Quinolones

Presented by
Asst. Prof Jagir Patel
Dept. Pharmacology
Quinolones
• These are synthetic antimicrobials having a quinolone structure that are active

primarily against gram-negative bacteria, though newer fluorinated

compounds also inhibit gram positive ones.

• The first member Nalidixic acid introduced in mid-1960s had usefulness

limited to urinary and g.i. tract infections because of low potency, modest

blood and tissue levels, limited spectrum and high frequency of bacterial

resistance.

• fluoroquinolones: substitution of pyperaizne ring on 7th position and

fluorination in 6th position results into fluoroquinolones

• Identifiable by their generic names, which typically end in “-floxacin”

Bacterial Spectrum
• The fluoroquinolones are widely used to treat common urogenital,
respiratory, and gastrointestinal infections caused
• Gram-negative microbes, including
• E. coli
• Klebsiella pneumoniae,
• Pseudomonas aeruginosa,
• Neisseria gonorrhoeae,
• Enterobacter,
• Salmonella,
• Shigella species.
Classification

1st generation 2nd generation 3rd generation 4th generation

• Nalidixic acid, • Norfoxacin • Sparfloxacin • Moxifloxacin

cinoxacin Ciprofloxacin Gatlifloxacin Trovafloxacin
Rosoxacin Ofloxacin Tosufloxacin Cinafloxacin
• Lomifloxacin Levofloxacin Finafloxacin
Nadifloxacin pazufloxacin Sitafloxain
Pefloxacin Gemifloxacin
Mechanism of action
• Inhibits bacterial gyrase the enzyme which nicks double-stranded DNA,
introduces negative supercoils and then reseals the nicked ends.

• This is necessary to prevent excessive positive supercoiling of the strands

when they separate to permit replication or transcription.

• The DNA gyrase consists of two A and two B subunits: The A subunit
carries out nicking of DNA, B subunit introduces negative supercoils and
then A subunit reseals the strands.
Jagir. Patel, Asst
Professor, APC
Jagir. Patel, Asst
Professor, APC
Mechanism of action
• FQs bind to A subunit with high affinity and interfere with its strand
cutting and resealing function.

• Recent evidence indicates that in gram-positive bacteria the major target of

FQ action is a similar enzyme topoisomerase IV which nicks and separates
daughter DNA strands after DNA replication. Greater affinity for
topoisomerase IV may confer higher potency against gram-positive
bacteria.
• There are 2 types of DNA topoisomerases in bacteria (eukaryotes)

DNA TOPOISOMERASE I -
Cuts 1 of the DNA strands at the
beginning of replication, thus causing
supercoil relaxation (preventing
hyper coil formation)

DNA TOPOISOMERASE II
“DNA gyrase”
Cuts both the DNA strands at the end of
replication, thus causing separation of
the 2 chromosomes
Fluoroquinolones
Mechanism of Resistance
DECREASED Due to decreased number of porins in the outer cell
UPTAKE membrane only in gram – bacteria (only gram – bacteria
have outer cell membrane)

DECREASED Due to structural alterations of DNA topoisomerase II

AFFINITY

INCREASED Due to increased energy-dependent transport of the

EXCRETION fluoroquinolones out of the cytoplasm through the inner
cell membrane
Nalidixic acid
• Anti bacterial spectrum: gram –ve bacteria only Like E. coli,
Proteus, Klebsiella, Enterobacter Shigella

• MOA: It Acts by inhibiting bacterial DNA gyrase and is bactericidal

• P.k.
• Absorbed orally, highly plasma protein bound and partly metabolized in
liver One of the metabolites is active.
• It is excreted in urine with a plasma tT/z -8 hrs.
• Concentration of the free drug in plasma and most tissues attained with the
usual doses is nontherapeutic for systemic infections.

• USE:
• Uncomplicated UTI
• Diarrhoea due to gram –ve Shigella or salmonella
• Adverse effect:

• These are relatively infrequent, consist mostly of g.i. upset and rashes.

• Most important toxicity is neurological-headache, drowsiness, vertigo,

visual disturbances,

• Occasionally seizures (especially in children).

• Phototoxicity is rare.

• Individuals with G-6-PD deficiency may develop hemolysis.

