Pharmacology Lecture Slides on Fluroroquinolones by Sanjaya Mani Dixit Assistant Professor of Pharmacology at Kathmandu Medical College

1. QUINOLONES
AND
FLUOROQUINOLONES
Sanjaya Mani Dixit
Assistant Prof of Pharmacology

2. Contents
• Quinolones: Synthetic antibacterial, Bactericidal
• Classification
• Advantage of FQs over Quinolones
• Antimicrobial spectrum
• Mechanism of action
• Mechanism of resistance
• Clinical Uses
• Adverse Effects, Drug Interactions & Contraindications
• Individual Drugs

3. QUINOLONES
The quinolones are a series of synthetic
antibacterial agents, the first of which was
nalidixic acid introduced in 1964.
Nalidixic acid is a urinary antiseptic. It is useful
in the treatment of
– uncomplicated UTI due to Gram negative bacteria
– diarrhoea due to Shigella or Salmonella

4. Quinolones
Broadly quinolones are divided into two categories
A) Non-Fluorinated Quinolones
Nalidixic acid
Oxolinic acid
They are useful for the treatment of urinary tract
infections (UTIs) caused by Gram -ve bacteria.
B) Fluorinated Quinolones (Fluoroquinolones)
Ciprofloxacin
Ofloxacin

5. Quinolones
Quinolones (1st
generation )
– Highly protein bound
– Mostly used in UTIs
Fluoroquinolones (2nd
, 3rd
, 4th
generation)
– Modified 1st
gen quinolones
– Not highly protein bound
– Wide distribution in urine and other tissues
– Limited CSF penetration

6. Classification of Fluoroquinolones

9. Advantage of Fluoroquinolones
over Quinolones
• Broad spectrum of activity
• Low MIC values
• Better bioavailability
• High serum half life
• High margin of safety
• Low bacterial resistance
• Versatility of dosage forms suitable both for oral and parenteral
administration.
• High penetration into tissues: Concentration in lung, sputum, muscle,
bone, prostate and phagocytes exceeds that in plasma.
• Urinary and biliary concentrations are 10-50 fold higher than in plasma.

10. Antimicrobial spectrum
• Fluoroquinolones are highly effective against many
Gram negative and some Gram positive organisms in
a concentration dependent manner.
• Concentration dependent (time independent) means that the
rate and extent of microorganism killing are a function
of the antimicrobial concentration (increase as the
concentration increases).
– Parameters used: peak/MIC, AUC/MIC
– Eg: FQs, aminoglycosides, and amphotericin B.

11. Antimicrobial spectrum
• Fluoroquinolones are bactericidal in action.
• Effective: Gram –ve >>>Gram +ve
• FQs are best for facultative and aerobic Gram –ve rods and cocci
• Excellent activity against Enterobacteriaceae (Gram –ve bacilli)
• Works in organisms resistant to Penicillins, Cephalosporins & Aminoglycosides.
• Gram +ve Streptococci & Pneumococci weak inhibition.
• High incidence of Staph resistance, best avoided in MRSA.
• Low activity against anaerobes
• Intracellular pathogens inhibited to a variable extent:
M. tuberculosis, Chlamydia, Legionella, Brucella.
• Orally active, hepatic metabolism and renal excretion.
Rang & Dale

12. Spectrum of activity
• E. coli
• Salmonella
• Klebsiella
• Pasteurella
• Moraxella
• Haemophilus
• Proteus
• Campylobacter
• Brucella
• Bordetella
• Staphylococci
• Erysepalothrix
Broad spectrum antibacterials active against Gram +ve and Gram -ve
organisms including Mycoplasma and Pseudomonas.
Organisms with the mean MIC of 0.008-0.06 mcg/ml are considered highly
susceptible.
Susceptible organism includes:

13. Mechanism of action
• Inhibit DNA gyrase or Topoisomerase 2..
– direct action...
– leading to an arrest in DNA replication...
– Gram negative bacteria more susceptible.
• Inhibit DNA Topoisomerase 4....
– indirect action……
– by blocking the enzymes function of delinking the
daughter DNA molecule. ....
– Gram positive bacteria...... develop resistance rapidly.

