Quinolones

1. QUINOLONES Dr.Rahul Asso. Prof. pharmacology RMC, PIMS (DU)

2. Quinolones Bactericidal broad spectrum drugs Increasingly used because of their relative safety, their availability both orally and parenterally and their favorable pharamacokinetics There is increasing concern about the emergence of resistance to these agents Parent drug: nalidixic acid

3. Classification Quinolones (1 st generation) Highly protein bound Mostly used in UTIs Fluoroquinolones (2 nd , 3 rd and 4 th generation) Modified 1 st generation quinolones Not highly protein bound Wide distribution to urine and other tissues; limited CSF penetration.

4. Generation Drug Names Spectrum 1st Nalidixic acid Cinoxacin Gram- but not Pseudomonas 2nd Norfloxacin Ciprofloxacin Ofloxacin Gram-(including Pseudomonas) some Gram+ (S. aureus ) some atypicals 3rd Levofloxacin Sparfloxacin Moxifloxacin Gemifloxacin Same as 2 nd generation : extended Gram+ and atypical coverage 4th * Trovafloxacin Same as 3 rd generation: broad anaerobic coverage * withdrawn from the market in 1999

5. FQs Spectrum of Activity Gram-positive Older agents with poor activity; newer FQs with enhanced potency Methicillin-susceptible Staphylococcus aureus Streptococcus pneumoniae (including PRSP) Group and viridans streptococci – limited activity Enterococcus sp. – limited activity

6. Gram-Negative all FQs have excellent activity ( cipro = levo > gati > moxi ) E . coli , Klebsiella sp , Enterobacter sp, Proteus sp Salmonella Shigella , Serratia marcescens , H . influenzae , M . catarrhalis , Neisseria sp. Pseudomonas aeruginosa significant resistance has emerged; ciprofloxacin and levofloxacin with best activity

7. FQs Spectrum of Activity Atypical Bacteria – All FQs have excellent activity against atypical bacteria including: Legionella pneumophila - DOC Chlamydia sp. Mycoplasma sp. Ureaplasma urealyticum

8. FQs Spectrum of Activity Anaerobes – only trovafloxacin has adequate activity against Bacteroides sp . Other Bacteria – Mycobacterium tuberculosis, Bacillus anthracis

9. Mechanism of action: Enzymes required for DNA replication Topoisomerase II (DNA gyrase ): GyrA and GyrB Topoisomerase IV: ParC and Pa rE Mechanism of DNA gyrase

10. Mechanism of Action Dual MOA: Inhibition of bacterial DNA Gyrase (Topoisomerase II) Formation of quinolone-DNA- Gyrase complex This conformational change results in the prevention of DNA supercoiling Induced cleavage of DNA Inhibition of bacterial Topoisomerase IV Inhibits sepration of replicated DNA into respective daughter cells

11. Mechanism of action: Inhibit bacterial DNA synthesis by inhibiting DNA gyrase and topoisomerase IV  rapid cell death Mostly Topo II inhibition in G- bacterias Topo IV inhibition more in G+ bacterias Post antibiotic effect: lasts 1 to 2 hours, increases with increasing concentration

12. Resistance Mechanisms Mutations that enhance antibiotic efflux capability Bacterial chromosomal mutations for genes that encode for bacterial DNA gyrase and Topo IV Mutations in outer membrane porins (Gram-)

13. PK and PD profile Absorption - good oral availability, but food will inhibit, as well as Al, Ca, Mag, Fe. Distribution - good tissue penetration, including prostate, bile, lung. Poor CNS coverage Elimination – renal (for 1 st generation) PD: Concentration dependent killing

14. USES UTI Bacterial gastroenteritis Intra abdominal infections Typoid fever Gonorrehea MDR- tuberculosis Leprosy Osteomyelitis Invasive otitis media Nosocomial pneumonia Septicemia Bacterial conjuctivitis Chronic bronchitis Sinusitis Anthrax

15. UTI Most commonly used antimicrobials Very effective against E.coli , proteus , Enterobacteriace Higher urine conc. than serum conc.good for complicated renal cysts & recurrent UTI from prostatitis Ciprofloxacin 750mg bd X 3 wks

16. Bacterial diarrheoas Very effective against shigella, salmonella,, E.coli. Norfloxacin, ciprofloxacin , ofloxacin are effecive

17. Intraabdominal or Gi Infections (Comparative studies) 1) ciprofloxacin + metronidazole 2) Imipenem 3 ) Trovafloxacin 4) amoxicillin/clavulanate  similar activity

18. Typhoid Ciprofloxacin 750mg BD X 10 days Pefloxacin, Ofloxacin can also be used

19. Gonnococcal infection Cervicitis Urethritis PID Single dose :Cipro..500mg, Oflox . 400mg Problem : resistance So Ceftriaxone first drug of choice

20. Mycobacterial infections MDR tuberculosis MAC infections Leprosy (ROM theraphy)

21. Skin and soft tissue infections  Trovafloxacin  approved by the FDA for treatment of soft-tissue infections, including DM foot  Levofloxacin  Superior to ciprofloxacin in SSTI caused by S. aureus

22. Clinical uses of New Fluoroquinolones ( Levofloxacin & Next G FQs) Community-acquired Pneumonia  Outpatients : new fluoroquinolones  Hospitalized General wards : new FQs monotherapy ICU :  -lactam + new FQs Upper respiratory infections : acute sinusitis, chronic bronchitis

23. Other uses Prophylaxis and treatment of infections in neutropenic patients Conjunctivitis due to G- ve bacteria Invasive otitis media Prophylaxis and exposure Anthrax Respiratory infection : (Levofloxacin) Chronic bronchitis Nosocomial pneumonia Sinusitis