Quinolones
- 1. Quinolones Presented by Asst. Prof Jagir Patel Dept. Pharmacology
- 2. Quinolones • These are synthetic antimicrobials having a quinolone structure that are active primarily against gram-negative bacteria, though newer fluorinated compounds also inhibit gram positive ones. • The first member 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, limited spectrum and high frequency of bacterial resistance. • fluoroquinolones: substitution of pyperaizne ring on 7th position and fluorination in 6th position results into fluoroquinolones • Identifiable by their generic names, which typically end in “-floxacin”
- 3. Bacterial Spectrum • The fluoroquinolones are widely used to treat common urogenital, respiratory, and gastrointestinal infections caused • Gram-negative microbes, including • E. coli • Klebsiella pneumoniae, • Pseudomonas aeruginosa, • Neisseria gonorrhoeae, • Enterobacter, • Salmonella, • Shigella species.
- 4. Classification 1st generation • Nalidixic acid, cinoxacin Rosoxacin 2nd generation • Norfoxacin Ciprofloxacin Ofloxacin • Lomifloxacin Nadifloxacin Pefloxacin 3rd generation • Sparfloxacin Gatlifloxacin Tosufloxacin Levofloxacin pazufloxacin 4th generation • Moxifloxacin Trovafloxacin Cinafloxacin Finafloxacin Sitafloxain Gemifloxacin
- 5. Mechanism of action • Inhibits bacterial gyrase the enzyme 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. • 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.
- 8. Mechanism of action • FQs bind to A subunit with high affinity and interfere with its strand cutting and resealing function. • Recent evidence indicates that 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 for topoisomerase IV may confer higher potency against gram-positive bacteria.
- 9. • There are 2 types of DNA topoisomerases in bacteria (eukaryotes) DNA TOPOISOMERASE I - Cuts 1 of the DNA strands at the beginning of replication, thus causing supercoil relaxation (preventing hyper coil formation) DNA TOPOISOMERASE II “DNA gyrase” Cuts both the DNA strands at the end of replication, thus causing separation of the 2 chromosomes
- 10. Fluoroquinolones
- 12. Mechanism of Resistance DECREASED UPTAKE Due to decreased number of porins in the outer cell membrane only in gram – bacteria (only gram – bacteria have outer cell membrane) DECREASED AFFINITY Due to structural alterations of DNA topoisomerase II INCREASED EXCRETION Due to increased energy-dependent transport of the fluoroquinolones out of the cytoplasm through the inner cell membrane
- 14. Nalidixic acid • Anti bacterial spectrum: gram –ve bacteria only Like E. coli, Proteus, Klebsiella, Enterobacter Shigella • MOA: It Acts by inhibiting bacterial DNA gyrase and is bactericidal • P.k. • 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 tT/z -8 hrs. • Concentration of the free drug in plasma and most tissues attained with the usual doses is nontherapeutic for systemic infections. • USE: • Uncomplicated UTI • Diarrhoea due to gram –ve Shigella or salmonella
- 15. • Adverse effect: • These are relatively infrequent, consist mostly of g.i. upset and rashes. • Most important toxicity is neurological-headache, drowsiness, vertigo, visual disturbances, • Occasionally seizures (especially in children). • Phototoxicity is rare. • Individuals with G-6-PD deficiency may develop hemolysis. • Nalidixic acid is contraindicated in infants
- 16. Ciprofloxacin Prototype • Antibacterial spectrum : 1st gen: Gram –ve rods 2nd gen: gram + cocci gram-ve rods mycoplasma chlamydia 3rd gen: gram +cocci gram-ve rods mycoplasma chlamydia 4th gen: gram +cocci, gram + bacilli, anaerobic organisms
- 17. Ciprofloxacin • The remarkable microbiological features of ciprofloxacin • Rapidly bactericidal activity and high potency: MBCs are close to MICs • Relatively long post-antibiotic effect on Enterobacteriaceae Pseudomonas & Staph. • Low frequency of mutational resistance • Low propensity to select plasmid type resistant mutants. • Protective intestinal streptococci and anaerobes are spared. • Active against many B-lactam and aminoglycoside resistant bacteria. • Less active at acidic pH.