14. (An enzyme that maintains the helical twist in DNA)
Interfere with the supercoiling of DNA
(Uncoiling the supercoil)

15. Mechanism of action
Dual MOA
1. Inhibition of bacterial DNA
Gyrase (Topoisomerase II)
• Formation of quinolone-DNA-
Gyrase complex
• Induced cleavage of DNA
2. Inhibition of bacterial
Topoisomerase IV
Mechanism of DNA Gyrase
Post antibiotic effect (PAE)
Lasts 1 to 2 hours,
increases with increasing concentration

16. Mechanism of resistance
• Chromosomal mutation producing a DNA gyrase or
Topoisomerase IV with reduced affinity for FQs
• Reduced permeability or increased efflux of these
drugs across bacterial membranes.
• Increasing resistance has been reported among
Salmonella, Pseudomonas,
Staphylococci, Gonococci, and pneumococci.

17. Clinical Uses
• Nalidixic acid is mainly used as a urinary antiseptic, as
a second line drug. Nitrofurantoin should not be used concurrently as
antagonism occurs.
• Nalidixic acid can be given in case of Ampicillin
resistant Shigella enteritis.
Ciprofolxacin
• UTIs-High cure rates
• Gonorrhoea
• Typhoid- DOC
• Bacterial gastroenteritis
• Meningitis

18. UTIs
• Most commonly used agents in UTIs.
• Very effective against Gram negative bacilli,
such as E coli, Proteus and Enterobacter.
• Superior to Cotrimoxazole for treatment of UTIs.
• Effective for the treatment of bacterial
prostatitis as they are concentrated in the
prostatic tissue (Ciprofloxacin 750mg bd for 3
weeks for upper UTIs)

19. Bacterial Diarrhoea
• Very effective for a variety of GI infections
caused by E.coli, Shigella, Salmonella, etc.
• Effective in travellers diarrhoea, used as a
susbtitute for Cotrimoxazole
• Norfloxacin, ciprofloxacin or Ofloxacin
therapy for 3-5 days is adequate.

20. Typhoid Fever
• Ciprofloxacin (500-750 mg bd for 10 days) is the
preferred drug for the treatment of typhoid.
• Pefloxacin and ofloxacin can be used too.
• Also effective in eliminating the chronic carrier
state of S. typhi when therapy is continued for 6
weeks.
• They are known to be effective in cases of Typhoid
fever that are resistant to Chloramphenicol.

21. Gonococcal Infections
• Cervicitis, urethritis and pelvic inflammatory
disease due to N. gonorrhoea respond to single
dose of Ciprofloxacin or 400 mg of Ofloxacin.
• However, since resistance is on the rise,
Ceftriaxone is the drug of choice now.
• Quinolones are also to be avoided in
pregnancy.

22. Skin, soft tissue and bone infections
SSTIs due to S. aureus and Gram negative bacilli
require prolonged antimicrobial therapy.
FQs are often used in combination with an
antianaerobic agent especially in diabetic foot
infections.

23. Meningiococcal carrier state
• Ciprofloxacin has been used to eradicate
meningiococci from nasopharynx and thereby
eliminate the carrier state, however, the
preferred drug is Rifampicin.

24. Mycobacterial Infections
In:
• MDR TB,
• atypical mycobacterial infections,
• MAC infections in AIDS patients and
• leprosy,
FQs are used in combination with other
antimicrobial agents.

25. Eye infections
• Ciprofloxacin eye drops 0.3% and ointments
0.1% are used topically for conjunctivitis due
to Gram negative organisms.

26. Neutropenic patients
• FQs are often used in combination with an
aminoglycoside for prophylaxis and treatment
of infections in neutropenic patients.

27. Adverse effects
It generally has a good safety record, however following cases of
toxicity may be observed.
1. GIT upsets (most common): nausea, vomiting, diarrhoea, bad
taste
2. Hypersensitivity reaction: rash, photosensitivity, pruritis, swelling
of lips
3. CNS disturbances: Dizziness, headache, confusion, convulsion
(uncoordinated contraction of muscles followed by alternating and
irregular relaxation), Seizures are rare and occur at high doses.
4. Hemolysis: in G6PD deficient patients
5. Bone deformities in the newborn infants born to the mothers
treated with fluoroquinolones also avoided in children below 12
yrs.

