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QUINOLONES.pptx
- 1. • QUINOLONES BY:- DR MAYUR PATEL
- 2. • The fluoroquinolonesare a family of broad spectrum, systemic antibacterial agents that have been used widely as therapy of respiratory and urinary tract infections. Fluoroquinolones are active against a wide range of aerobic gram-positive and gram-negative organisms.
- 3. • The firstmember Nalidixic acid introduced in mid-1960s 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. 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. • FLUOROQUINOLONES • The‘first generation’ fluoroquinolones (FQs) introduced in 1980s have one fluoro substitution. In the 1990s, compounds with additional fluoro and other substitutions have been developed— further extending antimicrobial activity to gram-positivecocci and anaerobes, and confering metabolic stability (longer t½). These are referred to as ‘second generation’ FQs
- 5. First generation fluoroquinolone 1.Norfloxacin (no longer clinically used) Second generation fluoroquinolone 1.Ciprofloxacin 2. Ofloxacin Third generation fluoroquinolone 1.Levofloxacin 3.Gemifloxacin 2. Moxifloxacin Fourth generation fluoroquinolone 1. Delafloxacin
- 6. SPECTRUM OF ACTIVITY •Fluoroquinolones are considered broad-spectrum antibiotics: Ciprofloxacin covers gram-negative rods the best • Levofloxacin and moxifloxacin provide excellent coverage of most potential respiratory pathogens • Delafloxacin covers both P. aeruginosa and MRSA.
- 7. MECHANISM OF ACTION •Fluoroquinolones directly inhibit bacterial DNA synthesis by binding to: • Topoisomerase II (DNA gyrase) in gram-negative organisms. • Topoisomerase IV in gram-positive organisms. • Topoisomerase enzymes: • Unwind DNA prior to replication • Have both nuclease (DNA cleaving) and ligase (DNA repairing) activity •
- 8. • Fluoroquinolone bindingto enzymes results in: • Inhibition of ligase activity only • DNA cleavage without the ability to repair the DNA • Cessation of DNA replication with broken DNA strands • Cell death → fluoroquinolones are Bactericidal
- 10. MECHANISMS OF RESISTANCE Thedominant mechanisms of fluoroquinolone resistance: • ↓ Accumulation of the drug within bacterial cells: • ↓ Expression of porin channels → ↓ entry of the drug into cells • ↑ Expression of efflux pumps • ↓ Affinity of the drug to the target: • Chromosomal point mutations change the structure of the topoisomerase and affect the binding site. • The mutations are drug and bug specific (e.g., gyrA genes in Neisseria gonorrhoeae) • Plasmid-mediated resistance (typically a low-level resistance)
- 11. CLINICALLY IMPORTANT RESISTANCEPATTERNS • As resistance to fluoroquinolones becomes more common, fluoroquinolone use may be limited for the following indications: • Neisseria gonorrhoeae • Pseudomonas aeruginosa • Urinary tract infections (UTIs) • Typhoid
- 12. • PHARMACOKINETICS • Absorption •Well absorbed in the upper GI tract • Good oral bioavailability: • Levofloxacin (99%) > moxifloxacin (90%) > gemifloxacin/ciprofloxacin (70%) > delafloxacin (60%) • Ingestion with dairy, mineral supplements, and most antacids can significantly ↓ bioavailability • Peak concentrations: 1–3 hours after an oral dose
- 13. • Distribution • Largevolumes of distribution (VD): most exceed the total body water volume → the drug accumulates in the tissue • Drugs concentrate in: • Prostate tissue • Bile and stool • Lungs • Kidneys (except moxifloxacin) • Neutrophils and macrophages
- 14. METABOLISM • < 15%of drug concentrations undergo hepatic metabolism (except moxifloxacin) • Moxifloxacin: • Approximately 50% of the drug is metabolized in the liver. • Metabolized via glucuronidation and sulfate conjugation rather than CYP450 mechanisms • Ciprofloxacin: • Inhibits CYP1A2 → can ↑ the levels of drugs metabolized by CYP1A2 • Some affected drugs include: • Clozapine • Theophylline • Tizanidine
- 15. EXCRETION • Elimination: • Primarilyvia renal tubular secretion (except moxifloxacin) • Some fecal excretion for ciprofloxacin, moxifloxacin, gemifloxacin, and delafloxacin • Moxifloxacin: • Hepatic clearance • May be used in renal failure • Should not be used for UTIs • Half-life: 3–9 hours (typically dosed twice daily
- 16. INDICATIONS • Compared toother antibiotics, fluoroquinolones are associated with a higher risk of potentially permanent and disabling adverse events. Therefore, fluoroquinolones are generally not used for uncomplicated infections and should only be used against susceptible bacteria.