• Nalidixic acid is contraindicated in infants

Ciprofloxacin Prototype
• Antibacterial spectrum :

2nd gen:
gram + cocci
1st gen:
gram-ve rods
Gram –ve rods
mycoplasma
chlamydia

3rd gen:
4th gen:
gram +cocci
gram +cocci,
gram-ve rods
mycoplasma gram + bacilli,
anaerobic organisms
chlamydia
Ciprofloxacin
• The remarkable microbiological features of ciprofloxacin

• Rapidly bactericidal activity and high potency: MBCs are close to MICs

• Relatively long post-antibiotic effect on Enterobacteriaceae

Pseudomonas & Staph.

• Low frequency of mutational resistance

• Low propensity to select plasmid type resistant mutants.

• Protective intestinal streptococci and anaerobes are spared.

• Active against many B-lactam and aminoglycoside resistant bacteria.

• Less active at acidic pH.

Pharmacokinetics
• Ciprofloxacin is administered orally, i.v., or topical routes

• Well absorbed from gut but food delays the absorption

• Widely distributed in the body, high concentration in kidney, lungs,

prostate gland, bile etc.

• It is excreted in urine
Adverse effect
• CNS: headache, vertigo and nausea, dizziness, insomnia

• G.I.T.: diarrhea, abdominal discomfort

• Skin: Phototoxicity leading to skin rashes, urticaria, itching

• Kidney: urolitihasis (“crystalluria”, due to poor solubility in the low pH of

the renal tubules and following crystal formation)

• Bones: articular cartilage erosion should be avoided in children

• Contraindicated in pregnancy
Uses
• UTI: mostly used for UTI, Effective against E.coli, Proteus and
Enterobacter

• Bacterial diarrhoeas: GIT infection of E.coli, Shigella &

Salmonella

• Typhoid fever: as it is bactericidal causes rapid resolution of

symptoms caused by S.typhi

• Sexually transmitted diseases:

• Gonnococal infection: cervicitis and urethritis dude to
N.gonorrhoeae

• Chancroid and chlamydial cervicitis and urethritis

• Skin, Soft tissue and bone infection: due to S.aureus and
grm-ve bacilli

• Diabetic foot diseases

• Mycobacterial infections: in Multidrug resistance

tuberculosis, and leprosy

• Respiratory infections: in community acquired pneumonia

and chronic bronchitis

• Eye: for topical conjunctivitis

Drug interactions
• Ciprofloxacin increases plasma concentration of warfarin

• NSAIDS+ Ciprofloxacin = potentiate CNS side effect

• Antacids, and sulculfrate reduces absorption of

Ciprofloxacin
Norfloxacin / Ofloxacin
Norfoxacin Ofloxacin
General information
General information
Administered orally and/or IV
Administered orally may not cross the May cross the blood-brain
barrier
blood-brain barrier
Medical uses
Treatment of chlamydia, trachoma
Medical uses
&/or lymphogranuloma due to
Treatment of cystitis due to chlamydia infection
Escherichia, Enterobacter, proteus
Gonorrhea due to Neisseria infection
and/or Klebsiella infection
Leprosy due to mycobacterium
infections
Side effects
Side effects
-same as ciprofloxacin
same as ciprofloxacin
Levofloxacin
• Spectrum: Strep. Pneumonine and some other gram-positive and gram
negative

• P.K
• Oral bioavailability of levofloxacin is nearly 100%; oral and i.v. doses are
similar.

• It is mainly excreted unchanged and a single daily dose is sufficient

because of slower elimination.

• warfarin, and zidovudine remain unchanged during levofloxacin

treatment.

• Use:
• community acquired pneumonia and exacerbations of chronic bronchitis
Gatlifloxacin
• P.K.
• Absorption: Not measurable as it is used topically
Distribution: Widely distributed into body tissues. Plasma protein binding:
Approx. 20%.
Metabolism: Limited metabolism.
Excretion: Via urine mainly as unchanged drug w/ <1% as metabolites;
faeces , Elimination half-life: 7-14 hr.

• ADV: Conjunctival irritation, increased lacrimation, keratitis, papillary

conjunctivitis, conjunctival haemorrhage, ocular dryness and redness

• Interactions: antiarrhythmic agents + gatlifloxacin= additive effect for

prolong QT interval

• Indications:  Ophthalmic: Bacterial conjunctivitis As 0.3% soln: Instill 1

drop 2 hrly into affected eye
Jagir. Patel, Asst
Professor, APC
Trovafloxacin
•  It had better gram+ve bacterial coverage and less gram-ve coverage than the previous FQ’s
• Pk.

