Fluoroquinolones

1. Quinolones and
flouroquinolones
By = Dr.Ishfaq Ahmad

2. Quinolones and
Fluoroquinolones
The quinolones are a family of synthetic
broadspectrum antibacterial drugs.
Quinolones, and derivatives, have
also been isolated from natural sources,
such as plants, animals and bacteria.
Quinolones exert their antibacterial effect
by preventing bacterial DNA from
unwinding and duplicating.

3. Broader spectrum, better safety profile
Nalidixic acid is predecessor of all
flouroquinolones
Wide clinical applications
Closely tied to clostridium difficile
infection and spread of antimicrobial
resistance in many organisms
Unfavourable effects of
flouroquinolones on the induction and
spread of antimicrobial resistance is
referred as collateral damage

4. Difference between Quinolones
and Fluoroquinolones:
Quinolones such as Nalidixic
acid has only limited spectrum
against some Gram negative
organism.
Fluorinated analogues such as
Fluoroquinolones have much
broader activity against
microorganisms.

5. Why they are preferred Drugs??
Good oral absorption
Deeper penetration into the body so
they have good activity against
Intracellular microorganisms such as
Chlamydia, Mycobacterium
tuberculosis, Legionella, Brucella etc.
Broad spectrum
Safer drugs
High potency

6. Fluoroquinolones: MOA
The fluoroquinolones enter the bacterium
by passive diffusion through water-filled
protein channels (porins) in the outer
membrane.
Once inside the cell, FQs inhibit the
replication of bacterial DNA by interfering
with the action of DNA gyrase
(topoisomerase II) and topoisomerase IV
during bacterial growth and reproduction.

7. Fluoroquinolones
Inhibition of DNA gyrase II by FQs
prevent the relaxation of positively
supercoiled DNA that is required for
normal transcription and replication of
bacteria.
Inhibition of topoisomerase IV
interferes with the separation of
replicated chromosomal DNA into
respective daughter cells during cell
division.

8. *withdrawn from the market in
1999
Generation Drug Names Spectrum
1st
nalidixic acid
cinoxacin
Gram- but not
Pseudomonas species
2nd
norfloxacin
ciprofloxacin
enoxacin
ofloxacin
Gram- (including
Pseudomonas species),
some Gram+ (S.
aureus) and some
atypicals
3rd
levofloxacin
sparfloxacin
gemifloxacin
Same as 2nd generation
with extended Gram+
and atypical coverage
4th
Moxifloxacin
*trovafloxacin
Same as 3rd generation
with broad anaerobic
coverage

9. Fluoroquinolones
First-generation quinolones
cinoxacin, nalidixic acid
These quinolones targeted gram
negative organisms including
Escherichia coli, Klebsiella and
Proteus species.

10. Fluoroquinolones 1st Gen.
Nalidixic acid was once the most
commonly used preparation, but
poor tissue and serum
concentrations now limit its use to
the treatment of simple urinary
tract infections.
Its utility is also limited due to its
short half-life , narrow spectrum of
activity and the rapid development
of bacterial resistance.

11. Fluoroquinolones
Second-generation
Fluoroquinolones
Ciprofloxacin, Enoxacin,
Lomefloxacin, Ofloxacin and
Norfloxacin.
They exhibit good activity
against gram-negative bacilli
and moderate-to-good activity
against Staphylococcus
species.

12. Fluoroquinolones 2nd Gen.
Ciprofloxacin and Ofloxacin have good
tissue penetration and reach macrophages
and polymorphonuclear leukocytes,
making them useful beyond the treatment
of urinary tract infections.
Their activity against Legionella
pneumophila is good.
Activity against Chlamydia pneumoniae
and Mycoplasma pneumoniae is more
variable.
Ciprofloxacin is also commonly used to
treat typhoid fever.

13. Fluoroquinolones 2nd Gen.
 Norfloxacin
Least potent fluoroquinolone
 Norfloxacin is a
"second-generation" quinoline
carboxylic acid antimicrobial agent
It is primarily indicated in urinary
tract infections and gonorrhea.
The ophthalmic solution may be
used in the treatment of
conjunctivitis.

14. Fluoroquinolones 2nd Gen.
Clinical uses:
ciprofloxacin and Ofloxacin are
effective in treating
(1) urinary tract infections caused by
susceptible organisms,
(2) respiratory tract infections caused
by susceptible gram negative
organisms.
(3) skin and soft-tissue infections
(4) osteomyelitis (ciprofloxacin only)
(5) typhoid fever

15. Fluoroquinolones
Third-generation fluoroquinolones
 Levofloxacin , Sparfloxacin ,
Ripafloxacin have expanded
coverage against streptococci and
atypical organisms.
 These fluoroquinolones are
useful in treating patients with
community acquired pneumonia,
acute sinusitis and acute
exacerbations of chronic
bronchitis and skin infection.

16. Fluoroquinolones
Fourth-generation fluoroquinolones
Clinafloxacin, Gatifloxacin,
Moxifloxacin and Trovafloxacin
add a significant anaerobic
coverage.
A long half-life allows once-daily
dosage, and extensive hepatic
metabolism makes dose adjustment
unnecessary in patients with renal
disease.

