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

Quinolones and Fluoroquinolones Have Quinolone structure Nalidixic acid is first member Fluorination of Quinolones - Fluoroquinolones Gram negative mainly (Plus gram positive New FQs) N to P

Why not human cells affected ? Mammalian cells have Topoiosmerase II 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

Resistance- Due to mutation in chromosomes Altered DNA gyrase and Topoisomerase IV Reduced permeability for drug Increased efflux of drug

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

M A N Can S P O T 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

Don’t give with Nitrofurantoin (Antagonism) 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-6PD deficiency Used as Urinary antiseptic, Bacterial Diarrhea. Don’t give with Nitrofurantoin (Antagonism)

First generation FQs Ciprofloxacin- Drug Interaction- Long Post Antibiotic Effect (PAE) Less active at acidic pH 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 – Ofloxacin- Pefloxacin – Less potent, Primarily used for UTI and GIT infections, Ofloxacin- Highly active against Mycobacterium leprae Pefloxacin – Methylated derivative of Norfloxacin, Oral bioavailability is 100%

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

Sparfloxacin – 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)

Gatifloxacin – Moxifloxacin – Prolongs Q-T interval, Unexpected Hypo or Hyperglycemia in Diabetes mellitus patients. ( Withdrawn ) Moxifloxacin – Most potent FQ against M. tuberculosis. Can prolong Q-T interval, Phototoxic Trovafloxacin – Hepatotoxic (Reserved and maximum of 15 days Tt.) Alatrofloxacin - Prodrug of Trovafloxacin Finafloxacin, 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, 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 500mg Chlamydia trachomatis- Ciprofloxacin one week or single dose Azithromycin

Summary Sulphonamides Quinolones 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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