• Absorption: Readily absorbed from GI tract. Peak plasma concentration: 1-2 hr. Oral
bioavailability: 88%.
Distribution: Widely distributed and found in breast milk. Protein binding: 76%.
Metabolism: Metabolized by conjugation. Half-life: 9-12 hr. After IV inj, alatrofloxacin, the
prodrug of trovofloxacin, is rapidly converted to Trovafloxacin.
Excretion: Excreted in urine and faeces as metabolites and unchanged drug.

• ADV: Dizziness, convulsions, CNS stimulation (e.g. tremor, restlessness, hallucinations),

phototoxicity, pancreatitis.
Potentially Fatal: Hapatotoxicity, anaphylactic reactions, severe hypotension, Stevens-
Johnson syndrome.
• Drug interactions: Trovafloxacin+ anatcids containing aluminum and
magnesium salts = decreased absorption
• Trovafloxacin + NSAIDs = Increased risk of convulsions

• Contraindication: Severe hepatic cirrhosis

• Indications
• Community-acquired pneumonia; Complicated skin and skin structure
infections, Nosocomial pneumonia, Pelvic infections, Complicated intra-
abdominal infections

• Dose 200-300 mg once daily

Gemifloxacin
• Spectrum: gram-positive microorganisms - Streptococcus pneumoniae including multidrug
resistance streptococcus pneumoniae and aerobic gram-ve organisms
• Pk
• Absorption: Rapidly absorbed from the GI tract. Absolute bioavailability: Approx 71%. Time to
peak plasma concentration: 0.5-2 hr.

• Distribution: Widely distributed into body tissues including bronchial mucosa and lungs. Volume
of distribution: 4.2 L/kg.
• Plasma protein binding: Approx 55-73%.

• Metabolism: Undergoes limited hepatic metabolism.

•
Excretion: Via faeces (61%) and urine (36%) as unchanged drug and metabolites. Elimination
half-life: Approx 7 hr.
• ADV: hypersensitive reactions are fetal

• Interactions: Additive effect on QT interval prolongation w/ class IA

(e.g. quinidine) 

• Contraindications: Renal impairment patients

• Indications
• Acute bacterial exacerbation of chronic bronchitis
• Community-acquired pneumonia
Why banned?
• Grepafloxacin- Withdrawn from use in 1999 due to deadly heart rhythm
known as a Prolonged QT Interval 
• Nalidixic acid
• Pefloxacin
• Temafloxacin (Omniflox) – Recalled 6 months after FDA approval due to 
Deadly Blood Coagulation Problems as well as kidney and liver failure(1). See
the FDA Press Release on the Recall of Omniflox.
• Trovafloxacin- Not removed, but restricted to use only in hospitals since 1999.
Severe liver damage (1) (3)
• Sparfloxacin- Withdrawn in most countries due to toxicity upon user sunlight
exposure and DNA Damage (2)
MCQ
• The following quinolone antimicrobial agent is not useful in systemic
infections:
• A. Lomefloxacin
• B. Ofloxacin
• C. Nalidixic acid
• D. Pefloxacin

• Indicate the enzyme(s) inhibited by fluoroquinolones:

• A. Both 'A' and 'C'
• B. Topoisomerase II
• C. Topoisomerase IV
• D. DNA gyrase
Nalidixic acid is primarily active against:
• A. Cocci
• B. Bacilli
• C. Gram positive bacteria
• D. Gram negative bacteria

• The fluoroquinolones have improved over Nalidixic acid in the

following respect(s):
• A. They have higher antimicrobial potency
• B. They have extended antimicrobial spectrum
• C. Development of bacterial resistance against them is slow and
infrequent
• D. All of the above
• Adverse effects of ciprofloxacin are referable primarily to the following
except:
• A. Gastrointestinal tract
• B. Kidney
• C. Skin
• D. Nervous system

A single oral dose of the following drug can cure most cases of
uncomplicated gonorrhoea:
• A. Ciprofloxacin
• B. Cotrimoxazole
• C. Spectinomycin
• D. Doxycycline
• Which fluoroquinolone has enhanced activity against gram positive
bacteria and anaerobes:
• A. Pefloxacin
• B. Ciprofloxacin
• C. Sparfloxacin
• D. Norfloxacin

• Ciprofloxacin is not active against:

• A. H.influenzae
• B. E.coli
• C. Enterobacter spp.
• D. Bacteroides fragilis
Thank You