1. Fluoroquinolones Mark S. Johnson, Pharm.D., BCPS Associate Professor and Director of Postgraduate Education

2. Fluoroquinolones Very popular class of antibiotics due to spectrum of coverage (gram positive, gram negative, atypicals), unique mechanism of action resulting in inhibition of bacterial DNA gyrase and topoisomerase IV, excellent PO bioavailability, fairly well tolerated – Has led to overprescribing, resistance Nalidixic acid was first quinolone (1962) – Had limited antibacterial activity – Associated with rapid development of bacterial resistance – Was only useful for lower UTI’s – Synthesis led to the evolution of the fluoroquinolones.

3. Fluoroquinolones 1 st generation2 nd generation3 rd generation Cinoxacin (Cinobac)Ciprofloxacin (Cipro)Levofloxacin (Levaquin) Nalidixic Acid (NegGram)Ofloxacin (Floxin)Sparfloxacin (Zagam) Lomefloxacin (Maxaquin)Trovafloxacin (Trovan) Norfloxacin (Noroxin)Gemifloxacin (Factive) Gatifloxacin (Tequin) Moxifloxacin (Avelox) Increased gram positive coverage with each generation

4. Nalidixic Acid http://www.rxlist.com/neggram-drug.htm

6. Fluoroquinolones Mechanism of action – Block bacterial DNA synthesis by inhibiting bacterial topoisomerase II (DNA gyrase) and topoisomerase IV Inhibition of DNA gyrase prevents the relaxation of positively supercoiled DNA that is required for normal transcription and replication Inhibition of topoisomerase IV interferes with separation of replicated chromosomal DNA into the respective daughter cells during cell division – Bactericidal

7. Quinolones Mechanism of Action

8. Fluoroquinolones Spectrum of Activity Gram (–) bacilli – Enterobacteriaceae (E. coli, Salmonella, Shigella, Enterobacter, Klebsiella, Proteus, Serratia); Campylobacter (increasing resistance); Pseudomonas aeruginosa (ciprofloxacin, levofloxacin) Gram (–) cocci – Neisseria meningitidis Gram (+) cocci – Staphylococci (MSSA/MRSA) – marginal-to-good activity (resistance can form) – Streptococci (S. pneumoniae) – 3 rd generations Intracellular/atypical bacterial – Chlamydia; Mycoplasma; Legionella; Brucella; Mycobacterium Anaerobic activity –moxifloxacin

9. Fluoroquinolones Resistance Resistance mediated by – Mutations in DNA gyrase – Change in outer bacterial membrane permeability – Variant of an aminoglycoside acetyltransferase

10. Fluoroquinolones PKS Absorption – Excellent BA (80-95%) Distribution – Widely distributed in body fluids and tissues Elimination – Mainly by renal tubular secretion or glomerular filtration – Moxifloxacin—hepatic metabolism, some urinary excretion – Gemifloxacin—both renal and hepatic

11. Fluoroquinolones Some Clinical Uses Urinary Tract Infections (not Moxifloxacin) Respiratory Tract Infections GI Infections Soft tissues, bones, joints Intra-abdominal infections Anthrax Others

12. Fluoroquinolones ADR’s GI—nausea, vomiting, diarrhea CNS – headache, dizziness, sleep disturbances, and confusion QT prolongation sparfloxacin >grepafloxacin > moxifloxacin > gatifloxacin > levofloxacin > ciprofloxacin > ofloxacin Tendonitis, tendon rupture Joint cartilage damage/arthropathy--<18yo Photosensitivity Hepatotoxity (moxifloxacin) Hyper/hypoglycemia Clostridium difficile diarrhea Skin rash (gemifloxacin)

13. Fluoroquinolones Drug Interactions Drug interactions: – Quinolones’ absorption reduced by: di-, tri-valent cations (antacids, Ca supplements, iron, MVI, diary products, etc), sucralfate, ddi – Space out as far apart as can (at least 2h, but more better) – Quinolones can inhibit metabolism of: theophylline, caffeine, warfarin

14. Fluoroquinolones 2 nd generation Ciprofloxacin (Cipro, Cipro XR, Proquin XR) Coverage: pseudomonas coverage, good gram – coverage (E. coli, salmonella, Shigella, Neirsseria, Legionella), some gram + ( no strep pneumo), Atypical coverage – Good for UTIs, pyelonephritis, prostatitis, osteomyelitis, anthrax, infectious diarrhea, travelers diarrhea, typhoid fever, intra-abdominal infections (with metronidazole), possible RTI’s, possible skin – Dosing: – PO 250-500-750mg BID – XR 500-1000mg QD – IV 400mg Q8-12h – Ophthalmic solution 0.3%

15. Fluoroquinolones 2 nd generation Ofloxacin (Floxin) Coverage similar to ciprofloxacin (except Pseudomonas) Used for: primarily for UTI’s and nongonococcal urethritis and cervicitis Dosing 200-400mg PO BID Ophthalmic Solution 0.3% (Ocuflox)

16. Fluoroquinolones 2 nd generation Norfloxacin (Noroxin) Used for UTI’s, prostatitis Dosing: PO 400mg BID

17. Fluoroquinolones 3 rd Generation Levofloxaxin (Levaquin) – L-isomer of ofloxacin – Improved Gram + coverage and similar Gram –, some Pseudomonas coverage – Used for CAP, COPD exacerbations, sinusitis, skin infections, complicated UTIs “Respiratory fluoroquinolone” – Dosing: 250mg-750mg PO/IV Q24h Ophthalmic solution (Iquix 1.5%, Quixin 0.5%)

18. Fluoroquinolones 3 rd Generation Moxifloxacin (Avelox) – No renal adjustment, no urinary penetration – Gram negative and positive coverage (high activity for Streptococcus pneumoniae (MDRSP), anaerobes – Uses: pneumonia, AECB, sinusitis, intra- abdominal infections, skin/skin structure “Respiratory Fluoroquinolone” – Dosing: 400mg IV/PO Q24h Ophthalmic 0.5% (Vigamox)

19. Fluoroquinolones 3 rd Generation Gemifloxacin (Factive) – Similar in coverage to other 3 rd generation FQ (not pseudomonas, not anaerobes) – Uses: pneumonia, AECB “Respiratory fluoroquinolone” – ADR’s: Rash (incidence higher in females, >5d therapy, < 40yo) – Dosing: 320 PO Q24h