Quinolones

These are synthetic antimicrobials having a quinolone structure.

They are active primarily against gram-negative bacteria, though the newer fluorinated compounds also inhibit gram positive ones.

The first member Nalidixic acid introduced in mid- l 960s

A breakthrough was achieved in the early 1980s by fluorination of the quinolone structure at position 6 and introduction of a piperazine substitution at position 7 resulting in derivatives called fluoroquinolones (FQs)

In the 1990s, compounds with additional fluoro an other substitutions have been developed, Further extending antimicrobial activity to gram-positive bacteria and anaerobes, and/or conferring metabolic stability (longer t½).

1. QUINOLONES Mr. Vijay Kevlani

2. These are synthetic antimicrobials having a quinolone structure. They are active primarily against gram-negative bacteria, though the newer fluorinated compounds also inhibit gram positive ones.

3. The first member Nalidixic acid introduced in mid- l 960s had usefulness limited to urinary and g . i . tract infections because of low potency, modest blood and tissue levels, restricted spectrum and high frequency of bacterial resistance .

4. A breakthrough was achieved in the early 1980s by fluorination of the quinolone structure at position 6 and introduction of a piperazine substitution at position 7 resulting in derivatives called f luoroquinolones (FQs) with high potency, expanded spectrum, Slow development of resistance, better tissue penetration and good tolerability.

5. Nalidlxic acid It is active against gram-negative bacteria , especially coliforms : E. coli, Proteus, Klebsiella , Enterobacter, Shigella but not Pseudomonas. It acts by inhibiting bacterial DNA gyrase and is bactericidal . Resistance to nalidixic acid develops rapidly .

6. Nalidixic acid is absorbed orally , highly plasma protein bound and partly metabolized in liver : one of the metabolites is active. It is excreted in urine with a plasma t½-8 hrs .

7. Concentration of the free drug in plasma and most tissues attained with the usual doses is non therapeutic for systemic infections. However, high concentration attained in urine (20-50 times that in plasma) and gut lumen is lethal to the common urinary pathogens and diarrhoea causing coliforms.

8. Adverse effects These are relatively infrequent, consist Mostly of g.i. upset and rashes . Most important toxicity is headache, drowsiness, Vertigo, visual disturbances, occasionally seizures (especially in children). Individuals with G-6-PD deficiency may develop hemolysis. Nalidixic acid is contraindicated in infants.

9. FLUOROQUINOLONES These are quinolone antimicrobials having one or more fluorine substitutions. The 'first generation' fluoroquinolones (FQs) introduced in 1980s have one fluoro substitution.

10. In the 1990s, compounds with additional fluoro and other substitutions have been developed, Further extending antimicrobial activity to gram-positive bacteria and anaerobes, and/or conferring metabolic stability (longer t½). These are referred to as 'second generation ' FQs. Some of the new ones have high activity against gram positive cocci.

11. Additionally Pazufloxacin and Balofoxacin are available

12. Mechanism of action The FQs inhibit the enzyme bacterial DNA gyrase , which nicks double -stranded DNA, introduces negative supercoils and then reseals the nicked ends. This is necessary to prevent excessive positive supercoiling of the strands when they separate to permit replication or transcription.

13. DNA Double Helix DNA Helicase DNA Polymerase

14. The DNA gyrase consists of two A and two B subunits: The A subunit carries out nicking of DNA, B subunit introduces negative supercoils and then A subunit reseals the strands. The FQs bind to A subunit with high affinity and interfere with its strand cutting and resealing function.

15. In gram-positive bacteria the major target of FQ action is a similar enzyme topoisomerase IV which nicks and separates daughter DNA strands after DNA replication. Greater affinity of a FQ for topoisomerase IV may confer higher potency against gram-positive bacteria. The bactericidal action probably results from digestion of the DNA by exonucleases whose production is signaled by the damaged DNA.

16. In place of DNA gyrase or topoisomerase IV, the mammalian cells possess an enzyme topoisomerase lI which has very low affinity for FQs- hence the low toxicity to host cells.

17. Mechanism of resistance Because of the unique mechanism of action, plasmid mediated transferable resistance is less likely. Resistance noted so far is due to chromosomal mutation producing a DNA gyrase or topoisomerase IV with reduced affinity for FQs, or due to reduced permeability/ increased efflux of these drugs across bacterial membranes.

18. Thank Y OU