Quinolones

1. QUINOLONES
Past …… Present and Future

2. Background
In 1962 nalidixic acid was discovered by George
lesher during synthesis of chloroquine and was
named as quinolone
Fluoroquinolones were derived by adding flourine
atom in nalidixic acid.
Earlier quinolones were useful only for treatment of
UTI.
Nalidixic acid was added to the OEHHA Prop 65 list
as a carcinogen on 15 May 1998.

3. • Fluorinated derivatives achieve
bactericidal levels in blood and tissues so
they have improved antibacterial
spectrum.
Synthetic antimicrobials
Bactericidal
Primarily gram negative bacteria
Bactericidal
antibiotic

4. Bactericidal vs. bacteriostatic
• Bactericidal compounds - kill
microorganisms
• Bacteriostatic compounds - inhibit or slow
growth

5. Bactericidal vs. bacteriostatic

6. Time dependent vs
Concentration dependent
• Time dependant AB
• whose killing respone depend on time
• Optimum killing response when time that ab
remains above Mic >or= dosing interval
• Eg .cephalosporins, pencillins, macrolides,
clindamycin

7. Time dependent vs
Concentration dependent
• Con.dependant AB
• Eradicate bacteria by achieveing high conc
at binding site
• Optimum killing response when Ab conc is
10 times higher than Mic
• Eg .quinolones& aminoglcosides

8. MECHANISM OF ACTION
They block bacterial DNA synthesis by
inhibiting bacterial DNA gyrase and
topoisomerase IV.
Inhibition of DNA gyrase prevents the
relaxation of supercoiled DNA that is
required for normal transcription and
replication

9. MECHANISM OF ACTION
• Inhibition of topoisomeraseIV interferes with
separation of replicated chromosomal DNA into
the respective daughter cells during cell division.
• In gram- bacteria, DNA gyrase is the primary
target.
• In gram + bacteria, topoisomerase IV is the
primary target (newer quinolones).

10. Quinolones

11. Pharmacokinectics
• Well absorbed orally with bioavailability 85-95%
almost equal to i.v.
• Half life 1.5-16 hours, cipro 3-5.4 h
• Oral absorption impaired by divalent
cations(Antacids containg Mg, Ca,or AL ).
• Most of fluoroquinolones eleminated by renal
mechanism so adjustment required in patients with
creatinine clearance <50 ml/min.
• Limited CSF penetration.(except Ofloxacin)

12. Pharmacokinectics
• Rapidly absorbed from the GI tract.
• Protien binding 10-40%
• Newer FQ’s have longer serum half-lives than
ciprofloxacin allowing for once daily dosing.
• Due to sickle-cell disease patients' being at
increased risk for developing osteomyelitis from
the Salmonella genus, fluoroquinolones are the
"drugs of choice" due to their ability to enter
bone tissue without chelating it, as
tetracyclines are known to do

13. Pharmacokinectics
• Urinary & biliary concentrations are 10-50 fold higher
than in plasma.
• Dose adjustments in patients with renal
insufficiency are required for cinoxacin, norfloxacin,
ciprofloxacin, ofloxacin, enoxacin, and lomefloxacin
but not for nalidixic acid, grepafloxacin, trovafloxacin,
and pefloxacin.
• A fluoroquinolone other than trovafloxacin,
grepafloxacin, or pefloxacin should be used in
patients with hepatic failure.(Metabolized by liver)

14. Adverse effects.
Gastrointestinal Nausa,vomitting,diarrhea
3-6% of patients
CNS Headache , Dizziness , patients of
Epilipssy
Photo-toxicity Avoid direct sun light.
Connective tissue Tendon ruptur & Articular
cartilage Erosion
Cardiovascular Prolong QTC interval
esp.Moxifloxacin

16. CONTRAINDICATIONS
• Children less than 18 years old and
pregnant or nursing women.
• A patient has epilepsy, QT prolongation,
pre-existing CNS lesions, or CNS
inflammation, or the patient has suffered a
stroke
• They are best avoided in the athlete
population

17. CONTRAINDICATIONS
• However, one meta-analysis looking at the
outcome of pregnancies involving quinolone
use in the first trimester found no increased
risk of malformations
• Their use in children is not absolutely
contraindicated, In the UK, is severely
restricted. Only inhalant anthrax and
pseudomonal infections in cystic fibrosis

18. • cystic fibrosis a hereditary disorder affecting the
exocrine glands. It causes the production of abnormally
thick mucus, leading to the blockage of the pancreatic
ducts, intestines, and bronchi and often resulting in
respiratory infection.
• American Academy of Pediatrics state that the use of
fluoroquinolines in children may be appropriate when the
infection is caused by multidrug-resistant bacteria, or
when alternative treatment options require parenteral
administration and oral therapy is preferred.

19. QT interval
• prolong the heart's QT interval by blocking
voltage-gated potassium channels lead to
a life-threatening arrhythmia,
• But in practice this appears relatively
uncommon in part because the most widely
prescribed fluoroquinolones (ciprofloxacin
and levofloxacin) only minimally prolong
the QT interval

20. Tendon rupture
• tendon rupture in patients treated with
ciprofloxacin or levofloxacin has been
estimated at 17 per 100,000 treatments
• Risk is substantially elevated in the elderly
and in those with recent exposure to
topical or systemic corticosteroid
therapy.

21. Antibiotic misuse and
bacterial resistances
• Fluoroquinolones had become the most commonly
prescribed class of antibiotics to adults in 2002.
Nearly half (42%) of these prescriptions were for
conditions not approved by the FDA, such as
acute bronchitis, otitis media, and acute upper
respiratory tract infection, according to a study
supported in part by the
Agency for Healthcare Research and Quality
• In addition, they are commonly prescribed for medical
conditions, such as acute respiratory illness, that are
usually caused by viral infections

22. RESISTANCE
• Efflux pumps can act to decrease
intracellular quinolone concentration.
• In Gram-negative bacteria, plasmid-
mediated resistance genes produce
proteins that can bind to DNA gyrase,
protecting it from the action of
quinolones.
• Mutations at key sites in DNA gyrase or
topoisomerase IV can decrease their

23. Efflux pumps

24. Generations
Drugs Spectrum
1st
(Quinolone)
Nalidixic acid
Cinoxacin
Gram-ve but not
Pseudomonas species
2nd
Norfloxacin
Ciprofloxacin
Enoxacin
Ofloxacin
Gram- ve(including
Pseudomonas species),
some Gram+ (S.
aureus) and some
atypicals
3rd
Levofloxacin
Sparfloxacin
Moxifloxacin
Gemifloxacin
Same as 2nd
generation
with extended Gram+ve
and atypical coverage
4th
*Trovafloxacin Same as 3rd
generation
with broad anaerobic
coverage

25. In development
• delafloxacin — an anionic fluoroquinoline
in clinical trials
• JNJ-Q2 — completed Phase II for MRSA
• Nemonoxacin
• MRSA methicillin-resistant
Staphylococcus aureus , a bacterium with
antibiotic resistance.