- 19. Pharmacokinetics • Ciprofloxacin is administered orally, i.v., or topical routes • Well absorbed from gut but food delays the absorption • Widely distributed in the body, high concentration in kidney, lungs, prostate gland, bile etc. • It is excreted in urine
- 20. Adverse effect • CNS: headache, vertigo and nausea, dizziness, insomnia • G.I.T.: diarrhea, abdominal discomfort • Skin: Phototoxicity leading to skin rashes, urticaria, itching • Kidney: urolitihasis (“crystalluria”, due to poor solubility in the low pH of the renal tubules and following crystal formation) • Bones: articular cartilage erosion should be avoided in children • Contraindicated in pregnancy
- 21. Uses • UTI: mostly used for UTI, Effective against E.coli, Proteus and Enterobacter • Bacterial diarrhoeas: GIT infection of E.coli, Shigella & Salmonella • Typhoid fever: as it is bactericidal causes rapid resolution of symptoms caused by S.typhi • Sexually transmitted diseases: • Gonnococal infection: cervicitis and urethritis dude to N.gonorrhoeae • Chancroid and chlamydial cervicitis and urethritis
- 22. • Skin, Soft tissue and bone infection: due to S.aureus and grm-ve bacilli • Diabetic foot diseases • Mycobacterial infections: in Multidrug resistance tuberculosis, and leprosy • Respiratory infections: in community acquired pneumonia and chronic bronchitis • Eye: for topical conjunctivitis
- 23. Drug interactions • Ciprofloxacin increases plasma concentration of warfarin • NSAIDS+ Ciprofloxacin = potentiate CNS side effect • Antacids, and sulculfrate reduces absorption of Ciprofloxacin
- 24. Norfloxacin / Ofloxacin Norfoxacin Ofloxacin General information Administered orally may not cross the blood-brain barrier Medical uses Treatment of cystitis due to Escherichia, Enterobacter, proteus and/or Klebsiella infection Side effects -same as ciprofloxacin General information Administered orally and/or IV May cross the blood-brain barrier Medical uses Treatment of chlamydia, trachoma &/or lymphogranuloma due to chlamydia infection Gonorrhea due to Neisseria infection Leprosy due to mycobacterium infections Side effects same as ciprofloxacin
- 25. Levofloxacin • Spectrum: Strep. Pneumonine and some other gram-positive and gram negative • P.K • 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. • warfarin, and zidovudine remain unchanged during levofloxacin treatment. • Use: • community acquired pneumonia and exacerbations of chronic bronchitis
- 26. Gatlifloxacin • P.K. • Absorption: Not measurable as it is used topically Distribution: Widely distributed into body tissues. Plasma protein binding: Approx. 20%. Metabolism: Limited metabolism. Excretion: Via urine mainly as unchanged drug w/ <1% as metabolites; faeces , Elimination half-life: 7-14 hr. • ADV: Conjunctival irritation, increased lacrimation, keratitis, papillary conjunctivitis, conjunctival haemorrhage, ocular dryness and redness • Interactions: antiarrhythmic agents + gatlifloxacin= additive effect for prolong QT interval • Indications: Ophthalmic: Bacterial conjunctivitis As 0.3% soln: Instill 1 drop 2 hrly into affected eye
- 27. Jagir. Patel, Asst Professor, APC
- 28. Trovafloxacin • It had better gram+ve bacterial coverage and less gram-ve coverage than the previous FQ’s • Pk. • Absorption: Readily absorbed from GI tract. Peak plasma concentration: 1-2 hr. Oral bioavailability: 88%. Distribution: Widely distributed and found in breast milk. Protein binding: 76%. Metabolism: Metabolized by conjugation. Half-life: 9-12 hr. After IV inj, alatrofloxacin, the prodrug of trovofloxacin, is rapidly converted to Trovafloxacin. Excretion: Excreted in urine and faeces as metabolites and unchanged drug. • ADV: Dizziness, convulsions, CNS stimulation (e.g. tremor, restlessness, hallucinations), phototoxicity, pancreatitis. Potentially Fatal: Hapatotoxicity, anaphylactic reactions, severe hypotension, Stevens- Johnson syndrome.
