FQ: MOA, specturm, resistance, classification, therapeutic uses and individual drug discussion.

1. Dr. kiran G.piparva
Assistant professor, Pharmacology
department
P
. D. U. Government medical
college, Rajkot

2. Contents……
• Introduction
• Chemical structure
• Classification
• Antibacterial spectrum
• Mechanism of action
• Mechanism of resistance
• Individual drugs

3. • Synthetic antimicrobial agent
• Having quinolone structure
• Primarily active against gram negative
bacteria
• First member is NALIDIXIC ACID

4. Breakthrough 1980-
• Fluorination of quinolone
structure at 6th position and
addition of piperazine at 7th
position resulting derivative
called-
“FLUROQUINOLONES”

5. Development of FQs……
• 1960s – Nalidixic acid
• 1970s – Cinoxacin and Rosoxcin
• 1980s – Norfloxacin , Ciprofloxacin, Ofloxacin
• 1990s – Lomefloxacin, Sparfloxacin
• 2000s – Lovofloxacin, Gatifloxacin, Trovafloxacin , Moxifloxacin,
Gemifloxacin

6. FQs
First
generation
One FLUORO
substitution
Effective against
gram-ve organism
Second
generation
- ADDITIONAL
FLUORO and other
substitutions ..
Antimicrobial
spectrum extendto gram
+ve and anaerobes

7. FQs
First generation
Norfloxacin,
Ciprofloxacin
Pefloxacin
Ofloxacin
Second generation
Levofloxacin,
Lomefloxacin
Sparfloxacin
Gemifloxacin
Moxifloxacin
prulifloxacin
Pazufloxacin and Balofloxacin in india

8. Bacterial DNA gyrase
Subunit B
Subunit A
Site of action
Mechanism of action of FQ….
Positive supercoiling
Negative supercoiling

9. Mechanism of action of FQ
Gram -ve Gram +ve

10.  Less likely & very slow to
develop
 Reduced permeability
 Increased efflux
 Chromosomal mutation
producing a DNA gyrase/
topoisomerase IV with
reduced affinity for FQs.
Mechanism of Resistant

11. •For individual drugs… DIFFERENCES….
• Antimicrobial spectrum
• Pharmacokinetic profile
• ADR

12. CIPROFLOXACIN (prototype)
• Most potent 1st generation FQ
• Spectrum :
• Aerobic gram – ve bacilli-
Enterobacteriaceae and Neisseria

13. Antibiotic spectrum
 Higley susceptible
Gram -ve bacilli Gram -ve cocci
-E.Coli - Neisseria
-Salmonella -H. influenzae
-Shigella -H, ducreyi
-Proteus -Compylobector
- K. pneumoniae jejuni
 Moderately susceptible
-Atypical organisms
-Pseudomonas aeruginosa
- Anthracis
- Brucella
- Chlamydia pneumophila
- Listeria
- Mycoplasma
- Mycobacterium
- Staph epidermidis
Low or variable
susceptibility (gm+Ve)
- Strep. Pyrogens
- Strep. Faecalis
- Strep. Pneumoniae
- MRSA
- Mycobact. Kansasii
- MAC
RESISTANT : ANAEROBES

14. Pharmacokinetics
• Absorption: good with empty
stomach
• Good tissue penetrability
• Renal excretion : required dose
reduction in kidney damage

15. ADR of FQ…
• Good safety record…..Mild ADRs
• GIT: N/V/A, bad taste
• CNS: Dizziness, headache, restlessness,
anxiety, insomnia, impairment of
concentration, dexterity- seizure when high
dose or predisposing factors
• HST: hypersensitivity reaction- rash pruritis,
photosensitivity, urticaria, swellings.
• Tendonitis and tendon rupture: higher in age
above 60yrs, patients receiving corticosteroids.
Children, seizure,
photosensitivity
While driving
C/I : pregnancy

16. Drug Interactions
• Absorption: Other drugs reduce absorption of FQs : Antacids,
sucralfate and iron salts
• Norfox/ ciproflox/ pefloxacin raises theophylline, caffeine and warfarin
concentration – Second generation are safe
• NSAIDs may enhance the CNS toxicity of FQs; seizures are reported

17. Important features of FQs………
Bactericidal
Rapid action
Post antibiotic effect
Mutational resistance is low
Susceptible to Penicillin , cephalosporin, aminoglycoside resistant
bacteria
Activity is pH dependent – reduced activity at acidic pH

18. Therapeutic uses of FQs…..
• Ciprofloxacin is highly effective because…..
 Wide spectrum
 Bactericidal activity
 Oral efficacy
 Good tolerability
 Best for gram –ve infections

EMPIRICAL THERAPY
DOSE:

19. Gram negative
infections
Urinary track infection
Bacterial gastroenteritis
Typhoid fever
Bone & soft tissue, gynecological and
wound infection
Gram negative septicemia
Conjunctivitis
Gonorrhoea
Meningitis

20. • Other infections:
• Chancroid
• Anthrax
• Respiratory infection
• Tuberculosis
• Prophylaxis

