QUINOLONES

Dr. Pushpalatha C.
MBBS (OMC), MD (OMC)
Professor & Head
Department of Pharmacology
 QUINOLONES

• Entirely synthetic antimicrobials

• Presence of quinolone structure
• Bactericidal
• More active against gram –ve than gram +ve
bacteria
 CLASSIFICATION
QUINOLONES
- Nalidixic acid
FLUOROQUINOLONES (FQs)
• First generation
- Ciprofloxacin - Pefloxacin
- Norfloxacin - Ofloxacin
• Second generation
- Levofloxacin - Prulifloxacin - Gemifloxacin
- Lomefloxacin - Moxifloxacin - Trovafloxacin
- Gatifloxacin - Sparfloxacin
Nalidixic acid
– First quinolone
– Usefulness limited to only lower UTI due to:
• Low potency
• Modest blood & tissue levels
• Systemic antibacterial levels can only be
achieved at the cost of toxicity
• Limited antibacterial spectrum
• ↑ bacterial resistance
Quinolone structure Fluoroquinolones
• At position 6 – Flourination
• At position 7 – Piperazine moiety
• At position 3 – Corboxilic acid
• Highly potent
• Long post-antibiotic effect
• Rapid bactericidal action
• Broad antimicrobial spectrum
• Protective intestinal Streptococci
& Aaerobes are spared
• Slow development of resistance
• Active against β-lactam &
aminoglycoside resistant bacteria
• Relatively safe
 Mechanism of action of
Quinolones/Fluoroquinolones
Mechanism of action
• Inhibit DNA gyrase enzyme in gram –ve and
Topoisomerase IV enzyme in gram +ve bacteria
→ Bactericidal effect
• In gram –ve organisms – Bind to & inhibit
bacterial DNA gyrase enzyme (A subunit) →
inhibit DNA replication or transcription
– DNA gyrase composed of 2 subunits
• A subunit – nicks & reseals DNA strand
• B subunit – introduces negative supercoils
• In gram +ve organisms – Inhibit topoisomerase
IV → inhibit separation of daughter DNA strands
after replication
• Bactericidal action – Due to digestion of DNA –
by exonucleases produced by damaged DNA
• Produce concentration-dependent & time-
dependent antibacterial effect
Mechanism of resistance
• Mutation in bacterial Chromosomal gene
encoding DNA gyrase or topoisomerase IV –
decreased affinity for fluoroquinolones
• Active transport of drug out of bacteria (efflux
mechanism)
Mechanism of action and Resistance
video clip

Fluoroquinolones Mechanisms of Action and Resistance clip.mp4

 FLUOROQUINOLONES
Antibacterial spectrum
– E. coli
– Salmonella
– Shigella
– Campylobacter
– Enterobacter
– Neisseria
– P. aeruginosa (Ciprofloxacin > Norfloxacin)
– Staphylococci
• Also effective against
- Streptococci (levofloxacin, gatifloxacin &
moxifloxacin)
- Legionella - Chlamydia
- Brucella - Mycoplasma
- Mycobacterium
- Anaerobic bacteria (gemifloxacin & several other FQs)
Pharmacokinetics
• Oral admn. – well absorption
• Vd – high (Widely distributed in tissues)
• Serum t ½ - 3-5 hrs.
• Conc. higher than serum conc. found in – urine,
kidney, lung, prostate tissue, stool, bile,
macrophages & neutrophils
• Conc. lower than serum conc. found in – CSF,
bone & prostatic fluid
• Secreted in milk (Ciprofloxacin, Ofloxacin &
Pefloxacin)
• Excretion – Mainly through Kidneys (dose should
be adjusted in renal failure)
• Metabolism – Predominantly through liver
(Pefloxacin & Moxifloxacin - C/I in hepatic
failure)
Therapeutic uses
1.Urinary tract infection
– Norfloxacin & Ciprofloxacin approved for UTI
– Nalidixic acid – only in UTI with susceptible organisms
2.Prostatitis
– Norfloxacin, Ciprofloxacin & Ofloxacin – for 4-6 wks
effective in pts. not responding to Cotrimoxazole
3.Sexually transmitted disease
– Chlamydial urethritis/cervicitis – Ofloxacin for 7 days
– N. gonorrhoeae – Ofloxacn/Ciprofloxacin single oral
dose (resistance develops usually)
– Chancroid – Ciprofloxacin for 3 days
4. GI & abdominal infections
– Traveller’s diarrhea (E. coli) – FQs as effective as
Cotrimoxazole
– Shigellosis – Ciprofloxacin/Norfloxacin/Ofloxacin
– Diarrhea due to Salmonella & Cholera – Norfloxacin
5. Typhoid fever
– Ciprofloxacin – reduces symptoms quickly, low
incidence of complications and relapse & prevents
carrier state
6. Respiratory tract infection
– In upper & lower RTI – Ciprofloxacin/Lovafloxacin
– Pneumonia & Chronic bronchitis – 2nd gen. FQs
7. Meningitis (Gram –ve) in immunocompromised pts.
8. Bone, joint & soft tissue infections
– Osteomyelitis & joint inf. – Prolonged Rx with high dose
– Diabetic foot – FQ in combination with other drugs
9. Anthrax
– For prophylaxis & treatment
10. Tuberculosis (Multidrug-resistant)
– As part of multiple-drug regimens
11. leprosy
12. Mycobacterium avium complex infection in AIDS
13. In neutropenic pts. – to ↓gram –ve rod infections
14. Bacterial conjunctivitis with Gram –ve organisms
Adverse effects
• Well tolerated
• GI tract adverse effects – Most common (3-17%)
– Nausea, vomiting & abdominal discomfort
– C. difficile colitis (Ciprofloxacin)
• Hypo- & hyper-glycemia in older adults
(Gatifloxacin)
• CNS side effects
– Headache, dizziness (1-11%)
– Hallucinations, delirium & seizures (rare)
• Rashes, pruritus, swelling of lips &
photosensitivity reactions
• Achilles tendon rupture or tendinitis
– In Patients - > 60 years old
- on corticosteroids
- solid organ transplant recipients
• Damage growing cartilage & cause arthropathy
in children
– FQs - Routinely not recommended in children
• Leucopenia, eosinophilia & mild ↑ serum
transaminases (rare)
• QT prolongation (sparfloxacin > gatifloxacin,
moxifloxacin)
Following drugs are withdrawn from market in US
– Lomefloxacin, sparfloxacin – Phototoxicity & QT
prolongation
– Gatifloxacin – Hypoglycemia
– Temafloxacin – Immune hemolytic anaemia
– Trovafloxacin – Hepatotoxicity
– Grepafloxacin – Cardiotoxicity
– Clinafloxacin – Phototoxicity
Drug interactions
• Antacids containing Al³⁺, Mg²⁺ & Ca²⁺ and also
Zn²⁺ & Fe²⁺ salts – form chelation complexes
with FQs → decrease absorption of FQs
• FQs – decrease metabolism & increase plasma
conc. of Theophylline & Warfarine
• FQs used with caution in Pts. receiving class IA,
class III antiarrhythmic drugs & other drugs
known to increase QT interval
• NSAIDs – enhance CNS toxicity of FQs – seizures
are reported
Contraindications
• Pregnancy
• Children below 18 years of age
• With drugs prolonging QT interval in Pts. with
cardiac arrhythmias & Pts. with hypokalemia

-----