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Transcript Fluoroquinolones

Mark S. Johnson, Pharm.D., BCPS
Associate Professor and Director of
Postgraduate Education
• 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.
1st generation
2nd generation
3rd 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
Nalidixic Acid
• 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
Mechanism of Action
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) – 3rd generations
• Intracellular/atypical bacterial – Chlamydia;
Mycoplasma; Legionella; Brucella; Mycobacterium
• Anaerobic activity –moxifloxacin
• Resistance mediated by
– Mutations in DNA gyrase
– Change in outer bacterial membrane permeability
– Variant of an aminoglycoside acetyltransferase
• 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
Some Clinical Uses
Urinary Tract Infections (not Moxifloxacin)
Respiratory Tract Infections
GI Infections
Soft tissues, bones, joints
Intra-abdominal infections
• 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)
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
2nd 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%
2nd generation
• Ofloxacin (Floxin)
• Coverage similar to ciprofloxacin (except
• Used for: primarily for UTI’s and nongonococcal
urethritis and cervicitis
• Dosing
• 200-400mg PO BID
• Ophthalmic Solution 0.3% (Ocuflox)
2nd generation
• Norfloxacin (Noroxin)
• Used for UTI’s, prostatitis
• Dosing:
• PO 400mg BID
3rd 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%)
3rd 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, intraabdominal infections, skin/skin structure
• “Respiratory Fluoroquinolone”
– Dosing:
• 400mg IV/PO Q24h
• Ophthalmic 0.5% (Vigamox)
3rd Generation
• Gemifloxacin (Factive)
– Similar in coverage to other 3rd 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