Quinolones.pptx

Quinolones

1. Quinolones & Fluoroquinolones Subramani Parasuraman Faculty of Pharmacy, AIMST University, Malaysia

2. Quinolones These are synthetic antimicrobials having a quinolone structure and are active primarily against gram-negative bacteria. The first member Nalidixic acid introduced in mid-1960s. Used to treat urinary and G.I. tract infections. The usefulness of quinolones is limited because of low potency. 2

3. Nalidixic acid It is active against gram-negative bacteria, especially 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. 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. Adverse effects: Relatively infrequent. Individuals with G-6-PD deficiency may develop haemolysis . Nalidixic acid is contraindicated in infants. 3

4. Fluoroquinolones Nalidixic acid has been largely superseded by fluoroquinolones. 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 with high potency, expanded spectrum, slow development of resistance, better tissue penetration and good tolerability. 4

5. Fluoroquinolones – Classification 5

6. Fluoroquinolones – Mechanism of action Most bacterial species maintain two distinct type II topoisomerases that assist with DNA replication, DNA gyrase and topoisomerase IV. DNA gyrase is an essential bacterial enzyme that catalyzes negative supercoiling of plasmid and chromosomal DNA. Topoisomerase IV assists in separating daughter chromosomes once replication is completed. Fluoroquinolones bind to these enzymes and interfere with DNA ligation. Fluoroquinolones have different targets for gram-negative (DNA gyrase) and gram-positive organisms (topoisomerase IV), resulting in rapid cell death. 6

7. Fluoroquinolones – Antimicrobial spectrum The fluoroquinolones are potent bactericidal agents against Proteus , E. coli, Klebsiella, and various species of Salmonella, Shigella, Enterobacter , and Campylobacter . Some fluoroquinolones are active against Pseudomonas spp., Activity against streptococci is significantly greater with the newer agents, including levofloxacin, gemifloxacin , and moxifloxacin. Ciprofloxacin, ofloxacin, and moxifloxacin are also active against Mycobacterium fortuitum , M. kansasii and M. tuberculosis . Moxifloxacin also has useful activity against anaerobes. 7

8. Fluoroquinolones – Bacterial Resistance Resistance to quinolones may develop during therapy via mutations in the bacterial chromosomal genes encoding DNA gyrase or topoisomerase IV or by active transport of the drug out of the bacteria. 8

9. Fluoroquinolones – Pharmacokinetics Most quinolones are well absorbed after oral administration. Peak serum levels of the fluoroquinolones are obtained within 1–3 h of an oral dose. The volume of distribution of quinolones is high, with concentrations in urine, kidney, lung, and prostate tissue and stool, bile, and macrophages and neutrophils higher than serum levels. Most fluoroquinolones are excreted renally. Therefore, dosage adjustments are needed in renal dysfunction. Moxifloxacin (metabolized primarily by the liver) should not be used in patients with hepatic failure. 9

10. Ciprofloxacin It is the most potent first-generation fluoroquinolones active against a broad range of bacteria, the most susceptible ones are the aerobic gram-negative bacilli . The MIC of ciprofloxacin against these bacteria is usually < 0.1 μg /ml, while gram-positive bacteria are inhibited at relatively higher concentrations. 10

11. Ciprofloxacin Clinical uses: Ciprofloxacin is effective in a broad range of infections. Urinary tract infections: ciprofloxacin is the most active against Pseudomonas. Chancroid (a bacterial sexually transmitted infection [STI] caused by infection with Haemophilus ducreyi ): Ciprofloxacin 500 mg BD for 3 days is a second line alternative drug to ceftriaxone/azithromycin. Typhoid: Ciprofloxacin given in a dose of 750 mg BD for 10 days is recommended. Patients unable to take the drug orally may be treated with 200 mg. i.v. 12 hourly in the beginning. 11

12. Ciprofloxacin Clinical uses: Ciprofloxacin is effective in a broad range of infections. Bone, soft tissue, gynaecological and wound infections: High cure rates have been obtained in osteomyelitis and joint infections but prolonged treatment (6–8 weeks) with high doses (750 mg BD) is required. Respiratory infections: Ciprofloxacin should not be used as the primary drug because pneumococci and streptococci have low and variable susceptibility. Anthrax: Ciprofloxacin is considered to be the drug of choice. Tuberculosis: Ciprofloxacin is less active against M. tuberculosis but is the most active FQ against Mycobact . avium complex (MAC). 12

13. Ciprofloxacin Clinical uses: Ciprofloxacin is effective in a broad range of infections. Meningitis: ciprofloxacin used in gram-negative bacterial meningitis. Prophylaxis: of infections in neutropenic/ cancer and other susceptible patients. Conjunctivitis: by gram-negative bacteria: topical therapy is effective Typical oral doses are 250–750 mg and intravenous doses are 200–400 mg twice daily 13

14. Ciprofloxacin Adverse effects: Ciprofloxacin has good safety record: side effects occur in ~10% patients but are generally mild; withdrawal is needed only in 1.5%. Gastrointestinal: nausea, vomiting, bad taste, anorexia. CNS: dizziness, headache, restlessness, anxiety, insomnia, impairment of concentration and dexterity (caution while driving). Skin/hypersensitivity: rash, pruritus, photosensitivity, urticaria and swelling of lips. Serious cutaneous reactions are rare. Erythema multiforme 14

15. Norfloxacin Slightly inferior to ciprofloxacin in terms of MIC values of gram-negative bacteria. It is primarily used for urinary tract infections and bacterial diarrhea. It is available in the form of 200, 400, and 800 mg tablets as well as 100 mg/5ml suspension. Side effect profiles are common to all fluoroquinolones. 15

16. Pefloxacin Pefloxacin is a fluoroquinolones and having higher lipid solubility. After oral administration, it is absorbed completely and attains higher plasma concentrations. Due to its lipophilicity, its CNS penetration is greater than other fluoroquinolones. Therefore, it is preferred for meningeal infections. It is available as 200 and 400 mg tablets and administered twice daily. 16

17. Ofloxacin It is less active than ciprofloxacin against gram-negative bacteria, but equally or more potent against Strep. pyogenes and other gram-positive cocci and certain anaerobes . It is the active levo (S) isomer of ofloxacin having improved activity against Strep. pneumoniae, M. tuberculosis and some other gram-positive and gram-negative bacteria. The dosing of levofloxacin ranges from 250 to 750 mg twice daily depending upon the condition. Levofloxacin 17

18. Moxifloxacin Moxifloxacin has enhanced activity against gram-positive organisms, gram-negative anaerobes, and Mycobacterium spp. It is used at a dose of 400 mg once daily. It is also available as an intravenous infusion. Gemifloxacin is indicated for the management of community-acquired respiratory infections. It is used at a dose of 320 mg once daily. Gemifloxacin 18

19. Prulifloxacin Prulifloxacin is a relatively newer generation lipophilic prodrug of ulifloxacin . It has been considered the most potent fluoroquinolone against E. coli and P. aeruginosa . It has a longer half-life, which allows it to be administered as once daily at a dose of 600 mg. Delafloxacin has improved activity against gram-positive cocci , including MRSA and Enterococcus spp. Delafloxacin 19

20. Ref: https://tmedweb.tulane.edu/pharmwiki/doku.php/fluoroquinolones Last assessed on 27 Apr. 2022 20

21. Ciprofloxacin and other fluoroquinolones are contraindicated during pregnancy. 21