Quinolones

Iqra Ahmed
Instructor
Dow College of Biotechnology
Dow University of Health Sciences
Synthetic antimicrobials

Bactericidal

Primarily against gram negative bacteria

 Nalidixic acid

• First member
Spectrum

• Gram negative bacteria especially coliforms

• E.coli
• Proteus
• Klebsiella
• Enterobacter
• Shigella
• Pseudomonas
Therapeutic uses

• Urinary antiseptic

• Diarrhea caused by coliforms

Treat Urinary tract infections for many years

 Low potency
 Narrow spectrum
 Rapid development of bacterial resistance.
 Limited therapeutic utility
 Fluoroquinolones

• Fluorination of quinolone structure at position 6 &

piperazine substitution at position 7 resulted in
derivatives called fluoroquinolones

• Important therapeutic advance

 High potency
Expanded spectrum/Broad antimicrobial activity
Slow development of resistance
Better tissue penetration &
Good tolerability

• Used for wide variety of infectious diseases

• Classification:
• Classified by generation based on their antimicrobial spectrum of
activity
• First Generation:
• Norfloxacin derived from nalidixic acid
• Activity against common pathogens of UTI
• Second generation:
• Ciprofloxacin, ofloxacin
• More active against gram negative organisms and also against gram
positive cocci, mycobacteria and agents of pneumonia
• Third generations:
• Levofloxacin, Gemifloxacin, Moxifloxacin

• Slightly less active than ciprofloxacin and ofloxacin in case of gram-

negative organisms but against gram positives showing greater
activity

• Generally referred as respiratory fluoroquinolones

• Broadest spectrum introduced to date, with enhanced activity

against anaerobes.
 Mechanism of Action
Target bacterial DNA gyrase & Topoisomerase IV

• Gram negative bacteria - DNA Gyrase

• Gram positive bacteria - Topoisomerase IV

 Mechanism of Action

• The fluoroquinolones interfere with bacterial DNA synthesis by

inhibiting topoisomerase II (DNA gyrase), especially in gram-
negative organisms, and topoisomerase IV, especially in gram-
positive organisms.
• They block the relaxation of supercoiled DNA that is catalyzed
by DNA gyrase, a step required for normal process
• Inhibition of topoisomerase IV by fluoroquinolones interferes
with the separation of replicated chromosomal DNA during cell
division
 Mechanism of Resistance

• Chromosomal mutation
bacteria produce DNA Gyrase/ Topoisomerase IV with
reduced affinity for FQs

• Efflux of these drugs across bacterial membranes

• No quinolone modifying/inactivating enzymes have been

identified in bacteria

• Resistance is slow to develop

 Spectrum
Potent bactericidal against Gram negative bacteria:
 E.coli
 Salmonella
 Shigella
 Enterobacter
 Campylobacter & Neisseria

Ciprofloxacin is more active against

 Pseudomonas aeruginosa
 Flouroquinolones also have good activity against
 Staph. aureus but not against methicillin resistant strains

 Intracellular bacteria are also inhibited

 Chlamydia
 Mycoplasma
 Mycobacterium including Mycobacterium tuberculosis
• Levofloxacin
• Gatifloxacin
• Moxifloxacin
Excellent Activity against streptococci

Several - anaerobic bacteria

• Gemifloxacin
• Ofloxacin, Gatifloxacin & Moxifloxacin
 Pharmacokinetics
• Rapid oral absorption
• High tissue penetrability
• CSF & aqueous levels are low
• Excreted in urine
• Excreted in urine
• Dose adjustment in renal failure

• Exception moxifloxacin
• Metabolized by liver
• Should not be used in hepatic failure
 Adverse effects
• Generally safe
• Nausea, vomiting, abdominal discomfort, bad taste
• CNS:
• headache, dizziness, rarely hallucinations
 Adverse effects
• Hypersenstivity; rashes including photosenstivity

• Tendonitis & tendon rupture

• Arthropathy in immature animals,

• Use in children contraindicated
 THERAPEUTIC USES

Urinary tract infections

• Most commonly used antimicrobials for UTI
• Very effective against Gram negative bacilli like
E.coli
Proteus
Enterobacter
Psuedomonas
 Antimycobacterial Drugs

• Chemotherapy of infection is complicated due to various factors:

• Development of resistance
• Intracellular location of MTB.
• Chronic infection require protracted drug treatment
• Patient compliance
• Major Drugs:
• Isoniazid

• Rifampicin

• Ethambutol

• Streptomycin

• Pyrazinamide
• Drug susceptibility is required before prescribing drug
• Initiation of treatment involve regimen of 3-4 drugs
combinations
• Isoniazid:
• Inhibition of the synthesis of mycolic acid, essential component of
mycobacterial cell wall

• High level of resistance associated with deletion in katG that codes

for catalase peroxidase and required for bio-activation of INH.
• Pharmacokinetics:
• Well absorbed orally
• Metabolized by liver through acetylation
• Half life 60-90 min

• Clinical use:
• Single important drug used in TB infection and is a component of most drug
regimen

• Toxicity:
• Neurotoxic effects
• Hepatotoxicity with jaundice and hepatitis
• Rifampicin:
• Mechanism:
• Derivative of rifamycin
• Bactericidal against MTB
• Inhibits DNA dependent RNA polymerase
• Pharmacokinetics:
• Well absorbed orally
• Distributed to body tissues including CNS
• Partially metabolized in liver
• Eliminated mainly in feces
• Clinical use:
• Always use in combination with other drugs
• Can also be used as a sole drug in latent TB infection
• Toxicity:
• May impair antibody response
• Skin rashes, thrombocytopenia, nephritis
• Ethambutol:
• Mechanism:
• Inhibits arabinosyl transferases involved in the synthesis of arabinogalactan,
a component of mycobacterial cell walls

• Pharmacokinetics:
• well absorbed orally and distributed to tissues, including CNS

• Large fraction is eliminated unchanged in urine

• Clinical Use:
• The main use of ethambutol is in tuberculosis, and it is always given in
combination with other drugs.

• Toxicity:
• Visual impairment, optic neuritis, headache
• Pyrazinamide:
• Mechanism:
• Not much known

• Bacteriostatic drug

• Pharmacokinetics:
• Well absorbed orally

• Penetrates to tissues including CNS

• Partly metabolized to pyrazinoic acid and excretes in urine

• Streptomycin:
• Aminoglycosides, now used frequently because of growing
prevalence of MTB resistant to other drug

• Used in life threatening infections

Antitubercular Drug Regimens
1. Standard regimens:

• For empiric treatment of pulmonary TB an initial 3-drug

regimen of INH, rifampin, and pyrazinamide is
recommended.

• If the organisms are fully susceptible pyrazinamide can be

discontinued after 2 months and treatment continued for a
further 4 months with a 2-drug regimen
2. Alternative regimens
• Alternative regimens in cases of fully susceptible organisms include
INH + rifampin for 9 months, or INH + ethambutol for 18 months
3. Resistance:

• If resistance to INH is observed, the initial drug regimen

should include ethambutol or streptomycin.

• Tuberculosis resistant only to INH (the most common form

of resistance) can be treated for 6 months with a regimen of
rifampin + pyrazinamide + ethambutol or streptomycin.
• Multidrug-resistant organisms (resistant to both INH and
rifampin) should be treated with 3 or more drugs to which the
organism is susceptible for a period of more than 18 months,
including 12 months after sputum cultures become negative