Antimicrobial Agents Sulfonamides and Quinolones Prof R K

Antimicrobial Agents (Sulfonamides and Quinolones) Prof. R. K. Dixit Pharmacology and Therapeutics K. G. M. U. Lucknow dixitkumarrakesh@gmail. com

Objectives After completion of this lecture you will be able to – Know about sulphonamides • • • Types (Classification) MOA Combination with Trimethoprim or Pyrimethamine Uses ADRs, DDI, and Contraindications Special points – Know about Quinolones • • • Types (Classification) MOA Uses ADRs, DDI, and Contraindications Special points

Quinolones and Fluoroquinolones ØHave Quinolone structure ØNalidixic acid is first member ØFluorination of Quinolones Fluoroquinolones ØGram negative mainly (Plus gram positive New FQs) N to P

• MOA- (Queen stops gyrating dancers) • In gram negative – • Inhibition of DNA gyrase enzyme (Inhibit negative super coiling) • In gram positive – • Inhibition of Topoiosmerase IV – Inhibition of nicking and separation of daughter DNA strands after DNA replication (Inhibition of Decatenation) • The malformed DNA is digested by Exonucleases Why not human cells affected ? Mammalian cells have Topoiosmerase II

Quinolones

ResistanceØDue to mutation in chromosomes ØAltered DNA gyrase and Topoisomerase IV ØReduced permeability for drug ØIncreased efflux of drug

Quinolones Members • Nalidixic acid Fluoroquinolones First Generation Ciprofloxacin Norfloxacin Pefloxacin Ofloxacin Fluoroquinolones New Generations • • • Lomefloxacin Levofloxacin Prulifoxacin Sparfloxacin Gatifloxacin Gemifloxacin Moxifloxacin Trovafloxacin Alatrofloxacin Finafloxacin Second Third Fourth MAN Can SPOT Good Life

Moxifloxacin Alatrofloxacin Norfloxacin Ciprofloxacin Sparfloxacin Pefloxacin Prulifoxacin Ofloxacin • • • Trovafloxacin Gatifloxacin Gemifloxacin Lomefloxacin Levofloxacin M A N Can S P O T Good Life

Nalidixic Acid • Gram negative, (Narrow spectrum) • Bactericidal, • Acts by DNA gyrase inhibition, • Highly protein bound, • High concentration is in Urine • Neurological toxicity(vertigo, visual and seizures) • Haemolysis in G-6 PD deficiency • Used as • Urinary antiseptic, • Bacterial Diarrhea. Don’t give with Nitrofurantoin (Antagonism)

First generation FQs Ciprofloxacin • Long Post Antibiotic Effect (PAE) • Less active at acidic p. H • Interacts with food and calcium • High tissue penetrability ( Except BBB) • High conc. in urine and bile • CNS side effects are common, • Tendonitis and tendon rupture • Drug Interaction • Inhibition of metabolism of other drug, • Chelation • QT interval prolongation

USES- (Extended spectrum) §CNSI, MFI, OI, ENTI, RTI, GITI, UTI, PID, STDs, SBI § Nosocomial Infections §Septicaemia §Tuberculosis- MDR TB and XDR TB §Typhoid §Treatment 2 weeks §Prevention of carrier state 2 months §Other drugs§Other FQs §Cephalosporins , Ceftriaxone (Fastest) §Chloramphenicol §Cotrimoxazole §Ampicillin

§Norfloxacin – üLess potent, üPrimarily used for UTI and GIT infections, §OfloxacinüHighly active against Mycobacterium leprae §Pefloxacin – üMethylated derivative of Norfloxacin, üOral bioavailability is 100%

Second Generation FQs ØLomefloxacin – • Once a day dose ØLevofloxacin – • Levo-isomer of Ofloxacin, • Oral absorption is 100% • Single daily dose • Minimal drug interactions

ØSparfloxacin – • • Enhanced action against Chlamydia, Maximum half life and Plasma Protein Binding Second line Anti-tubercular drug MAC in AIDS, Leprosy No interaction with Theophylline and Warfarin, Photoxicity Single daily dose, May prolong Q-T interval ( Avoid with Cisapride, TCAs, Phenothiazines, Anti-arrhythemics, Hypokalemia)

ØGatifloxacin – • Prolongs Q-T interval, • Unexpected Hypo or Hyperglycemia in Diabetes mellitus patients. ( Withdrawn ) ØMoxifloxacin – • Most potent FQ against M. tuberculosis. • Can prolong Q-T interval, • Phototoxic ØTrovafloxacin – • Hepatotoxic (Reserved and maximum of 15 days Tt. ) ØAlatrofloxacin - Prodrug of Trovafloxacin ØFinafloxacin, Prulifoxacin, Gemifloxacin

Elimination of Fluoroquinolones Renal • Norfloxacin • Ofloxacin • Ciprofloxacin • Lomefloxacin • Levofloxacin • Gatifloxacin Hepatic • Pefloxacin • Moxifloxacin • Trovafloxacin • Sparfloxacin • Gemifloxacin Fluoroquinolones safe in renal failure Pefloxacin Moxifloxacin Trovafloxacin

Miscellaneous points about Quinolones • No FQs effective against spirochaetes • Ofloxacin and Pefloxacin are effective against M. leprae • Moxifloxacin is the only FQ NOT used in UTI as its concentration is poor in urine

• Levofloxacin, Moxifloxacin, Gemifloxacin, Gatifloxacin, Sparfloxacin have good activity against S. pneumonia and also called Respiratory FQs. They also have good activity against anaerobes • Chronic Prostatitis Tt. Ciprofloxacin for 1 to 2 months • Gonorrhea- Tt. Single dose Ciprofloxacin 500 mg • Chlamydia trachomatis- Ciprofloxacin one week or single dose Azithromycin

• Sulphonamides Summary – Act by inhibition of folic acid synthesis – Combined with Trimethoprim – Produce Stevens Johnson Syndrome – Prolonged use may produce hypothyroidism, goitre, arthritis and drug fever • Quinolones – Act by inhibition of DNA gyrase or Topoiosmerase IV – Have extended spectrum – Have chelating and enzyme inhibition property – Used for multiple infective diseases

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