17. Fluoroquinolones 4th Gen.
Moxifloxacin: not only has
enhanced activity against gram-
positive organisms (S. pneumoniae)
but also has excellent activity against
many anaerobes.
It has very poor activity against
P. aeruginosa.
Moxifloxacin does not concentrate in
urine, so not used in the treatment of
UTIs.

18. Fluoroquinolones 4th Gen.
1. Indications for use include
nosocomial pneumonia,
2. intra-abdominal infections
3. serious penicillin or
cephalosporin resistant S.
pneumoniae infections.
4. Gatifloxacin has FDA-labeled
indications for urinary tract
infections and gonorrhea.

19. Fluoroquinolones
Resistance:
With the introduction of
fluoroquinolones , there
was optimism that
resistance would not
develop.
 However, it emerged due
to chromosomal
mutations.
. The mechanisms
responsible for this
resistance include the
following.

20. Altered target:
Mutations in the bacterial DNA
gyrase and Topoisomerase IV
have developed a decreased
affinity for fluoroquinolones.
Resistance is frequently
associated with mutations in
both gyrase and topoisomerase
IV.
Resistance:

21. Resistance:
•Decreased accumulation:
Reduced intracellular
concentration of the drugs in the
bacterial cell is linked to two
mechanisms.
One mechanism is associated
with an energy-dependent efflux
system in the cell membrane.

22. The other mechanism
involves a decreased
number of porins in the
outer membrane of the
resistant cell, thereby
impairing access of the
drugs to the intracellular
topoisomerases.
Resistance:

23. Fluoroquinolones
Absorption:
Only 35 to 70 percent of
norfloxcin is absorbed orally ,
compared with 85 to 95 percent of
the other fluoroquinolons.
Intravenous preparations of
ciprofloxacin, levofloxacin,and
ofloxacin are available.

24. Absorption:
Ingestion of the fluoroquinolones with
sucralfate, antacids or dietary supplements
containing iron or zinc can interfere with the
absorption of these drugs.
Calcium and other divalent cations also
interfere with the absorption of these
agents.
The fluoroquinolones with the longest half-
lives (levofloxacin and moxifloxacin)
permit once-daily dosing.

25. Distribution
 All the fluoroquinolones distribute
well into all tissues and body fluids.
•Levels are high in bone, urine, kidney,
and prostatic tissue
Concentrations in lungs exceed those
in serum.
•Penetration into cerebrospinal fluid is
low.

27. Elimination
•The fluoroquinolones also accumulate
in macrophages and
polymorphonuclear leukocytes,
• thus effective against intracellular
organisms such as Legionella
pneumophilia.
•They are excreted by the renal route.
•Moxifloxacin is excreted primarily by
the liver, thus no dose adjustment

28. Adverse drug reactions:
Gastrointestinal system:
Nausea
Vomiting
Gastric distress

29.  Adverse reactions
Central nervous system :
headache
dizziness
light-headedness.
Thus, patients with CNS
disorders, such as epilepsy,
should be treated cautiously
with these drugs.

30. Adverse reactions
Connective tissue problems:
 should be avoided in pregnancy,
nursing mothers, children under 18
years of age,
because articular cartilage erosion
(arthropathy) occurs in immature
experimental animals.
Fluoroquinolones can infrequently
cause ruptured tendons in patients over
60 years of age.

31. Adverse reactions
Phototoxicity:
Patients taking fluoroquinolones
are advised to avoid excessive
sunlight and to apply
sunscreens.

32. Contraindications:
Quinolones are contraindicated if a
patient has epilepsy
QT prolongation
CNS lesions or CNS inflammation
or the patient has suffered a stroke.
Contraindicated in pregnancy
unless no other safe alternative
antibiotic exists.

33.  Contraindications:
Contraindicated in children due
to the risks of damage to the
musculoskeletal system.

34. Drug interactions:
Ciprofloxacin and ofloxacin can
increase the serum levels of
theophylline by inhibiting its
metabolism
Third and fourth generation
fluoroquinolones, may raise the
serum levels of warfarin, caffeine,
and cyclosporine.

35. Usual Dose Of Fluoroquinolone
Agent Usual Dose
Norfloxacin (Noroxin) 400 mg twice daily orally
Lomefloxacin (Maxaquin) 400 mg per day orally
Enoxacin (Penetrex) 200 to 400 mg b.i.d. orally
Ofloxin (Floxin) 200 to 400 mg b.i.d. orally
400 mg every 12 hours I.V.
Ciprofloxacin (Cipro) 250 to 750 mg b.i.d. orally
400 mg every 12 hours I.V.
Levofloxacin (Levaquin) 250 to 500 mg per d
500 mg every 24 hours I.V.

36. Usual Dose of of Fluoroquinolone
Agent Usual dose
Sparfloxacin(Zagam) 200 mg per day orally
Gatifloxacin (Tequin) 400 mg per day orally
400 mg every 24 hours
I.V.
Moxifloxacin (Avelox) 400 mg per day
orally
Trovafloxacin (Trovan) 100 to 200 mg per
day orally
Alatrofloxacin (Trovan) 200 mg every 24
hours I.V.

37.  THANK YOU