FLURO QUINOLONESfor MBBS studentsppt.ppt

medical

1. FLUOROQUINOLONES

2. COMPETENCY &
SPECIFIC LEARNING
OBJECTIVES
•COMPETENCY -PH1.42, PH1.43
The student should able to
Describe the Antibacterial spectrum, MOA,
resistance, Uses & adverse effects of
Fluoroquinolones

3. SPECIFIC LEARNING OBJECTIVES
At the end of the class, the student should able
to:
•Classify Fluoroquinolones (FQ) with examples.
•Describe the mechanism, spectrum, resistance and
pharmacokinetics of FQ.
•Describe the clinical uses, adverse effects, interactions
and contraindications of FQ.
•Compare and contrast between I & II generation FQ

4. Quinolones –accidental discovery
Quinine
Chloroquine
Mefloquine
Quinolones
1960’s
GEORGE LESHER & Co workers
Distillate of chloroquine

5. QUINOLONES
SYNTHETIC ANTIMICROBIALS
QUINOLONE STRUCTURE
GRAM NEGATIVE BACTERIA
FLUORINATED COMPOUNDS –ALSO GRAM
POSTIVE ONES.

6. NN
O
H
3C
CH
3
COOH
Nalidixic acid N
NH
N
F
O
CH
3
CO
2
H
Norfloxacin - Noroxin
® Ciprofloxacin - Cipro
®
N
NH
N
F
O
CO
2
H STRUCTURE

7. NALIDIXIC ACID
SPECTRUM –Gram negative bacteria.
E. Coli, proteus, klebsiella,
Enetrobacter, Shigella.
BACTERICIDAL DRUG
metabolism –liver
t
1/2 –8 hours.
excretion –urine.
1.Resistance –rapid
2.Potency –low
3.Spectrum –limited
4.Resistance –high
5.For gi&urinary
infections
6.Tissue levels -low
HIGH CONCENTRATION –URINE ( 20 –50 TIMES)

8. ADVERSE EFFECTS
GIT, rashes.
Neurological –headache, drowsiness, vertigo, visual
disturbances, seizures.
Long term use –Parkinsonism like symptoms.
Leucopenia, biliarystasis.
Phototoxicity-Rare
G
6PD deficiency –Hemolysis.
C/I -INFANTS.

9. USES
URINARY ANTISEPTIC.
DIARRHOEA –proteus, E.coli, shigella, salmonella.
Ampicillinresistant shigellaenteritis.

10. FLUROQUINOLONES
Quinoloneswith one or more substitutions.
I Generation -1980
II Generation -1990N
NH
N
F
O
CH
3
CO
2
H
Norfloxacin - Noroxin
® Ciprofloxacin - Cipro
®
N
NH
N
F
O
CO
2
H

11. Quinolones
Fluoroquinolone
(1970’s)
-Fluorine addition at C 6
-increased activity against
the DNA gyrase
-increased penetration into
the bacterial cell
Ciprofloxacinintroduced
Piperazinegroup was added to C-7
Improved gram -ve& +vecoverage
Better serum and tissue levels
1
st
quinoloneto be used for
conditions other then UTI’s
1987

12. FLUROQUINOLONES
INorfloxacin II Lomefloxacin
Ciprofloxacin Sparfloxacin
Ofloxacin Levofloxacin
Pefloxacin Moxifloxacin
Gatifloxacin
III Gemifloxacin
Plurifloxacin
Sitafloxacin,
Pazufloxacin
Balofloxacin

13. MECHANISM OF ACTION
Inhibit
DNA gyrase
DNA TopoisomeraseIV

14. DNA gyrase
MECHANISM OF ACTION

15. Fluoroquinolone: Mechanism of Action
Cell Wall
Cell Membrane
DNA Gyrase
DNA Topoisomerase IV
fq
fq
fq
fq
fq
fq
fq
Fluoroquinolone
DNA
Excessive positive
supercoiliing
DNA
digestion

