Introduction

      Newer Fluoroquinolones

      Pharmacological aspects of newer quinolones

     Major clinical applications   

Introduction

The interest of the medical community in flouroquinolones has not decreased despite more than ten years of continuous and growing use of these agents.  This constant need for new anti microbials has produced a variety of newer flouroquinolones termed as I, II, III, and IV  generation as well as a handful of  relatively similar compounds . With I generation compounds like Nalidixic acid, Pipemidic acid, and cinoxacin by virtue of their limited activity against Gram negative organisms with poor plasma concentration and high urinary concentration  are indicated only in uncomplicated urinary tract infections. With older quinolones many of the organisms are not covered or inadequately covered, Gram positive organisms, Atypical intracellular pathogens, Mycobacteriae and anaerobic organisms  are excluded and because of poor blood concentrations they are not suitable for systemic infections and hence the search for newer quinolones to cover the Gram positive  organisms  including  resistant strains of Streptococci pneumoniae, Enterococci, Staphylococci epidermides, Staphylococci aureus ,Mycobactriae, Chlamydiae, Mycoplasmae and Legionellae species.

DEVELOPMENT OF NEWER QUINOLONES

 Major factors that are likely to determine  the development of newer  Quinolones include;

�        Greater clinical efficacy

�        Less toxic with greater safety

�        Lower tendency for induction of resistance

�        Short effective duration of therapy

�        Better patient compliance

�        Better cost-benefit ratio.

Substantial progress has been made recently in the development of Safe & Effective agents primarily because of the advances made in ;

�        Chemistry

�        Molecular mechanisms of quinolones

�        Factors leading to development of resistance etc.,

The first and key discovery was the identification of the enzyme DNA Gyrase or Toposiomerase II and IV and the second major advantage contributing to the rapid expansion was the ability to chemically manipulate the nucleus of 4-Quinolones.

Classification of Flouroquinolones

Earlier compounds like Nalidixic acid, Norfloxacin, Pefloxacin, Ofloxacin and ciprofloxacin enjoyed great success particularly in Gram negative infections. They are excluded for use in children (except- Ciprofloxacin in cystic fibrosis, and Nalidixic acid for UTI in children) because of the fear of Chondrotoxicity. The newer generation of quinolones has greater activity against �

• pneumococci, Str.pneumoniae, MRSA, Staph aureus, S.epidermides, Enterococci, anaerobic organisms  and IC pathogens like Chlamydiae, Mycoplasmae, legionellae, Mycobactriae etc.,

• Newer quinolones are;

-         Levofloxacin

-         Trovafloxacin

-         Grepafloxacin

-         Sparfloxacin  and

the following quinolones are undergoing various phases of clinical trials viz.,

-         Moxifloxacin

-         Clinafloxacin

-         Gatifloxacin

-         Sitafloxacin

-         Gemifloxacin.

Quinolones  in earlier phases of development are;

-         Ecinofloxacin

-         Balofloxacin

-         Nadifloxacin etc.,

                     -         Prulifloxacin

MAJOR CLINICAL INDICATION:

Bacterial infections of ;

• Respiratory tract- Acute Exacerbation of Chronic Bronchitis, (AECB), Pneumonia.

• Urinary Tract Infection (uncomplicated & complicated) .

• Skin, Soft tissue, bone and joint .

• Gastro Intestinal Tract � diarrhoea due to E.coli, Salmonellosis, Shiegellae, Campylobacter, Aeromonas, Vibrio, Plesiomonas shigelloides. Intra abdominal infection, Post surgical infection and obstetric and gynecological infections � Excellent with Trovafloxacin.

• Central Nervous System Infections (Trovafloxacin has greater penetrability into CNS) .

• Immuno compromised patients .

