|Flouroquinolones - A Review||
Dr.T R Ramanujam.M.D.,
Substantial progress has been made recently in the development of Safe & Effective agents primarily because of the advances made in ;
The first and key discovery was the identification of the enzyme DNA Gyrase or Toposiomerase II and IV and the second major advantage contributing to the rapid expansion was the ability to chemically manipulate the nucleus of 4-Quinolones.
Earlier compounds like Nalidixic acid, Norfloxacin, Pefloxacin, Ofloxacin and ciprofloxacin enjoyed great success particularly in Gram negative infections. They are excluded for use in children (except- Ciprofloxacin in cystic fibrosis, and Nalidixic acid for UTI in children) because of the fear of Chondrotoxicity. The newer generation of quinolones has greater activity against –
Newer quinolones are;
Newer quinolones are;
MAJOR CLINICAL INDICATION:
PHARMACOLOGICAL ASPECTS OF NEWER QUINOLONES:
Trovafloxacin, Rulofloxacin & Clinafloxacin –
DOSAGE AND ADMINISTRATION
concentration dependent killing and therefore adminsitered O/day,twice a day
regimen. In animal models a 24 hour AUC/MIC (Area under the concentration-time
curve/minimum inhibitory concentration) ratio to be the best predictor of
bacterial killing in vivo. With the peak plasma concentration Cmax /
MIC ratio being important for some bacteria to prevent emergence of
resistance during treatment. Human studies
( and animal models) with ciprofloxacin, Grepafloxacin,
and Levofloxacin show that a 24 hrs AUC/MIC
ratio of about 100, or a Cmax / MIC ratio of about 10
gives maximum clinical and bacteriological efficacy. These values can
be used to predict the efficacy of different agents against different
pathogens , and to define" Pharmacodynamic Breakpoints".
The dosage schedules for
the following quinolones have “Break points” ranging from 0.25 to 1
Antibacterial efficacy of
quinolones depends on;
Activity against the target enzyme DNA Gyrase
Uptake by the bacterial cell
properties like – Hydrophobicity
- Acid base properties and
- Affinity for divalent cations.
primary target is DNA Gyrase(Topoisomerase II ) in many of the gram-ve
organisms whereas in the case of gram+ve organisms Topoisomerase IV
appears to be the primary target as is
the case of Ciprofloxacin, Norfloxacin, and Sparfloxacin.
For Sparfloxacin in the
case of Strerptococci
gyrase appears to be the primary target.
Peculiarly in case of
Sitafloxacin both DNA Gyrase -Topoisomerase
II & Topoisomerase IV appears to be the targets and hence it is
expected that there is little
or no chance for development of resistance.
Adverse Drug Effects
2. Central Nervous System effects- The mechanism is not known probably interfering with GABA activity ? A direct pharmacological effect.
3. Cardio Vascular System Toxicity :- Both Sparfloxacin and Grepafloxacin are implicated in producing QT prolongation syndrome often mild but assumes significance when administered together with other agents like antiarrythmics, Macrolides, Cisapride, Azole antifungals, H1 antagonists like astemizole,cetrizine, terfinadine etc.,
4. Phototoxicity: Skin reactions like erythema,pruritus,urticaria and rashes with phototoxicity are often associated. Sun burns occur when exposed to UV rays of UVA 320-400nm especially transmitted by the clouds & window panes.
5. Arthropathy- Interest has been focussed on proteoglycan synthesis and mitochondrial function. Occurrence of this adverse effect precludes the use of very good antibacterials in paediatrics. Human data from the experience with 3 compound have revealed that Nalidixic acid has poor tissue penetrability and hence did not manifest chodrotoxicity and in the case of ciprofloxacin and norfloxacin there was reduced AUC and therefore low systemic exposure. In case of Pefloxacin with 5-10 times higher systemic exposure ( Higher AUC) is well known to be associated with high incidence of arthropathy in humans because the drug affects articular cartilage & epiphyseal growth plate. The importance of this toxicity is that it is irreversible and manifest later after the drug is discontinued. The use of Nalidixic acid in UTI and ciprofloxacin in cystic fibrosis (pseudomonal) are officially permitted to be used in paediatrics. Recently many clinical studies revealed that newer quinolones might appear to be safer for paediatric use.
Review of 31 reports involving 7045 paediatric patients use of Ciprofloxacin,Nalidixic acid,Pefloxacin,Norfloxacin, Ofloxacin in paediatric cystic fibrosis, no arthropathy was observed.
Similarly the use of Norfloxacin, Trovafloxacin, and Ciprofloxacin in shigellosis, Salmanellosis, Meningococcal meningitis showed in incidence of arthropathy in paediatric group. Trovafloxacin, Gatifloxacin, Clinafloxacin, and Moxifloxacin appears more promising for paediatric use.
Further studies are planned in selected paediatric age groups with quinolones before concluding for official use of quinolones (except those already approved) in paediatric infections.
Tendinopthy: In 1991 Flouroquinolone associated Tendinopathy and tendon rupture have been reported. More than 1000 cases of quinolone induced tendinitis have been reported as per French surveillance in 1997. Clinically manifested as congestion and /or inflammation and oedema of tendon leading to pain and swelling and in more than 50% of cases it was bilateral and then tendon ruptures. 400 cases with in 18 months of treatment with Ofloxacin, Norfloxacin, Ciprofloxacin and Pefloxacin. In more than 70% patients aged 60yrs or above and in 10% of patients receiving concurrent steroid medication. Achilles tendon rupture reported to have occurred 120 days after the start of treatment and can occur even after withdrawal of the drug. Pathologically there was ultrastructure alteration in tendinocytes. In animals ,Mg deficiency aggravated tendinopathy.
. Interact with
. Interact with
X Warfarin = enhanced anticoagulation
X H2 Antagonists =
X Cyclosporin = toxicity
X Rifampicins = decreases serum concentration of quinolone
X Insulin & oral hypoglycemics = hypoglycemia.
Once /day alatrovafloxacin/Trovafloxacin
IV to oral treatment is clinically effective as twice/day IV to oral
ciprofloxacin for treatment of nosocomial infections with no additional