16. MECHANISM OF ACTION
DNA gyraseNicks double stranded DNA.
Introduce negative supercoils.
Reseals the nicked ends.
Prevents excessive positive supercoiling
RESISTANCE
MUTATION OF DNA gyrase-Reduce affinity to FQs.
Reduced permeability of drugs

17. Efflux Pump
Chrosomal
mutation
Resistance to
FQ
Altered DNA gyrase
Altered
TopoisomeraseIV

18. CIPROFLOXACIN
MOST POTENT DRUG
Aerobic gram negative bacilli
Enterobactericeae
Neisseria
HIGHLY SUSCEPTIBLE
E. Coli Neisseria
K. Pneumoniae H. influenza
Enterobacter H. ducreyi
S. Typhi& other salmonella C.jejuni
Shigella Y. enterocolitica
Proteus. V. cholerae

19. MODERATIVELY SENSITIVE
Pseudomonas
S. Aureus( MRSA)
S. Epidermidis
branhemellacatarrhalis
legionalla
Brucella
Listeria
Mycobact. Tuberculosis
LOW
S. Pyogens. Faecalis,
mycoplasma
Clamydia
Mycobact. Kansasii/ avium

20. SPECIAL FEATURES
Rapid bactericidal activity
High potency
Long post –antibiotic effect
Mutational resistance –Low frequency
Plasmid type mutants –Low
Intestinal streptococci & anaerobes –Protected.
Against βlactam& aminoglycosideresistant bacteria
Acidic pH -Less active

21. RESISTANCE
Bacteroids
Clostridia
Anaerobic cocci.

22. PHARMACOKINETICS
Oral absorption good. food delays absorption.
High tissue penetrability
Lung, sputum, muscle, bone, prostate & phagocytes
concentration –high.
Excretion –glomerularfiltration, tubular secretion.
Urinary / biliaryconcentration -10-50 fold more

23. ADVERSE EFFECTS
safety -good.
GIT -Nausea, vomiting, bad taste, anorexia.
CNS -Headache, dizziness, restlessness, anxiety, insomnia,
impairementof concentration & dexterity, tremor.
Seizures –rare. (?GABA RECEPTOR binding)
Skin -Rash, pruritis, photosensitivity, urticaria, swelling of
lips etc.,
Tendonitis & tendon rupture.
bothers

24. C/I –PREGNANCY
ARTHROPATHY --IMMATURE ANIMALS
CARTILAGE DAMAGE (?)
Drug interactions
Inhibits metabolism –Theophylline(CYP 450 1A2)
Caffeine
Warfarin
NSAIDS enhance fluroquinolonestoxicity
Antacids, sucralfate, Iron salts –Reduce absorption of FQs.

25. THERAPEUTIC USES
(1)UTI –complicated / uncomplicated
-High cure rates.
(2) Chancroid-500 mg BD x 3 days.
(3) Gonorrhoea-500mg single dose.
(4) Bacterial gastroenteritis –E.Coli
Shigella
Salmonella
C. Jejuni
Travellorsdiarrhoea(ETEC)
Decrease stool volume –Cholera.

26. (5)TYPHOID -1st drug of choice.
500 mg –750 mg BD x 10 days.
(or)
200 mg IV BD.
advantages (1) quick defervescence
(2) Relief of symptoms early.
Complications, relapse –low
(3) Prevention of carrier state
Cidalaction
good penetration
biliary/ Intestinal concentration.
For typhoid carriers. 750 mg BD –4-8weeks.
92% Eradication.

27. (6) Bone, soft tissue, gynaecological& wound infections –by
resistant staphlococci.
Gram negative bacteria.
+ metronidazole/ clindamycin--Diabetic foot.
(7) Respiratory infections.
Mycoplasma
Legionella
B. catarrhalis
Inhalational anthrax -US FDA
Tuleremia.