28. Tendon damage- BNF

29. Drug Interactions
• FQs inhibit the microsomal enzymes
and thereby increase the plasma
concentration of Theophylline,
caffeine and warfarin owing to
inhibition of metabolism.
• Drugs like Sucralfate, Al & Mg
antacids and Iron salts if given
concurrently interfere with the
absorption of FQs.
• NSAIDs may enhance CNS toxicity of
FQs, seizures reported

30. Contraindications
• Pregnant women category C
• Children-chrondotoxicity (chondrocytes from
articular cartilage)
Category C
• Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and
well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant
women despite potential risks.

31. Nalidixic Acid
• Effective against Gram negative bacteria, especially E. coli, Shigella, and
many strains of Proteus.
• Relatively ineffective against Gram positive organisms.
• Readily absorbed from gut, approximately 80% eliminated in urine within 8
hours. 20% active form, and remaining inactive and conjugated
forms. Useful in UTIs.
• Nausea, vomiting, and diarrhoea.
Allergy: Pruritus, rash, urticaria, fever, eosinophilia and photosensitivity.
CNS: Headache, drowsiness, malaise, myalgia.
• Rarely hemolytic anemia in infants and known to increase intracranial
pressure in young children.

32. Ciprofloxacin
• Ciprofloxacin is rapidly absorbed orally, but food is
known to delay is absorption.
• The MIC of ciprofloxacin against Gram negative
bacteria is usually ‹ 0.1microgram/ml, while Gram
positive bacteria need higher concentrations.
• Their MBCs are close to MICs.
• Though penetration in CSF is not good, it yields
excellent results in treatment of meningitis.

33. Norfloxacin
Less potent than Ciprofloxacin, MIC values for Gram
negative bacteria are 2-4 times higher.
It is primarily used for urinary and genital tract
infections.
It is also good for bacterial diarrhoea , since high
concentrations are present in the gut, and
anaerobic flora is not disturbed.

34. Ofloxacin
• Intermediate activity between Ciprofloxacin and Norfloxacin
against gram negative bacteria, comparable to or more potent
than Ciprofloxacin for Gram positive organisms and certain
anaerobes.
• Good activity against Chlamydia and Mycoplasma so is an
alternative drug for non specific urethritis, cervicitis and atypical
pneumonia.
• It also inhibits M. tuberculosis and can be used instead of
Ciprofloxacin.
• It is highly active against M. leprae: is being used as alternative
multi drug therapy regimens.
• Useful for chronic bronchitis and other respiratory ENT
infections.

35. Levofloxacin
• It is the levo isomer of Ofloxacin.
• Has improved activity against Strep. pneumoniae and some other
Gram positive and Gram negative bacteria.
Anaerobes are moderately susceptible.
• Oral bioavailability is almost 100%. Single daily dosing is possible
owing to slower elimination.
• The primary indication is community acquired pneumonia and
exacerbation of chronic bronchitis in which 87-96% cure rate has
been obtained.
• Sinusitis, enteric fevers, pyelonephritis, and skin and soft tissue
infections are also known to have high cure rates.

36. Sparfloxacin
• Second generation difluorinated quinolone enhanced activity against
Gram positive bacteria (Strep. pneumoniae, Staphylococcus,
Enterococcus),
Bacteroides fragilis, other anaerobes and mycobacteria.
• Indications pneumonia, exacerbations of chronic bronchitis,
sinusitis and other ENT infections.
• Good efficacy in TB, MAC infection in AIDS patients and in leprosy.
• Chlamydial STD infections
• Higher occurrence of photo toxic reactions.
• Longer half life allows single daily dosing.

38. Concentration independent
(time dependent)
• It means that the rate and extent of
microorganism killing remain unchanged
regardless of antimicrobial concentration.
– Parameter T>MIC, AUC/MIC
– Examples : Beta-lactams, vancomycin, macrolides,
aztreonam, carbapenems, clindamycin,
tetracyclines, quinupristin/dalfopristin,
flucytosine, and azole antifungals.

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