1. DNA gyrase inhibitors Quinolones
Dr. Naza M. Ali Lec

3. DNA gyrase inhibitors Quinolones
Fluoroquinolones are classified by generation
All the fluoroquinolones are bactericidal.
Like aminoglycosides, the quinolones exhibit
Post antibiotic effects.

4. Mechanism of action
The fluoroquinolones enter the bacterium by passive
diffusion
Once inside the cell, they inhibit the replication of
bacterial DNA
by interfering with the action of DNA gyrase
(topoisomerase II) and topoisomerase IV during
bacterial growth and reproduction.

5. Topoisomerases are enzymes that change
configuration or topology of DNA
Inhibition of the DNA gyrase prevent relaxation of
supercoiled DNA that is required for normal
transcription & replication.
Inhibition of topoisomerase IV interferes with
separation of replicated chromosomal DNA into
respective daughter cells during cell division.

6. In gram-negative organisms ( Escherichia coli) the inhibition of DNA gyrase is more significant than that of topoisomerase IV
Whereas in gram-positive organisms ( streptococci), the opposite is true.

23. Resistance Two mechanism of resistance 1)Altered target:
mutations in bacterial DNA gyrase & Topoisomerase IV
2)Decreased accumulation:
reduced intracellular concentration of the drugs by:
decreased number of porin proteins in the outer membrane of the bacterial cell.
other mechanism is associated an energy-dependent efflux system in cell membrane.

24. DNA gyrase inhibitors Quinolones
Dr. Naza M. Ali Lec

25. Classification
Fluoroquinolones classified into generations based on their antimicrobial targets.
First generation:
Narrow spectrum of susceptible organisms in UTI.
Nonfluorinated
Example: Nalidixic acid
Norfloxacin

26. Second generation:
Greater activity against aerobic gram-negative,
many gram posittive cocci & atypical bacteria,
Psudomounus aeruginosa
Example: Ciprofloxacin
Ofloxacin

27. Third generation:
Have greater activity against gram-positive bacteria
Its less activity against gram-negative
Has excellent activity against Streptococcus pneumoniae
Example: Levofloxacin ( Respiratory floroquinolon)

28. Fourth generation: Are the broadest spectrum fluoroquinolones
with enhanced activity against anaerobic as well as
gm +ve organisms.
Example: Moxifloxacin, ( nonrenal)
Gemifloxacin ( Renal and nonrenal)

29. Antibacterial spectrum
Generation
Antibacterial spectrum
Example
First
narrow spectrum in UTI, -ve gm
Nalidixic acid, Norfloxacin
Second
greater activity for aerobic gram -ve ,
gram + cocci,
Chlamydia,
Mycoplasma
Ciprofloxacin, Ofloxacin
Third
have greater activity against gram + ve,
less activity against gram-negative ,
excellent activity against S. pneumoniae
Levofloxacin
Fourth
broadest spectrum
enhanced activity against anaerobic
& gm +ve
Moxifloxacin, Gemifloxacin

30. Clinical use Norfloxacin
It is effective in treating nonsystemic infections
(urinary tract infections).

31. Ciprofloxacin The serum levels of ciprofloxacin are effective against
many systemic infections
1. Enterobacteriaceae and other gram-negative bacilli.
For example, traveler’s diarrhea caused by E. coli
2. Pseudomonas aeruginosa it is used for pseudomonal infections associated with cystic fibrosis.
3. Treating resistant tuberculosis.
4. Treat typhoid fever
5. Drug of choice for prophylaxis & treatment of anthrax

32. Levofloxacin ( is L- isomer of ofloxacin)
1. Treatment of prostatitis
2. Treatment of sexually transmitted diseases
as alternative therapy in gonorrhea
3. in skin infections
4. Chronic bronchitis, acute sinusitis
community-acquired pneumonia.

33. Pharmacokinetics They have good oral bioavailability & penetrate most
body tissue
Ingestion of fluoroquinolones with sucralfate,
antacids( Al, Mg , iron , zinc ) interfere with absorption
Calcium and other divalent cations interfere with
the absorption of these agents.

35. Elimination is through the kidney by active tubular
secretion & dosage reduction in renal dysfunction.
Moxifloxacin are eliminated partly by hepatic
metabolism and by biliary excretion.

36. Adverse reactions Gastrointestinal: NVD
2. CNS problems in epileptic patient
3. Phototoxicity : Patient are avoid excessive sunlight.

37. 4. Connective tissue problems: should be avoided in pregnancy, in nursing mothers, and in children under 18 years of age, because articular cartilage erosion occur in animal. FDA added to Black Box warning about increase risk of Tendinitis or tendon rupture with systemic use and may damage growing cartilage

39. Contraindications:
Moxifloxacin prolong the QTc interval , should not
be used in patient taking antiarrhythmic medications.
Drug interactions:
Ciprofloxacin & ofloxacin can increase the serum
levels of theophylline by inhibiting its metabolism
raise the serum levels of warfarin, caffeine,
cyclosporine.