03/09/2012

Fluoroquinolones

Gabor Pozsgai
Pharmacology and Pharmacotherapy
University of Pécs
2012

Mechanism of action
• Discovered during synthesis of antimalarial
drug chloroquine in 1962
• Inhibit topisomerase II (DNA gyrase) and IV
– topoisomerase II relieves stretches in DNA arising
from unfolding for transcription or replication
– inhibition prevents these processes
– topoisomerase IV separates replicated
chromosomes
• Bactericidal

1
 03/09/2012

Resistance
• Mutation of topoisomerase II
• Decreased permeability
• Plasmid mediated resistance
– Qnr protein that protects topoisomerase II from
the drug
– aminoglycoside acetyltransferase that can modify
the drug

Spectrum
• Gram negative
– E. Coli, Klebsiella, Proteus
– Pseudomonas
– H. influenzae, M. catarrhalis
– N. meningitidis
– salmonellosis
• Gram positive
– some strains of S. aureus and S. pneumoniae
– anthrax
• Intracellular pathogens
– Chlamydia, Mycoplasma, Legionella
• Mycobacterium tuberculosis and other Mycobacteria
• Anaerobic bacteria

2
 03/09/2012

Pharmacokinetics
• Excellent oral bioavailability
– same plasma levels after i.v. and oral application
– mostly taken p.o., but can be given i.v.
• nalidixic, oxolinic acid and norfloxacin cannot be given
i.v.
• bivalent cations interfere with absorption
• Widely distributed
– except CNS
– reach IC compartment

Pharmacokinetics
• Some drugs are metabolized in the liver
• They are ecxreted via the kidneys
– tubular secretion and glomerular filtration
– excretion of moxifloxacin is nonrenal
– newer drugs have long half lives and can be given
once daily

3
 03/09/2012

Generations
• Generation 0
– nalidixic acid, oxolinic acid
• Generation 1
– norfloxacin
• Generation 2
– ciprofloxacin, ofloxacin, pefloxacin, nadifloxacin,
rufloxacin
• Generation 3
– levofloxacin, sparfloxacin, balofloxacin, pazufloxacin,
tosufloxacin
• Generation 4
– moxifloxacin, trovafloxacin, clinafloxacin, gemifloxacin,
sitafloxacin, prulifloxacin

Generation 0
• „Quinolones”
• Active against Gram negative enteric bacteria
– Coli, Klebsiella, Proteus
– resistance develops readily
• Only used orally
• Only reach effective levels in the GI tract and
urinary tract
• For the treatment of urinary tract infections
• Carcinogenic

4
 03/09/2012

Generation 1
• Used p.o.
• Active against Gram negative enteric bacteria
– Coli, Klebsiella, Proteus
– weak activity against P. aeruginosa
• Does not produce effective systemic plasma
level
• For the treatment of urinary tract infections

Generation 2
• Used mostly p.o., but available for i.v. application
• Spectrum
– Gram negative bacteria
• Coli, Klebsiella, Proteus
• P. aeruginosa
– Gram positive bacteria
• Staphylococci, Streptococcus pneumoniae
– intracellular pathogens
• Chlamydia, Mycoplasma, Legionella
– Mycobacteria
• Ciprofloxacin has the best activity against Gram
negatives of all fluoroquinolones

5
 03/09/2012

Generation 3
• Used mostly p.o., but available for i.v.
application
• A bit weaker activity against Gram negative
germs
• Better coverage for Gram positive and
intracellular pathogens

Generation 4
• Superior Gram positive activity
– S. pneumoniae
• Moxifloxacin is effective against anaerobes
• Excretion of moxifloxacin is nonrenal
– not suitable for urinary tract infections
– ineffective urine levels

6
 03/09/2012

Clinical usage
• Eradication of meningococcus from carriers
• Pneumonia, atypical pneumonia
– especially generations 3 and 4
• Anthrax
• Tuberculosis and other mycobacterial
infections

Clinical usage
• Traveller’s diarrhoea, salmonellosis
• Urinary tract infections
– chlamydial urethritis, cervicitis
• Mixed soft tissue infections, penetrating
wounds of body cavities
– often in combination with drugs against
anaerobes

7
 03/09/2012

Unwanted effects
• CNS effects
– tremor, agitation, seizures, hallucinations,
psychosis
• GI tract
– nausea, vomiting, abdominal discomfort
– elevated liver enzymes
• Photosensitization
– pefloxacin

Unwanted effects
• Prolonged QT interval
– levofloxacin, moxifloxacin
• Damage growing cartilages
– not to be used during pregnancy and in small
children
– arthropathy
• Tendinitis, tendon rupture
– especially in senile patients with renal
insufficiency taking glucocorticoids