PHARMACOLOGICAL ASPECTS OF NEWER QUINOLONES:

Pharmacokinetics / Pharmacodynamics                       

1. Excellent oral absorption

2. Good tissue distribution

3. Excellent interstitial fluid concentration

4. Significant entry into phagocytic cells

5. Excellent urinary concentration on oral administration

6. Longer plasma half life and o/d drug regimen

7. [Grepafloxacin, Sparfloxacin, Trovafloxacin, Moxifloxacin,Gatifloxacin,Gemifloxacin and Sitafloxacin]

ABSORPTION

The absorption of quinolones are reduced by Antacids containing Al+++, Ca++, Mg++, and Fe++ salts and dairy products . Some of the quinolones are available for IV use viz., Ciprofloxacin, Ofloxacin.  Almost all the newer quinolones have excellent tissue distribution and attain high concentration in the interstitial fluid but only a few quinolones viz., Trovafloxacin, Ciprofloxacin, Pefloxacin, and Ofloxacin penetrate blood barrier. Protein binding varies to  some extent.

      Norfloxacin, Lomefloxacin & Gatifloxacin  - Lowest binding

      Trovafloxacin, Rulofloxacin & Clinafloxacin � Highest binding  

EXCRETION

Similarly quinolones exhibit differences the route of elimination Viz.,

Predominanatly by  by  Renal  elimination include;  Ofloxacin,   Levofloxacin,Lomefloxacin,Rufloxacin, and Gatifloxacin.                                                

While those predominantly by hepatic elimination include; Nalidixic acid,Pefloxacin,Sparfloxacin and Grepafloxacin.

DOSAGE AND ADMINISTRATION

Flouroquinolones exhibit concentration dependent killing and therefore adminsitered O/day,twice a day regimen. In animal models a 24 hour AUC/MIC     (Area under the concentration-time curve/minimum inhibitory concentration) ratio to be the best predictor of bacterial killing in vivo. With the peak plasma concentration C_max / MIC ratio being important for some bacteria to prevent emergence of resistance during treatment. Human  studies ( and animal models) with ciprofloxacin, Grepafloxacin,  and Levofloxacin show that a 24 hrs AUC/MIC  ratio of about 100, or a C_max / MIC ratio of about 10  gives maximum clinical and bacteriological efficacy. These values can be used to predict the efficacy of different agents against different pathogens , and to define" Pharmacodynamic Breakpoints".  

DRUG REGIMEN

The dosage schedules for the following quinolones have �Break points� ranging from 0.25 to 1  namely.,

�         Ciprofloxacin                                 500mg bd

�         Norfloxacin                                   400mg bd

�        Pefloxacin                                      200mg bd

�        Ofloxacin                                       400mg/d  or 200mg bd

�        Fleroxacin                                      400mg/d

�        Gatifloxacin                                    400mg/d

�        Grepafloxacin                                  400mg/d

�        Livofloxacin                                    500mg/d

�        Lomefloxacin                                  400mg/d

�        Moxifloxacin                                   500mg/d

�        Sparfloxacin                                   200mg/d

�        Trovafloxacin                                  200mg/d   

�        Sitafloxacin                                    100mg bd

MAJOR CLINICAL APPLICATION

Antibacterial efficacy of quinolones depends  on;

�      Activity against the target enzyme DNA Gyrase

�      Uptake by the bacterial cell

Physicochemical properties like � Hydrophobicity

                                          - Acid base properties   and

                     -  Affinity for divalent cations.

Quinolones  primary target is DNA Gyrase(Topoisomerase II ) in many of the gram-ve organisms whereas in the case of gram+ve organisms Topoisomerase IV  appears to be the primary target as is  the case of Ciprofloxacin, Norfloxacin, and Sparfloxacin.

For Sparfloxacin in the case of  Strerptococci pneumoniae ,DNA gyrase appears to be the primary target.

Peculiarly in case of Sitafloxacin  both DNA Gyrase -Topoisomerase II & Topoisomerase IV appears to be the targets and hence it is expected  that there is little or no chance for development of resistance.