- 17. COMPLICATED INFECTIONS • Abdominalinfections: • Complicated intra-abdominal infections (in combination with metronidazole for anaerobic coverage) • Peritonitis and infection related to a peritoneal dialysis catheter • Genitourinary infections: • Complicated UTIs and pyelonephritis • Prostatitis (acute and chronic) • Pelvic inflammatory disease • May be used in uncomplicated cystitis when no alternative options exist
- 18. • Respiratory infections: •Hospital-acquired pneumonia • Pneumonia caused by multidrug-resistant (MDR) S. pneumoniae • Atypical pneumonia • Tuberculosis (levofloxacin and moxifloxacin (2nd-line agents)) • May be used in uncomplicated infections when no alternative options exist: • Bacterial sinusitis • Chronic obstructive pulmonary disease (COPD) exacerbations • Nervous system infections: Bacterial meningitis
- 19. • Skin, softtissue, and musculoskeletal infections: • Bone and joint infections (including prosthetic joint infections) • Diabetic foot infections • Skin infections • Surgical prophylaxis in patients allergic to 1st-line agents (e.g., cephalosporins) • Infections from bite wounds
- 20. ADVERSE EFFECTS • Neurologiceffects: • Common mild effects: • Headache • Dizziness • Insomnia (transient) • Less common, more serious effects: • Peripheral neuropathy (may be permanent) • Delirium, psychosis, and/or hallucinations • Seizures • Exacerbation of myasthenia gravis
- 21. • Musculoskeletal effects(especially in growing children and teenagers): • Tendinopathy, including tendon rupture: • Most often the Achilles tendon • Advise individuals to stop taking fluoroquinolone if pain and/or swelling develop. • Arthropathy: • Cartilage erosions • Noninflammatory effusions
- 22. • GI effects: •Nausea, vomiting, and/or abdominal discomfort • Diarrhea (less common) • Cardiovascular effects: • QT prolongation • Aortic aneurysm and dissection • Other effects: • Skin rashes • Phototoxicity • Dysglycemia (highest risk is with moxifloxacin in diabetic individuals
- 23. CONTRAINDICATIONS • Hypersensitivity tofluoroquinolones • Pregnancy • Growing children and teenagers • Concurrent use with other medications prolonging the QT interval • Myasthenia gravis • Use with caution with: Diabetes Rheumatoid arthritis Aortic aneurysm/dissection
- 24. CIPROFL NORFL PEFLXACI N OFLLEVOFL GEMI PRULI MOXI Oral bioavailability 60–80 35–45 90–100 85–95 ~100 70 90 85 Plasma protein binding 20–35 15 20–30 25 25 55–73 45 40 Vol. of distribution (L/kg) 3-4 2 2 1.5 1.3 - - 2 Percent metabolized 20 25 85 5–10 5 >90 70-80 Elimination t½ (hr) 3–5 4-6 8-14 5-8 8 7 10-12 10-15 Routes of administration oral, i.v oral oral, i.v oral, i.v oral, i.v oral oral oral, i.v
- 25. Routes of administration oral, i.voral oral, i.v oral, i.v oral, i.v oral oral oral, i.v Dose (mg) : oral 250–750 BD 400 BD 400 BD 200-400 BD 500 OD 320 OD 600 OD 400 OD IV: 100–200 - 400 200 500 - - 400 CIPROFL NORFL PEFLXACI N OFL LEVOFL GEMI PRULI MOXI DOSES OF FLUOROQUINOLONE
- 26. COMPARISON BASED ONCOVERAGE • Different antibiotics have varying degrees of activity against different bacteria. The table below outlines the antibiotics with activity against 3 important classes of bacteria: gram-positive cocci, gram-negative bacilli, and anaerobes.
- 28. NORFLOXACIN • Norfloxacin isprimarily used for urinary and genital tract infections. Given for 8–12 weeks,it can treat chronic UTI. It is also good for bacterial diarrhoeas, because high concentrations are present in the gut, and anaerobic flora of the gut is not disturbed. Norfloxacin is not recommended for respiratory and other systemic infection. • NORBACTIN, NORFLOX 200, 400, 800 mg tab, • 3 mg/ml eye drops; • UROFLOX, NORILET 200, 400 mg tab. BACIGYL 400mg tab, 100 mg/5 ml susp.
- 29. LEVOFLOXACIN • It isthe active levo(s) isomer of ofloxacin having improved activity against Strep. pneumoniae and some other gram-positive and gram-negative bacteria. Anaerobes are moderately susceptible. Oral bioavailability of levofloxacin is nearly 100%; oral and i.v. doses are similar. It is mainly excreted unchanged, and a single daily dose is sufficient because of slower elimination and higher potency. Theophylline, warfarin, cyclosporine and zidovudine pharmacokinetics has been found to remain unchanged during levofloxacin treatment.
- 30. The primary indicationof levofloxacin is community acquired pneumonia and exacerbations of chronic bronchitis in which upto 90% cure rted in sinusitis, pyelonephritis, prostatitis and other UTI, as well as skin/soft tissue infections. • TAVANIC, GLEVO 500 mg tab, 500 mg/100 ml inj. • LOXOF, GLEVO, LEVOFLOX, LEVODAY 250, 500, 750 mg tabs, • 500 mg/100 ml inj; • VELOXIN-750/100 INJ • GLEVO 0.5% eye drops. • Routes of administration:-oral, i.v. • Dose (mg);-Oral500 (OD) IV (500)