10-25 or less 34,37,38,40 . A number of agents are cleared almost exclusively by glomerular filtration and tubular secretion, notably ofloxacin (levofloxacin), lomefloxacin, and, to a lesser extent, fleroxacin. These group members require dosage modification in significant renal...

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...

Chemical Properties

Fluoroquinolones as a class are generally fairly insoluble in water. All modern quinolone agents are zwitterionic in character, due to the presence of both a carboxylic acid and a basic amine pKa values for these functional groups have been reported as 5.5-6.3 for the carboxylic acid and 7.6-9.3 for the distal amino group 134 . At low pH, both the amine and the carboxylic acid are protonated, giving the molecule an overall positive charge. Conversely, at high pH the amine is in the free base...

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...

History and Overview

Senior Lecturer (Honorary), School of Biomedical Sciences, University of St. Andrews, St. Andrews, Fife KY16 9AL, Scotland, United Kingdom Structure-Activity Relationships (SARs) Antibacterial Activity Mode of Action Spectrum of Activity Bacterial Resistance to Fluoroquinolones Clinical Pharmacology Penetration into Respiratory Tissues Elimination Pathways Pharmacodynamics of Quinolones Clinical Uses Urinary Tract Infections Sexually Transmitted Diseases Respiratory Infections Gastrointestinal...

Interactions Reducing Absorption

Metallic cations significantly reduce oral absorption of fluoroquinolones by chelation in the gut. Coadministration of antacids notably combinations of aluminum and magnesium hydroxide (Maalox) from 2 hours before to 6 hours after dosing consistently reduces bioavailability by 30-90 . Sucralfate has similar effects. Such combinations may result in therapeutic failure 109 . Oral iron and, to a lesser extent, multivitamin-zinc complexes reduce quinolone bioavailability 110 . Although most such...

Mode of Action

Quinolone antibacterials act by inhibition of bacterial topoisomerase II (DNA gyrase) and topoisomerase IV in Gram-positive species, thus inhibiting tertiary negative supercoiling of bacterial DNA 4-8 . This effect, probably associated with binding of quinolones to a DNA gyrase complex 9 , is rapidly bactericidal 8 . The minimum bactericidal concentration is usually only two- to fourfold the MIC, and a prolonged post-antibiotic effect is produced at concentrations exceeding the MIC....

In vivo Activity

In a number of cases in the research literature, improved half-life and tissue penetration are observed on alkylation of a quinolone agent 2 . This may once more be a result of alkylation serving to increase the lipophilicity of the quinolones. This phenomenon is exemplified by some of the agents in Figures 5 and 6 that possess long half-lives appropriate for once-daily dosing. Grepaflox-acin can be looked at as dimethylated ciprofloxacin this molecular modification results in substantially...

Introduction

The development of quinolone antibacterials, since the discovery of the naph-thyridine agent nalidixic acid some 40 years ago 1 , has progressed with periods of great clinical innovation, alternating with periods of apparent inactivity following unexpected recognition of rare, but severe, adverse reactions associated with specific agents. Initially, within a decade, the 4-quinolones oxolinic acid and cinoxacin, which had improved activity against a limited range of Gram-negative bacteria, had...

Selectivity Activity against Mammalian Topoisomerase ii and Genetic Toxicity

Selectivity for DNA gyrase and topoisomerase IV over the related mammalian enzyme topoisomerase II is of course desirable for antibacterial therapy with quinolones. In the course of selectivity testing of the many quinolones synthesized to date, a number have been found to exhibit potent activity versus the mammalian enzyme the potential for use of quinolone agents of this type as anticancer agents has been reviewed 127-129 . Certain structural features, most particularly those at N-1, C-7, and...

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...