Quinolones

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

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, l imited spectrum and high frequency of bacterial resistance . fluoroquinolones: substitution of pyperaizne ring on 7 th position and fluorination in 6 th position results into fluoroquinolones I dentifiable 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. C lassification

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 .

6. Jagir. Patel, Asst Professor, APC

7. Jagir. Patel, Asst Professor, APC

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 I V may confer higher potency against gram-positive bacteria.

9. T here 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

11. 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

12. 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: U ncomplicated UTI D iarrhoea due to gram –ve Shigella or salmonella

13. 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

14. Ciprofloxacin Prototype Antibacterial spectrum :

15. 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.

16. 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

17. 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

18. 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 chlamydia l cervicitis and urethritis

19. 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

20. Drug interactions Ciprofloxacin increases plasma concentration of warfarin NSAIDS+ Ciprofloxacin = potentiate CNS side effect Antacids, and sulculfrate reduces absorption of Ciprofloxacin

21. N orfloxacin / O floxacin 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

22. 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

23. 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

24. Jagir. Patel, Asst Professor, APC

25. 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 .

26. 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

27. 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.

28. 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

29. 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 )

30. 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

31. 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

32. 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

33. 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

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