FLUOROQUINOLONES the separation of interlinked daughter chromosomes i.e.

FLUOROQUINOLONES

The
fluoroquinolones are systemic antibacterial agents, from a family of broad
spectrum, used widely as therapy of urinary and respiratory tract infections
29. Fluoroquinolones target two enzyme, i.e. DNA gyrase and topoisomerase
IV, in the bacteria’s cell; both are essential targets for bacterial DNA
replication. 23

Microbiology:

A wide range of aerobic
gram-positive and gram-negative organisms are sensitive against flouroquinolones.

Gram-positive coverage includes:

1.      Penicillinase

2.      non-penicillinase
producing Staphylococci, Streptococcus pneumoniae and viridans,

3.      Enterococcus
faecalis,

4.       Listeria monocytogenes,

5.      Nocardia
species. 

Gram negative coverage includes:

1.      Neisseria meningitides

2.      Gonorrhoeae

3.      Haemophilus
influenzae,

4.      Enterobacteriaceae
species,

5.      Pseudomonas
aeruginosa

6.      Vibrio
species. 30

Types:

Older:

·        
Ciprofloxacin

·        
ofloxacin

Newer:

·        
levofloxacin

·        
sparfloxacin

·        
grepafloxacin

·        
trovafloxacin.

·        
gatifloxacin

·        
moxifloxacin

Mechanism of action:

Introduction of negative super helical twists into DNA is only
done by bacterial enzyme DNA gyrase 24. For initiation of DNA
replication, negatively super twisted DNA is important. DNA replication are also
facilitates by DNA gyrase DNA gyrase which removing twists of positive super helical
that accumulate ahead of the replication fork or as a result of the
transcription of certain genes 24, 25. The terminal stages of DNA
replication is acted by Topoisomerase IV, allowing for the separation of
interlinked daughter chromosomes i.e. decatenation so that daughter cells can
be segregated 26, 27. Inhibition of these enzymes by Fluoroquinolones
is done by stabilizing either the DNA-topoisomerase IV complex or the DNA-DNA
gyrase complex 22. Movement of the replication fork is blocked by
the stabilized DNA-DNA gyrase complex, causing formerly reversible DNA-enzyme
complexes that become irreversible 28. Damage to DNA and the
breakage of the generation of DNA-strand then a set of events trigger, as yet defined
poorly, the rapid inhibition of DNA synthesis are followed and eventual cell
death is the result23, 25 .

The fluoroquinolones are interacted with two bacterial
targets, topoisomerase IV  and the
related enzymes DNA gyrase, DNA replication are involved by both enzymes, form enzymes
complexes with DNA, movement of the DNA-replication fork are blocked by that complexes
and causes inhibition of  DNA
replication.

Indications:

Indication of flouroquinolones includes 31bacterial
bronchitis, pneumonia, sinusitis, urinary tract
infections, septicemia, intraabdominal infections, joint and bone infections, soft
tissue, skin infections, typhoid fever, bacterial gastroenteritis, urethral and
gynecological infections, pelvic inflammatory disease and several other
infectious conditions.

Pharmacokinetics:

1.       Common Features

The fluoroquinolones’ pharmacokinetic features have been
summarised in recent times. 19 They oral absorption and
bioavailability are moderate to excellent, marginally affected by food.  Generally rapid absorption, within 1 to 2
hours, peak plasma concentrations (Cmax) achieved. divalent cations, including
Al+++, Mg++, Ca++ and Fe++ are frequently found in antacids and other
medications as well as in dairy products reduce the absorption,.13 Most drugs
have volumes of distribution exceed 1.5 L/kg, consistent with significant
distribution into tissues and cells while moderate clearance and elimination
half-lives (4 to 10 hours).

2.       Variable Features

The variation of predominant route of elimination is widely
between fluoroquinolones. The l-isomer of Ofloxacin, levofloxacin,
lomefloxacin, rufloxacin and gatifloxacin have minimal metabolism (<10%) and predominant renal excretion. In contrast pefloxacin, nalidixic acid, grepafloxacin and sparfloxacin undergo extensive hepatic metabolism (>35%). The other
drugs undergo modest metabolism but as well as have significant levels of renal
excretion. To some extent Protein binding also varies, the degree of binding with
norfloxacin, gatifloxacin and lomefloxacin having the lowest, and rufloxacin, clinafloxacin
and trovafloxacin the highest. 20-22

3.       Tissue Penetration

For most fluoroquinolones, tissue concentrations are usually
higher than plasma concentrations. This tissue penetration is not related to
lipid solubility. In contrast, fluoroquinolones have relatively poor CSF
penetration into uninflamed meninges, but at least 4 agents ? ciprofloxacin,
pefloxacin, ofloxacin and trovafloxacin ? are known to penetrate to a moderate
extent in the presence of inflammation. 19

Side effects:

The fluoroquinolones’ common side effects are:

·        
Disturbances
of gastrointestine

·        
skin
rash

·        
Allergic
reactions.

·        
headaches

More severe side effects but less common include:

·        
QT
prolongation

·        
tendon
rupture

·        
Hallucinations

·        
Seizures

·        
Photosensitivity

·        
Angioedema.32
 

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