- 29. • Drug interactions: Trovafloxacin+ anatcids containing aluminum and magnesium salts = decreased absorption • Trovafloxacin + NSAIDs = Increased risk of convulsions • Contraindication: Severe hepatic cirrhosis • Indications • Community-acquired pneumonia; Complicated skin and skin structure infections, Nosocomial pneumonia, Pelvic infections, Complicated intra- abdominal infections • Dose 200-300 mg once daily
- 30. Gemifloxacin • Spectrum: gram-positive microorganisms - Streptococcus pneumoniae including multidrug resistance streptococcus pneumoniae and aerobic gram-ve organisms • Pk • Absorption: Rapidly absorbed from the GI tract. Absolute bioavailability: Approx 71%. Time to peak plasma concentration: 0.5-2 hr. • Distribution: Widely distributed into body tissues including bronchial mucosa and lungs. Volume of distribution: 4.2 L/kg. • Plasma protein binding: Approx 55-73%. • Metabolism: Undergoes limited hepatic metabolism. • Excretion: Via faeces (61%) and urine (36%) as unchanged drug and metabolites. Elimination half-life: Approx 7 hr.
- 31. • ADV: hypersensitive reactions are fetal • Interactions: Additive effect on QT interval prolongation w/ class IA (e.g. quinidine) • Contraindications: Renal impairment patients • Indications • Acute bacterial exacerbation of chronic bronchitis • Community-acquired pneumonia
- 32. Why banned? • Grepafloxacin- Withdrawn from use in 1999 due to deadly heart rhythm known as a Prolonged QT Interval • Nalidixic acid • Pefloxacin • Temafloxacin (Omniflox) – Recalled 6 months after FDA approval due to Deadly Blood Coagulation Problems as well as kidney and liver failure(1). See the FDA Press Release on the Recall of Omniflox. • Trovafloxacin- Not removed, but restricted to use only in hospitals since 1999. Severe liver damage (1) (3) • Sparfloxacin- Withdrawn in most countries due to toxicity upon user sunlight exposure and DNA Damage (2)
- 33. MCQ • The following quinolone antimicrobial agent is not useful in systemic infections: • A. Lomefloxacin • B. Ofloxacin • C. Nalidixic acid • D. Pefloxacin • Indicate the enzyme(s) inhibited by fluoroquinolones: • A. Both 'A' and 'C' • B. Topoisomerase II • C. Topoisomerase IV • D. DNA gyrase
- 34. Nalidixic acid is primarily active against: • A. Cocci • B. Bacilli • C. Gram positive bacteria • D. Gram negative bacteria • The fluoroquinolones have improved over Nalidixic acid in the following respect(s): • A. They have higher antimicrobial potency • B. They have extended antimicrobial spectrum • C. Development of bacterial resistance against them is slow and infrequent • D. All of the above
- 35. • Adverse effects of ciprofloxacin are referable primarily to the following except: • A. Gastrointestinal tract • B. Kidney • C. Skin • D. Nervous system A single oral dose of the following drug can cure most cases of uncomplicated gonorrhoea: • A. Ciprofloxacin • B. Cotrimoxazole • C. Spectinomycin • D. Doxycycline
- 36. • Which fluoroquinolone has enhanced activity against gram positive bacteria and anaerobes: • A. Pefloxacin • B. Ciprofloxacin • C. Sparfloxacin • D. Norfloxacin • Ciprofloxacin is not active against: • A. H.influenzae • B. E.coli • C. Enterobacter spp. • D. Bacteroides fragilis
- 37. Thank You