21. Therapeutic uses…….
1. Urinary tract infection(UTI)
• FQ are superior to Trimethoprim-sulfamethoxazole
• Good concentration in urine
• High cure rate even in complicated UTI
• All FQ are equally effective
2. Bacterial gastroenteritis:
Empirical therapy- most common
3. Gonorrhoea: 100% curative in PPNG/ NPPNG- not used now
4. Bone soft tissue, gynaecological and wound infection:
high cure rate is obtained with prolonged Rx (6-8wk) with high dose
(750mgBD)

22. 5. Typhoid fever
• First line drugs
• Ciprofloxacin is the drug of choice
• 750mg BD orally or 200mg I.V. 12 hrly for 10-14 days
Other options:
• Ceftriaxone: fastest acting bactericidal, prevent relapse and carrier state,
preferred over FQs in children, pregnant women & FQ resistant cases
• Fluroquinolones: equally efficacious alternative ceftriaxone
• Azithromycin: 2nd line alternative in multidrug resistant typhoid
• Chloramphenicol: Resistant and unreliable
• Cotrimoxazole: Resistant, rarely used.

23. 6. Respiratory infections
• Not as primary drug
• DOC only for Atypical pneumonia due to Mycoplasma, legionella, H.
influenzas, Chlamydia pneumonia
• 2nd generation (Levofloxacin/ Gemifloxacin/ Moxifloxacin) – used
7. Tuberculosis
• Moxifloxacin/ levofloxacin : 2nd line antitubercular drug & for combination drugs
in MDR TB
• Ciprofloxacin most active against MAC
8. Meningitis: Only for gm –ve bacterial meningitis especially in
immunocompromised patients

24. Properties of 1st generation FQs
• No activity against S. Pneumoniae & anaerobes
• No significant CNS concentration
• Short action – twice daily dosing
• DI: Raises warfarin and theophylline concentration
Common to
Ciproflox/
Oflox /
Pefloxacin

25. Properties of 2nd generation FQs
• Spectrum: Active against Gm +ve bacteria & anaerobes
• PK: Longer action – OD- good compliance
• CNS concentration is poor
• NO DI: Levoflox/ sparflox do not interact with warfarin and
theophylline
• ADR:
• Prolongs QT interval/ Phototoxicity –
sparflox/gatiflox/moxiflox/gemiflox

26. • Pefloxacin:
• Better PK- lipid soluble, long t1/2- better CSF concentration
• Metabolized to norfloxacin- dose adjustment required in
liver disease but NOT in renal insufficiency
• Ofloxacin:
• More active on strep. Pyogenes and gram+ve / anaerobes, chlamydia,
Mycoplasma, mycobacterium
• MDR TB: Alternative therapy for multidrug resistant tuberculosis

27. • Levofloxacin
• Levo isomer of ofloxacin
- Good PK- 100% bioavailability orally – long half life- OD- NO Drug
interaction
- Primary indication:
- CAP- community acquired pneumonia, pyelonephritis, prostatis, skin/ soft
tissue infection
- MDR TB : 2nd line antitubercular drug- combined regimen for MDR TB
• Moxifloxacin:
• MDR TB : Most potent against M. tuberculosis- used in MDR TB
• Should not given to predisposed to seizure- QT prolongation
2nd generation FQs

28. • Sparfloxacin:
• 2nd generation difluorinated quinolones
• Phototoxic, QT prolongation
• Lomefloxacin
• 2nd generation difluorinated - higher
phototoxicity- Q-T prolongation
• Gemifloxacin:
• Broad spectrum/ aerobic/ resistant orgasnim
• QT prolongation, DI
QT
PROLONGATION,
PHTOTOXICITY

29. • Prulifloxacin
Prodrug- Good spectrum- Good PK
NO QT - PROLONGATION
• Pazufloxacin:
• Only injectable formulation as “ Mesylate”
• Rarely seizure- limit dose
• Balofloxacin
• Marketed only in India and few other countries

30. HEPATIC
HEPATIC

31. Pharmacokinetics
Absorption Distribution Metabolism Elimination
Ciprofloxacin is
well absorbed on
empty stomach
F= 70-95% except
norfloxacin – 40%
Excellent tissue
penetration (lungs,
sputum, prostate ,
muscle, bone)
Poor penetration in
brain and eyes
Pefloxacin and
Moxifloxacin ,
Trovafloxacin are
metabolised by
liver- require dose
reduction in hepatic
dysfunction (PMT)
Most Quinolones are
cleared by kidney -
require dose
reduction in renal
dysfunction
• Clinically significant post antibiotic effect (2-6 hours)
• Sparfloxacin has longest action (18-20 hrs)
• 1st generation drugs given twice a day –
• 2nd generation drugs once only

32. Some withdrawn FQs
• Gatifloxacin – Dysglycemia
• Lomiflxacin/ sparfloxacin – photosensitivity & QT prolongation
• Trovafloxacin – Hepatotoxicity
• Grepafloxacin – Cardiotoxicity