28. (8) Tuberculosis -Combination therapy
-Resistant TB.
(9) Gram negative septicaemias.
Ciprofloxacin + III gen. cephalsporin/Aminoglycoside.
(10) Meningitis-gram negative organisms
Immunocompromised.
CSF shunts.
(11) Prophylaxis –Neutropenia/ cancer patients.
(12)Conjunctivitis –Gram negative bacteria.
Topical therapy

29. NORFLOXACIN
Less protentthan ciprofloxacin
Use –Urinary / genital tract infections.
Bacterial diarrhoeas.
PEFLOXACIN
Methyl derivative of norfloxacin.
More lipid soluble.
Oral –complete absorption.
High CSF concentration.
T
1/2 –long.
Alternative to ciprofloxacin in typhoid.

30. OFLOXACIN
Intermediate between ciprofloxacin & norfloxacin.
More portent than cipro-gram positive & anaerobes.
Chlamydia, mycoplasma.

31. PK –Lipid soluble
Plasma concentration –High.
Excretion –Urine ( unchanged)
Use –Systemic & mixed infections.
For chronic bronchitis.
Respiratory / ENT infections.
Gonorrhoea–200mg single dose.
Non gonococcalurethritis/ cervicitis.
TB / leprosy.

32. Levoisomer
More activity –strep. pneumonia.
-Gm + ve& Gm -ve
TB, Anaerobes.
OBA –100% single dose.500 mg oral
For community acquired pneumonia.
Exacerbation of chronic bronchitis.
Sinusitis.
Enteric fever.
Pyelonephritis.
Skin & soft tissue infection.
LEVOFLOXACIN
Difluronatedquinolone
Equal to Ciprofloxacin
More active against gram negative
bacteria & Chlamydia.
T
1/2 –long, single dose.
Dose –400mg 0.3% eye drops.
Phototoxicity
QTcprolongation
LOMEFLOXACIN

33. Increased activity –gram positive
bacteroidefragilis&
anaerobes,mycobacteria.
Phototoxic reactions
Slight prolongation of QTcinterval -3%
Dose : 200, 400 mg single dose
0.3% eye drops.
• pneomonia
• Exacerbations of chronic bronchitis
• Sinusitis / ENT infections
• Tuberculosis / leprosy
• MAC infection –AIDS patients
• Chlamydialinfections
SPARFLOXACIN
Str.pnemonia
Atypical respiratory pathogens
Anaerobes
Myco. Tuberculosis
QTcprolongation.
swelling of face.
•Community acquired pneumonia.
•Exacerbation of chronic bronchitis.
•other URI/LRI.
GATIFLOXACIN

34. MOXIFLOXACIN
Long activity drug
High activity –St. pneumoniae
Other gram positive ones
some anaerobes
TB –most potent.
Use –Pneumonia.
Bronchitis.
Sinusitis
Otitismedia
Dose –400 mg OD 0.5% eye drops.

35. CIPRO NORFL PEFL OFL
1.Oral bioavailability (%) 60-80 35-45 90-100 85-95
2. Plasma protein binding (%) 20-35 15 20-30 25
3. Vol. of distribution (L/kg) 3-4 2 2 1.5
4. Percent metabolized 20 25 85 5-10
5. Elimination t
1/2 3-5 4-6 8-14 5-8
6. Routes of administration oral, i.v. oral oral, i.v. oral
7. Dose (mg BD) oral: 250-750 400 400 200-400
iv : 100-200 - 400 200

36. LEVO LOME SPAR GATI
1.Oral bioavailability (%) ~100 >90 90 96
2. Plasma protein binding (%) 25 10 40 20
3. Vol. of distribution (L/kg) 1.3 1.7-2.5 3.6 -
4. Percent metabolized 5 20 60 <5
5. Elimination t1/2 8 6-9 15-20 8
6. Routes of administration oral,i.v. oral oraloral,i.v.
7. Dose (mg BD) oral: 500 400 200-400 200-400
(OD) (OD) (OD) (OD)
iv : 500 - - 200-400