2. HISTORY
The first quinolone- Nalidixic Acid was isolated in 1962 by George lesher as a byproduct of
synthesis of chloroquine.
It was made available for treatment of UTIs.
Norfloxacin was first fluoroquinolone approved in 1983 for medical use.
3. The Fluoroquinolones- Classification
Generation Agents Antimicrobial Properties
1st Generation (quinolones) Nalidixic acid Activity against aerobic, gram-
negative bacteria
2nd Generation Norfloxacin, Ciprofloxacin, Ofloxacin,
Levofloxacin, Lomefloxacin, and
Pefloxacin,
Activity against aerobic, gram-
negative as well as gram-positive
bacteria
3rd Generation Grepafloxacin, Gatifloxacin**,
Sparfloxacin, Temafloxacin, Tosufloxacin
and Pazufloxacin
Similar to 2nd generation with
greater potency against
pneumococci and additional
antianerobic activity
4th Generation Trovafloxacin, Clinafloxacin,
Moxifloxacin and Gemifloxacin
Similar to 3rd generation but more
potent.
**Systemic form
4. List of banned fluroquinolones
S.No Fluroquinolone Reason for ban
1. Lomefloxacin & sparfloxacin Phototoxicity & QT prolongation
2. Gatifloxacin (systemic form) Dysglycemia
3. Temafloxacin AIHA
4. Trovafloxacin Hepatotoxicity
5. Grepafloxacin Cardiotoxicity
6. Clinafloxacin Phototoxicity
5. The Quinolones- Mechanism of Action
Inhibits DNA gyrase (gr -ve bacteria) & Topoisomerase IV (gr +ve bacteria).
Interference with DNA replication.
Cell death
7. The Quinolones- Mechanism of Resistance
Mutation in gene encoding DNA gyrase or Topoisomerase IV.
Active efflux of drug.
Production of Topoisomerase IV protecting proteins.
8. The Quinolones- Pharmacokinetics
Absorption-
◦ Well absorbed after oral administration.
◦ Tmax (oral)- 1 to 3 hrs.
Distribution-
◦ Widely distributed, large volume of distribution.
Metabolism-
◦ Metabolised in liver.
Excretion-
◦ All active/metabolites are excreted in urine (except moxifloxacin)
Longest acting fluoroquinolone-
Sparfloxacin (T1/2= 19hrs)
9. The Quinolones- Pharmacological
Properties
Individual Agents
1. Norfloxacin:
◦ Good Gr-ve activity. (Enterobacteriaceae)
◦ Low serum level as compared to ciprofloxacin.
◦ Dose= 400 mg PO q12h.
2. Ciprofloxacin:
◦ Good oral bioavailability (70%).
◦ Can be used by oral & i.v. route.
◦ Typical Dosing= 250-750 mg i.v & 250-500 mg PO twice daily.(max. 1.5g/d)
10. The Quinolones- Pharmacological
Properties
Individual Agents
3. Ofloxacin/Levofloxacin:
◦ Ofloxacin has additional activity against Gram +ve bacteria.
◦ L-isomer (Levofloxacin) has still better activity against strep.
◦ Excellent oral bioavailability. Thus both oral & i.v. dose are same.
◦ Typical dosing:
◦ Levofloxacin 250-750 mg once daily.
◦ Ofloxacin 100-200 mg twice daily
11. The Quinolones- Pharmacological
Properties
Individual Agents
4. Moxifloxacin:
◦ Has further improved activity against gr +ve bacteria. (S.pneumoniae)
◦ Also active against anaerobes. (B.fragilis)
◦ Excellent oral bioavailability. Thus, both oral & i.v. dose are same.
◦ Metabolized in liver and excreted in bile
◦ Not excreted in urine thus not suitable for UTIs.
◦ T1/2= 12hrs
◦ Typical dosing- 400 mg once a day
12. The Quinolones- Pharmacological
Properties
Individual Agents
5. Gatifloxacin/ Gemifloxacin
◦ Antimicrobial spectrum similar to moxifloxacin.
◦ Enhanced potency against Gr+ve
◦ Less active against B.fragilis.
◦ Gatifloxacin no longer used for systemic purpose but ophthalmic preparations are used.
◦ Typical dosing- Gemifloxacin 320 mg once a day
13. The Quinolones- Therapeutic Uses
1. Urinary Tract Infections:
◦ Fluroquinolones are mainstay therapy for both Upper & Lower UTIs.
◦ More efficacious than TMP-SMX & oral β-lactam.
◦ All except Moxifloxacin.
◦ Typical duration of therapy for uncomplicated cystitis is 3 days & 5-7 days for uncomplicated
pyelonephritis.
2. Prostatitis:
◦ Norfloxacin/ Ciprofloxacin/ Ofloxacin/ Levofloxacin used for patients not responding to TMP-SMX.
◦ Duration of therapy 4-6 weeks.
14. The Quinolones- Therapeutic Uses
3. Sexually Transmitted Diseases:
◦ Chlamydia urethritis/ cervicitis: Alternative to Azithromycin/ Doxycycline. 7 day therapy with
ofloxacin/levofloxacin.
◦ Chancroid (H.ducreyi): Alternative to Azithromycin. 3 day therapy with Ciprofloxacin.
4. GI & Abdominal infections:
◦ Traveler's Diarrhea: 1-3 day therapy with Norfloxacin/Ofloxacin/levofloxacin/Ciprofloxacin for
treatment. Ciprofloxacin single daily dose for prophylaxis.
◦ Enteric fever: Ciprofloxacin/ Ofloxacin.
◦ Intra-abdominal infections: Ciprofloxacin/Ofloxacin/Levofloxacin + Metronidazole. Moxifloxacin as
single agent is comparable to piperacillin + tazobactam for complicated intra-abdominal infections.
16. The Quinolones- Therapeutic Uses
7. Other infections:
◦ Ciprofloxacin/ levofloxacin for prophylaxis of Anthrax & t/t of Tularemia.
◦ Moxifloxacin for MDR TB, atypical mycobacterial infections & MAC.
◦ Ciprofloxacin/ levofloxacin for prophylaxis & treatment of plague.
17. The Quinolones- Adverse Drug Reactions
1. Gastrointestinal:
◦ Common (3%-17%)
◦ Nausea, vomiting, abdominal discomfort.
◦ Common Cause of C.difficile colitis.
2. Neurological:
◦ Less common (1%-11%).
◦ Mild headache, dizziness are more common.
◦ Rarely neuropsychiatric reactions s/a hallucinations, delirium & seizures.
◦ Seizures particularly occurs in patients on theophylline or NSAIDs.
18. The Quinolones- Adverse Drug Reactions
3. Musculoskeletal:
◦ Arthralgia, joint pain.
◦ Tendon rupture (usually of Achilles tendon) in elderly or pts. On corticosteroids.
◦ Cartilage damage (in animal studies not in humans) Typically avoided in pregnancy & children <8
years
4. Other:
◦ Moxifloxacin: QT prolongation.
19. The Quinolones- Drug Interactions
1. Ca/Fe/Al preparations & All quinolones: Inhibits absorption of quinolones.
2. Methylxanthines & Ciprofloxacin: Increased toxicity of methylxanthine.
3. NSAIDS & quinolones: Increased risk of seizures.
4. Class III & Class IA antiarrhythmics + quinolones: Increased chances of QT prolongation &
Torsade-de-pointes.
